PF 2002 Vol 28 Issues 1 3

,.
]fhe Journal of Standards Development and Official Compendia Revision
PHARMACOPEIAL
FORUM
NUMBER 1
BIMONTHLY: January-February 2002
HIGHLIGHTS
• Announcement of the Pharmacopeia!

Education Course Schedule
• First Interim Revision Announcement

Pertaining to USP25 and NF 20
U.S. PHARMACOPEIA
The Standard of Quality™
Table of Contents*
PHARMACOPEIAL FORUM VOL. 28 No. l JAN.-FEB. 2002
STANDARDS DEVELOPMENT 5
HOW TO USE PF 9
Section Descriptions > 11
Committee Designations 13
Staff Directory 14
POLICIES AND ANNOUNCEMENTS 17
How to Comment 20
Schedules 21
FIRST INTERIM REVISION ANNOUNCEMENT 23
USP MONOGRAPHS 27
Hydroxyzine Hydrochloride Tablets 27
Oxycodone and Acetaminophen Capsules 27
IN-PROCESS REVISION 29
General Notices and Requirements 32
"Official" and "Official Articles"—USP 32
"Official" and "Official Articles"—NF 88
MONOGRAPHS (USP) , 33
Acebutolol Hydrochloride Capsules [erratum] (USP 26) 33
Alendronate Sodium Tablets [new] (2nd Supp) 33
Amoxicillin Capsules (USP 26) 36
Amoxicillin Tablets (USP 26) 36
Amoxicillin and Clavulanate Potassium for Oral Suspension (USP 26) 36
Amoxicillin and Clavulanate Potassium Tablets (USP 26) 37
Atenolol Tablets (USP 26) 38
Barium Sulfate (USP 26) 38
Barium Sulfate Suspension (USP 26) 38
Barium Sulfate for Suspension (USP 26) 39
Benazepril Hydrochloride Tablets [new] (USP 26) 39
Benzethonium Chloride Concentrate [new] (USP 26) 41
Benzylpenicilloyl Polylysine Concentrate (USP 26) 42
Bismuth Subsalicylate Magma [new] (USP 26) 43
Cefpodoxime Proxetil [new] (USP 26) 44
Cefpodoxime Proxetil for Oral Suspension [new] (USP 26) 48
Cefpodoxime Proxetil Tablets [new] (USP 26) 49
Chlorothiazide Sodium for Injection (USP 26) 51
Cholestyramine for Oral Suspension (USP 26) 51
Cimetidine Tablets (USP 26) 52
Clomipramine Hydrochloride Capsules [new] (USP 26) 52
Clonazepam Tablets (USP 26) 54
Clorazepate Dipotassium Tablets (USP 26) 54
Clorsulon [erratum] (2nd Supp) 55
Digoxin Tablets (USP 26) 55
Dinoprostone [new] (USP 26) 56
Ergoloid Mesylates Tablets [erratum] (2nd Supp) 59
Fluoxymesterone (USP 26) 59
Furosemide Oral Solution (Proposal for 3rd IRA) 59
Glutaral Concentrate (USP 26) 60
Glyburide Tablets (USP 26) 60
* The USP-NF (USP25-NF20), the Supplement (Supp), or the Interim Revision Announcement (IRA) for which the revision proposal is
targeted is shown in parentheses next to each proposed item.
Pharmacopeial Forum
I Contents* Vol. 28(1) [Jan.-Feb. 2002]
Hydrochlorothiazide (USP 26) 60

Hydrocodone Bitartrate (USP 26) 63
Hydrogen Peroxide Concentrate (USP 26) 65
Insulin Human (USP 26 & 1st Supp) 65
Insulin Lispro [new] (USP 26) 66
Insulin Lispro Injection [new] (USP 26) 69
Iohexol [errata] (2nd Supp) 70
Isosorbide Concentrate (USP 26) 71
Lactulose Concentrate (USP 26) 71
Letrozole Tablets [erratum] (2nd Supp) 71
Levocarnitine (USP 26) 71
Lincomycin Hydrochloride Soluble Powder [erratum] (2nd Supp) 73
Mannitol Injection (USP 26) 73
Methadone Hydrochloride Oral Solution (USP 26) 74
Methyltestosterone (USP 26) 74
Misoprostol Dispersion [new] (USP 26) 76
Myrrh (2nd Supp) 78
Nifedipine Capsules (USP 26) 78
Norgestimate and Ethinyl Estradiol Tablets [new] (USP 26) 79
Oxycodone Hydrochloride [erratum] (2nd Supp) 84
Pentazocine and Naloxone Hydrochlorides Tablets (USP 26) 84
Praziquantel [erratum] (2nd Supp) 84
Pseudoephedrine Hydrochloride Extended-Release Tablets (USP 26) 85
Streptomycin Injection (USP 26) 86
Streptomycin for Injection (USP 26) 86
Streptomycin Sulfate (USP 26) 87
Thyroid Tablets (USP 26) 88
MONOGRAPHS (NF) 89
Garlic Delayed-Release Tablets [new] (NF 21) 89
Glucosamine Hydrochloride [new] (NF 21) 92
Glucosamine Potassium Sulfate Chloride [new] (NF 21) 94
Glucosamine Sodium Sulfate [new] (NF 21) 95
Glucosamine Tablets [new] (NF 21) 97
Glucosamine and Chondroitin Sulfate Tablets [new] (NF 21) 98
Kava [new] (NF 21) 100
Powdered Kava [new] (NF 21) 104
Nettles [new] (NF 21) 105
Powdered Nettle [new] (NF 21) 108
Powdered Nettle Extract [new] (NF 21) 109
GENERAL CHAPTERS Ill
(11) Reference Standards (USP 26) Ill
(281) Residue on Ignition (USP 26) 112
(1191) Stability Considerations in Dispensing Practice (USP 26) 112
REAGENTS, INDICATORS, AND SOLUTIONS 115
Reagent Specifications 115
FD&C Blue No. 1 [new] (USP 26) 115
Water, HPLC Grade (USP 26) 115
REFERENCE TABLES 115
Containers Specifications for Capsules and Tablets 115
Glucosamine Tablets [new] (USP 26) 115
Glucosamine and Chondroitin Sulfate Tablets [new] (USP 26) 115
Description and Relative Solubility of USP and NF Articles 116
Carboprost Tromethamine [new] (USP 26) 116
Insulin [new] (USP 26) 116
© 2002 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
Vol. 28(1) [Jan.-Feb. 2002] Contents* 3
HARMONIZATION 127
GENERAL CHAPTERS 129
PHARMACOPEIAL PREVIEWS 131
MONOGRAPHS (USP) 133
Bismuth Subsalicylate Tablets [new] 133
Nystatin 134
Nystatin Cream 134
Nystatin Lozenges 135
Nystatin Ointment 135
Nystatin Topical Powder 136
Nystatin Oral Suspension 136
Nystatin Tablets 137
Nystatin and Triamcinolone Acetonide Cream 137
Nystatin and Triamcinolone Acetonide Ointment 138
MONOGRAPHS (NF) 139
Chaste Tree [new] 139
Powdered Chaste Tree [new] 142
(1072) Disinfectants and Antiseptics [new] 143
(1198) Standardized Imprint Codes for Solid Oral Dosage Forms [new] 143
(1223) Validation of Alternative Microbiological Methods [new] 143
STIMULI TO THE REVISION PROCESS 161
Instructions to Authors 163
Method Considerations for Caco-2 Permeability Assessment in the Biopharmaceutics Classification System,
Sanna Tolle-Sander and James E. Polli 164
FIP Recommendations for Biopharmaceutical Characterisation of Herbal Medicinal Products,
Friedrich Lang, Konstantin Keller, Michael Ihrig, Joy Oudtshoorn-Eckard, Helga Moller, Srini Srinivasan,
and Yu He-ci, Hankintatukku 173
NOMENCLATURE 183
INDEX 191
REFERENCE STANDARDS CATALOG
ORDER FORM
INTENT TO COMMENT FORM
CHROMATOGRAPHIC REAGENTS USED IN USP-NF AND PF
Pharmacopeial Forum
Contents* Vol. 28(1) [Jan.-Feb. 2002]
THE JOURNAL OF STANDARDS DEVELOPMENT AND OFFICIAL COMPENDIA REVISION
Executive Vice President and Chief Executive Officer Please address comments on PF
Roger L. Williams, M.D. content to Executive Secretariat
Vice President, Information and Standards Development USP-NF, 12601 Twinbrook Pkwy.,
Eric B. Sheinin, Ph.D. Rockville, MD 20852
Director, Information and Administration
Stefan P. Schuber, Ph.D. Telephone: 1-301-816-8345
Director, Executive Secretariat Fax: 1-301-816-8373
John W. Gasper, J.D. http://www.usp.org
Manager, ISD Editorial Group
Jerry T. Wadsworth
Senior Editors Pharmacopeial Forum is covered in Current Contents/Life
Jesusa D. Cordova; Lorraine M. Scheinman; Melissa M. Smith Sciences and in the Science Citation Index (SCI), in International
Editors Pharmaceutical Abstracts, and in Current Awareness in Biological
Erika L. Barrowclough; Celia Hamilton; Reuben Meisel; Sciences.
Anthony Owens
Editorial Coordinator The United States Pharmacopeial Convention comprises represen-
Susan Maida tatives from colleges and national and state organizations of med-
Senior Editorial Assistant icine and pharmacy. It publishes the U.S. Pharmacopeia and
M. T. Samahon National Formulary, the legally recognized compendia of stan-
Editorial Assistants dards for drugs and products of other health care technologies.
Micheline Tranquille; Milagro Welter The USP and NF include assays and tests for the determination
Director, Product Development of strength, quality, and purity and requirements for packaging
Linda M. Guard and labeling.
Supervisor, Publishing Technologies
Debbie Miller
Production Coordinator Moving?
Evelyn Bryant Our subscribers' records and publication labels are computer-gen-
Electronic and Desktop Publishing erated. Please send your new address, and your latest label, or an
Debbie James; Donna A. Singh exact copy of it, to: USPC, PF Customer Service Dept., 12601
Twinbrook Parkway, Rockville, MD 20852.
Fax (301)816-8148.
STANDARDS DEVELOPMENT
This section presents an overview of the public review and comment process, conducted through Pharmacopeia! Forum
(PF), for the development of official pharmaceutical standards.
Pharmacopeia! Forum
Vol. 28(1) [Jan.-Feb. 2002] STANDARDS DEVELOPMENT
USP publishes Pharmacopeial Forum (PF) bimonthly as the working vehicle of the USP Council of Experts. PF provides
interested parties an opportunity to review and comment as the Council of Experts develops or revises standards for the
United States Pharmacopeia and the National Formulary (USP-NF).
PF includes the following:

1. Potential revisions—entirely new standards, revision ideas, and drafts not yet targeted for official adoption (Pharmaco-
peial Previews)
2. Proposed revisions—new or revised standards targeted for official adoption (In-Process Revision)
3. Adopted revisions—new or revised standards that become official and binding before the publication of the next USP—
NF or Supplement (Interim Revision Announcement)
USP welcomes comments and data on potential, proposed, or official standards.* Comments, along with USP's responses,
will be published either in PF Briefings, the Commentary section of PF, the Commentary section ofSupplements to USP-NF,
or the Commentary section of USP—NF.
The chart below shows the public review and comment process and its relationship to standards development.
Public Review and Comment Process

for Standards Development
USP Expert Committee approves item

for publication in
Pharmacopeial Forum (PF)
USP Scientific Staff Liaison and the

Executive Secretariat review item
Item published in PF for public review
Public comment received
JL
USP Expert Committee reviews comments
and responds to the
USP Scientific Staff Liaison
USP Scientific Staff Liaison compiles and

analyzes comments and
USP Expert Committee responses
Further revision needed No further revision needed
/ Revision proposal becomes official;

/ revision published in Interim
Comments and responses
I Revision Announcement or
published in PF Briefings with
\ Supplement to USP-NF; comments
proposal for further revision
\ and responses published under
\ Commentary in Supplement/
\ PF/ USP-NF
Questions on the process should be addressed to John W. Gasper, M.A., J.D., Director, Office of the Executive Secretariat, U.S. Pharma-
copeia, 12601 Twinbrook Parkway, Rockville, MD 20852 (e-mail: jg@usp.org).
If you are not immediately able to submit comments but you intend to do
so, please notify USP by using the Intent to Comment form provided before
the section Chromatographic Reagents Used in USP-NF and PF.
HOW TO USE PF
This section provides descriptions of the various parts ofPF. It also includes Committee Designations and the StaffDirectory.
Pharmacopeia! Forum
Vol. 28(1) [Jan.-Feb. 2002] HOW TO USE PF 11
The contents of the different sections of PF are briefly described below. Readers will get an idea of how each section is
relevant to their job functions. They may contact USP scientific staff liaisons or staff members of the Executive Secretariat
(listed in the Staff Directory) if they have any questions. A more detailed description of each section is provided at the begin-
ning of that section.
Proposed and Adopted Revisions
Section Content How Readers Can Respond

Pharmacopeial Previews •BRIEFING: Scientific rationale for potential inclusion or change. Review drafts and provide comments
Early ideas for revisions May include other information useful to the analyst such as the to the appropriate staff liaison cited in
brand name of the column used in developing the proposed method the Briefing preceding each Preview.
and the USP scientific staff liaison who handled the issue
•Potential revisions not yet targeted for official adoption that re-
quire a longer public review and comment process because of is-
sues such as
—The controversial nature of an item
—The application of new technologies that require further
study
—Articles produced by multiple sources
In-Process Revision •BRIEFING: Scientific rationale for proposed changes. May include Review material and send comments
Revisions targeted for other information useful to the analyst such as the brand name of promptly to USP staff liaison (see the
adoption the column used in developing the proposed method and the USP Staff Directory). Guidelines on how to
scientific staff liaison who handled the issue. comment are found at the end of the Po-
•New and revised standards that have been approved for publica- licies and Announcements section.
tion by the appropriate USP Committee when it is considering
whether to advance standards to official status (see Standards De-
velopment). New or revised text is marked with symbols (" _ or
• « or AA) to specify the tentative, earliest date on which the
revision would be officially adopted.
Harmonization •BRIEFING: Scientific rationale for the potential inclusion or Review material and provide com-
Items the Pharmacopoeial change or for the proposed change. The designated stage of harmo- ments to the appropriate staff liaison ci-
Discussion Group (PDG) nization. The stage determines whether an item appears under ted in the Briefing preceding each
is trying to harmonize in- Pharmacopeial Previews or under In-Process Revision, both sep- Preview or In-Process Revision.
ternationally arate sections of Harmonization.
•F'or In-Process Revision, new or revised text is marked with sym-
bols (• m) to specify the tentative, earliest date on which the
revision would be officially adopted.
•If there is no proposed revision to a test or section, "No change"
precedes the text.
Interim Revision Standards that have been adopted and will become officially bind- Review to see if affected by any of the
Announcement ing on the specified date. Effective date is specified in the section's changes.
Adopted standards introductory page or within parentheses following a particular Note effective date when standards be-
item. New or revised text is set off by the symbols, come official and ensure compliance.
•
© 2002 The United States Pharmacopeial Convention, Inc. All Rights Reserved
Pharmacopeial Forum
12 HOW TO USE PF Vol. 28(1) [Jan.-Feb. 2002]
Other Sections
Committee Designations
Names of the committees (composed of volunteer scientific experts) that USP staff work with on the development of stan-
dards.
Staff Directory
Names of all USP scientific staff liaisons with contact information.
Policies and Announcements

• General scientific and policy issues affecting USP-NF standards and processes
• Update on standards-related issues being considered by USP
• Summaries of meetings of the Council of Experts
• Guidelines on how to comment
• Publication and comment schedules
Stimuli to the Revision Process

• Articles on standards development issues authored by the USP Council of Experts, USP staff, or other interested parties
• Discussions of issues on which USP desires public input prior to further development
Nomenclature
Latest adopted United States Adopted Names (USAN) and International Nonproprietary Names (INN) for drugs
• Revisions to existing names as a supplement to the USP Dictionary of USAN and International Drug Names
• Suggested, proposed, and recommended USAN and INN
• Information on how nonproprietary drug names are devised
Articles relevant to compendial nomenclature issues
Index
Cumulative directory for the content of all issues of P F beginning with Pi 7 28(1).
Reference Standards Catalog

List of official USP Reference Standards specified in USP-NF, along with availability and ordering information.
Chromatographic Reagents Used in USP-NF and Pharmacopeial Forum

Update of chromatographic reagents based on the proposals published in this issue of PF.
Pharmacopeial Forum
EXPERT COMMITTEE DESIGNATIONS'
The names of the Committees and their abbreviations are as follows:
AER Aerosols
AMB Analytical Microbiology
BBP Blood and Blood Products
BNA Bioavailability and Nutrient Absorption
BNT Biotechnology and Natural Therapeutics—Diagnostics
BPC Biopharmaceutics
BST Biostatistics
CRX Compounding Pharmacy
DSB Dietary Supplements—Botanicals
DSN Dietary Supplements—Non-Botanicals
EMC Excipient Monograph Content1"
ESC Excipients—Substances and Characterization*
ETM Excipients—Test Methods
GCT Gene Therapy, Cell Therapy, and Tissue Engineering
GTB General Toxicity and Biocompatability
NL Nomenclature and Labeling
PA1 Pharmaceutical Analysis 1
PA6 Pharmaceutical Analysis 6—Actives
PA7 Pharmaceutical Analysis 7—Antibiotics
PDF Pharmaceutical Dosage Forms
PPC Parenteral Products—Compounding and Preparation
PPI Parenteral Products—Industrial
PSD Packaging, Storage, and Distribution
PW Pharmaceutical Waters
RMI Radiopharmaceuticals and Medical Imaging
SMU Safe Medication Use
VET Veterinary Drugs
VVI Vaccines, Virology, and Immunology
* HDQ Indicates USP Headquarters items.

f
The Expert Committee has been renamed. The old name, Excipients—Substances and Characterization (ESC) has been
changed to Excipient Monograph Content (EMC).
Pharmacopeial Forum
14 HOW TO USE PF Vol. 28(1) [Jan.-Feb. 2002]
STAFF DIRECTORY
This is an updated directory that reflects assignment changes based on the reorganization of USP. The general USP tele-
phone number, (301) 881 -0666, may still be used for general inquiries or when a particular Committee is not identified. The FAX
number is (301) 816-8373.
STAFF E-MAIL PHONE ASSIGMENT

Clydewyn M. Anthony, cma@usp.org (301)816-8139 Pharmaceutical Analysis 1 (PA1)
Senior Scientific Associate
Frank P. Barletta, Scientist fpb@usp.org (301)816-8328 Pharmaceutical Waters (PW)
Parenteral Products—
Industrial (PPI);
Radiopharmaceuticals and
Medical Imaging (RMI)
Charles H. Barnstein, Consultant chbamstein@ (301)774-9457 Nomenclature and Labeling (NL)
email.msn.com
John R. Bergeron, Director jxb@usp.org (301)816-8289 USP Reference Standards
Reference Standards
Production
Lokesh Bhattacharyya, Senior lb@usp.org (301)816-8201 Blood and Blood Products (BBP);
Vaccines, Virology, and
Scientist Immunology (VVI)
Biopharmaceutics (BPC);
William E. Brown, Scientist web@usp.org (301)816-8380 Biostatics (BST)
New monograph development

Todd L. Cecil, Director, tlc@usp.org (301)816-8234
Non-Complex Actives
Elizabeth Cowley, epc@usp.org (301)816-8217 Safe Medication Use (SMU)
Communications Coordinator,
Practitioner and Product
Experience
Blood and Blood Products (BBP)
Roger Dabbah, Director, Complex rd@usp.org (301)816-8336
Actives
Ian F. DeVeau, Scientist ifd@usp.org (301)816-8178 Biologic, Biotechnological, and
Veterinary Product
Monographs; Cell Therapy,
Gene Therapy, and Tissue
Engineering (CGT)
Shawn F. Dressman, Scientist sfd@usp.org (301)816-8261 Pharmaceutical Analysis
6—Actives (PA6);
Pharmaceutical Analysis 7—
Antibiotics (PA7)
John L. Esker, Scientist je@usp.org (301)816-8193 Pharmaceutical Analysis 5 (PA5)
L. Valentin Feyns, Director, lvf@usp.org (301) 816-8121 USP Reference Standards
Reference Standards Evaluation
John W. Gasper, Director, jg@usp.org (301) 816-8241 General Issues
Executive Secretariat
Gabriel I. Giancaspro, Scientist gig@usp.org (301)816-8343 Dietary Supplements—Botanicals
and Latin American Liaison (DSB); Dietary
Supplements—
Non-Botanicals (DSN);
Bioavailability and
Nutrient Absorption (BNA)
Elena Gonikberg, Scientist eg@usp.org (301)816-8251
Pharmacopeial Forum
STAFF DIRECTORY {Continued)
STAFF E-MAIL PHONE ASSIGMENT

Sue C. Harris, Director, Excipients sch@usp.org (301) 816-8275 Excipient Monograph Content
(EMC); Excipients—Test
Methods (ETM)
Gloria Huang, Senior Scientific ggh@usp.org (301) 816-8183 Pharmaceutical Dosage Forms
Associate (PDF)
James W. Kelly, Senior Scientific jwk@usp.org (301)816-8167 Pharmaceutical Analysis 2
Associate (PA2)
Justin J. Lane, Senior Scientific jl@usp.org (301) 816-8323 Excipients—Test Methods
Associate (ETM)
Anju K. Malhotra, Manager, akm@usp.org (301)816-8346 USP Correspondence and Open
Corporate Administrative Conferences
Services
Ronald G. Manning, Vice rgm@usp.org (301)816-8562
President Standards Operations
Margareth R. Marques, Scientist mrm@usp.org (301)816-8106 Biopharmaceutics (BPC);
and Latin American Liaison Reagents
Azra M. Medjedovic, Scientific am@usp.org (301)816-8179
Associate Pharmaceutical Analysis 4 (PA4)
C. David Nash, Director, dn@usp.org (301)816-8298
Veterinary Medicine Veterinary Issues
Claudia C. Okeke, Scientist cco@usp.org (301) 816-8243 Compounding Pharmacy (CRX);

Compounding and Preparation
(PPC); Packaging, Storage, and
Distribution (PSD)
W. Larry Paul, Director, General wlp@usp.org (301)816-8331 Nomenclature and Labeling (NL)
Policies and Requirements
David A. Porter, Scientist dap@usp.org (301) 816-8225 Analytical Microbiology (AMB);
Biotechnology and Natural
Therapeutics— Diagnostics
(BNT); General Toxicity and
Biocompatability (GTB)
Salvador Salado, Scientist and ss@usp.org (301) 816-8165 Pharmaceutical Analysis (PA1),
Latin American Liaison (PA3)
Catherine M. Sheehan, Scientific cxs@usp.org (301)816-8262 Excipient Monograph Content
Associate (EMC); Excipients—Test
Methods (ETM)
Eric B. Sheinin, Vice President, es@usp.org (301)816-8103
Information and Standards
Development
V. Srini Srinivasan, Director, OTC vs@usp.org (301)816-8334 Dietary Supplements—
Drugs and Dietary Supplements Information
Jerry T. Wadsworth, Manager, jtw@usp.org (301) 816-8353 Standards Publications
Corporate Editorial Services
William W. Wright, Scientific www@usp.org (301)816-8335 Pharmaceutical Analysis 7-
Fellow Antibiotic Actives (PA7)
Kahkashan Zaidi, kxz@usp.org (301)816-8269 Aerosols (AER)
POLICIES AND
ANNOUNCEMENTS
In this section, readers may find statements about general scientific and policy issues that may have an impact on USP-NF
standards and processes, announcements about issues being considered by USP, and summaries of Council of Experts meet-
ings. This section also includes publication and comment schedules.
Pharmacopeial Forum
Vol. 28(1) [Jan.-Feb. 2002] POLICIES AND ANNOUNCEMENTS 19
UPDATE ON THE ANNUAL EDITION OF USP-NF. CHROMATOGRAPHIC REAGENTS NOW AVAILABLE.

Starting in 2002, USP-NF will be published annually. Chromatographic Reagents lists the brand names of the
Traditionally, USP—NF has been published every five column reagents cited in every proposal for new or
years with two Supplements a year. Now, one main revised gas- or liquid-chromatographic test methods that
edition and two Supplements will be published every year, have been published in Pharmacopeial Forum (PF) since
bringing users more frequent updates—at shorter intervals- 1980. Chromatographic Reagents also helps to track
on the latest official standards and test methods. The first which column reagents were used to validate methods that
annual edition was shipped in November 2001 and have become official and are included in USP-NF. The
became official on January 1, 2002. The annual edition branded column reagents list is updated bimonthly
will be available in hardcover and electronic formats for through Pharmacopeial Forum. Chromatographic
user convenience. Supplement One becomes official on Reagents can be ordered by calling USP's Customer
April 1, 2002, and Supplement Two becomes official on Service Department at 1-800-227-8772 or 301-881-0666.
August 1, 2002 (deadline to submit comments is February
15, 2002). Comments on previously published PHARMACOPEIAL EDUCATION COURSES. USP's
Pharmacopeial Forum proposals that are received too late Pharmacopeial Education series has been developed to
to permit adequate review and evaluation will be enhance the knowledge, skills, and expertise of
considered as suggestions for future revisions. pharmaceutical industry personnel. Three interactive
courses are currently being offered:
VISIT THE USP WEB SITE AT <http://www/usp.org).
• "Fundamentals of Dissolution" helps participants be-
Various resources related to Pharmacopeial standards are
presented, including highlights from PF. come proficient in USP-NF-b&sed dissolution equip-
ment, calibration, tests, methods development, and
USP-NF AVAILABLE IN THREE ELECTRONIC validation.
FORMATS. The trusted reference for official • "Standards 100: USP-NF Overview, Applications, and
pharmaceutical standards is available in three convenient Development Process" provides an overview of USP-
electronic formats—CD, intranet, and online. The CD is NF sections and applications, use of USP Reference
ideal for single users who prefer to have USP-NF on their Standards, and participation in the official standards de-
hard drives. The intranet format allows Web browser-based velopment process.
access to multiple users within a company, through their
own intranet server. The online format can be accessed by • "Standards 101: USP-NF Monograph Development,
individual registered users through the World Wide Web. General Notices & Chapters" builds on Standards
All three electronic formats provide fast and easy access 100, with an in-depth review of USP-NF monographs,
to official USP-NF content. More information can be General Notices, and General Chapters, and focuses on
obtained by visiting www.usp.org/products or by calling the technical aspects of the monograph development
USP's Customer Service Department at 1-800-227-8772 process.
or 301-881-0666.
The following list indicates tentatively scheduled course
dates.
Pharmacopeial Forum
20 POLICIES AND ANNOUNCEMENTS Vol. 28(1) [Jan.-Feb. 2002]
Calendar of Pharmacopeial Education Courses-2002

Date Name of course Location
January 28 and 29 Fundamentals of Dissolution (English) USP Headquarters, Rockville, MD
February 11 and 12 Fundamentals of Dissolution (English) USP Headquarters, Rockville, MD
February 20 Standards 100: Fundamentals of the Use of USP-NF USP Headquarters, Rockville, MD
and the Standards Development Process
February 21 Standards 101: Advanced Use of USP-NF, General USP Headquarters, Rockville, MD
Notices, & Monograph Chapters
March 4 and 5 Fundamentals of Dissolution (English) USP Headquarters, Rockville, MD
March 18-21 Courses to be determined PITCON 2002, New Orleans, LA
April 15 and 16 Fundamentals of Dissolution (English) USP Headquarters, Rockville, MD
April 22 Standards 100: Fundamentals of the Use of USP-NF USP Headquarters, Rockville, MD
April 23 Standards 101: Advanced Use of USP-NF, General USP Headquarters, Rockville, MD
May 6 and 7 Fundamentals of Dissolution (English) USP Headquarters, Rockville, MD
June 3 Standards 100: Fundamentals of the Use of USP-NF USP Headquarters, Rockville, MD
June 4 Standards 101: Advanced Use of USP-NF, General USP Headquarters, Rockville, MD
June 10 and 11 Fundamentals of Dissolution (English) USP Headquarters, Rockville, MD
July 15 and 16 Fundamentals of Dissolution (English) USP Headquarters, Rockville, MD
For further information, contact Barbara B. Hubert, Director

Secretariat of the Pharmacopoeia of Japan
Pharmacopeial Education, bbh@usp.org, 301-816-8333, or Safety Division, Pharmaceutical Affairs Bureau
Diana Lenahan, Program Associate, dpl@usp.org, 301-816- Ministry of Health and Welfare
8530. 1-2-2, Kasumigaseki, Chiyoda-ku
Tokyo, 100-45
INTERNATIONAL CORRESPONDENCE. Individuals Japan
who wish to correspond with the European and Japanese
Pharmacopoeias concerning monographs in the Official
Inquiry and Consensus stages of international HOW TO SUBMIT COMMENTS. The USP welcomes
harmonization should address their comments to the and encourages interested parties to submit comments and
coordinating pharmacopeia for a given article. The data regarding potential, proposed, or adopted (official)
addresses for the European and Japanese Pharmacopoeias standards. Submissions concerning a particular item that
are as follows: has appeared in a PF should be submitted to the
appropriate USP scientific staff liaison identified at the
Technical Secretariat of the end of the Briefing accompanying each item. To submit
European Pharmacopoeia Commission comments and data to a liaison, use the e-mail address
B.P. 907
F 67029 Strasbourg Cedex 1 and telephone numbers listed in the Staff Directory
France included in every PF.
For general inquiries or in cases where a particular liaison is
not identified, use the general USP telephone number (301)
881-0666 or FAX number (301) 816-8373.
Pharmacopeial Forum
Vol. 28(1) [Jan.-Feb. 2002] POLICIES AND ANNOUNCEMENTS 21
All official revisions are published in Supplements to USP-NF (twice yearly). Between Supplements official revisions are
published in PF under Interim Revision Announcement; these revisions are also incorporated in the upcoming Supplement.
The electronic version of USP-NF is updated as each Supplement becomes available and, therefore, contains all official text
up to and including the contents of the latest Supplement.
PUBLICATION SCHEDULES
Publication Publication Date Official Date

st
7 Supplement Feb. 2002* Apr. 1,2002*
PF 28(2) [Mar-Apr. 2002] Mar. 2002* Not Applicable
nd
2 IRA [published in PF 28(2)] Mar. 2002* Apr. 1,2002*
PF 28(2) [June-July 2002*] June 2002* Not Applicable
3rd IRA [published in PF 28(3)] June 2002* July 1,2002*
nd
2 Supplement June 2002* Aug. 1, 2002*
Tentative
Comment Submissions
Publication Due Date

2nd Supplement Feb. 15,2002
INTERIM REVISION
ANNOUNCEMENT
In this section readers will find the following:
• The list of new USP Reference Standards that have become available
• The list of assays or tests that are adopted but held in abeyance pending availability of required USP Reference Standards
• New adopted (official) revisions to the USP-NF that become effective before the effective date of the next Supplement or
that were not ready for adoption by the closing date for the upcoming Supplement. (The effective date for these revisions is
stated on the next page.)
Readers should review this section to determine if they are affected by any of the changes.
Symbols—Interim revisions are shown with new text (if any) enclosed in circles, *new text.. Text enclosed in squares, •new
textB, has already been adopted in a Supplement. Where the symbols appear together with no enclosed text, such as • • or • m, it
means that text has been deleted and no new text was proposed to replace it. In all revisions, the closing symbol is accompanied by a
number that indicates the IRA or Supplement in which the revision first appeared. For example, «2 indicates that the revision
was officially adopted in the Second Interim Revision Announcement, and m2 indicates that the revision was officially adopted
in the Second Supplement.
Pharmacopeial Forum
24 FIRST INTERIM REVISION ANNOUNCEMENT Vol. 28(1) [Jan.-Feb. 2002]
FIRST INTERIM REVISION ANNOUNCEMENT 25

USP 25 MONOGRAPHS 27
Hydroxyzine Hydrochloride Tablets 27
Oxycodone and Acetaminophen Capsules 27
Pharmacopeial Forum
Vol. 28(1) [Jan-Feb. 2002] FIRST INTERIM REVISION ANNOUNCEMENT 25
FIRST INTERIM REVISION

ANNOUNCEMENT
to USP 25 and to NF 20
By authority of the United States Pharmacopeial Convention, Inc.

Prepared by the Council of Experts and published by the Board of Trustees
Mary Anne Koda-Kimble, Chair Roger L. Williams, Executive Vice President

USP Board of Trustees and Chairman, USP Council of Experts
John W. Gasper, Director, Executive Secretariat
Official February 1, 2002. Released January 2, 2002.
All inquiries and comments regarding USP 25 text and NF 20 text should be addressed to the Executive Se-
cretariat. USP-NF. 12601 Twinbrook Parkway. Rockville, MD 20852.
Pharmacopeial Forum
26 FIRST INTERIM REVISION ANNOUNCEMENT Vol. 28(1) [Jan.-Feb. 2002]
New USP Reference Standards

USP Ethchlorvynol RS
The following USP Reference Standards, which were in- USP Fenbendazole RS
dicated in past Supplements to USP 24 and to NF 19 as USP Fludeoxyglucose RS
USP Gadopentetate Monomeglumine RS
being not yet available, have since become available. Thus, USP Ginseng Extract RS
the official date of each USP 25 or NF 20 standard, test, or USP Gonadorelin Hydrochloride RS
assay requiring the use of the following Reference Stan- USP Homosalate RS
USP Hypericin RS
dards is indicated individually in this list. USP Hyperoside RS
USP Ioversol RS
USP 5-Allyl-L-Cysteine RS (June 1, 2002) USP Ioxaglic Acid RS
USP Arsanilic Acid RS (February 1, 2002) USP Ioxilan RS
USP Avobenzone RS (February 1, 2002) USP Isometheptene Mucate RS
USP Bismuth Citrate RS (February 1, 2002) USP Lactase RS
USP Cefixime RS (February 1, 2002) USP Lactitol RS
USP Chromium Picolinate RS (June 1, 2002) USP Menotropins RS
USP Dihydroxyacetone RS (February 1, 2002) USP Meradimate RS
USP Ethopabate Related Compound A RS (June 1, 2002) USP Methyldopa-Glucose Reaction Product RS
USP Finasteride RS (June 1, 2002) USP Mibolerone RS
USP Gabapentin RS (June 1, 2002) USP Monensin Sodium RS
USP Gabapentin Related Compound A RS (June 1, 2002) USP Narasin RS
USP Gadodiamide RS (June 1, 2002) USP Octinoxate RS
USP Gadodiamide Related Compound A RS (June 1, 2002) USP Octisalate RS
USP Gadodiamide Related Compound B RS (June 1, 2002) USP Octocrylene RS
USP y-Glutamyl-(5)-Allyl-L-Cysteine RS (February 1, 2002) USP Ondansetron Hydrochloride RS
USP Iopromide RS (June 1, 2002) USP Ondansetron Related Compound A RS
USP Iopromide Related Compound A RS (February 1, 2002) USP Ondansetron Related Compound B RS
USP Iopromide Related Compound B RS (June 1, 2002) USP Ondansetron Related Compound C RS
USP Ioversol Related Compound A RS (February 1, 2002) USP Ondansetron Related Compound D RS
USP Ioversol Related Compound B RS (February 1, 2002) USP Oxfendazole RS
USP Ioxilan Related Compound A RS (June 1, 2002) USP Poloxalene RS
USP Sodium Butyrate RS (February 1, 2002) USP Potassium Perchlorate RS
USP Pyrethrum Extract RS
The official dates of any USP 25 or NF 20 standards, tests, USP Quercetin RS
or assays requiring the use of the following new USP Ref- USP Rimexolone RS
erence Standards are postponed until further notice pending USP Sargramostim RS
USP Selenomethionine RS
availability of the respective Reference Standards. USP Sulfaquinoxaline RS
USP Sulfaquinoxaline Related Compound A RS
USP Alfentanil Hydrochloride RS USP Sulisobenzone RS
USP Alteplase RS USP A8-Tetrahydrocannabinol RS
USP Amiloxate RS USP A9-Tetrahydrocannabinol RS
USP Amitraz RS USP Thiacetarsamide RS
USP Positive Bioreaction RS USP Tiletamine Hydrochloride RS
USP Cefpiramide RS USP Tilmicosin RS
USP Cinoxate RS USP Tinidazole RS
USP Decoquinate RS USP Tinidazole Related Compound A RS
USP Desflurane RS USP Tinidazole Related Compound B RS
USP Desflurane Related Compound A RS USP Trenbolone RS
USP Dextran 40 RS USP Trenbolone Acetate RS
USP Dextran 40 System Suitability RS USP Triclosan RS
USP Dextran 70 RS USP Triclosan Related Compound A RS
USP Dextran 70 System Suitability RS USP Triclosan Related Compound B RS
USP Dextran Calibration RS USP Tylosin RS
USP Dextran Vo Marker RS USP Valerenic Acid RS
USP Dichloralphenazone RS USP Powdered Valerian RS
USP Diethylene Glycol Monoethyl Ether RS USP Vasopressin RS
USP Diethylstilbestrol Diphosphate RS USP Zalcitabine Related Compound A RS
USP Dirithromycin RS
USP Enalapril Related Compound B RS
USP Enzacamene RS
Pharmacopeial Forum
Vol. 28(1) [Jan.-Feb. 2002] FIRST INTERIM REVISION ANNOUNCEMENT 27
solution with 1 volume of methanol. Make adjustments if

necessary (see System Suitability under Chromatography (621)).
USP 25 MONOGRAPHS Oxycodone standard stock solution—Dissolve an accurately
weighed quantity of USP Oxycodone RS in Solvent mixture to
obtain a solution having a known concentration of about 0.075
mg per mL.
Standard preparation—Transfer about 0.75J mg of USP
Acetaminophen RS, accurately weighed, J being the ratio of the
labeled amount, in mg, of acetaminophen to that of oxycodone
Hydroxyzine Hydrochloride Tablets equivalent, to a 25-mL volumetric flask, add about 10 mL of
Solvent mixture, and mix to dissolve. Add 10.0 mL of
Oxycodone standard stock solution, dilute with Solvent mixture
Change to read: to volume, and mix. Transfer 5.0 mL of the solution so obtained
Dissolution (711)— to a 50-mL volumetric flask, dilute with Mobile phase to
Medium: water; # 800 mL.#1 volume, and mix. This solution contains about 0.003 mg of USP
Oxycodone RS and 0.003 J mg of USP Acetaminophen RS per
*Apparatus—Proceed as directed for Uncoated Tablets under mL.
Disintegration (701) beginning with "Place 1 Tablet in each of Assay preparation—Weigh the contents of not fewer than 20
the six tubes of the basket", with these exceptions: (a) the disks are Capsules. Mix the contents, and transfer an accurately weighed
not used; (b) the apparatus is adjusted so that the bottom of the portion of the powder, equivalent to about 4.5 mg of oxycodone,
basket-rack assembly descends to 1.0 ± 0.1 cm from the inside to a suitable container. Add 150.0 mL of Solvent mixture, and
bottom surface of the vessel on the downward stroke; (c) the 10- shake by mechanical means for 1 hour. Transfer 5.0 mL of the
mesh, stainless-steel cloth in the basket rack is replaced wih 40- solution so obtained to a 50-mL volumetric flask, dilute with
mesh, stainless-steel cloth; and (d) 40-mesh, stainless-steel cloth Mobile phase to volume, and mix. Pass the resulting solution
is fitted to the top of the basket-rack assembly if necessary to through a membrane filter having a 0.5-um or finer porosity,
prevent any dosage unit from floating out of the tubes of the discarding the first 10 mL of the filtrate. Use the filtrate.
assembly. a i Chromatographic system (see Chromatography (621))—The
Time: 45 minutes. liquid chromatograph is equipped with a 214-nm detector and a
Procedure—Determine the amount of C 21 H 27 C1N 2 O 2 • 4.6-mm x 25-cm column that contains 5-um packing LI. The
2HC1 dissolved by employing UV absorption at the wavelength column is maintained at a temperature of 40°. The flow rate is
of maximum absorbance at about 230 nm on filtered portions of about 2 mL per minute. Chromatograph the Standard
the solution under test, suitably diluted with Dissolution preparation, and record the peak responses as directed for
Medium, if necessary, in comparison with a Standard solution Procedure: the relative retention times are about 0.6 for
having a known concentration of USP Hydroxyzine oxycodone and 1.0 for acetaminophen; the resolution, R,
Hydrochloride RS in the same Medium. Calculate the amount of between acetaminophen and oxycodone is not less than 2.4; and
C21H2JC1N2O2 • 2HC1 dissolved in each Tablet. the relative standard deviation for replicate injections is not more
Tolerances—Not less than 75% (Q) of the labeled amount of than 2.0%.
C21H27C1N2O2 • 2HC1 is dissolved in 45 minutes. Procedure—Separately inject equal volumes (about 20 uL) of
the Standard preparation and the Assay preparation into the
chromatograph, record the chromatograms, and measure the
responses for the major peaks. Calculate the quantity, in mg, of
oxycodone (C18N21NO4) in the portion of Capsules taken by the
formula:
Oxycodone and Acetaminophen
Capsules in which C is the concentration, in mg per mL, of USP Oxycodone
RS in the Standard preparation; and rv and rs are the oxycodone
peak responses obtained from the Assay preparation and the Stan-
Change to read: dard preparation, respectively. Calculate the quantity, in mg, of
acetaminophen (C8H9NO2) in the portion of Capsules taken by
Assay— the formula:
Solvent mixture—Prepare a suitable mixture of 0.05 M dibasic
potassium phosphate and methanol (9:1), and adjust with 1500(7^/r 5 ),
phosphoric acid to a pH of 4.0. Make adjustments if necessary
(see System Suitability under Chromatography (621)). in which C is the concentration, in mg per mL, of USP Acetami-
Mobile phase—*Add 950 mg of monobasic potassium nophen RS in theStandard preparation; and ru and rs are the acet-
phosphate to 1000 mL of water.«, Add 1 mL of phosphoric acid, aminophen peak responses obtained from the Assay preparation
and stir until dissolved. While stirring, add 1 mL of H-nonylamine, and the Standard preparation, respectively.
and stir until a clear solution is obtained. Adjust with potassium
hydroxide TS to a pH of 4.9 ± 0.1. • , , Mix 9 volumes of this
IN-PROCESS REVISION
This section contains proposals for adoption as official USP or NF standards (either proposed new standards or proposed
revisions of current USP or NF standards). These may be any of the following: (1) items that previously appeared under
Pharmacopeial Previews and are now formally proposed as revisions; (2) proposed revisions placed directly under In-Pro-
cess Revision; or (3) modifications of revisions previously proposed under In-Process Revision. Readers should review ma-
terial in this section and provide comments to the staff liaison (use the Staff Directory to find the contact information).
Information on how to comment is found in the Policies and Announcements section. It is important to send comments
promptly so that the Committee members can consider readers' input as they are deciding whether to advance standards
to official status.
Briefings Each Proposal is preceded by a Briefing in the following format:
BRIEFING
Name of Item, citations of the most recent USP publications in which this item appeared. Rationale for
the revision. Other relevant information. (For example, if a chromatographic method is being proposed,
column specifications and retention times for compounds of interest.) Finally, the Committee designation
(see How to Use PF), the name of the scientific staff liaison who handled the particular issue, and USP
tracking correspondence number, as shown in the example below:
(PA5: J. Esker) RTS—55678-1
Symbols Proposed revisions are shown with language proposed for deletion or replacement crossed off. New text (if any)
follows, and is enclosed in symbols and set off from the current official text by a paragraph break and by larger type, thus:
•new text.
if slated for an Interim Revision Announcement to USP 24-NF 19 (IRA), thus:
A
new textAUSP25
if slated for USP 25-NF 20, and thus:
"new textB
if slated for a Supplement to USP 25-NF 20. The same symbols not set off by an extra paragraph break and enclosing text
with no increase in type size indicate recent revisions that are already official. Where the symbols appear together with no
enclosed text, such as or • » or • u or AA, it means that text has been deleted, and no new text was proposed to replace it. In all
revisions, the closing symbol is accompanied by an identifier that indicates the particular IRA or Supplement or indicates USP
25 or NF 20, as the publication where the revision will appear if approved. For example, »2 indicates that the revision is
proposed for the Second Interim Revision Announcement, and m2 indicates that the proposed revision is slated for the Second
Supplement, and AUSP2S and ANF20 indicate that the revisions are proposed for USP 25 and NF 20, respectively.
Errata These are corrections of typographical or other errors in text that do not require formal action by the Council of
Experts. Changes based on these Errata will appear in the next published Supplement and become official with that
Supplement.
Official Title Changes Where the specification "Monograph title change" is found, it indicates that the official title stated
after that specification will be substituted for the former title in the appropriate places throughout that monograph once this
revision becomes official.
Pharmacopeial Forum
30 IN-PROCESS REVISION Vol. 28(1) [Jan.-Feb. 2002]
"Official" and "Official Articles"—USP 32
"Official" and "Official Articles"—NF 88
MONOGRAPHS (USP) 33
Acebutolol Hydrochloride Capsules [erratum] (USP 26) 33
Alendronate Sodium Tablets [new] (2nd Supp) 33
Amoxicillin Capsules (USP 26) 36
Amoxicillin Tablets (USP 26) 36
Amoxicillin and Clavulanate Potassium for Oral Suspension (USP 26) 36
Amoxicillin and Clavulanate Potassium Tablets (USP 26) 37
Atenolol Tablets (USP 26) 38
Barium Sulfate (USP 26) 38
Barium Sulfate Suspension (USP 26) 38
Barium Sulfate for Suspension (USP 26) 39
Benazepril Hydrochloride Tablets [new] (USP 26) 39
Benzethonium Chloride Concentrate [new] (USP 26) 41
Benzylpenicilloyl Polylysine Concentrate (USP 26) 42
Bismuth Subsalicylate Magma [new] (USP 26) 43
Cefpodoxime Proxetil [new] (USP 26) 44
Cefpodoxime Proxetil for Oral Suspension [new] (USP 26) 48
Cefpodoxime Proxetil Tablets [new] (USP 26) 49
Chlorothiazide Sodium for Injection (USP 26) 51
Cholestyramine for Oral Suspension (USP 26) 51
Cimetidine Tablets (USP 26) 52
Clomipramine Hydrochloride Capsules [new] (USP 26) 52
Clonazepam Tablets (USP 26) 54
Clorazepate Dipotassium Tablets (USP 26) 54
Clorsulon [erratum] (2nd Supp) 55
Dinoprostone [new] (USP 26) 56
Ergoloid Mesylates Tablets [erratum] (2nd Supp) 59
Fluoxymesterone (USP 26) 59
Furosemide Oral Solution (Proposal for 3rd IRA) 59
Glutaral Concentrate (USP 26) 60
Glyburide Tablets (USP 26) 60
Hydrochlorothiazide (USP 26) 60
Hydrocodone Bitartrate (USP 26) 63
Hydrogen Peroxide Concentrate (USP 26) 65
Insulin Human (USP 26 & 1st Supp) 65
Insulin Lispro [new] (USP 26) 66
Insulin Lispro Injection [new] (USP 26) 69
Iohexol [errata] (2nd Supp) 70
Isosorbide Concentrate (USP 26) 71
Lactulose Concentrate (USP 26) 71
Letrozole Tablets [erratum] (2nd Supp) 71
Levocamitine (USP 26) 71
Lincomycin Hydrochloride Soluble Powder [erratum] (2nd Supp) 73
Mannitol Injection (USP 26) 73
Methadone Hydrochloride Oral Solution (USP 26) 74
Methyltestosterone (USP 26) 74
Misoprostol Dispersion [new] (USP 26) 76
Myrrh (2nd Supp) 78
Nifedipine Capsules (USP 26) : 78
Oxycodone Hydrochloride [erratum] (2nd Supp) 84
Pentazocine and Naloxone Hydrochlorides Tablets (USP 26) 84
Pharmacopeial Forum
Vol. 28(1) [Jan.-Feb. 2002] IN-PROCESS REVISION 31
Praziquantel [erratum] (2nd Supp) 84

Pseudoephedrine Hydrochloride Extended-Release Tablets (USP 26) 85
Streptomycin Injection (USP 26) 86
Streptomycin for Injection (USP 26) 86
Streptomycin Sulfate (USP 26) 87
Thyroid Tablets (USP 26) 88
MONOGRAPHS (NF) 89
Garlic Delayed-Release Tablets [new] (NF 21) 89
Glucosamine Hydrochloride [new] (NF 21) 92
Glucosamine Potassium Sulfate Chloride [new] (NF 21) 94
Glucosamine Sodium Sulfate [new] (NF 21) 95
Glucosamine Tablets [new] (NF 21) 97
Glucosamine and Chondroitin Sulfate Tablets [new] (NF 21) 98
Kava [new] (NF 21) 100
Powdered Kava [new] (NF 21) 104
Nettles [new] (NF 21) 105
Powdered Nettle [new] (NF 21) 108
Powdered Nettle Extract [new] (NF 21) 109
GENERAL CHAPTERS Ill
(11) Reference Standards (USP 26) Ill
(1191) Stability Considerations in Dispensing Practice (USP 26) . 112
FD&C Blue No. 1 [new] (USP 26) 115
Water, HPLC Grade (USP 26) 115
Glucosamine Tablets [new] (USP 26) 115
Glucosamine and Chondroitin Sulfate Tablets [new] (USP 26) 115
Carboprost Tromethamine [new] (USP 26) 116
Insulin [new] (USP 26) 116
Pharmacopeial Forum
when the article is recognized in the USP. The standards apply

GENERAL NOTICES AND equally to articles bearing the official titles or names derived by
transposition of the definitive words of official titles or transposi-
REQUIREMENTS tion in the order of the names of two or more active ingredients in
official titles, whether or not the added designation "USP" is used.
Names considered to be synonyms of the official titles may not be
used for official titles.
Although both compendia, the United States Pharmacopeia and
the National Formulary, currently are published under one cover,
they remain separate compendia. The designation USP-NF or sim-
ilar combination may be used on the label of an article, provided
the label also bears a statement such as "Meets NF standards as
published by the USP", indicating the particular compendium to
which the article purports to apply.
Where an article differs from the standards of strength, quality,
BRIEFING and purity, as determined by the application of the assays and tests
set forth for it in the Pharmacopeia, its difference shall be plainly
General Notices and Requirements, USP 25 page 1 and page stated on its label. Where an article fails to comply in identity with
2687 of PF 27(4) [July-Aug. 2001]. It is proposed to revise the the identity prescribed in the USP, or contains an added substance
General Notices and Requirements in order to clarify that an article that interferes with the prescribed assays and tests, such article
must comply with all of the standards in its corresponding mono- shall be designated by a name that is clearly distinguishing and dif-
graph in order to be labeled as USP, NF, or USP-NF in conjunction ferentiating from any name recognized in the Pharmacopeia.
with the official title or labeling. Articles listed herein are official and the standards set forth in the
monographs apply to them only when the articles are intended or
(DSB: G. Giancaspro) RTS—35644-1 labeled for use as drugs, as nutritional or dietary supplements, or as
medical devices and when bought, sold, or dispensed for these pur-
poses or when labeled as conforming to this Pharmacopeia.
An article is deemed to be recognized in this Pharmacopeia
when a monograph for the article is published in it, including its
Change to read: supplements, addenda, or other interim revisions, and an official
date is generally or specifically assigned to it.
The following terminology is used for distinguishing the articles
"OFFICIAL" AND "OFFICIAL ARTICLES" for which monographs are provided: an official substance is an ac-
tive drug entity, a recognized nutrient, a dietary supplement ingre-
The word "official", as used in this Pharmacopeia or with ref- dient, or a pharmaceutic ingredient (see also NF 20) or a
erence hereto, is synonymous with "Pharmacopeial", with component of a finished device for which the monograph title in-
"USP", and with "compendial". cludes no indication of the nature of the finished form; an official
The designation "USP" in conjunction with the official title or preparation is a drug product, a nutritional supplement, a dietary
elsewhere on the label of an article motma that tho artiolo supplement or a.finisheddevice. It is the finished or partially fin-
ished (e.g., as in the case of a sterile solid to be constituted into a
indicates that a monograph is included in the USP and that solution for administration) preparation or product of one or more
official substances formulated for use on or for the patient or con-
the articleAMSP2tf sumer; an article is an item for which a monograph is provided,
purports to comply with whether an official substance or an official preparation.
'Products Not Marketed in the United States—Interest in

USP standards.
A
the USP outside the United States has always existed. From
Any language modifying or limiting this representation
time to time, monographs may be adopted for articles not
shall be accompanied by a statement that the article is
legally marketed in the United States as a service to autho-
"notUSP".AMSWtf
auoh apooifio rities in other countries where USP standards are recognized
AaS p2<$
and applied. Appearance of any such monograph does not
designation
grant any marketing rights whatsoever, and the status of the
A.USP26
on the label article in the United States must be checked with the U.S.
A
may not AUSretf Food and Drug Administration in the event of any ques-
does not constitute a representation, endorsement, or incorporation
by the manufacturer's labeling of the informational material con- tion. _,
tained in the USP monograph, nor does it constitute assurance by
USP that the article is known to comply with USP standards. An
article may only purport to comply with a USP standard
A
or other requirementsAas.p2<5
Pharmacopeial Forum
Nutritional and Other Dietary Supplements—The designation BRIEFING

of an official preparation containing one or more recognized nutri-
ents as "USP" or the use of the designation "USP" in conjunction Alendronate Sodium Tablets, page 398 of P F 26(2) [Mar-
with the title of such nutritional or dietary supplement preparation Apr. 2000]. It is proposed to change the time in the test for Disso-
may be made only if the preparation meets lution from 30 minutes to 15 minutes. This modification is based
on results obtained from both 10-mg and 40-mg tablets of this sin-
AUSP2(J gle-source drug product.
the applicable requirements contained in the individual monograph
and general chapters. Any additional ingredient in such article that (BPC: M. Marques) RTS—21428-1
is not recognized in the Pharmacopeia and for which nutritional
value is claimed shall not be represented nor imply that such ingre-
dient is of USP quality or recognized by USP. If a preparation does
not comply with
Add the following:
applicable requirements but contains nutrients or dietary supple-
ment ingredients that are recognized in the USP, the article may not •Alendronate Sodium Tablets
designate the individual nutrients or ingredients as complying with
USP standards or being of USP quality without designating on the
label that the article itself does not comply with USP standards.
» Alendronate Sodium Tablets contain not less
than 90.0 percent and not more than 110.0 percent
MONOGRAPHS (USP) of the labeled amount of alendronate sodium
(C4H12NNa07P2 • 3H2O).
Packaging and storage—Preserve in tight containers.
USP Reference standards (11)—USP Alendronate Sodium

BRIEFING
RS.
Acebutolol Hydrochloride Capsules, USP 25 page 13 and
page 1743 of PF 27(1) [Jan.-Feb. 2001]. Identification—The retention time of the major peak in the
(PA5: J. Esker) RTS—35823-1 chromatogram of the Assay preparation corresponds to that

in the chromatogram of the Standard preparation, as
Erratum: obtained in the Assay.

Chromatographic purity, Test 2, line 7 under Procedure:
Change "prior to" to: after Change to read:
Dissolution (711)—
Medium: water; 900 mL.

Apparatus 2: 50 rpm.
Time: 2QAl5AUSP26
minutes.
Determine the amount of C4Hi2NNaO7P2 • 3H2O dis-

solved by employing the following method.
Buffer solution and Mobile phase—Prepare as directed in
the Assay.
0.05% 9-Fluorenylmethyl chloroformate solution—
Transfer 100 mg of 9-fluorenylmethyl chloroformate to a
©2002 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
200-mL volumetric flask, dilute with acetonitrile to volume, screw-cap centrifuge tube".
and mix. This solution must be freshly prepared. Chromatographic system (see Chromatography
—Boratc solution—ânsfor 38.1 g of sodium borato to a 1 (621))—Prepare as directed in the Assay. Chromatograph
liter volumotrio flask, diooolvo in and dilute with water to the Standard solution, and record the peak responses as
volume, and mix. directed for Procedure: the capacity factor, k1, is not less
Borate buffer—Dissolve 6.2 g of boric acid in than 2.0; the column efficiency is not less than 1500
approximately 950 mL of water, adjust with 1 N sodium theoretical plates; the tailing factor is not more than 1.5;
hydroxide to a pH of 9.0, and dilute with water to 1 liter. and the relative standard deviation for replicate injections
Diluent—Transfer 176.4 g of sodium citrate dihydrate to a is not more than 2.0%.
1000-mL volumetric flask, dissolve in and dilute with Procedure—Separately inject equal volumes (about 50
Dissolution Medium to volume, and mix. uL) of the Standard solution, the Test solution, and the
Standard stock solution—Dissolve an accurately weighed Reagent blank into the chromatograph, record the
quantity of USP Alendronate Sodium RS in Dissolution chromatograms, and measure the responses for the major
Medium, and dilute quantitatively and stepwise with the peaks. Calculate the quantity, in mg, of alendronate
same solvent to obtain a solution having a known sodium (C4H12NNa07P2 • 3H2O) dissolved by the formula:
concentration corresponding to the concentration that
0.9C(ra/rs),
would be obtained by dissolving one Tablet in 900 mL of
in which C is the concentration, in ug per mL, of USP Alen-
the same Medium.
dronate Sodium RS in the Standard stock solution; and rv
Standard solution—Transfer 5.0 mL of the Standard
and rs are the peak responses obtained from the Test solution
stock solution to a 50-mL polypropylene screw-cap
and the Standard solution, respectively.
centrifuge tube containing 1.0 mL of Diluent and 5.0 mL
Tolerances—Not less than 80% (Q) of the labeled amount
of Borate solution buffer, and mix for about 3 minutes.
of C4H12NNa07P2 • 3H2O is dissolved in 30 minutoa.A15
Add 3.0 mL of 0.05% 9-Fluorenylmethyl chloroformate
mimites.AUSP26
solution, and agitate for about 30 seconds. Allow the
solution to stand at room temperature for 25 minutes. Add
25 mL of methylene chloride, and agitate for about 40 Uniformity of dosage units (905): meet the requirements.
seconds. Centrifuge the mixture for 10 minutes. Use a

Assay—
portion of the clear upper aqueous layer.
Diluent—Transfer 29.4 g of sodium citrate dihydrate to a
Reagent blank—-Using 5 mL of water, proceed as directed
1000-mL volumetric flask, dissolve in and dilute with water
for Standard solution, beginning with "to a 50-mL
to volume, and mix.
polypropylene screw-cap centrifuge tube".
Buffer solution—Transfer 14.7 g of sodium citrate
Test solution—After 30 minutes, withdraw a portion of
dihydrate and 7.05 g of anhydrous dibasic sodium
the solution under test, and filter immediately. Using 5.0
phosphate to a 1000-mL volumetric flask, dissolve in
mL of the filtrate, proceed as directed for Standard
about 900 mL of water, adjust with phosphoric acid to a
solution, beginning with "to a 50-mL polypropylene
pH of 8.0, dilute with water to volume, and mix.
Pharmacopeial Forum
0.1% 9-Fluorenylmethyl chloroformate solution— screw-cap centrifuge tube".

Transfer 250 mg of 9-fluorenylmethyl chloroformate to a Reagent blank—Using 5 mL of Diluent, proceed as
250-mL volumetric flask, dilute with acetonitrile to directed for Standard preparation, beginning with "to a
volume, and mix. Prepare this solution fresh just prior to 50-mL polypropylene screw-cap centrifuge tube".
use. Chromatographic system (see Chromatography
Borate solution—Transfer 38.1 g of sodium borato t o a (621))—The liquid chromatograph is equipped with a
100 mL volumetric flaak, di33olvo in and dilute with 266-nm detector and a 4.1-mm x 25-cm column that
water to volume, and mix; Prepare a 0.1 M sodium borate contains 10-um packing L21. The column is maintained at
solution. a constant temperature of about 35°. The flow rate is about 1
Mobile phase—Prepare a filtered and degassed mixture of mL per minute. Chromatograph the Standard preparation,
Buffer solution, acetonitrile, and methanol (75:20:5). Make and record the peak responses as directed for Procedure:
adjustments if necessary (see System Suitability under the capacity factor, k', is not less than 2.0; the column
Chromatography (621)). efficiency is not less than 1500 theoretical plates; the
Standard stock preparation—Transfer about 25 mg of tailing factor is not more than 1.5; and the relative
USP Alendronate Sodium RS, accurately weighed, to a standard deviation for replicate injections is not more than
1000-mL volumetric flask, dissolve in and dilute with 2.0%.
Diluent to volume, and mix. Procedure—Separately inject equal volumes (about 50
Standard preparation—Transfer 5.0 mL of the Standard JIL) of the Standard preparation, Assay preparation, and
stock preparation to a 50-mL polypropylene screw-cap the Reagent blank into the chromatograph, record the
centrifuge tube containing 5 mL of Borate solution, and chromatograms, and measure the responses for the major
mix for about 3 minutes. Add 4 mL of 0.1% 9- peaks. Calculate the quantity, in mg, of alendronate
Fluorenylmethyl chloroformate solution, and agitate for sodium (C4H12NNa07P2 • 3H2O), in the portion of Tablets
about 30 seconds. Allow the solution to stand at room taken by the formula:
temperature for 25 minutes. Add 25 mL of methylene
chloride, and agitate for about 40 seconds. Centrifuge the in which W is the weight, in mg, of USP Alendronate So-
mixture for 10 minutes. Use the clear upper aqueous layer. dium RS taken to prepare the Standard stock preparation;
Assay preparation—Weigh and finely powder not fewer and rv and rs are the peak responses obtained from the Assay
than 20 Tablets. Transfer an accurately weighed portion of preparation and the Standard preparation, respectively. B2
the powder, equivalent to about 25 mg of alendronate
sodium, to a 1000-mL volumetric flask, dilute with
Diluent to volume, and mix. Stir with the aid of a
magnetic stirrer for 30 minutes. Centrifuge a portion of
this solution for about 20 minutes. Using 5.0 mL of the
solution so obtained, proceed as directed for Standard
preparation, beginning with "to a 50-mL polypropylene
Pharmacopeial Forum
to obtain 4 liters of solution, and mix.

BRIEFING Mobile phase—Prepare a mixture of pH 5.0 Buffer and
acetonitrile (3900:100), and pass through a filter having a 0.5-
Amoxicillin Capsules, USP 25 page 133. Based on com- um or finer porosity. Make adjustments if necessary (see System
ments received, it is proposed to change the conditions in the test Suitability under Chromatography (621)).
for Dissolution to Apparatus 7 at 100 rpm for all strengths of Cap- Standard solution—Dissolve an accurately weighed quantity of
sules because products that have been on the market for a long time USP Amoxicillin RS mpH 5.0 Buffer to obtain a solution having a
do not meet the Dissolution requirements with the use of Appara- known concentration of about 0.05 mg per mL. Use this solution
tus 2 at 75 rpm. within 6 hours.
Test solution—Pass a portion of the solution under test through a
filter having a 0.5-um or finer porosity. Dilute an accurately
(BPC: M. Marques) RTS—32556-1 measured volume of the filtrate quantitatively with water to
obtain a solution having an estimated concentration of about
0.045 mg of amoxicillin per mL. Use this solution within 6 hours.
Chromatographic system (see Chromatography (621))—The
liquid chromatograph is equipped with a 230-nm detector, a 3.9-
Change to read: mm x 30-cm analytical column that contains packing LI, and a
2-mm x 2-cm guard column that contains packing L2. The
Dissolution (711)— analytical column is maintained at a constant temperature of
Medium: water; 900 mL. about 40 ± 1°. The flow rate is about 0.7 mL per minute.
Apparatus 1: 100 rpm., for Capauloa containing 250 mg: Chromatograph the Standard solution, and record the peak
—Apparatus 2: 75 rpm, for Capauloa containing 500 mg. responses as directed for Procedure: the capacity factor, k', is
• between 1.1 and 2.8; the column efficiency is not less than 1700
A.USP26 theoretical plates; the tailing factor is not more than 2.5; and the
relative standard deviation for replicate injections is not more
Time: 60 minutes. than 1.5%.
Procedure—Determine the amount of C16H19N3O5S dissolved Procedure—Separately inject equal volumes (about 10 uL) of
by employing UV absorption at the wavelength of maximum the Standard solution and the Test solution into the
absorbance at about 272 nm on filtered portions of the solution chromatograph, record the chromatograms, and measure the
under test, suitably diluted with water, if necessary, in responses for the major peaks. Calculate the quantity, in mg, of
comparison with a Standard solution having a known amoxicillin (C16H19N3O5S) dissolved by the formula:
concentration of USP Amoxicillin RS in the same Medium.
Tolerances—Not less than 80% (Q) of the labeled amount of 0.9DCP{ru/rs),
C16H19N3O5S is dissolved in 60 minutes.
in which D is the dilution factor used in preparing the Test solution;
C is the concentration, in mg per mL, of USP Amoxicillin RS in the
Standard solution; P is the stated content, in \ig of amoxicillin
(C 16 H 19 N 3 O 5 S) per mg, of USP Amoxicillin RS; and rv and rs
are the amoxicillin peak responses obtained from the Test solution
Tolerances—Not less than 80% ( 0 of the labeled amount of
Cj^H19N3O5S is dissolved in 90 minutes.
FOR PRODUCTS LABELED AS CHEWABLE TABLETS—Proceed as di-
rected above.
Tolerances—Not less than 70% (Q) of the labeled amount of
BRIEFING C16Hj9N3O5S is dissolved in 90 minutes.
Amoxicillin Tablets, USP 25 page 135. It is proposed to

change the rotation of the paddles in the test for Dissolution from
75 rpm to 100 rpm. This higher speed provides less coning and
greater dispersion of the particles in the dissolution vessel.
(BPC: M. Marques) RTS—35022-1
BRIEFING
Change to read:
Amoxicillin and Clavulanate Potassium for Oral Suspen-
Dissolution (711)— sion, USP 25 page 136 and page 2702 of PF 27(4) [July-Aug.
Medium: water; 900 mL. 2001]. On the basis of comments received, a new proposal is pre-
Apparatus 2:75 rpm? sented to clarify the limits in the test for Water for different dosage
MOO vpm.AUSP26 strengths of this article.
Time: 90 minutes. (PA7: W. Wright) RTS—35542-3; 35557-1

Determine the amount of C, 6 H 19 N 3 O 5 S dissolved by employing
the following method.
pH 5.0 Buffer—Dissolve 27.2 g of monobasic potassium
phosphate in 3 liters of water, adjust with a 45% (w/w) solution
of potassium hydroxide to a pH of 5.0 ± 0 . 1 , dilute with water
Pharmacopeial Forum
45 minutes and not less than 80% ( 0 of the labeled amount of

CgHgNOj is dissolved in 30 minutes. These modifications are
Change to read: based on m-vivo studies showing that the pharmacokinetic proper-
pH (791): between 4 ^ ties of amoxicillin are not affected by the presence of clavulanate
potassium. It is proposed to reduce the Time from 45 minutes to 30
minutes for Tablets labeled as chewable to be in accordance with
and b.6, in the suspension constituted as directed in the labeling, the approved NDA. Also, on the basis of comments received, it is
the test being performed immediately after constitution. proposed to clarify the limits in the test for Water for different do-
sage strengths of this article.
Change to read:
Water, Method 7(921): not more than 7.5%, where the label indi- (BPC: M. Marques; PA7: W. Wright) RTS—35542-4;
cates that after constitution as directed, the suspension contains 3# 35557-2; 35579-1
Hlg-
*loss than 40 mg ^
of amoxioillin per mL; not moro than 8.5%, whoro tho labol indi
oatos that aftor constitution as dirootod, tho suspension contains
Change to read:
*botwoon40-, Dissolution (711)— [NOTE—Tablets labeled for veterinary use
only are exempt from this requirement.]
*and 50 mg of amoxicillin por mL; Medium: water; 900 mL.
and not moro than 12:0%, whoro tho labol indioatos that aftor Tim e: 30 minutoa
A
oonotitution ao dirootod, tho suspensionoontains more than 45 minutes for amoxicillin, and 30 minutes for clavulanic
50 mg of amoxicillin por mL.^,
A
an amount of amoxicillin that is less than 40 mg per mL; •; or 45 minutes A30 minutes for both amoxicillin and cla-
not more than 8.5% where the label indicates that after con- vulanic
stitution as directed the suspension contains an amount of where the Tablets are labeled as chewable. B1
amoxicillin that is equal to or more than 40 mg per mL Procedure—Determine the amount of amoxicillin
(C 16 Hj^N 3 O 5 S) and clavulanic acid (C 8 H 9 NO 5 ) dissolved,
and is less than or equal to 50 mg per mL; not more than employing the procedure set forth in the Assay, making any
necessary volumetric adjustments.
11.0% where the label indicates that after constitution as di- Tolerances—Not less than 85%
rected the suspension contains an amount of amoxicillin that
is more than 50 mg per mL and is less than or equal to 80 mg ( 0 of the labeled amount of C15H,9N3O5S
A
is dissolved in 45 minutes,*USP26
per mL; and not more than 12.0% where the label indicates and not less than 80% ( 0 of the labeled amount of C8H9NO5 is
dissolved in 30 minutes.
that after constitution as directed the suspension contains an
A
FOR TABLETS LABELED AS CHEWABLE—Not less than
amount of amoxicillin that is more than 80 mg per mL.At/OT(!
80% (Q) of the labeled amount of C16H19N3O5S and not
less than 80% ( 0 of the labeled amount of C8H9NO5 is
dissolved in 30 minutes.
Change to read:
Water, Method I (921): not moro than 6.0% whoro tho Tablets aro
labeled ao boing ohowablo;
A.USP26
BRIEFING
not more than 7.5% where the labeled amount of amoxicillin in
each Tablet is 250 mg or less; not more than 10.5% whoro tho la-
Amoxicillin and Clavulanate Potassium Tablets, USP 25 beled amount of amoxioillin in oaoh Tablet is groator than 250 mg.
page 137 and page 2702 of PF 27(4) [July-Aug. 2001]. It is pro- A
posed to change the Time and Tolerances in the test for Dissolution 10.0% where the labeled amount of amoxicillin in each
from " N o t less than 85% (Q) of the labeled amount of
CjgHjgÔjS and not less than 80% ( 0 of the labeled amount Tablet is more than 250 mg but less than or equal to 500
of C 8 H 9 NO 5 are dissolved in 30 minutes" to "Not less than
80% ( 0 of the labeled amount of C 16 H 19 N 3 O 5 S is dissolved in mg; not more than 11.0% where the labeled amount of
Pharmacopeia! Forum
amoxicillin in each Tablet is more than 500 mg. Where Ta- obtained from the Test solution and the Standard solution, respec-
tively.
blets are labeled as chewable, not more than 6.0% where the Tolerances—Not less than 80% (Q) of the labeled amount of
^•14^22^2^3 *s dissolved in 30 minutes.
labeled amount of amoxicillin in each Tablet is 125 mg or
less; not more than 8.0% where the labeled amount of amox-
icillin in each Tablet is more than 125 mg. Where the Tablets
are labeled for veterinary use only, not more than
BRIEFING
Barium Sulfate, USP 25 page 199; Barium Sulfate for Sus-

pension, USP 25 page 200 and page 3246 of PF 27(6) [Nov.-Dec.
2001]; Barium Sulfate Suspension, USP 25 page 200. It is pro-
posed to delete the tests for Bulkiness under Barium Sulfate, Bar-
ium Sulfate for Suspension, and Barium Sulfate Suspension. The
intent of this test was to ensure that the Barium Sulfate-containing
dosage forms would stay in suspension. However, the official drug
product monographs apply to suspensions of varying concentra-
BRIEFING tions. The test for Bulkiness is not required because it was included
in the monograph at a time when the products lacked suspending
Atenolol Tablets, USP 25 page 179. In the test for Dissolu- agents. Currently the products contain suspending agents and the
tion, it is proposed to replace the current Medium, water, with 0.1 N manufacturers perform a suspendability release test on products of
acetate buffer, pH 4.6, a more physiologically relevant medium higher concentration. The Expert Committee decided that the addi-
having a better buffer capacity. tion of such a test would be inappropriate because its application is
concentration dependent, and instead proposes a rewording of the
Definitions of Barium Sulfate Suspension and Barium Sulfate for
(BPC: M. Marques) RTS—21459-1 Suspension to ensure that the drug products are uniform suspen-
sions when mixed according to the labeling.
(RMI: F. Barletta) RTS—34322-1

Change to read:
A
0.1 N acetate buffer, pH 4.6, prepared by mixing 44.9 parts Delete the following:
A
Bulkiness—Plaoo 5.0 g, previously gifted through a No. 60 atan
(v/v) of sodium acetate TS with 55.1 parts (v/v) of 0.1 N dard sieve, in a dry, graduated, glaao stoppered cylinder having tho
50 mL graduation 11 om to M cm from tho bottom. Dilute with
acetic acid solution;AC/5P2(S water to make tho mixture moaouro 50 mL. Shako the mixture
900 mL. briskly for 1 minuto, aoouratoly timod, and sot it aside for sodimon •
Apparatus 2: 50 rpm. tation: tho Barium Sulfato dooo not aettle below tho 11 mL gradua
Time: 30 minutes. tion within 15 minutes.AUSP26
Determine the amount of C ^ P ^ dissolved by employing
Mobile phase and Chromatographic system—Proceed as
directed in the Assay under Atenolol.
Standard solution—Quantitatively dissolve an accurately
weighed quantity of USP Atenolol RS in a solution of
phosphoric acid (1 in 1000) to obtain a solution having a known
concentration of about 0.01 mg per mL.
Test solution—Prepare a filtered portion of the solution under
test. Quantitatively dilute an accurately measured volume of the
nitrate with a solution of phosphoric acid (1 in 1000) to obtain a
solution estimated to contain about 0.01 mg of atenolol per mL. BRIEFING
Procedure—Proceed as directed in the Assay, except to inject the
Test solution instead of the Assay preparation. Calculate the Barium Sulfate Suspension, USP 25 page 200—See briefing
quantity, in mg, of C 14 H 22 N 2 O 3 dissolved by the formula: under Barium Sulfate.
900CD(rt,/r5),
in which C is the concentration, in mg per mL, of USP Atenolol RS
in the Standard solution; D is the dilution factor involved in pre-
paring the Test solution; and rv and rs are the atenolol peak areas
Pharmacopeia! Forum
Change to read: Change to read:

» Barium Sulfate Suspension is an aqueous suspension pH (791): between 3.5 and 10.0, in a 60% (w/w) aqueous suspen-
of Barium Sulfato containing sion,
•or constituted for its intended use as directed in the label-

not less than 90.0 percent and not more than 110.0 per-
cent of the labeled amount of barium sulfate (BaSO4). in
g-.2
A
It contains suitable dispersing and/or suspending
agents so that when mixed as directed in the label-
ing, it yields a uniformly dispersed suspension. It
may contain one or more suitable colors, flavors,
fluidizing agents, and preservatives.AUSP26
BRIEFING
Benazepril Hydrochloride Tablets, page 3250 of PF 27(6)

[Nov.-Dec. 2001]. It is proposed to change the Tolerances in the
test for Dissolution from "Not less than 85% (Q) of the labeled
amount of £ 2 4 ^ 3 ^ 0 , 5 "HC1 is dissolved in 30 minutes" to
" N o t less than 80% (Q) of the l a b e l e d amount of
C24H2gN2O5 • HC1 is dissolved in 30 minutes". The tolerance of
not less than 85% is too tight, causing testing to go to level S2
in a high percentage of the batches produced.
BRIEFING
Barium Sulfate for Suspension, USP 25 page 200 and page
3246 of PF 27(6) [Nov.-Dec. 2001]. See briefing under Barium
Sulfate.
Add the following:
•Benazepril Hydrochloride Tablets
Change to read:
» Benazepril Hydrochloride Tablets contain aft
» Barium Sulfate for Suspension is a dry mixture of
Barium Sulfato and one or more suitable dispersing amount of Bcnazopril Hydrochlorido equivalent
and/or suspending agents. It
AUSP26 te not less than 90.0 percent and not more than
contains not less than 90.0 percent and not more than
110.0 percent of the labeled amount of barium sulfate 110.0 percent of the labeled amount of benazepril
(BaSO4).
hydrochloride (C24H28N2O5 • HC1).
A
It contains suitable dispersing and/or suspending
agents so that when constituted and mixed as di- Packaging and storage—Preserve in well-closed
containers.
rected in the labeling, it yields a uniformly dis-
USP Reference standards (11)—USP Benazepril
persed suspension.AM.W(5
It may contain one or more suitable colors, flavors, Hydrochloride RS. USP Benazepril Related Compound B
fluidizing agents, and preservatives.
RS. USP Benazepril Related Compound C RS.
Identification—
A: Thin-Layer Chromatographic Identification Test
(201)-
Pharmacopeial Forum
Test solution—Finely powder not fewer than 20 Tablets, Tolerances—Not less than 85% A80%A[/iS.P2(J (Q) of the
and transfer an accurately weighed portion of the powder, labeled amount of C24H2gN2O5 • HC1 is dissolved in 30
equivalent to about 50 mg of benazepril hydrochloride, to minutes.
a 50-mL volumetric flask. Add about 30 mL of methanol, Uniformity of dosage units (905): meet the requirements.
and shake by mechanical means for 15 minutes. Dilute PROCEDURE FOR CONTENT UNIFORMITY—
with methanol to volume, mix, and centrifuge. Pass an Tetrabutylammonium bromide solution, Mobile phase,
aliquot of the supernatant through a suitable filter, System suitability solution, Standard preparation, and
discarding the first 6 mL of the filtrate. Chromatographic system—Proceed as directed in the Assay.
Application volume: 20 uL. Test solution—Transfer 1 Tablet to a 100 mL suitable
Developing solvent system: a mixture of ethyl acetate, volumetric flask, add about60 50 mL a volume of Mobile
methanol, and ammonium hydroxide (80:20:15). phase, equivalent to about 50% of the volume of the
B: The retention time of the major peak in the flask, sonicate for 5 minutes, and then shake by
chromatogram of the Assay preparation corresponds to mechanical means for not less than 10 minutes. Dilute
that in the chromatogram of the Standard preparation, as quantitatively, and stepwise if necessary, with ouffioiont
obtained in the Assay. Mobile phase to volume, obtain a final concentration of
Change to read: about 0.2 mg per mL, mix, and pass a portion of the
solution through a suitable filter, discarding the first 6 mL
of the filtrate.
Procedure—Proceed as directed in the Assay, except to
inject the Test solution instead of the Assay preparation.
Time: 30 minutes.
Calculate the quantity, in mg, of benazepril hydrochloride
Determine the amount of C24H28N2O5 • HC1 dissolved by
(C24H28N2O5 • HC1) in the Tablet taken by the formula:
employing the following method.
Tetrabutylammonium bromide solution, Mobile phase,
System suitability solution, and Chromatographic
VDC(ru/rs),
system—Proceed as directed in the Assay.
Procedure—Inject about 60 uL about 60 uL or an amount in which Fis the volume, in mL, of the initial flask used to
of a filtered portion of the solution under test, equivalent to prepare the Test solution; D is the dilution factor in subse-
about +3-pg 1.2 ug of benazepril, into the chromatograph. quent dilutions of V, if necessary, to prepare the Test solu-
The amount of benazepril injected should not exceed 1.5 ug. tion;C is the concentration, in mg per mL, of USP
Record the chromatogram, and measure the responses for Benazepril Hydrochloride RS in the Standard preparation;
the major peaks. Determine the quantity, in mg, of and rv and rs are the benazepril hydrochloride peak re-
C24H28N2O5 • HC1 dissolved in comparison with a Standard sponses obtained from the Test solution and the Standard
solution having a known concentration of USP Benazepril preparation, respectively.
Hydrochloride RS in the same Medium and similarly
chromatographed.
Pharmacopeial Forum
Related compounds—
Tetrabutylammonium bromide solution, Mobile phase, Assay—
System suitability solution, and Chromatographic Tetrabutylammonium bromide solution, Mobile phase,
system—Proceed as directed in the Assay. System suitability solution, Standard preparation, and
Standard solution—Dissolve an accurately weighed Chromatographic system—Proceed as directed in the
quantity of USP Benazepril Related Compound C RS in Assay under Benazepril Hydrochloride.
Mobile phase, and dilute quantitatively, and stepwise if Assay preparation—Finely powder not fewer than 20
necessary, to obtain a solution having a known Tablets, and transfer an accurately weighed portion of the
concentration of about 0.006 mg per mL. powder, equivalent to about 50 mg of benazepril
Test solution—Use the Assay preparation. hydrochloride, to a 250-mL volumetric flask. Add about
Procedure—Separately inject equal volumes (about 80 150 mL of Mobile phase, and shake by mechanical means
uL) of the Standard solution and the Test solution into the for 30 minutes. Dilute with Mobile phase to volume, mix,
chromatograph, record the chromatograms, and measure the and centrifuge. Pass an aliquot of the supernatant through
responses of the peaks for benazepril related compound C. a suitable filter, discarding the first 6 mL of the filtrate.
Calculate the percentage of benazepril related compound C Procedure—Separately inject equal volumes (about 25
in the portion of Tablets taken by the formula: uL) of the Standard preparation and the Assay
preparation into the chromatograph, record the
chromatograms, and measure the areas for all the peaks.
in which Cs is the concentration, in mg per mL, of USP Be-
Calculate the quantity, in mg, of benazepril hydrochloride
nazepril Related Compound C RS in the Standard solution;
(C24H28N2 O5 • HC1) in the portion of Tablets taken by the
CT is the concentration, in mg per mL, of benazepril hydro-
formula:
chloride in the Test solution; and rv and rs are the peak re- 250C(ra/rs),
sponses for benazepril related compound C obtained from
in which C is the concentration, in mg per mL, of USP Be-
the Test solution and the Standard solution, respectively:
nazepril Hydrochloride RS in the Standard preparation;
not more than 3.0% of benazepril related compound C is
and rv and rs are the benazepril hydrochloride peak re-
found. Calculate the percentage of each impurity (other than
sponses obtained from the Assay preparation and the Stan-
benazepril related compound C) in the portion of Tablets ta-
dard preparation, respectively.u2
ken by the formula:
in which r, is the peak response for each impurity obtained

from the Test solution; and rs is the sum of the responses of
all the peaks (including related compound C): not more than
1.0% of any individual impurity is found; and not more than BRIEFING
2.0% of total impurities is found, the results for all impuri-
Benzethonium Chloride Concentrate, page 2979 of PF
ties (including excluding benazepril related compound C) 27(5) [Sept.-Oct. 2001]; Benzylpenicilloyl Polylysine
Concentrate, USP 25 page 218; Glutaral Concentrate, USP
being added. 25 page 806; Hydrogen Peroxide Concentrate, USP 25 page
Pharmacopeial Forum
865; Isosorbide Concentrate, USP 25 page 965; Lactulose Oxidizing substances—To 5 mL of Concentrate add 0.5
Concentrate, USP 25 page 983; Misoprostol Dispersion, page
1308 of PF 26(5) [Sept-Oct. 2001]—The statement now indicated mL of potassium iodide TS and a few drops of 3 N
for Labeling in this proposed monograph is that which has been
adopted by the Expert Committee on Nomenclature and Labeling. hydrochloric acid: the solution does not acquire a yellow
The committee determined that this statement is to be used for la-
beling articles that are concentrated preparations which must be color.
subjected to further processing to prepare articles of appropriate
concentration for administration to humans or animals. This ap- Limit of nitrites—To 1 drop of Concentrate on a spot plate
proach to labeling such articles, to express limitations of use rather
than to relate to manufacturing or compounding dosage forms, was add 1 drop each of glacial acetic acid, sulfanilic acid in
preferred by the Committee.
It is also proposed to add this same statement to monographs on acetic acid solution (1 in 100), and 1-naphthylamine-
five official articles and two proposed monographs on articles, all
seven of which are concentrated preparations that must be sub- acetic acid solution (prepared by boiling 30 mg of 1-
jected to further processing to prepare formulations that are suit-
able for administration to humans or animals. The proposed naphthylamine in 70 mL of water, decanting the colorless
additions are indicated elsewhere in this number of P F for Benzyl-
penicilloyl Polylysine Concentrate, Bismuth Subsalicylate Magma, solution from the blue-violet residue, and mixing with 30
Isosorbide Concentrate, Glutaral Concentrate, Hydrogen Perox-
ide Concentrate, Lactulose Concentrate, and Misoprostol Disper- mL of glacial acetic acid): no red color develops in the
resulting solution within 10 minutes.
(PA7: B. Gilbert; NL: C. Barnstein) RTS—35638-1
Assay—Transfer a volume of Concentrate, equivalent to
about 200 mg of benzethonium chloride, to a glass-
Add the following: stoppered flask, and proceed as directed in the Assay
A under Benzethonium Chloride, beginning with "Add 0.4
Benzethonium Chloride Concentrate
mL of bromophenol blue solution (1 in
» Benzethonium Chloride Concentrate contains

not less than 94.0 percent and not more than
106.0 percent of the labeled amount of benzetho-
nium chloride (C27H42CINO2).
Packaging and storage—Preserve in tight, light-resistant BRIEFING
containers. Benzylpenicilloyl Polylysine Concentrate, USP 25 page

218—See briefing under Benzethonium Chloride Concentrate.
Labeling—Labol it to Btato that it is for manufacturing
(NL: C. Barnstein) RTS—35638-1
purpoBoa only. Label it to state that this article is not
intended for direct administration to humans or animals.
Identification—Evaporate a volume of Concentrate,
Add the following:
A
equivalent to about 200 mg of benzethonium chloride, on Labeling—Label it to state that this article is not intended
a steam bath: the residue so obtained meets the for direct administration to humans or animals.
requirements of the tests for Identification under
Benzethonium Chloride.
Pharmacopeial Forum
USP Reference standards (11)—USP Bismuth Sub-

BRIEFING
salicylate RS. USP Salicylic Acid RS.
Bismuth Subsalicylate Magma, page 981 of PF 26(4)
[July-Aug. 2000]. A Labeling requirement is being added to this Identification—
proposed new monograph (see Briefing under Benzethonium Chlo-
ride Concentrate appearing elsewhere in this number of PF). A: Infrared Absorption (197M).
Based on comments received, changes have been made in the De-
finition for clarification of statements as to the nature of the suspen- B: It meets the requirements of the tests for Bismuth
sion. In the Assayfor bismuth and in the Assay for total salicylates,
the use of dried magma is indicated. Other changes in this proposed (191).
new monograph are editorial in nature.
Other requirements—It meets the requirements for Limit
(PA2: J. Kelly; NL: C.Bamstein) RTS—31891-1 ; 32910-1
of nitrate, Limit of free salicylic acid, Limit of copper,
lead, and silver, and Limit of soluble bismuth under
Add the following: Bismuth Subsalicylate. portiono of Magma previously
A dried at 105° for 3 houro and adequate to provido the
Bismuth Subsalicylate Magma
atatcd quantities of biomuth aubaalioylato being uood.
Assay for bismuth—Using a quantity of dried Magma,
» Bismuth Subsalicylate Magma is a suspension
equivalent to about 300 mg of bismuth subsalicylate,
that contains not less than 50.0 percent and not
proceed as directed in the Assay for bismuth under
more than 65.0 percent of bismuth (Bi) and not
Bismuth Subsalicylate.
loss than 32.0 percent and not more than 13.0 per Assay for total salicylates—
cent of total salicylates. of Bismuth Subsalicylate
Ferric ammonium sulfate solution, Standard stock
in water that contains not less than 90.0 percent solution, Standard preparation, and Blank—Proceed as
and not more than 110.0 percent of the labeled directed in the Assay for total salicylates under Bismuth
amount of C7H5O4Bi. Bismuth Subsalicylate is a Subsalicylate.
basic salt that when dried at 105° for 3 hours con- Assay preparation—Using a quantity of dried Magma,
tains not less than 56.0 percent and not more than equivalent to about 52 mg of bismuth subsalicylate,
59.4 percent bismuth and not less than 36.5 per- proceed as directed for the Assay preparation in the Assay
for total salicylates under Bismuth Subsalicylate.
cent and not more than 39.3 percent of total sali-
Procedure—Proceed as directed in the Assay for total
cylates.
salicylates under Bismuth Subsalicylate. Calculate the
percentage of total salicylates in the portion of dried
NOTE—Dry at 105° for 3 hours to determine
Magma taken by the formula:
the solids content and, after determining the solids
\0,000(C/W)[(AUr - AVu - B)/(ASr - ASu- B)},
content, perform all tests on a portion of the dried
magma. in which W is the weight, in mg, of bismuth subsalioylato
dried Magma taken to prepare the Assay preparation; -and
the other tormo are aa defined therein. AVr is the absorbance
Labeling—The label states that this article is not intended
of the Reacted assay preparation; AUu is the absorbance of
for direct administration to humans or animals.
Pharmacopeial Forum
the Unreacted assay preparation; ASr is the absorbance of (±)-l-Hydroxyethyl(+)-(6i?,7i?)-7-[2-(2-amino-4-thiazo-

the Reacted standard preparation; ASu is the absorbance lyl)glyoxylamido]-3-methoxymethyl)-8-oxo- 5-thia-1 -
of the Unreacted standard preparation; and B is the differ- azabicyclo[4.2.0]oct-2-ene-2-carboxylate, 72-(Z)-(O-
ence in the absorption of the Reacted blank solution and the methyloxime), isopropyl carbonate (ester)
absorption of the Unreacted blank solution. AUSP26 [87239-81-4].
» Cefpodoxime Proxetil contains the equivalent of

not less than 690 Lig and not more than 804 jag of
cefpodoxime (C15H17N5O6S2), calculated on the
anhydrous basis.
BRIEFING
Packaging and storage—Preserve in tight containers, at a
Cefpodoxime Proxetil, page 5853 of PF 24(2) [Mar-Apr.
1998]; Cefpodoxime Proxetil for Oral Suspension, page 5855 temperature not exceeding 25°.
of P F 24(2) [Mar-Apr. 1998]; Cefpodoxime Proxetil Tablets,
page 5856 of P F 24(2) [Mar-Apr. 1998]. Based on comments,
data, and suggestions received, further modifications of these pro- USP Reference standards (11)—USP Cefpodoxime
posed new monographs are presented. A new isocratic liquid chro-
matographic Assay is proposed for inclusion in the monographs on Proxetil RS.
Cefpodoxime Proxetil, Cefpodoxime Proxetilfor Oral Suspension,
and Cefpodoxime Proxetil Tablets. The new Assay procedure is Identification—
based on analyses performed with the Kromasil C18 brand of 5-
um LI packing, and the detection wavelength is 235 nm. Typical A: Infrared Absorption (197M).
retention times are about 9 minutes for cefpodoxime proxetil S-iso-
mer and 10 minutes for cefpodoxime proxetil i?-isomer. In the B: Ultraviolet Absorption (197U)—
monograph on Cefpodoxime Proxetil, new tests for Specific rota-
tion, Residue on ignition, and Heavy metals are added. The test for Solution: 15 jxg per mL.
Isomer ratio is modified to specify that the ratio of the cefpodox-
ime proxetil i?-isomer peak in relation to the sum of the cefpodox- Medium: acetonitrile.
ime proxetil R- and 5-isomer peaks is between 0.5 and 0.6. A new
gradient liquid chromatographic test for Chromatographicpurity is C: Dissolve 1 mg of it in 4 mL of water, add 1 mL of 1
added. This procedure is based on analyses performed with the
Kromasil C18 brand of 5-um LI packing, and the detection wave- N sulfuric acid while cooling in an ice bath, add 1 mL of a
length is 260 nm. This method separates process impurities and
degradation products from the cefpodoxime proxetil R- and S-iso- freshly prepared solution of sodium nitrite (1 in 100), allow
mers. Typical retention times are about 25 to 38 minutes for cefpo-
doxime proxetil 5-isomer and 37 to 42 minutes for cefpodoxime to stand for 2 minutes, then add 1 mL of ammonium
proxetil i?-isomer.
sulfamate solution (1 in 100). Allow to stand for 1
(PA7: W. Wright) RTS—33537-1 ; 34461-1 minute, and add 1 mL of iV-(l-naphthyl)ethylenediamine
dihydrochloride TS: a red-purple color develops.
Add the following: Specific rotation (78IS): between +35.0° and +48.0°.
A Test solution: 10 mg per mL, in methanol.
Cefpodoxime Proxetil
(Chemical structure to come) Water, Method I (921): not more than 3.0%.
Residue on ignition (281): not more than 0.2%.
C21H27N5O9S2 557.61
Heavy metals, Method I (231): 0.002%.
5-Thia-l-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, 7-
[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]- Isomer ratio—Using the chromatogram of the Assay
3-(methoxymethyl)-8-oxo-, 1 -[[(1 -methylethoxy)car- preparation obtained in the Assay, calculate the ratio of
bonyl]oxy]ethyl ester, [6R-[6a,70(Z)]]-. the cefpodoxime proxetil S opimor /?-epimer peak
Pharmacopeial Forum
response to the sum of the peak responses of the podoxime proxetil S-epimer and 1.0 for cefpodoxime prox-
cefpodoxime proxetil S-epimer peak and the cefpodoxime etil i?-epimer; the resolution, R, between cefpodoxime
proxetil i?-epimer peak: the ratio is between 0.5 and 0.6. proxetil S-epimer and cefpodoxime proxetil R-epimer is
Chromatographic purity— not less than 4.0; the column efficiency is not less than
Solution A—Prepare filtered and degassed 0.02 M 19,000 theoretical plates determined from the cefpodoxime
ammonium acetate. proxetil i?-epimer peak; and the relative standard deviation
Solution B—Use filtered and degassed acetonitrile. determined from the sum of the areas of the cefpodoxime
Mobile phase—Use variable mixtures of Solution A and proxetil S-epimer and cefpodoxime proxetil i?-epimer peaks
Solution B as directed for Chromatographic system. Make for replicate injections is not more than 2.0%.
adjustments if necessary (see System Suitability under

Time Solution A Solution B
Chromatography (621)).
(minutes) (%) (%) Elution
Diluent—Prepare a degassed mixture of water and
0 90 10 equilibration
acetonitrile (2:1).
(10 minutes)
System suitability solution—Dissolve a quantity of USP
0-10 90->68 10^32 linear gradi-
Cefpodoxime Proxetil RS in Diluent to obtain a solution
ent
containing about 10 ug per mL. [NOTE—A volume of
lo^to 68 32 isocratic
methanol not exceeding 10% of the total volume in the
40-80 68^50 32-+50 linear gradi-
final solution may be used to facilitate dissolution.]
ent
Test solution—Transfer about 50 mg of Cefpodoxime
80-85 50 50 isocratic
Proxetil, accurately weighed, to a 50-mL volumetric flask,
85-90 50-*25 50-+75 linear gradi-
dissolve in 5 mL of methanol, using sonication if
ent
necessary, dilute with Diluent to volume, and mix. This
solution should be injected promptly, but may be analyzed
95-100 25-+90 75-»10 linear gradi-
within 24 hours when stored at 8°.
ent
Chromatographic system (see Chromatography (621))—
Procedure—Inject a volume (about 20 uL) of the Test
The liquid chromatograph is equipped with a 260-nm
solution into the chromatograph, record the chroma-
detector and a 4.6-mm x 25-cm column that contains 5-
togram, and measure all of the peak areas. Calculate the
um packing LI. The column temperature is maintained at
percentage of each impurity in the portion of
a constant temperature of about 30°. The flow rate is
Cefpodoxime Proxetil taken by the formula:
about 2 mL per minute. The chromatograph is
programmed as follows. lOOfa/r,),
Chromatograph the System suitability solution, and record in which r, is the peak area for each impurity; and rs is the
the peak responses as directed for Procedure: the retention sum of the areas of all the peaks: not more than 3.0% of any
time for cefpodoxime proxetil i?-epimer is between 37 and peak at a relative retention time of about 0.86 is found; not
42 minutes; the relative retention times are about 0.9 for cef- more than 1.0% for any peak at relative retention times of
Pharmacopeial Forum
about 1.27, 1.39, and other individual peaks having relative contains 5 urn packing LI and i3 maintained at a constant
retention times higher than 2.0 is found; not more than 0.5% temperature of about 40°. Tho flow rate is about 0.8 mL
of any other individual impurity is found; and not more than por minuto. Chromato graph tho Standard preparation, and
6.0% of total impurities is found, impurity peaks of less than record tho peak responses as diroetod under Procedure: tho
0.05% being disregarded. relative retention times aro about 0:7 0.8 for cofpodoximo
Assay— proxctil S opimor, 0.8and 1.0 for oefpodoximo proxotil R
—Mobile phase—Diooolvo 230 mg of fe- hiatidino opimor, and 1.0 for propylparabon; tho column efficiency,
hydroohlorido in a mixture of water and mothanol determined from tho oofpodoxime proxotil R opimor peak,
(580:420). Adjuat with 2 iVsulfuric acid to a pH of 2.5 ± is not less than 300 theoretical platos; tho tailing factor for
0.1. Malco adjustments if necessary (soo System Suitability tho oofpodoximo proxotil R opimor peak is not loss than 0.8
under Chromatography (62Ar)). Increasing tho proportion and not moro than 1.1; tho resolution between tho
of mothanol reduces the retention times: oofpodoximo proxotil R opimor poak and the cofpodoximo
—Diluent—Prepare a mixture of acctonitrile, water, and proxotil £ opimor peak is not loss than 1; and tho relative
glacial aootio aoid (195:195:10). standard deviation for roplioato injections is not moro than
o no/
—Internal standard solution—Prepare a solution of
propylparabon in Diluent containing about 10 mg per mix —Procedure [NOTE—Use poak areas whoro poak
Standard preparation—Accurately weigh about 42 mg of responses are indicated.] Separately injoot oqual volumes
USP Cofpodoximc Proxotil RS, add 3.0 mL of Internal (about 2 uL) of tho Standard preparation and tha Assay
standard solution and 25 mL of Diluent, and swirl to preparation into the ohromatograph, rooord tho
dissolve.Transfer about 42 mg of USP Cofpodoximo ohromatograms; and-measure the responses for tho major
Proxotil RS, aoouratoly weighed, to a 25 mL volumotrio peaks: Calculate tho quantity, in ug, of cofpodoximo
flask, add 10 mL of Diluent, and swirl to dissolve. Dilute ft-^HtfNsQpSa) in oaoh mg of Cofpodoximo Proxotil taken
with Diluent to volume; and mix:—[NOTE—Discard this by tho formula:
solution after 48 hours.]

—Assay preparation—Aoouratoly weigh about 42 mg of
Cofpodoximo Proxotil, add 3.0 mL of Internal standard
solution and 25 mL of Diluent, and swirl to dissolve.
Transfer about 42 mg of Cefpodoximo Proxotil, aoourately in which Pg is tho designated potency, in jjig por mg, of oof
weighed, to a 25 mL volumetric flask; add 10 mL of podoximo (C^jH^N-sQ^Sa) in USP Cofpodoximo Proxotil
Diluent, and swirl to dissolve. Dilute with Diluent to RS, Wg and W# aro tho weights;in mg; of USP Cofpodoximo
volume, and mix. [NOTE—Discard this solution aftor 48 Proxctil RS taken to proparo the Standard preparation and
TrtTtTTTJTT
of Cofpodoximo Proxotil taken to prepare tho Assay pre-
—Chromatographic system (300—Chromatography paration, Fjjfrf and ?varo tho oofpodoximo proxotil R opimor
(6S4-))—Tho liquid ohromatograph is equipped with a poak responses obtained from tho Assay pivpamtion and tho
254 nm detector and a 4.6 mm x 15 cm column that Standard preparation, rospootivoly, f^ and r-S aro the pro
Pharmacopeial Forum
pylparabon poakroaponoos obtained from tho Assay pro 30°. Chromatograph the Standard preparation, and record
partition and the Standard preparation, respootivoly, and the peak responses as directed for Procedure: the relative
*to and fgg aro tho oofpodoximo proxotil S opimor poak ro retention times are about 0.9 for cefpodoxime proxetil 5-epi-
oponooo obtained from tho Assay pwparation and tho Stan mer and 1.0 for cefpodoxime proxetil i?-epimer; the resolu-
dard preparation;roopootivoly. tion, R, between cefpodoxime proxetil S-epimer and
Mobile phase—Prepare a filtered and degassed mixture of cefpodoxime proxetil /?-epimer is not less than 2.5; the tail-
0.02 M ammonium acetate and acetonitrile (6:4). Make ad- ing factor for cefpodoxime proxetil i?-epimer is not more
justments if necessary (see System Suitability under Chro- than 1.5; and the relative standard deviation determined
matography (621)). from the sum of the areas of the cefpodoxime proxetil S-epi-
Diluent—Prepare a degassed mixture of water and aceto- mer and cefpodoxime proxetil /?-epimer peaks for replicate
nitrile (6:4). injections is not more than 1.0%.
Standard preparation—Transfer about 25 mg of USP Procedure—Separately inject equal volumes (about 20
Cefpodoxime Proxetil RS, accurately weighed, to a 50- uL) of the Standard preparation and the Assay preparation
mL volumetric flask, dissolve in 5 mL of methanol, dilute into the chromatograph, record the chromatograms, and
with Diluent to volume, and mix. Transfer 5.0 mL of this measure the responses for the major peaks. Calculate the
solution to a 100-mL volumetric flask, dilute with Diluent quantity, in ug of cefpodoxime (C15H17N5O6S2), in each
to volume, mix, and pass through a filter having a 0.45- mg of Cefpodoxime Proxetil taken by the formula:
um or finer porosity.
Assay preparation—Transfer about 50 mg of Cefpodox-
in which C is the concentration, in ug per mL, of USP Cef-
ime Proxetil, accurately weighed, to a 100-mL volumetric
podoxime Proxetil RS in the Standard preparation; P is the
flask, dissolve in 10 mL of methanol, dilute with Diluent
designated potency, in [ig per mg, of cefpodoxime
to volume, and mix. Transfer 5.0 mL of this solution to a
(C15H17N5O6S2) in USP Cefpodoxime Proxetil RS; W is
100-mL volumetric flask, dilute with Diluent to volume,
the weight, in mg, of Cefpodoxime Proxetil taken to prepare
mix, and pass through a filter having a 0.45-um or finer po-
the Assay preparation; and rv and rs are the sums of the
rosity
peak responses for cefpodoxime proxetil S-epimer and cef-
podoxime proxetil i?-epimer obtained from the Assay pre-
The liquid chromatograph is equipped with a 235-nm detec-
paration and the Standard preparation, respectively.^^,*
tor and a 4.6-mm x 25-cm column that contains 5-um pack-
ing LI. The flow rate is about 2 mL per minute. The column
temperature is maintained at a constant temperature of about
Pharmacopeial Forum
pH (791): between 4.0 and 5.5, in the suspension

BRIEFING
constituted as directed in the labeling.
Cefpodoxime Proxetil for Oral Suspension, page 5855 of
PF 24(2) [Mar.-Apr. 1998]—See Briefing under Cefpodoxime Loss on drying (^34-)—Dry about 100 mg in vacuum at a
Proxetil. The test for Loss on drying is replaced with the more re-
producible titrimetric test for Water. pressure not oxoooding 5 mm of moroury at 80° for 16 houra:
(PA7: W.Wright) RTS—34461-3 it loses not moro than 0.5% of ita weight.
Water (921): not more than 1.5%.

Assay—
Add the following:
—Mobile phase, Diluent, Internal standard solution,
A
Cefpodoxime Proxetil for Oral Standard preparation; -and Chromatographic system—
Suspension
Prooood as dirootod in tho Assay under Cefpodoxime
» Cefpodoxime Proxetil for Oral Suspension con-

Assay preparation—Constitute- a container of
tains Cefpodoxime Proxetil and one or more buf- Cofpodoximo Proxotil for Oral Suspension as dirootod in
fers, suspending agents, sweeteners, flavorings, tho labeling. Transfer an aoouratolymeasured portion of
and preservatives. When constituted as directed the well shaken suspension, free from air bubbles,
in the labeling, it contains the equivalent of not equivalent to about 50 mg of oofpodoximo, to a glass
less than 90.0 percent and not more than 110.0 stoppered 50 mL volumotrio flask, add about oonical
percent of the labeled amount of cefpodoxime flask; add 5.0 mL of Internal standard solution and25 mL
of Diluent, and shake by mechanical means for 30
(Ci 5 Hi7N 5 O 6 S 2 ).
minutes. Centrifuge for about 10 minutes, and then
Packaging and storage—Preserve in tight containers, at a withdraw 1.0 mL of the supernatant liquid, add to it 1.0
temperature not exceeding 30°. Store the constituted Oral mL of Diluent, and mix.Dilute with Diluent to volume,
Suspension in a refrigerator. and mix. Centrifuge for about 10 minutes, and use the
USP Reference s t a n d a r d s (11)—USP Cefpodoxime clear supernatant liquid as the Assay preparation.
Proxetil RS. /TVOTE—Discard this solution after 48 hours:]
Identification—The retention times of the cefpodoxime —Procedure—Prooood as directed fax Procedure in the
proxetil i?-epimer peak and the cefpodoxime proxetil S- Assay under Cefpodoxime Proxetil. Calculate the quantity,
epimer peak in the chromatogram of the Assay in ug, of cefpodoxime (C^sff^qN^Qî) in the portion of
preparation correspond to those in the chromatogram of Suspension taken by the formula:
the Standard preparation, as obtained in the Assay.
Uniformity of dosage units (905)—
FOR SOLID PACKAGED IN SINGLE-UNIT CONTAINERS: m e e t s
the requirements.
Deliverable volume (698): meets the requirements.
Pharmacopeial Forum
in whioh tho other terms ore as dofinod therein: and rs are the sums of the peak responses for cefpodoxime
Mobile phase, Diluent, and Chromatographic system— proxetil S-epimer and cefpodoxime proxetil i?-epimer ob-
Prepare as directed in the Assay under Cefpodoxime tained from the Assay preparation and the Standard pre-
Proxetil. paration, respectively.AUSP26
Standard preparation—Transfer about 30 mg of USP
Cefpodoxime Proxetil RS, accurately weighed, to a 50-
mL volumetric flask, dissolve in 5 mL of methanol, dilute
with Diluent to volume, and mix. Transfer 5.0 mL of this
solution to a 100-mL volumetric flask, dilute with Diluent
to volume, and mix. Pass through a filter having a 0.45- BRIEFING
um or finer porosity. Cefpodoxime Proxetil Tablets, page 5856 of PF 24(2)

[Mar.-Apr. 1998]—See Briefing under Cefpodoxime Proxetil.
Assay preparation—Constitute a container of The test for Loss on drying is replaced with the more reproducible
titrimetric test for Water.
Cefpodoxime Proxetil for Oral Suspension as directed in
(PA7: W.Wright) RTS—34461-2
the labeling. Shake the resulting suspension thoroughly,
and determine its density. Transfer an accurately weighed
quantity of the suspension, equivalent to about 50 mg of Add the following:
cefpodoxime, to a 100-mL volumetric flask. Add 10 mL A
Cefpodoxime Proxetil Tablets
of water, and shake to disperse. Add 20 mL of
acetonitrile, and sonicate for 15 minutes. Cool to room
» Cefpodoxime Proxetil Tablets contain an
temperature, dilute with Diluent to volume, and mix.
Transfer 5.0 mL of this solution to a 100-mL volumetric
amount of Cefpodoxime Proxetil equivalent to
flask, dilute with Diluent to volume, mix, and pass not less than 90.0 percent and not more than
through a filter having a 0.45-um or finer porosity. 110.0 percent of the labeled amount of cefpodox-
Procedure—Separately inject equal volumes (about 20 ime (C15H17N5O6S2).
uL) of the Standard preparation and the Assay
Packaging and storage—Preserve in tight containers, at
controlled room temperature.
chromatograms, and measure the responses for the major
USP Reference standards (11)—USP Cefpodoxime
peaks. Calculate the quantity, in mg of cefpodoxime
Proxetil RS.
(C15H17N5O6S2) in the portion of Oral Suspension taken
Identification—The retention times of the cefpodoxime
by the formula:
proxetil i?-epimer peak and the cefpodoxime proxetil S-
2CP{rulrs), epimer peak in the chromatogram of the Assay
in which C is the concentration, in mg per mL, of USP Cef- preparation correspond to those in the chromatogram of
podoxime Proxetil RS in the Standard preparation; P is the the Standard preparation, as obtained in the Assay.
designated potency, in jig per mg, of cefpodoxime
(C15H17N5O6S2) in USP Cefpodoxime Proxetil RS; and rv
Pharmacopeial Forum
Dissolution (711)— the powder, equivalent to about 300 mg of oofpodoximo, to

Medium—Dissolve 54.5 g of glycine and 42.6 g of a glass stoppered oonioal flask, add 30.0 mL oflntcrnal
sodium chloride in about 500 mL of water in a 1000-mL standard solution, 100 mL volumetric flask, add about 30
volumetric flask. Cautiously add, with swirling, 14.2 mL mL of Diluent, and shake by mechanical means for 30
of hydrochloric acid, and allow to cool. Dilute with water minutes. Dilute withDilucnt to volume, and mix.
to volume, and mix. Transfer 50 mL of this stock solution Centrifuge for about JO minutes, and then withdraw 1.0
to a flask, and dilute with water to 900 mL to obtain a 3.0 mL of the supernatant liquid, add to it 9.0 7.0 mL of
solution having a pH of 3.0 ± 0 . 1 . [NOTE—If necessary, Diluent, and mix. [NOTE—Disoard-thissolution after 48
adjust the pH of the stock solution with 10 N sodium \%fîitTT
HV/UIU.
ill
I
hydroxide so that when 50 mL is diluted with water to —Procedure—Proceed as directed for Procedure in the
900 mL the pH of the Dissolution Medium is 3.0 ± 0.1.] Assay-under Cefpodoxime Proxetil. Calculate the quantity,
Apparatus 2: 75 rpm. in \ig, of cefpodoxime (C^sff^Ns^^) in the portion of
Time: 30 minutes. Tablets taken by the formula:
Procedure—Determine the amount of cefpodoxime
(Ci5Hi7N5O6S2) dissolved by employing UV absorption at
about 259 nm on filtered portions of the solution under
test in comparison with a Standard solution having a
known concentration of USP Cefpodoxime Proxetil RS
in-whioh the other terms are as defined therein:
prepared by dissolving an accurately weighed portion in a
Mobile phase, Diluent, and Chromatographic system—
small volume of methanol and diluting quantitatively with
Prepare as directed in the Assay under Cefpodoxime
Dissolution Medium.
Proxetil.
of cefpodoxime (C15H17N5O6S2) is dissolved in 30 minutes. Cefpodoxime Proxetil RS, accurately weighed, to a 50-
Uniformity of dosage units (905): meet the requirements. mL volumetric flask, dissolve in 5 mL of methanol, dilute
Loss on drying (334-)—Dry about 100 mg in vacuum at a with Diluent to volume, and mix. Transfer 5.0 mL of this
pressure not oxoooding 5 mm of morcury at 80° for 16 hours: solution to a 100-mL volumetric flask, dilute with Diluent
it loooo not moro than 5.0% of its weight. to volume, and mix. Pass through a filter having a 0.45-
Water (921:) not more than 5.0%. um or finer porosity.
Assay— Assay preparation—Weigh and finely powder not fewer
—Mobile phase; Diluent, Internal standard solution, than 20 Tablets. Transfer an accurately weighed portion of
Standard preparation, and Chromato graphic system— the powder, equivalent to about 50 mg of cefpodoxime to a
Prooood ao dirootod in the Assay under Cefpodoxime 100-mL volumetric flask. Dissolve in 40 mL of Diluent,
sonicating for 5 minutes. Cool to room temperature, dilute
—Assay preparation—Weigh and finely powder not loss with Diluent to volume, and mix. Transfer 5.0 mL of this
than 20 Tablets.Transfer an accurately woighod portion of solution to a 100-mL volumetric flask, dilute with Diluent
Pharmacopeial Forum
to volume, mix, and pass through a filter having a 0.45-um Change to read:
Identification,
or finer porosity. —A-s—Tho ultraviolet absorption spectrum of theaolution
prepared for measurement of abaorbanoo in tho Assay exhibits
Procedure—Separately inject equal volumes (about 20 maxima and minima at tho oamo wavelengths ao that of a 1 in
100,000 aolution of USP Chlorothiazido RS in oodium hydroxido
uL) of the Standard preparation and the Assay prepara- solution (1 in 250), oonoomitantly moasurod.
tion into the chromatograph, record the chromatograms, •
AUSP26
and measure the responses for the major peaks. Calculate Ultraviolet Absorption (197U)—
Solution: 10 ug per mL.
the quantity, in mg of cefpodoxime (C15H17N5O6S2) in the Medium: sodium hydroxide solution (1 in 250).
portion of Tablets taken by the formula:
2CP(rv lrs),
in which C is the concentration, in mg per mL, of USP Cef-
podoxime Proxetil RS in the Standard preparation; P is the
designated potency, in jig per mg, of cefpodoxime

BRIEFING
(C,5H17N5O6S2) in USP Cefpodoxime Proxetil RS; and rv
Cholestyramine for Oral Suspension, USP 25 page 414. It
and rs are the sums of the peak responses for cefpodoxime is proposed to specify that the determination by Weight Variation in
the test for Uniformity of dosage units is suitable and sufficient, and
proxetil 5-epimer and cefpodoxime proxetil i?-epimer ob- the procedure for Content Uniformity is not necessary. The test for
Exchange capacity is being renamed as the Assay, to more accu-
tained from the Assay preparation and the Standard pre- rately reflect the type of test and results obtained from the method.
The calculation in this test is also being revised to express the result
paration, respectivery.Aas/,2(s in g of cholestyramine resin per g of Cholestyramine for Oral Sus-
pension. These units are used in the product labeling and would
allow the result of the test to be easily correlated with the percen-
tage tolerances in the monograph Definition (percentage of labeled
amount of dried cholestyramine resin). In cases where the ex-
change capacity of the Resin used to prepare the dosage form can-
not be established, an estimated value of 2.0 g of sodium
glycocholate per g of Resin is assumed.
(PA4: A. Medjedovic) RTS—34195-1
BRIEFING
Chlorothiazide Sodium for Injection, USP 25 page 396. On

the basis of comments received noting that Identification test A and Change to read:
Identification test B are essentially duplicate UV tests, differing Uniformity of dosage units (905): meets the requirements
only in style, it is proposed to delete Identification test A and to A
retain the more recent version, Identification test B that first ap- for Weight Variation.AUSP26
peared in USP 23. The earlier wet chemistry test that appeared in
USP 22 as Identification test B will not be reinstated because the
procedure did not specifically identify Chlorothiazide and identi- Change to read:
fied only degradation products of thiazides (chlorothiazide, hydro-
chlorothiazide, etc.) and any other compounds containing both Exchange capacity—
sulfur and hydrolyzable amines. Interested parties are encouraged Assay AUSP26
to submit suitable chromatographic procedures for the Assay and
the tests for Chromatographic purity and Related compounds Mobile phase, Potassium phosphate buffer, Sodium
along with a second test for Identification that will reflect current glycocholate solution, Reference solution, Standard solution,
USP technical and compendial standards. System suitability solution, and Chromatographic system—
Proceed as directed in the test for Exchange capacity under
(PA5: J. Esker) RTS—35697-1 Cholestyramine Resin.
Test solution—Transfer an accurately weighed portion of
Cholestyramine for Oral Suspension, equivalent to about 100 mg
of cholestyramine resin, to a 25-mL conical flask. Pipet 15.0 mL of
Sodium glycocholate solution into the flask, and stir by mechanical
means for 2 hours. Transfer the contents to a centrifuge tube, and
centrifuge for 15 minutes. Transfer 5.0 mL of the supernatant to a
Pharmacopeial Forum
50-mL volumetric flask, and dilute with water to volume. : 100 rpm.
Procedure—Separately inject equal volumes (about 50 uL) of Time: 15 minutes.
the Reference solution, the Standard solution, and the Test Procedure—Determine the amount of CJQH 1 6 N 6 S dissolved, by
solution into the chromatograph, record the chromatograms, and employing UV absorption at the wavelength of maximum
measure the responses for the major peaks. Caloulato tho absorbance at about 218 nm on filtered portions of the solution
quantity, in mg, of oodium glyoooholato absorbed in tho portion under test, suitably diluted with Dissolution Medium, in
of Cholo9tyramino for Oral Suaponaion taken by tho formula: comparison with a Standard solution having a known
concentration of USP Cimetidine RS in the same Medium.
M(2.5f Tolerances—Not less than 80% (Q) of the labeled amount of
C10H16N6S is dissolved in 15 minutes.
^Calculate the quantity, in mg, of cholestyramine resin per
mg of Cholestyramine for Oral Suspension taken by the for-
mula:
[M(2.5rR - ru)Ws] I [(2.5rR - r^W^^x
in which M is the stated value, in mg, of sodium glycocholate ab- BRIEFING

sorbed per g of USP Cholestyramine Resin RS; rR, rv, and rs are
the peak responses obtained from the Reference solution, the Test
solution, and the Standard solution, respectively; and W i3 tho Clomipramine Hydrochloride Capsules, page 2531 of PF
weight, in mg, of USP Cholootyramino Rosin RS taken to proparo 27(3) [May-June 2001]. It is proposed to change the Medium in
tho Standard solution. the test for Dissolution from water to 0.1 N hydrochloric acid to
be in accordance with the approved NDA and AND A for this pro-
A
WS is the weight, in mg, of USP Cholestyramine Resin RS duct.
taken to prepare the Standard solution; Wv is the weight, in (BPC: M. Marques) RTS—35079-2
mg, of Cholestyramine for Oral Suspension taken to prepare
the Test solution; and Q is the quantity of sodium glycocho-
Add the following:
late absorbed per g of dried cholestyramine resin, as ob-
tained in the test for Exchange capacity under •Clomipramine Hydrochloride
Cholestyramine Resin. Capsules
» Clomipramine Hydrochloride Capsules contain

not less than 9&S 90.0 percent and not more than
105.0 110.0 percent of clomipramine hydrochlor-
ide (C19H23C1N2 • HC1).
BRIEFING
Cimetidine Tablets, USP 25 page 421. It is proposed to

Packaging and storage—Preserve in well-closed
change the apparatus used in the test for Dissolution from Appara- containers.
tus 1 to Apparatus 2 because it is difficult tofitlarge tablets into the
basket to ensure proper hydrodynamics.
USP Reference standards (11)—USP Clomipramine
(BPC: M. Marques) RTS—34178-1 Hydrochloride RS.
Identification, Infrared Absorption (197K)—

Test specimen—Transfer the contents of a number of
Change to read:
Dissolution (711)— Capsules, equivalent to about 125 mg of clomipramine
Medium: 0.01 N hydrochloric acid; 900 mL. hydrochloride, to a suitable container, add 25 mL of
Apparatus 4-
chloroform, stir for 5 minutes, and filter. Evaporate on a
Pharmacopeial Forum
steam bath to a volume of about 5 mL, chill in an ice bath, blank. Calculate the quantity, in mg, of clomipramine
add ethyl ether, and stir until crystals form. Filter, and dry at hydrochloride (C19H23C1N2 • HC1) in the Capsule taken
100° for 1 hour. by the formula:
Change to read:
Dissolution (711)— in which T is the labeled quantity, in mg, of clomipramine
Medium: water;- A 0.1 N hydrochloric ^c\d;^VSP26 hydrochloride in the Capsule; C is the concentration, in ug
500 mL. per mL, of USP Clomipramine Hydrochloride RS in the
Apparatus 2: 50 rpm. Standard solution; D is the concentration, in jig per mL,
Time: 30 minutes. of clomipramine hydrochloride in the Test solution, based
Procedure—Determine the amount of C19H23C1N2 • HC1 on the labeled quantity per Capsule and the extent of dilu-
dissolved by employing UV absorption at the wavelength of tion; and Ay and As are the absorbances of the Test solution
maximum absorbance at about 252 nm on filtered portions and the Standard solution, respectively.
of the solution under test, suitably diluted with Dissolution
Medium, if necessary, in comparison with a Standard Assay—
solution having a known concentration of USP Sodium 1-heptanesulfonate solution, Mobile phase,
Clomipramine Hydrochloride RS in the same Medium. System suitability solution, Standard preparation, and
Tolerances—Not less than 80% (Q) of the labeled amount Chromatographic system—Proceed as directed in the
of C19H23C1N2 • HC1 is dissolved in 30 minutes. Assay under Clomipramine Hydrochloride.

Assay preparation—Remove as completely as possible
Uniformity of dosage units (905): meet the requirements. the contents of not fewer than 20 Capsules. Transfer an
PROCEDURE FOR CONTENT UNIFORMITY— accurately weighed portion of the contents, equivalent to
Standard solution—Prepare a solution of USP about 160 mg of clomipramine hydrochloride, to a 200-
Clomipramine Hydrochloride RS in methanol having a mL volumetric flask, add 130 mL of methanol, shake by
known concentration of about 30 ug per mL. mechanical means for 1 hour, and dilute with methanol to
Test solution—Quantitatively transfer the contents of 1 volume. Transfer 10 mL of this solution to a 25-mL
Capsule to a 100-mL volumetric flask with the aid of volumetric flask, dilute with methanol to volume, mix,
methanol, add about 75 mL of methanol, shake by and filter.
mechanical means for 1 hour, and dilute with methanol to Procedure—Separately inject equal volumes (about 10
volume. Further dilute an aliquot of this solution uL) of the Standard preparation and the Assay
quantitatively, and stepwise if necessary, with methanol to preparation into the chromatograph, record the
obtain a solution having a concentration of about 30 ug chromatograms, for a total of not loao than twioo tho
per mL. retention time of tho olomipramino hydroohlorido peak;
Procedure—Concomitantly determine the absorbances of and measure the responses for the major peaks. Calculate
the Standard solution and the Test solution in 1-cm cells, at the quantity, in mg, of clomipramine hydrochloride
the wavelength of maximum absorbance at about 252 nm, (C19H23C1N2 • HC1) in the portion of Capsules taken by
with a suitable spectrophotometer, using methanol as the the formula:
Pharmacopeial Forum
Procedure—Separately inject equal volumes (about 100 uL) of

the Standard solution and the solution under test into the
responses for the major peaks. Calculate the quantity of
C 15 H 10 ClN 3 O 3 dissolved by comparison of the peak responses
obtained from the Standard solution and the test solution.
in which C is the concentration, in mg per mL, of USP Clo- Tolerances—Not less than 80% (Q)
A
mipramine Hydrochloride RS in the Standard preparation; 75% (Q).USP26
of the labeled amount of C15H10ClN3O3 is dissolved in 60 mur
and £&. rv and &s rs are the response ratios peak responses
A
4 5 minutes. A K S M ( f
obtained from the Assay preparation and the Standard pre-
paration, respectively. m2
BRIEFING
BRIEFING
Clorazepate Dipotassium Tablets, USP 25 page 456. It is
proposed to replace the current Medium, water, in the test for Dis-
Clonazepam Tablets, USP 25 page 453. It is proposed to solution with 0.01 N hydrochloric acid. This new medium is more
modify the rotation specification of Apparatus 2 from 100 rpm physiologically relevant and has a better buffering capacity. It is
to 50 rpm in the test for Dissolution. Also, it is proposed to change sufficiently discriminating with acceptably low variability for all
the Tolerancesfrom"not less than 80% (Q) of the labeled amount products currently on the U.S. market. Also, because of spectral
of CJCH 1 0 C1N 3 (X is dissolved in 60 minutes" to "not less than shifts at a lower pH, it is proposed to change the wavelength for
75% (Q) of the labeled amount of C,5H10ClN3O3 is dissolved in the UV determination from 231 to 240 nm.
45 minutes". These modifications will provide a more discriminat-
ing test for all of the products currently on the market.
Change to read:
Change to read: Md
Dissolution (711)— A
Medium: degassed water; 900 mL. 0.01 N hydrochloric acidAUSP2(J
Apparatus 2: ; 900 mL.
A
50 ipm Apparatus 2: 50 rpm.
Time: 30 minutes.
Time: 60 minutes. Procedure—Determine the amount of C^HuClK^N^Cs
dissolved by employing UV absorption at the wavelength of
A
4 5 minutes. A U S W t f maximum absorbance at about 334-
Determine the amount of C15H10ClN3O3 dissolved by employ- A £sp2<5
ing the following method. nm on filtered portions of the solution under test, suitably diluted
Mobile phase—Prepare a filtered and degassed mixture of water, with Dissolution Medium, if necessary, in comparison with a Stan-
methanol, and acetonitrile (40:30:30). Make adjustments if dard solution having a known concentration of USP Clorazepate
necessary (see System Suitability under Chromatography (621)). Dipotassium RS in the same Medium.
Standard solution—Prepare a solution of USP Clonazepam RS Tolerances—Not less than 80% (Q) of the labeled amount of
in methanol having a known concentration of about 0.05 mg per C 16 H n ClK 2 N 2 O 4 is dissolved in 30 minutes.
mL. Quantitatively dilute a portion of this solution with
Dissolution Medium to obtain a Standard solution having a
known concentration similar to the expected concentration in the
solution under test.
liquid chromatograph is equipped with a 254-nm detector and a
4-mm x 30-cm column that contains packing LI. The flow rate
is about 1 mL per minute. Chromatograph replicate injections of
the Standard solution, and record the peak responses as directed
for Procedure: the relative standard deviation is not more than
2.0%; and the tailing factor is not more than 2.0.
Pharmacopeial Forum
Procedure—Proceed as directed for Procedure in the test for
Related glycosides under Digoxin, except to omit the use of the
BRIEFING Gitoxin standard solution. Examine the plate under long-
wavelength UV light: the RF value of the principal spot obtained
from the Test solution corresponds to that obtained from the
Clorsulon, USP 25 page 457. Standard solution.
B: The retention time of the major peak in the chromatogram
(VET: I. DeVeau) RTS—35497-1 of the Assay preparation corresponds to that in the chromatogram
of the Standard preparation, as obtained in the Assay.
Erratum: Change to read:

Assay, line 2 under Mobile phase: Change "(70:30:1)." to: Dissolution (711) [NOTE—Throughout this proooduro, uso ooru
(70:30:0.1). pulously oloan glassware, which previously has boon ringed auo
ooooivoly with hydroohlorio aoid, wator, and aloohol, and
oarofully driod. Tako precautions to provont contamination from
fluorescent particles and from metal and rubber surfaooo:]
Medium: 0.1 N hydroohlorio aoid; 500 mL. NOTE UOO tho
same batoh of Dissolution Medium throughout tho toot.
—Apparatus 1: 120 rpm.
—Time: 60 minutes.
—Ascorbic acid mcthanol solution—Prop arc a solution containing
2 mg of asoorbio aoid por mL of mothanol:
—Hydrogen peroxide mcthanol solution—On tho day of uso,
dilute 2.0 mL of recently aaaayed 30 poroont hydrogen poroxido
BRIEFING with mothanol to 100 mL. Storo in a refrigorator. Juot prior to
use, dilute 2.0 mL of this solution with mothanol to 100 mL.
Digoxin Tablets, USP 25 page 573 and page 2537 of PF Standard solutions Tranofor about 25 mg of USP Digoxin RS,
27(3) [May-June 2001]. It is proposed to replace the fluorometric aoouratoly woighod, to a 500 mL volumetrio flaak. Diooolvo in a
titration in the test for Dissolution with an HPLC method. The ti- minimum amount of aloohol, add dilute aloohol (4 in 5) to
tration is a very lengthy, laborious, and nonspecific procedure, and volume, and mix. Dilute 10.0 mL of thio solution with dilute
the presence of interferences can slow the reaction. The HPLC aloohol (4 in 5) to 100.0 mL, and mix. Just prior to uoo, dilute
method was validated using the Supelcosil LC-18 brand of LI col- suitable aliquota of tho rooulting oolution with Dissolution
umn. Other modifications in the test for Dissolution are also pro- Medium to 50.0 mL to prepare Standard solutions equivalent to
posed: to replace the current Medium, 0.1 N hydrochloric acid, 20%, 10%, 60%, 80%, and 100%, respectively, of tho labolod
with water because digoxin hydrolyzes in acid medium; and to amount of digoxin in 500 mL.
use Apparatus 2 at 100 rpm instead of Apparatus 1 at 120 rpm. —Test solution—Promptly after withdrawal; pass a portion of tho
solution undor tost through a filter having a 0.8 urn or finer
porosity, discarding tho first 10 mL of the filtrate. This i3 tho Test
—Procedure—Transfer to individual glass stoppered flasko
duplicate 1.0 mL portions of tho Test solution, 1.0 mL portions
of oaoh of tho Standard solutions, and 1.0 mL of tho Dissolution
Medium to provide a blank. Begin with tho Standard solutions, and
Change to read: koop allflaoksin tho aamo sequonoo throughout, so that tho olap3od
timo from addition of reagents to reading offluoroooonoois tho
Identification— oame for each flask in tho oot. Treating ono flaok at a timo, add
A: Chloramine T-trichloroacetic acid reagent Spotting tho following three roagonto, in tho order named, in as rapid a
solvent, andStandard solution sequonoo as poooiblo, swirling after oaoh addition: 1.0 mL of
m
•1 Ascorbic acid mcthanol solution, 5.0 mL of hydroohlorio aoid,
and 1.0 mL of Hydrogen peroxide mcthanol solution. Inoort tho
—Prepare as directed for Identification test B under Digoxin Elixir. stoppers in tho flasko, and aftor 2 hours, measure tho
fluorosoonoo at about 485 nm, tho oxoitation wavelength being
'Spotting solvent—Use dehydrated alcohol., L about 372 nm. To ohook tho stability of tho fluoromotor, ropoat
Test solution—Transfer an accurately weighed portion of finely tho measurement of fluoroooonoo on ono or moro treated
powdered Tablets, equivalent to 0.5 mg of digoxin, to a 10-mL Standard solutions. Correct oaoh reading for tho blank, and plot
centrifuge tube. Add 2 mL of Spotting solvent, ahako for 10 a standard curve of fluoroooonoo vorau3 percentage dissolution.
Dotormino tho poroontago dissolution of digoxin in tho Test
solution by reading from tho standard graph.
"sonicate for 10 to 15 B , —Tolerances Not less than 80% (Q) of the labeled amount of
minutes, and centrifuge. Decant and use the supernatant. G^H^Q^ io diooolvod in 60 minutes. Tho requirement is mot if
tho quantities dissolved from tho Tablets tested conform to the
'Standard solution—Dissolve an accurately weighed accompanying aoooptanoo table instead of the table shown undor
Dissolution { )
quantity of USP Digoxin RS in Spotting solvent to obtain
a solution having a known concentration of about 0.25 mg
per mL. B1
Pharmacopeial Forum
Acceptance Table chromatograms, and measure the responses for the major
loooptanoo peaks. Determine the amount of C41H64O14 dissolved by

Staco
Eaoh unit ia not loao the formula:
than Q + 5%.
Avorago of 12 units 50,000(C/I)(r f/ /r 5 ),
(S4.-4-&s) i 3 oqual to
or groator than Q,
and no unit is loaa in which C is the concentration, in mg per mL, of USP Di-
than 0 5%.
goxin RS in the Standard solution; L is the labeled amount
of digoxin in mg per Tablet; and rv and rs are the digoxin
^Medium: water; 500 mL.
peak responses obtained from the solution under test and
Apparatus 2: 100 rpm. the Standard solution, respectively.
Time: 60 minutes.
Determine the amount of C 41H64O14 dissolved by em-
of C41H64O14 is dissolved in 60 minutes. AUSP2s
ploying the following method.
Mobile phase—Prepare a filtered and degassed mixture of
water and acetonitrile (75:25). Make adjustments if
necessary (see System Suitability under Chromatography
(621)) so that digoxin elutes after about 8 minutes.
Standard solution—Transfer about 25 mg of USP
BRIEFING
Digoxin RS, accurately weighed, to a 200-mL volumetric
flask, add 25 mL of methanol, place the flask in a water Dinoprostone, page 3273 of PF 27(6) [Nov.-Dec. 2001]. It is
proposed to modify the limits in the test for Specific rotation to
bath at 40°, and swirl to dissolve. Remove from the bath, reflect the actual values obtained when alcohol is used as the sol-
vent for the Test solution.
cool to room temperature, dilute with methanol to volume,
(PA1: S. Salado) RTS—35079-1;; 35540-2
and mix. Transfer 2.0 mL to a 500-mL volumetric flask,
dilute with water to volume, and mix.
Chromatographic system—The liquid chromatograph is Add the following:
A
equipped with a 218-nm detector and a 4.6-mm x 15-cm Dinoprostone
column that contains packing LI. The flow rate is about 1
(Chemical structure to come)
mL per minute. Chromatograph the Standard solution, and
record the peak responses as directed for Procedure: the C20H32O5 352.47
tailing factor is not more than 2.0; and the relative Prosta-5,13-dien-l-oic acid, ll,15-dihydroxy-9-oxo-,
standard deviation for replicate injections is not more than (5Z,lla,13£,155)-.

2.5%. (£,Z)-(l/?,2i?,3i?)-7-[3-Hydroxy-2-[(35)-(3-hydroxy-l-oc-
Procedure—Separately inject equal volumes (about 200 tenyl)]-5-oxocyclopentyl]-5-heptenoic acid.
uL) of the filtered portions of the Standard solution and Prostaglandin E2 [363-24-6].
the solution under test into the chromatograph, record the
Pharmacopeial Forum
» Dinoprostone contains not less than 97.0 percent than 12,300 6000 theoretical plates; and the relative
and not more than 103.0 percent of C20H32O5. standard deviation for replicate injections is not more than
2.0%. Chromatograph the Test solution, and record the peak
Packaging and storage—Preserve in well-closed, light-
responses as directed for Procedure: the resolution, R,
resistant containers. between dinoprostone and any other adjacent peak is not
USP Reference standards (11)—USP Dinoprostone RS. less than-4-^ 1.0.
NOTE—Prepare all solutions in all tests immediately prior Procedure—Separately inject equal volumes (about 20
to use. uL) of the Standard solution and the Test solution into the
Identification— chromatograph, record the chromatograms, and measure the
A: Infrared Absorption (197K). peak responses. Calculate the percentage of each rolatod
B: The retention time of the major peak in the compound impurity in the portion of Dinoprostone taken
chromatogram of the Assay preparation corresponds to by the formula:
that in the chromatogram of the Standard preparation, as
obtained in the Assay. (C/W){\/F){rilrs),
Specific rotation (781S): between 88.0° and 06.0°, -82.0°
and -90.0°, at 20°. in which C is the concentration, in ug per mL, of USP Di-
Test solution:-^- 5 mg per mL, in chloroform alcohol. noprostone RS in the Standard solution; Wis the weight, in
Water, Method I (921): not more than 0.5%. mg, of Dinoprostone taken to prepare the Test solution; F is
Residue on ignition (281): not more than 0.5%. the relative response factor and is equal to 2.6 for any peak
Related compounds—Chromatographic purity— at a relative retention timo of 0.79, 4.0 for any poak at a ro
Mobile phase—Proceed as directed in the Assay. lativo retention time of 1.8^1.6 for any peak at a relative ro
Standard stock solution—Prepare as directed for tcntion timo of 1.9, and 1.0 for any other poak; (see Table 1
Standard preparation in the Assay. for values); r, is the peak response for each rolatod oom
Standard solution—Transfer 0.5 mL of the Standard pound impurity obtained from the Test solution; and rs is
stock solution to a 50-mL volumetric flask, dilute with the peak response for dinoprostone obtained from the Stan-
Mobile phase to volume, and mix. dard solution. For any poak at a relative retention timo of
Test solution—Prepare as directed for Assay preparation. 1.15, not moro than 2.0% is found; for any poak at a rolativo
Chromatographic system (see Chromatography (621))— retention timo of 1.8 or 1.9, not more than 1:0% ia found;
Prepare as directed in the Assay. Chromatograph the and tho sum of all othor impurities is not moro than 1.0%.
Standard stock solution, and record the peak responses as

directed for Procedure: the column efficiency is not less
Pharmacopeia! Forum
dilute quantitatively, and stepwise if necessary, with

Table 1.
Mobile phase to obtain a solution having a known
Relative
Retention
Assay preparation—Transfer about 25.0 mg of
Impurity Time F Limit
Dinoprostone, accurately weighed, to a 10-mL volumetric
15-oxo-dinoprostone 0.79 flask, dissolve in and dilute with Mobile phase to volume,
15-epi-dinoprostone 0.85 1.1 *
and mix.
8-isodinoprostone 0.90 1.0 *
5,6-trans- 1.15 1.0 Not more The liquid chromatograph is equipped with a 210-nm
dinoprostone than detector and a 4.6-mm x 25-cm column that contains
2.0% packing LI. The flow rate is about 1 mL per minute. The
(5Z,13£,15S)-15-hy- 1.80 QS&5 Not more column temperature is maintained at 30°. Chromatograph
droxy-9-oxo- than the Standard preparation, and record the peak responses
prosta- 5,10,13- 1.0% as directed for Procedure: the resolution, R, between
triene-1-oic dinoprostone and any other adjacent peak is not less than
acid 4-r£ 1.0; and the relative standard deviation for replicate
(5Z,13£,15S)-15-hy- 1.90 OMIA:3 Not more injections is not more than 2.0%.
droxy-9-oxo- than Procedure—Separately inject equal volumes (about 20
prosta-5,8(12),13- 1.0% uL) of the Standard preparation and the Assay
trien-1-oic acid preparation into the chromatograph, record the
— 1.0
Any other impurity Not more chromatograms, and measure the responses for the major
than 0.1% peaks. Calculate the quantity, in mg, of C2oH3205 in the
of total portion of Dinoprostone taken by the formula:
other
impuri-
ties in which C is the concentration, in mg per mL, of USP Di-
presents noprostone RS in the Standard preparation; and rv and rs

are the peak responses obtained from the Assay preparation
* The sum of these three impurities is not more than 1.0%.
and the Standard preparation, respectively.ÛSP26
Assay—
methanol and 0.2% acetic acid (58:42). Make adjustments if
(621)).
Standard preparation—Dissolve an accurately weighed
quantity of USP Dinoprostone RS in Mobile phase, and
Pharmacopeial Forum

BRIEFING
(minutes) Elution
Ergoloid Mesylates Tablets, USP 25 page 668. 0-20 100->60 0->40 linear gradient
20-40 60-»0 40-* 100 linear gradient
40-45.0 0 100 isocratic
(BPC: M. Marques) RTS—35556-1 45.0-45.1 0^100 100-*0 linear gradient
45.1-60 100 0 isocratic
Chromatograph the Test solution, and record the peak responses as

Erratum: directed for Procedure: the column efficiency is not less than
Dissolution, line 3 under Standard solution: Change "Transfer 4 15,000 theoretical plates.
mL of this solution" to: Transfer 4 mL of this solution for every 0.5 A
mg of ergoloid mesylates contained in the Tablets Chromatograph the System suitability solution, and record
the peak responses as directed for Procedure: the signal-to-
noise ratio for the fluoxymesterone peak is not less than
Procedure—Injoot a volume
Separately inject equal volumesAl/sw<5
(about 5 uL) of the
A
BRIEFING Blank solution and the±USP26
Test solution into the chromatograph, record the ohromatogram,
Fluoxymesterone, USP 25 page 761. It is proposed to add a A
chromatograms, AasW( j
Blank solution to the test for Chromatographic purity to help iden-
tify the peaks of the diluent used. It is also proposed to add a Sys- and measure the areas for tho major poako;
tem suitability solution to the test for Chromatographic purity to A
for any peaks that do not appear in the Blank solution that
ensure that the sensitivity of the test is met.
have an area equal to or greater than 0 . 1 % of the fluoxymes-
(PA1: S. Salado) RTS—34880-2
terone peak.AKSM(f
Calculate the percentage of each impurity in the portion of Fluox-
ymesterone taken by the formula:
lOOfo/r,),
Change to read: in which r, is the peak response for each impurity; and rs is the sum
Chromatographic purity— of the responses of all the peaks: not more than 1.0% of any indi-
Solution A—Prepare a filtered and degassed mixture of methanol vidual impurity is found; and not more than 2.0% of total impuri-
and water (55:45). ties is found.
Solution B—Use filtered and degassed methanol.
Mobile phase—Use variable mixtures of Solution A and Solution
B as directed for Chromatographic system.
A
Blank solution—Use Solution B.
System suitability solution—Dilute a volume of the Test
solution quantitatively, and stepwise if necessary, with
methanol to obtain a solution having a concentration of
BRIEFING
about 5 ug of fluoxymesterone per mL.AUSP26
Furosemide Oral Solution, USP 25 page 779 and page 2159
Test solution—Prepare a solution of Fluoxymesterone in ofPF27(2) [Mar.-Apr. 2001]. On the basis of comments received,
Solution B containing about 0.5 mg per mL. it is proposed to broaden the limit in the test for pH to agree with
Chromatographic system (see Chromatography (621))—The that for products already approved by the FDA. The purpose of the
liquid chromatograph is equipped with a 254-nm detector and a proposed revision is to change the limit from that recently adopted
4.6-mm x 25-cm column that contains packing LI. The column in USP 25 (between 7.0 and 9.2) to between 7.0 and 10.0. Com-
temperature is maintained at 40°. The flow rate is 1.0 mL per ments regarding this proposal should be received at USP by March
minute. The chromatograph is programmed as follows. 2, 2002. In the absence of any significant adverse comment, it is
Pharmacopeia! Forum
proposed to implement this revision via the Third Interim An-

nouncement pertaining to USP 25-NF 20, with an official date BRIEFING
of June 1,2002.
Glyburide Tablets, USP 25 page 808. On the basis of com-
(PA5: J. Esker) RTS—35641-1 ments received, it is proposed to add a test for Dissolution that ap-
plies only to tablets that contain nonmicronized glyburide.
(BPC: M. Marquues) RTS—22575-1
Add the following:
•Packaging and storage—Preserve in tight, light-resistant

Add the following:
containers. m2
^Dissolution (711)—(for Tablets containing nonmicro-
Change to read:
nized Glyburide only)
pH (791): between 7.0 and 9r2
Medium: 0.5% hexadecyltrimethylammonium bromide
•10.0..,
in 0.025 M alkaline borate buffer, pH 8.0; 900 mL.
NOTE—Throughout the following procedures, protect test or as- [NOTE—Prepare by mixing a volume of 1.0% aqueous
say specimens, the USP Reference Standards, and solutions con-
taining them, by conducting the procedures without delay, under solution of hexadecyltrimethylammonium bromide with
subdued light, or using low-actinic glassware.
an equal volume of 0.05 M alkaline borate buffer, pH 8.0.]
Time: 60 minutes.
Procedure: Determine the amount of C23H28C1N3O5S
dissolved, employing the procedure set forth in the Assay,
BRIEFING making any necessary modifications.

Glutaral Concentrate, USP 25 page 806—See briefing un-
der Benzethonium Chloride Concentrate. of C23H28C1N3O5S is dissolved in 60 mm\itQS.AUSP26
Add the following:

^Labeling—Label it to state that this article is not intended
for direct administration to humans or animals.AUSP26
BRIEFING
Hydrochlorothiazide, USP 25 page 848 and page 2736 of

PF 27(4) [July-Aug. 2001]. Based on comments received, it is
proposed to delete column efficiency from the system suitability
requirements in the test for Chromatographic purity and in the As-
say. With suitable resolution requirements, the requirements for
column efficiency were considered redundant.
© 2002 The United States Pharmacopeia! Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
between 4-amino-6-chloro-l,3-benzenedisulfonamide and

Change to read: chlorothiazide is not less than 2.0 and the resolution, R,
USP Reference standards (\\)—USP 4-Amino-6-chloro-l,3-
benzenedisulfonamide RS. between chlorothiazide and hydrochlorothiazide is not less
'USP Chlorothiazide RS.9{
USP Hydrochlorothiazide RS. than 1.5; tho oolumn offioionoy io moro than 1000
thoorotioal plato&t AAUSP26 the tailing factor for the 4-
Delete the following:
"4 Amino 6 ehloro 1,3 bcnzencdisulfonamide— amino-6-chloro-l,3-benzenedisulfonamide, chlorothiazide,
—Mobile phase, System suitability solution, and Chromatographic
system—Prooood as directed in tho Assay. and hydrochlorothiazide peaks is not more than 1.5; and
—Test preparation—Prooood aa directed for Assay preparation in
the relative standard deviation for replicate injections
—Standard preparation—[NOTD—A volumo of aootonitrilo not
oxoooding 10% of tho total volume of tho solution may bo uaod determined from 4-amino-6-chloro-l,3-benzenedi-
to dissolve tho Roforonoo Standard.] Dissolve an aocuratoly
w e i g h e d q u a n t i t y of USP 4 A m i n o 6 ohloro 1,3 sulfonamide and chlorothiazide is not more than 5.0%.
bonzonodisulfonamido RS in Mobile phase to obtain a solution
having a known concentration of about 1.5 ug per mL. Chromatograph three replicate injections of the
—Procedure—Separately injoot equal volumes (about 20 uL) of
tho Standard preparation and tho Test preparation into tho Quantitation limit solution, and record the peak responses
ohromatograph, record the ohromatograms, and moaouro tho
responses for the major peaks. Calculate tho quantity, unrig, of as directed for Procedure.the relative standard deviation is
4-amino-6 ohloro 1,3 bonzonodisulfonamido in the portion of
Hydroohlorothiazido takon by tho formula: not more than 25%. [NOTE—The relative retention times for
4-amino-6-chloro-l,3-benzenedisulfonamide, chloro-
in which C is tho oonoontration; in ug per mL, of USP 4 Amino 6 thiazide, h y d r o c h l o r o t h i a z i d e , 5-chlorohydro-
ohloro 1,3 bonzonodisulfonamido RS in tho Standard preparation,
and r^ and r^ aro tho poalc rosponsos of 4 amino 6 ohloro 1,3 ben chlorothiazide, and hydrochlorothiazide dimer [6-chloro-
zonodisulfonamido obtained from tho Test preparation and the
Standard preparation, rospootivoly: not moro than 1.0% io pro iv~-[(6-chloro-7-sulfamoyl-2,3-dihydro-4H-l,2,4-benzothia-
diazine-4-yl 1,1 -dioxide)methyl]3,4-dihydro-2H-1,2,4-
Add the following: benzothiadiazine-7-sulfonamide 1,1-dioxide] are about
"Chromatographic purity— 0.5, 0.8, 1.0, 2.1, and 2.6, respectively.]
Diluent, Solution A, Solution B, Mobile phase, and Procedure—Inject a volume (about 10 uL) of the Test
System suitability solution—Proceed as directed in the solution into the chromatograph, record the chroma-
Assay. togram, and measure the peak responses. Calculate the
Quantitation limit solution—Dissolve an accurately percentage of each impurity in the portion of
weighed quantity of USP Hydrochlorothiazide RS in Hydrochlorothiazide taken by the formula:
Diluent, sonicate if necessary, and dilute quantitatively,
and stepwise if necessary, with Diluent to obtain a
in which ric is the ratio of the peak area for each impurity to
solution having a known concentration of about 0.16 ug
its response factor; and rsc is the sum of ratios of all the peak
per mL.
areas to their respective response factors, the response fac-
Test solution—Proceed as directed for the Assay
tors being 0.54, 0.63, and 1.0 for 4-amino-6-chloro-l,3-ben-
preparation in the Assay.
zenedisulfonamide, chlorothiazide, and all other peaks,
Chromatographic system (see Chromatography
respectively: not more than 1.0% of 4-amino-6-chloro-l,3-
(621))— Prepare as directed in the Assay. Chromatograph
benzenedisulfonamide is found; not more than 0.5% of any
the System suitability solution, and record the peak
responses as directed for Procedure: the resolution, R,
Pharmacopeial Forum
other impurity is found; and not more than 0.9% of total solution and acetonitrile (7:3).
other impurities excluding 4-amino-6-chloro-l,3-benzene- Solution A—Prepare and degas a mixture of acetonitrile
disulfonamide is found. B1 and methanol (3:1).
Solution B—Prepare and degas a solution of anhydrous
Change to read:
Assay— formic acid in water (5 in 1000).
—Mobile phase—Proparo a dogassod mixture of 0.1 M monobasio
aodium phosphate and aootonitrilo (9:1), adjust with phosphorio Mobile phase—Use variable mixtures of Solution A and
acid to a pH of 3.0 ± 0.1, and filter. Mako adjustments if
necessary (aee System Suitability undor Chromatography (6£4-))r Solution B as directed for Chromatographic system. Make
—System suitability solution—[NOTE—A volume of aootonitrilo
not oxoooding 10% of tho total volume of solution may bo used adjustments if necessary (see System Suitability under
to dissolve tho Roforonoo Standards.] Dissolve accurately
w e i g h e d q u a n t i t i o a of o h l o r o t h i a z i d o and U S P Chromatography (621)).
Hydroohlorothiazido RS in Mobile phase to obtain a solution
containing about 0.15 mg of oaoh por mL. System suitability solution—Dissolve suitable quantities
—Standai«d preparation—[NOTE—A volumo of aootonitrile not
oxoooding 10% of tho total volume of tho solution may bo used of USP Hydrochlorothiazide RS, USP Chlorothiazide RS,
to dissolve tho Roforonoo Standard.] Dissolve an accurately
weighed quantity of USP Hydroohlorothiazido RS in Mobile and USP 4-Amino-6-chloro-l,3-benzenedisulfonamide RS
phase to obtain a solution having a known oonoontration of
about 0.15 mg por mL. in Diluent, sonicate if necessary, and dilute with Diluent
—Assay preparation—Transfer a b o u t 30 mg of
Hydroohlorothiazido, accurately woighod, to a 200 mL to obtain a solution containing about 0.32 mg per mL,
volumotrio flask, dissolve in a small volumo of aootonitrilo not
oxoooding 10% of tho total volumo of tho solution, dilute with 0.0032 mg per mL, and 0.0032 mg per mL, respectively.
Mobile phase to volumo, and mix.
Chromatographic system (soo Chmmatogmphy (6H)) Tho Pass a portion through a filter having a 0.45-um or finer
liquid ohromatograph is equipped with a 254 nm dotootor and a
4.6 mm x 25 om column that contains packing LI. Tho flow porosity.
rato is about 2.0 mL por minute. Chromatograph tho System
suitability solution, and record tho poak responses as directed for Standard preparation—Dissolve an accurately weighed
Procedure: tho relative retention timos arc about 0.8 for
ohlorothiazido and 1.0 for hydroohlorothiazido; and tho quantity of USP Hydrochlorothiazide RS in Diluent,
rooolution, R, botwoon ohlorothiazido and hydroohlorothiazido is
not loss than 2.0. Chromatograph tho Standard preparation, and sonicate if necessary, and dilute quantitatively, and
record tho poak responses as directed for Procedure: tho relative
standard deviation for roplioato injootions is not more than 1.5%. stepwise if necessary, with Diluent to obtain a solution
—Procedure—Separately injoot equal volumes (about 20 uL) of
tho Standard preparation and tho Assay preparation into tho having a known concentration of about 0.32 mg per mL.
ohromatograph, record tho ohromatograms, and moasuro tho
rosponaos for tho major poalcs. Caloulato tho quantity^ in mg, of Pass a portion through a filter having a 0.45-jim or finer
G Q N Q S in tho portion of Hydrochlorothiazido takon by tho
porosity before injection.
onn/~y., /„ \
Assay preparation—Transfer about 32 mg of
in which C is tho oonoontration, in mg por mL; of USP Hydroohlor
othiazido RS in tho Standard preparation; and r^ and r# aro tho Hydrochlorothiazide, accurately weighed, to a 100-mL
poak responses obtained from tho Assay preparation and tho Stan
dard preparation, respectively volumetric flask. Add about 70 mL of Diluent, sonicate
'Sodium phosphate solution—Transfer 2.76 g of for 10 minutes if necessary to dissolve, and allow to cool
monobasic sodium phosphate, accurately weighed, into a to ambient temperature. Dilute with Diluent to volume,
1000-mL volumetric flask, and add about 990 mL of mix, and pass a portion through a filter having a 0.45-um
water. Adjust with phosphoric acid to a pH of 2.7 ± 0 . 1 , or finer porosity before injection.
and dilute with water to volume. Make adjustments if Chromatographic system (see Chromatography
necessary (see System Suitability under Chromatography (621))—The liquid chromatograph is equipped with a
(621)). 275-nm detector and a 4.6-mm x 5-cm column that
Diluent—Prepare a mixture of Sodium phosphate contains 3.5-um packing LI. The flow rate is about 1.0
Pharmacopeial Forum
mL per minute. The column temperature is maintained at in which C is the concentration, in mg per mL, of USP Hy-
35°. The chromatograph is programmed as follows. drochlorothiazide RS in the Standard preparation; and rv
Chromatograph the Diluent to check for interference by and rs are the peak responses obtained from the Assay pre-
system related peaks. Chromatograph the System paration and the Standard preparation, respectively.B1
suitability solution, and record the peak responses as
directed for Procedure: the relative retention times are
about 0.5 for 4-amino-6-chloro-l,3-benzenedisulfonamide,
0.8 for chlorothiazide, and 1.0 for hydrochlorothiazide;
the resolution, R, between 4-amino-6-chloro-l,3-
benzenedisulfonamide and chlorothiazide is not less than
BRIEFING
2.0 and the resolution, R, between chlorothiazide and
Hydrocodone Bitartrate, USP 25 page 850 and page 3012 of
hydrochlorothiazide is not less than 1.5; the column PF 27(5) [Sept.-Oct. 2001]. On the basis of data received from the
pharmaceutical industry, which indicate that the calculation of spe-
offioionoy is more than 1000 thcorotioal plates; AAUSP26 cific rotation should be on the "as is" basis, it is proposed to add a
statement to the test for Specific rotation so as to exclude this arti-
and the tailing factor for the 4-amino-6-chloro-l,3-benzene- cle from the requirement of calculation on the dried basis stated
under Optical Rotation (781). It is also proposed to replace the test
disulfonamide, chlorothiazide, and hydrochlorothiazide for Ordinary impurities with a test for Related compounds using a
stability-indicating high-pressure liquid chromatographic method
peaks is not more than 1.5. Chromatograph the Standard that resolves all known process impurities. The previously-pro-
posed thin-layer chromatographic method is reported to be inade-
preparation, and record the peak responses as directed for quate for separation of known process impurities because of
rapidly-fading spots and the nonrobustness of the method. The sta-
Procedure: the relative standard deviation for replicate in- bility-indicating high-pressure liquid chromatographic procedure
in the test for Related compounds is based on analyses performed
jections is not more than 1.0%. with the Zorbax-C8 brand of L7 column.
(PA2: J.Kelly) RTS—34780-1; 35659-1

Change to read:
0-5 3 97 isocratic USP
m
Reference standards (11)—
USP Dihydrocodeine Bitartrate RS.m
5-14 3^36 97->64 linear gradient USP Hydrocodone Bitartrate RS.
A
USP Hydrocodone Bitartrate Related Compound A
14-18 36—3 64->97 linear gradient
RS- AUSP26
18-20 3 97 re-equilibration
Procedure—Separately inject equal volumes (about 10 Change to read:
uX) of the Standard preparation and the Assay Specific rotation (78IS): between -79° and -84°.
Test solution: 20 mg, undried, per mL, in water.
preparation into the chromatograph, record the A
Calculate the result on the basis of the undried
chromatograms, and measure the responses for the
hydrochlorothiazide peaks. Calculate the quantity, in mg,
of C7HgClN3O4S2 in the portion of Hydrochlorothiazide Delete the following:
A
taken by the formula: Ordinary impurities (466)—
—Test solution: a mixture of mothanol and wator (1:1).
—Standard solution: a mixturo of mothanol and wator (1:1):
—Eluant: a mixturo of hoxanoa, aoctono, mothanol, and
ammonium hydroxide? (60:40:20:1.5).
Pharmacopeial Forum
—Visualisation: 3; followed by ovoropraying with hydrogen Chromatographic system (see Chromatography

poroxido TS.—[NOTE—Covor tho thin layor ohromatographio
plate with a glass plato to 3low fading of tho apota. Exoludo tho (621))—The liquid chromatograph is equipped with a
origin spot, if prooont, from the determination of tho total
impurities.] 278-nm detector and a 4.6-mm x 25-cm column that
contains a 5-um packing L7. The column temperature is
Add the following:
A
Related compounds—[NOTE—Dry both the USP Hydro- maintained at 50°. The flow rate is about 2.2 mL per
codone Bitartrate RS and the Hydrocodone Bitartrate mate- minute. The chromatograph is programmed as follows.
rials in vacuum at 105° for 2 hours. Immediately transfer the Chromatograph the System suitability solution, and record
dried materials to a desiccator containing phosphorus pent- the peak responses as directed for Procedure: the
oxide. Weigh each dried material individually within 1 min- resolution, R, between hydrocodone and hydrocodone
ute, and proceed with the Related Compounds test.] bitartrate related compound A is not less than 4.1; the
Solution A—Prepare a filtered and degassed mixture of capacity factor, k', is in the range of 17 to 20 for
0.15 M monobasic sodium phosphate buffer, adjust with hydrocodone bitartrate; and the relative standard
phosphoric acid to a pH of 3.3 ± 0 . 1 . deviation, determined from analyte peaks, is not more
Solution B—Prepare a filtered and degassed mixture of than 15%.
acetonitrile and Solution A (50:50). Time Solution A Solution B Elution

Mobile phase—Use variable mixtures of Solution A and (minutes) (%)
(%)
Solution B as directed for Chromatographic system. Make
0 95 5 equilibrium
0-17 95->90 5->10 linear gradi-
ent
Diluent: a mixture of methanol and water (50:50).
17-24 90->88 10-»12 linear gradi-
Benzophenone stock solution—Transfer about 16 mg of
ent
benzophenone, accurately weighed, to a 100-mL
24-40 88^30 12->70 linear gradi-
volumetric flask. Dissolve in and dilute with dehydrated
ent
alcohol to volume, and mix.
System suitability solution—Transfer about 25 mg of
50-54 30->95 70->5 linear gradi-
previously dried USP Hydrocodone Bitartrate RS to a
ent
100-mL volumetric flask, add about 25 mg of USP
Procedure—Inject a volume (20 uL) of the Test solution
Dihydrocodeine Bitartrate RS, 17 mg of USP Hydro-
into the chromatograph, record the chromatogram, and
codone Bitartrate Related Compound A RS, and 5 mL of
measure the peak responses. Calculate the percentage of
phosphoric acid. Add 5.0 mL of Benzophenone stock
each individual impurity in the portion of Hydrocodone
solution, dilute with water, and mix.
Bitartrate taken by the formula:
Test solution—Transfer an accurately weighed quantity
100
of previously dried Hydrocodone Bitartrate, equivalent to
about 100 mg of hydrocodone bitartrate C 18 H 21 NO 3 - in which F is the relative response factor and is equal to 1.24
C 4 H 6 O 6 , to a 100-mL volumetric flask, dissolve in and for dihydrocodeine bitartrate, 2.27 for hydrocodone bitar-
dilute with Diluent to volume, and mix. trate related compound A, and 13.73 for benzophenone; r,
Pharmacopeial Forum
is the individual peak response of hydrocodone related com- Change to read:

pound A, dihydrocodeine bitartrate, and benzophenone in
•Store, j
the Test solution; and rs is the sum of all peak responses. in a freezer, and protect from light.
Not more than 0.5% each of hydrocodone bitartrate related Change to read:
compound A, dihydrocodeine bitartrate, and benzophenone Identification—
A: The retention time of the major peak in the chromatogram
is found; and the sum of all impurities is not more than of the Assay preparation corresponds to that in the chromatogram
B: Determine the peptide fragments, using the following
peptide mapping procedure.
Sulfate buffer—Mix equal volumes of 2.0 M ammonium sulfate
and 0.5 M sulfuric acid, and filter.
Enzyme solution—Prepare a solution of Staphylococcus aureus
V-8 protease in HPLC grade
•
A.USP26
water having an activity of 500 units per mL.
HEPES buffer—Dissolve 2.38 g of HEPES (N-2-
hydroxyethylpiperazine-Ar'-2-ethanesulfonic acid) in about 90
mL of water in a 100-mL volumetric flask. Adjust with 5 M
BRIEFING sodium hydroxide to a pH of 7.5, dilute with water to volume,
and mix.
Hydrogen Peroxide Concentrate, USP 25 page 865—See Solution A—Prepare a filtered and degassed mixture of 100 mL
briefing under Benzethonium Chloride Concentrate. of acetonitrile, 700 mL of water, and 200 mL of Sulfate buffer.
Solution B—Prepare a filtered and degassed mixture of 400 mL
of acetonitrile, 400 mL of water, and 200 mL of Sulfate buffer.
(NL: C. Barnstein) RTS—35638-1 Mobile phase—Use variable mixtures of Solution A and Solution
B as directed for Chromatographic system. Make adjustments, if
necessary (see System Suitability under Chromatography (621)).
Standard digest solution—Dissolve about 6 mg of USP Human
Insulin RS, aoouratoly weighed,
•
Change to read:
Labeling—Label it to indioato tho name and amount of any added in 3 mL of 0.01 N hydrochloric acid, and transfer 500 uL of the
proaorvativo. resulting solution to a clean vial. Add 2.0 mL of HEPES buffer and
Label it to state that this article is not intended for direct 400 (xL of Enzyme solution, and incubate at 25° for 6 hours.
Quench the digestion by adding 2.9 mL of Sulfate buffer.
administration to humans or animals.AkVSP26 Test digest solution—To 1 mg of Insulin Human^ aoouratoly
aad 500 uL of 0.01 N hydrochloric acid, and mix to dissolve. Pro-

ceed as directed for Standard digest solution, beginning with "Add
2.0 mL of HEPES buffer".
Chromatographic system (see Chromatography (621))—A
4.6-mm x 25 om
•l0-cm f l
column that contains packing LI. The flow rate is about 1 mL per
minute. The column temperature is maintained at 40°. The chro-
BRIEFING matograph is programmed as follows.
Insulin Human, USP 25 page 914 and page 2554 of PF 27(3) Time Solution A Solution B
[May-June 2001]. It is proposed to clarify the existing procedure (minutes) % % Elution
for the preparation of the Enzyme solution in Identification test B 0 90 10 equilibration
by replacing "HPLC grade water" with "water". HPLC grade 0-60 90->30 10->70 linear gradient
water meets the definition of USP Purified Water and should be 60-65 30->0 70->100 linear gradient
included in the general category "water". 65-70 0 100 isocratic
70-71 0-*90 100^10 linear gradient
(BNT: G.Huang) RTS—35362-1 71-86 90 10 re-equilibration
Chromatograph the Standard digest solution, and record the peak

responses as directed for Procedure: the chromatogram of the
Standard digest solution corresponds to that of the standard chro-
matogram provided with USP Insulin Human RS. For the chroma-
togram of the Standard digest the tailing factor is not greater than
1.5; and the resolution, R, is not less than 3.4 for digest fragments II
Pharmacopeial Forum
and III. [NOTE*—Fragment I elutes at the same time in insulin de- tency is not less than 27.0 USP Insulin Lispro
rived from pork and Insulin Human; Fragment II elutes at the same
time in all insulins; and Fragment III elutes at the same time in in- Units per mg, calculated on the dried basis. The
sulin derived from beef and pork.]
Procedure—Using the gradient program, run a blank. Inject proinsulin content of Insulin Lispro, determined
equal volumes of the Standard digest solution and the Test digest
solution into the chromatograph, and record the chromatograms.
The chromatographic profile of the Test digest solution by an appropriate and validated method, is not
corresponds to that of the Standard digest solution.
more than 10 ppm. The host cell-derived protein
content, determined by an appropriate and vali-
dated method, is not more than 10 ppm.
NOTE—One USP Insulin Lispro Unit is equiva-

lent to 0.0347 mg of pure Insulin Lispro.
BRIEFING
Packaging and storage—Preserve in tight containers,
Insulin Lispro, page 2864 of PF 27(4) [July-Aug. 2001]; protected from light, and store in a freezer.
Insulin Lispro Injection, page 2866 of PF 27(4) [July-Aug.
2001]. These new monographs, which previously appeared in Labeling—Label it to indicate that it has been prepared by
Pharmacopeial Previews, are now forwarded with minor editorial
changes to In-Process Revision. microbial synthesis.
(BNT: I. DeVeau) RTS—35353-1 USP Reference standards (11)—USP Endotoxin RS. USP
Insulin Lispro RS.
Add the following: Identification—

A A: The retention time of the major peak in the
IhsuIin Lispro
chromatogram of the Assay preparation corresponds to
(Chemical structure to come) that in the chromatogram of the Standard preparation, as
C257H383N65O77S6 5807.58 obtained in the Assay.
Insulin (human), 28B-L-lysine-29B-L-proline-. B: Determine the peptide fragments, using the
28 B -L-Lysine-29 B -L-prolineinsulin (human) [133107- following peptide mapping procedure.
64-9]. Sulfate buffer, Enzyme solution, HEPES buffer, Solution

A, Solution B, Mobile phase, Standard digest solution, Test
» Insulin Lispro is identical in structure to Insu- digest solution, and Procedure—Using Insulin Lispro and
lin Human, except that it has proline and lysine at USP Insulin Lispro RS instead of Insulin Human and USP
positions 28 and 29, respectively, of chain B, Insulin Human RS, respectively, proceed as directed for
Identification test B under Insulin Human.
whereas this sequence is reversed in Insulin Hu-
Chromatographic system—Proceed as directed for
man. Insulin Lispro is produced by microbial
Identification test B under Insulin Human, except to use a
synthesis via a recombinant DNA process. Its po-
4.6-mm x 10-cm column that contains packing LI, set the
* Fragment I consists of amino acids A5 to A17 and B1 to B13. Fragment II flow rate to about 0.8 mL per minute, and program the
consists of amino acids A18 to A21 and B14 to B21. Fragment III consists
of amino acids B22 to B30. Fragment IV consists of amino acids Al to A4. chromatograph as follows.
A refers to the A-chain of Insulin Human, and B refers to the B-chain of
Insulin Human.
Pharmacopeial Forum
Mobile phase—Use variable mixtures of Solution A and

Time Solution A Solution B Solution B as directed for Chromatographic system. Make
(minutes) (%) (%) Elution adjustments if necessary (see System Suitability under
0-3 95 5 isocratic Chromatography (621)).
3-30 95->41 5^59 linear gradi- System suitability solution—Dissolve an accurately
ent weighed quantity of Insulin Lispro in 0.01 N hydrochloric
30-35 41->20 59->80 linear gradi- acid to obtain a solution containing about 3.5 mg per mL.
ent Allow to stand at room temperature to obtain a solution
35-40 80->5 linear gradi- containing between 0.8% and 11% A-21 desamido insulin
20->95
lispro.
ent
40-50 95 5 re-equilibra- Test solution—Dissolve about 3.5 mg of Insulin Lispro,
tion accurately weighed, in 1.0 mL of 0.01 N hydrochloric

acid. Store this solution for not more than 56 hours in a
Bioidentity—Proceed as directed for Bioidentity Test under refrigerator.
Insulin Assays (121), except to obtain the first blood Chromatographic system (see Chromatography
specimen at 45 minutes, instead of 1 hour, after the time (621))—The liquid chromatograph is equipped with a
of injection: meets the requirements. 214-nm detector and a 4.6-mm x 25-cm column that
Microbial limits (61)—The total aerobic microbial count contains packing L I . The column temperature is
does not exceed 100 per g, a portion of about 0.3 g, maintained at 40°, and the flow rate is about 1 mL per
accurately weighed, being used. minute. The chromatograph is programmed as follows.
Bacterial endotoxins (85): not more than 10 USP Adjust the Mobile phase composition and duration of the
Endotoxin Units per mg, the kinetic-chromogenic method isocratic elution to obtain a retention time of about 41
under Photometric Techniques being used. minutes for insulin lispro, with A-21 desamido insulin
lispro eluting near the start of the linear gradient phase.
Loss on drying (731)—Dry about 300 mg, accurately
Chromatograph the System suitability solution, and record
weighed, at 105° for 16 hours: it loses not more than
the peak responses as directed for Procedure: the
10.0% of its weight.
resolution, R, between insulin lispro and A-21 desamido
Limit of high molecular weight proteins—Proceed as
insulin lispro is not less than 2.5; and the tailing factor for
directed in the test for Limit of high molecular weight
the insulin lispro peak is not more than 2.0.
proteins under Insulin: not more than 0.25% is found.
Related compounds— Time Solution A Solution B
Solvent—Proceed as directed in the Assay. (minutes) (%) (%) Elution
Solution A—Prepare a filtered and degassed mixture of 0-60 81 19 isocratic
Solvent and acetonitrile (82:18). 60-83 81->51 19-+49 linear gradient
Solution B—Prepare a filtered and degassed mixture of 83-84 51->81 49^19 linear gradient
Solvent and acetonitrile (50:50). 84-91 81 19 re-equilibration
Pharmacopeial Forum
maintained at 40°, and the flow rate is about 0.8 mL per

Procedure—Proceed as directed for Procedure in the test
minute. Adjust the Mobile phase to provide a retention
for Related compounds under Insulin: not more than 1.00%
time of about 24 minutes for the main insulin lispro peak.
of A-21 desamido insulin lispro is found; not more than
Chromatograph three replicate injections of the System
0.50% of any other individual insulin lispro related
suitability solution, and record the peak responses as
compound is found; and not more than 2.00% of total
directed for Procedure: the resolution, R, between insulin
impurities, excluding A-21 desamido insulin lispro, is
lispro and A-21 desamido insulin lispro is not less than
found.
3.0; the tailing factor for the insulin lispro peak is not
Zinc content (591)—Determine the zinc content of about
more than 1.5; and the relative standard deviation for
20 mg of Insulin Lispro, accurately weighed: between
replicate injections is not more than 1.1%.
0.30% and 0.60% is found, calculated on the dried basis.
Procedure—Separately inject equal volumes (about 20
Assay—
Solvent—Dissolve 28.4 g of anhydrous sodium sulfate in
1000 mL of water, mix, and adjust with phosphoric acid to a
chromatograms, and measure the areas for the major
pHof2.3.
peaks. Calculate the potency, in USP Insulin Lispro Units
Mobile phase—Mix 745 mL of Solvent and 255 mL of
per mg, on the as-is basis by the formula:
acetonitrile. Make adjustments if necessary (see System
Suitability under Chromatography (621)).
System suitability solution—Dissolve an accurately in which Cs is the concentration, in USP Insulin Lispro
weighed quantity of Insulin Lispro in 0.01 N hydrochloric Units per mL, of USP Insulin Lispro RS in the Standard pre-
acid to obtain a solution having a concentration of about 1 paration; Cv is the concentration, in mg per mL, of Insulin
mg per mL. Allow to stand at room temperature to obtain a Lispro in the Assay preparation; and rv and rs are the insulin
solution containing between 0.8% and 11% A-21 desamido lispro peak areas obtained from the Assay preparation and
insulin lispro. the Standard preparation, respectively. From the value ob-
Standard preparation—Dissolve an accurately weighed tained in the test for Loss on drying, calculate the potency on
quantity of USP Insulin Lispro RS in 0.01 N hydrochloric the dried basis.Aas/,26
acid to obtain a solution having a known concentration of
about 0.7 mg per mL.
Assay preparation—Dissolve an accurately weighed
portion of Insulin Lispro in 0.01 N hydrochloric acid to
obtain a solution having a concentration of about 0.8 mg
per mL.
(621))—The liquid chromatograph is equipped with a
214-nm detector and a 4.6-mm x 10-cm column that
contains packing L I . The column temperature is
Pharmacopeial Forum
Sterility(71)—It meets the requirements when tested as

BRIEFING
directed for Membrane Filtration Method under Test
Insulin Lispro Injection, page 2866 of PF 27(4) [July-Aug.
2001]—See briefing under Insulin Lispro. Procedures.
(BNT: I. DeVeau) RTS—35356-1 pH (791): between 7.0 and 7.8.

Participate matter (788): meets the requirements for
small-volume injections.
Add the following:
Limit of high molecular weight proteins—
A
Insulin Lispro Injection Arginine solution, Mobile phase, Resolution solution, and
Chromatographic system—Proceed as directed in the test
» Insulin Lispro Injection is an isotonic, sterile for Limit of high molecular weight proteins under Insulin.
solution of Insulin Lispro in Water for Injection. Test solution—Quantitatively add 4 mL of 6 N
It has a potency of not less than 95.0 percent hydrochloric acid per mL of an accurately measured
and not more than 105.0 percent of the potency volume of Injection, and mix.
stated on the label, expressed as USP Insulin Lis- Procedure—Proceed as directed for Procedure in the test
for Limit of high molecular weight proteins under Insulin:
pro Units in each mL.
not more than 1.50% is found.
Packaging and storage—Preserve in tight, multiple-dose Related compounds—
containers, and store in a refrigerator. Avoid freezing. 9.7 N Hydrochloric acid—Prepare as directed in the
Protect from sunlight. Dispense it in the unopened, Assay.
multiple-dose container provided by the manufacturer. Solvent—Dissolve 28.4 g of anhydrous sodium sulfate in
Labeling—The labeling states that it has been prepared 1000 mL of water, mix, and adjust with phosphoric acid to a
with Insulin Lispro obtained from microbial synthesis. pHof2.3.
Label it to state that it is to be stored in a refrigerator and Solution A—Prepare a filtered and degassed mixture of
that freezing is to be avoided. The label states the potency Solvent and acetonitrile (82:18).
in USP Insulin Lispro Units per mL. Solution B—Prepare a filtered and degassed mixture of
USP Reference standards (U)—USP Endotoxin RS. USP Solvent and acetonitrile (50:50).
Insulin Lispro RS. Mobile phase—Use variable mixtures of Solution A and
Identification—The retention time of the major peak in the Solution B as directed for Chromatographic system. Make
chromatogram of the Assay preparation corresponds to that adjustments if necessary (see System Suitability under
in the chromatogram of the Standard preparation, as Chromatography (621)).
obtained in the Assay. System suitability solution—Dissolve an accurately
Bacterial endotoxins (85): not more than 80 USP weighed quantity of Insulin Lispro in 0.01 N hydrochloric
Endotoxin Units per 100 USP Insulin Lispro Units, the acid to obtain a solution containing about 3.5 mg per mL.
kinetic-chromogenic method under Photometric Allow to stand at room temperature to obtain a solution
Techniques being used. containing between 0.8% and 11% A-21 desamido insulin
Pharmacopeia! Forum
lispro. Assay—
Test solution—Acidify each mL of Injection with 3 uL of 9.7 N Hydrochloric acid—Transfer 4 mL of hydrochloric
9.7 N Hydrochloric acid. acid to a 5-mL volumetric flask, dilute with water to volume,
Chromatographic system (see Chromatography and mix.
(621))— The liquid chromatograph is equipped with a Solvent, Mobile phase, System suitability solution,
214-nm detector and a 4.6-mm x 25-cm column that Standard preparation, and Chromatographic system—
contains packing L I . The column temperature is Proceed as directed in the Assay under Insulin Lispro.
maintained at 40°, and the flow rate is about 1 mL per Assay preparation—Acidify each mL of Injection with 3
minute. The chromatograph is programmed as follows. uL of 9.7 N Hydrochloric acid. Quantitatively dilute a
portion of the acidified solution with 0.01 N hydrochloric
acid to obtain a solution containing about 20 USP Insulin
Lispro Units per mL.
60-83 81->51 19-+49 linear gradient
83-84 51^81 49->19 linear gradient
84-91 81 19 re-equilibration
Adjust the Mobile phase composition and duration of the
peaks. Calculate the potency, in USP Insulin Lispro Units,
isocratic elution to obtain a retention time of about 41 min-
in each mL of the Injection taken by the formula:
utes for insulin lispro, with A-21 desamido insulin lispro CD(ru/rs),
eluting near the start of the linear gradient phase. Chromato-
in which C is the concentration, in USP Insulin Lispro Units
graph the System suitability solution, and record the peak
per mL, of USP Insulin Lispro RS in the Standard prepara-
responses as directed for Procedure: the resolution, R, be-
tion; D is the dilution factor used to prepare theAssay pre-
tween insulin lispro and A-21 desamido insulin lispro is
paration; and rv and rs are the insulin lispro peak areas
not less than 2.5; and the tailing factor for the insulin lispro
obtained from the Assay preparation and the Standard pre-
peak is not more than 2.0.
paration, respectively.AUS.P2(5
for Related compounds under Insulin: not more than 1.50%
of A-21 desamido insulin lispro is found; and not more than
4.00% of total impurities, excluding A-21 desamido insulin
lispro, is found.
Zinc content (591): between 14 and 35 ug for each 100 BRIEFING
USP Insulin Lispro Units.

Iohexol, USP 25 page 929 and page 2748 of PF 27(4) [July-
Aug. 2001]
Other requirements—It meets the requirements under
Injections (1). (RMI: F. Barletta) RTS—35101-1
Pharmacopeial Forum
Errata:
BRIEFING
Limit ofmethanol, isopropyl alcohol, and methoxyethanol, line
3 under Reference solution 1: Change "1.2 g" to: 0.6 g
Limit ofmethanol, isopropyl alcohol, and methoxyethanol, line Letrozole Tablets, USP 25 page 988 and page 1800 of PF 27
4 under Reference solution 1: Change "1.250 g" to: 0.6 g (1) [Jan.-Feb. 2001].
(PA6: S. Dressman) RTS—35339-1
Erratum:
Related compounds, line 7 under Procedure: Change "total" to:
all other
BRIEFING
Isosorbide Concentrate, USP 25 page 965—See briefing un-

der Benzethonium Chloride Concentrate.
BRIEFING
Add the following: Levocarnitine, USP 25 page 994 and page 2565 of PF 27(3)
A [May-June 2001]. It is proposed to replace the current test for Spe-
Labeling—Label it to state that this article is not intended cific rotation with a test for Limit of D-carnitine, using an HPLC
column after precolumn derivitization with a chiral reagent. The
for direct administration to humans or animals. A.VSP26 proposed method is reported to be much more sensitive than spe-
cific rotation for the detection of the enantiomeric impurity.
(DSN: G. Giancaspro) RTS—30410-1; 35501-1

^Specific rotation (?84S): botwoon 20° and 32°.
BRIEFING —Test solution: 100 mg por mL, in wator. AUSP26
Lactulose Concentrate, USP 25 page 983—See briefing un- Change to read:

der Benzethonium Chloride Concentrate.
Chloride (221): not more than 0.494.
(NL: C. Barnstein) RTS—35638-1 •—A 0.090-g portion shows no more chloride than corre-
sponds to 0.50 mL of 0.020 N hydrochloric acid (0.4%).B1
Add the following:

Add the following: A
Limit of D-carnitine—
^Labeling—Label it to state that this article is not intended
Derivatizing solution—A solution of (+)-l-(9-fluorenyl)-
for direct administration to humans or animals.AUSP26
ethyl chloroformate having a concentration greater than
18mM in acetone. Store in a refrigerator under argon or
nitrogen.
Carbonate Buffer solution—Transfer 338 mg of sodium
carbonate and 152 mg of sodium bicarbonate to a 100-mL
volumetric flask, and dissolve in and dilute with water to
Pharmacopeia! Forum
volume. retention times are about 0.85 for D-carnitine and 1.0 for
Buffer solution pH4.2—Transfer 3.0 mL of acetic acid to levocarnitine; and the resolution, R, between D-carnitine
a suitable flask, add 900 mL of water, adjust with sodium and levocarnitine is not less than 2.0. Chromatograph the
hydroxide solution (3 in 10) to a pH of 4.2, and dilute Standard solution, and record the peak responses as
with water to 1000 mL. directed for Procedure: the relative standard deviation for
Solution A—Transfer 6.8 mL of triethylamine to a replicate injections is not more than 5.0%.
suitable flask, add 950 mL of water, adjust with
phosphoric acid to a pH of 2.6, and dilute with water to
1000 mL.
0->30 73 27 equilibration
Solution B—Use acetonitrile.
30->31 73-+2 27^98 linear gradi-
ent
31-+45 2 98 isocratic
45-+46 2-+73 27-+98 linear gradi-
ent
Resolution solution—Transfer about 25 mg of DL-
46->51 73 27 re-equilibra-
carnitine to a 5-mL volumetric flask, dissolve in and
tion
dilute with water to volume, and mix. Transfer 1 mL of
Procedure—Transfer 30 uL of the Test solution, 30 uL of
this solution to a 100-mL volumetric flask, and dilute with
the Standard solution, 30 uL of the Resolution solution, and
water to volume
30 uL of water as the blank, each to a separate 5-mL
Standard solution—Prepare a solution of USP
volumetric flask. Add 30 uL of Carbonate buffer and 80
Levocarnitine RS in water to obtain a solution having a
uL of Derivatizing solution to each flask, and mix. Heat
known concentration of about 0.025 mg per mL.
the solutions to 45° for 1 hour, cool to room temperature,
Test solution—Transfer about 25 mg of Levocarnitine,
and dilute with Buffer solution pH 4.2 to volume.
accurately weighed, to a 5-mL volumetric flask, dissolve
Separately inject equal volumes (about 50 uL) of the
in and dilute with water to volume, and mix.
Standard solution, the Resolution solution, the Test
solution, and the blank into the chromatograph, and
record the chromatograms. Identify the peaks for D-
fluorescence detector with the excitation wavelength at
carnitine and levocarnitine in the chromatogram of the
260 nm and the emission wavelength at 310 nm, a 4-mm
Test solution by comparison with the chromatograms of
x 4-cm guard column that contains packing LI, and a
the Standard solution, the Resolution solution, and the
4.0-mm x 25-cm column that contains 5-|im end-capped
blank. Measure the peak responses for the D-carnitine
packing LI. The flow rate is about 2.0 mL per minute.
derivative in the chromatogram of the Test solution and
The chromatograph is programmed as follows.
the peak response of the levocarnitine derivative in the
Chromatograph the Resolution solution, and record the
peak responses as directed for Procedure: the relative
© 2002 The United Stales Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
chromatogram of the Standard solution. Calculate the practitioners should have this important information readily visible
on the product and not have to refer to the Definition in the USP
percentage of D-carnitine in the portion of Levocarnitine monograph.
taken by the formula: (NL: W. L. Paul) RTS—35160-1
in which C is the concentration of levocarnitine, in mg per

Change to read:
mL, in the Standard solution; Wis the weight, in mg, in the » Mannitol Injection is a sterile solution, which may
be supersaturated, of Mannitol in Water for Injection. It
portion of Levocarnitine taken; rv is the peak response of the
may require warming or autoclaving before use if crys-
D-carnitine derivative obtained from the Test solution; and rs tallization has occurred. It contains not less than 95.0
percent and not more than 105.0 percent of the labeled
is the peak response of the levocarnitine derivative obtained amount of
from the Standard solution: not more than 1.0 % is •mannitol B2
(C6H14O6). It contains no antimicrobial agents.
found. AUSP26
Change to read:
Labeling—The label states the total osmolar concentration in
mOsmol per liter. Where the contents are less than 100 mL, or
where the label states that the Injection is not for direct injection
but is to be diluted before use, the label alternatively may state the
total osmolar concentration in mOsmol per mL.
A
The label also states that it should be warmed to dissolve
BRIEFING any crystals, that may have formed, before use.AUSP26
Lincomycin Hydrochloride Soluble Powder, USP 25 page

1009. Change to read:
Specific rotation (781S)Tranofor an aoouratoly moaourod volumo
(VET: I. DeVeau) RTS—35357-1 of Injootion, equivalent to about 1 g of mannitol aa determined by
tho Assay, to a 100 mL volumetrioflaolc:it moota tho roquiromonto
of the teat for Specific wtation under Mannitol.
•: between +137° and +145°.
Erratum:
Assay, line 5 under Assay preparation: Change "80 mg" to: Test solution—Transfer an accurately measured volume of
80 mL
Injection, equivalent to about 1 g of mannitol, as determined
by the Assay, to a 100-mL volumetric flask, and add 40 mL
of an ammonium molybdate solution (1 in 10), which has
previously been filtered if necessary. Add 20 mL of 1 N
sulfuric acid, dilute with water to volume, and mix.B2
BRIEFING
Change to read:
Mannitol Injection, USP 25 page 1050 and page 3020 of PF Assay—
27(5) [Sept.-Oct. 2001]. Based on comments received, it is pro- Mobile phase, Resolution solution^ and Chpotnato graphic
posed to add a statement to the Labeling requirements that if crys-
tals have formed, warm to dissolve before use. The current
Definition contains such a statement but it is believed that actual
Proceed as directed in the Assay under Mannitol.
'Resolution solution—Dissolve sorbitol and USP
Mannitol RS in water to obtain a solution having
concentrations of about 4.8 mg of each per mL.B2
Pharmacopeial Forum
Standard preparation—Dissolve an accurately weighed quantity BRIEFING

of USP Mannitol RS in water, and quantitatively dilute with water
to obtain a solution having a known concentration of about 5 mg Methadone Hydrochloride Oral Solution, USP 25 page 1098.
per mL. It is proposed to revise the alcohol content specification from be-
Assay preparation—Transfer an accurately measured volume of tween 7.0% and 9.0% to not less than 90.0% and not more than
Injection, equivalent to about 500 mg of mannitol, to a 100-mL 115.0% of the labeled amount of CUHjOH in accordance with la-
volumetric flask, dilute with water to volume, and mix. beling requirements. Because it has been demonstrated that alcohol
m is not required for the stability of Oral Solution and alcohol-free
Chromatographic system (see Chromatography formulations are available, the name for the test for Alcohol has
been changed to Alcohol content.
refractive index detector that is maintained at a constant (PA2: J.Kelly) RTS—33534-1; 33333-1
temperature and a 4-mm x 25-cm column that contains

packing L I 9 . The column temperature is maintained
Change to read:
between 30° and 85°, controlled within ± 2° of the
Alcohol
selected temperature. The flow rate is about 0.5 mL per A
content, Method ILUSP26
(611)
minute. Chromatograph the Resolution solution, and A
(if present). USP26
record the peak responses as directed for Procedure: the : between 7.0% and 9.0% of CJAJSHT
A
resolution, R, between sorbitol and mannitol is not less between 90.0% and 115.0% of the labeled amount of
than 2.0. Chromatograph the Standard preparation, and C 2 H 5 OH, determined by the gas-liquid chromatographic
record the peak responses as directed for Procedure: the procedure, acetone being used as the internal standard.Aas.p2<s
relative standard deviation for replicate injections is not

more than 2.0%.B2
Procedure—Prooood ao directed for Procedure in tho Assay

undor Mannitol.
"Separately inject equal volumes (about 20 uL) of the Stan-
dard preparation and the Assay preparation into the chro-
BRIEFING
matograph, record the chromatograms, and measure the
Methyltestosterone, USP 25 page 1135 and page 2568 of PF
responses for the major peaks. B2 27(3) [May-June 2001]. It is proposed to make several corrections
Calculate the quantity, in mg, of mannitol (C6H14O6) in each mL of to the gradient profile in the program of the liquid chromatographic
the Injection taken by the formula: system in the test for Chromatographic purity. It is also proposed
to add a System suitability solution to ensure that the method
works properly.
in which
"C is the concentration, in mg per mL, of USP Mannitol RS (PA1: S. Salado) RTS—35100-1
in the Standard preparation;m2

V\s the volume, in mL, of Injection taken; and tho othor torms aro
as dofinod thoroin.
m
Change to read:
rv and rs are the peak responses obtained from the Assay Chromatographic purity—
—Standard solutions—Diooolvo an aoouratoly weighed quantity of
preparation and the Standard preparation, respectively.m2 USP Mothyltostoaterono RS in a mixturo of ohloroform and
methanol (9:1) to obtain Standard solution 1 having a known
concentration of-20 mg per mL. Dilute quantitatively with tho
mixture of ohloroform and mothanol (9:1) to obtain Standard
solutions having tho following compositions:
Pharmacopeial Forum

Peroontago (%,
Concentration for comparison (621))— The liquid chromatograph is equipped with a
(mg RS per with teat spooi
Xl/ltU IlU'11 HflJLjy moii11 254-nm detector and a 4.6-mm x 25-cm column that
(undiluted) |QQ contains 5-um packing LI. The flow rate is 1 mL per
(1 in 100)
n in
minute. The chromatograph is programmed as follows.
System suitability solution—Dissolve 10 mg of USP Chromatograph the Test solution and the System suitability
•Tofltootorono RS in 0.5 mL of Standard solution 1, dilute with
the mixture of chloroform and mothanol (0:1) to 10.0 mL, and mix. solution, and record the peak responses as directed for
—Test solution—Dissolve an accurately weighed quantity of
mothyltostostorono in tho mixture of chloroform and mothanol Procedure: the column efficiency is not less than 33,000
(9:1) to obtain a oolution containing 20 mg per mL.
—Procedure—Apply separately 5 uL of tho Test solution, 5 uL of theoretical plates; and the relative standard deviation for
oaoh Standardsolution, and 5 uL of tho System suitability solution
to a suitable thin layer ohromatographio plate (aoo replicate injections for the methyltestosterone peak in
Chromatography (634-)) ooatod with a 0.25 mm layer of
ohromatographio silica gel mixture: Position tho plate in a thechromatogram of the Test solution is not more than
ohromatographio ohamber, and dovolop tho ohromatograms in a
solvent system consisting of a mixture of butyl acetate, hoxanos, 2.0%; and t h e s i g n a l - t o - n o i s e r a t i o of t h e
and glacial acetic acid (70:30:1) until tho solvent front has
moved about throo fourtho of the length of tho plato. Romovo the methyltestosterone peak in the chromatogram of the
plate from tho developing ohambor, mark tho solvent front, and
allow tho solvent to evaporate in air. Examine the plato under System suitability solution is not less than 100.
short wavelength UV light. Tho tost is valid if tho ohromatogram
obtained from tho System suitability solution shows two clearly Time Solution A Solution B
separated spots. Compare the intensities of any secondary spots (minutes) Elution
observed in tho ohromatogram of tho Test solution with tho3o of
the prinoipal spots in tho ohromatograms of tho Standard 0 1AA
100. C(\ 0. cr\ equilibration
solution: tho gum of tho intonsitios of secondary spots obtainod 1 \J\J * \J\J
A
linear gradient
OQ AQ
from tho Test solution corresponds to not more than 1.0% of mQ 40 isooratio
AQ / t c gQ At\ . 1 AA
related oompounds, with no single impurity corresponding to } TTT^^ 1 UU linear gradient
moro than 0.5%. 0-20 100-^60 0->40 linear gradient
20-40 60->0 40->100 linear gradient
^Solution A—Prepare a filtered and degassed mixture of 45-60 0-^100 100-»0 re-equilibration
methanol and water (55:45). Procedure—Inject a volume (about 5 uL) of the Test
Solution B—Use methanol. solution into t h e c h r o m a t o g r a p h , record t h e
Mobile phase—Use variable mixtures of Solution A and chromatogram, and measure all of the peak areas.
Solution B as directed for Chromatographic system. Make Calculate the percentage of each impurity in the portion of
adjustments if necessary (see System Suitability under Methyltestosterone taken by the formula:
System suitability solution—Dilute a volume of the Test
solution quantitatively, and stepwise if necessary, with in which rt is the peak response for each impurity; and rs is
methanol to obtain a solution having a concentration of the sum of the responses of all the peaks, disregarding any
about 0.005 mg of methyltestosterone per mL. impurity having a peak less than 0.05%. Not more than
Test solution—Dissolve an accurately weighed quantity 0.5% of any individual impurity is found, and not more than
of Methyltestosterone in methanol to obtain a solution 1.0% of total impurities is found.
containing about 0.5 mg per mL.
Pharmacopeia! Forum
hydroxypropyl methylcellulose.
BRIEFING
B: The retention time of the major peak in the
Misoprostol Dispersion, page 1308 of PF 26(5) [Sept.-Oct.
2000]—See briefing under Benzethonium Chloride Concentrate. chromatogram of the Assay preparation corresponds to
obtained in the Assay.
Water, Method Ic, (921): not more than 1.5%, using a

Add the following:
sample of 300 mg 40 to 110 mg.
A
Misoprostol Dispersion Heavy metals, Method II (231): 0.001%.
» Misoprostol Dispersion is a mixture of Miso- Diluent, Phosphate buffer, and Mobile phase—Prepare as
prostol and Hydroxypropyl Methylcellulose directed in the Assay.
(1:100). It contains not less than 9&S 90.0 percent Standard solution I—Dissolve accurately weighed
and not more than 105.0 110.0 percent of the la- quantities of USP Misoprostol Related Compound A RS,
beled amount of misoprostol (C22H38O5). USP Misoprostol Related Compound B RS, and USP
Misoprostol Related Compound C RS in Mobile phase
Packaging and storage—Preserve in light-resistant,
Diluent to obtain a solution having known concentrations
hermetic containers.
of about 0.1 ug of each USP Reference Standard per mL.
Labeling—Label it to state that this article is not intended Standard solution 2—Dissolve accurately weighed
for direct administration to humans or animals. quantities of USP Misoprostol Related Compound A RS,
USP Reference standards (11)—USP Misoprostol RS. USP Misoprostol Related Compound B RS, and USP
USP Misoprostol Related Compound A RS. USP Misoprostol Related Compound C RS in Diluent to obtain
Misoprostol Related Compound B RS. USP Misoprostol a solution having known concentrations of about 0.5 ug per
Related Compound C RS. mL, 0.3 ug per mL, and 0.5 [ig per mL, respectively.
Identification— System suitability solution—Dissolve accurately weighed
A: Ultraviolet Absorption (197U)— quantities of USP Misoprostol RS, USP Misoprostol
Solution 1: 1.6 mg per mL. Related Compound A RS, USP Misoprostol Related
Medium: a mixture of methanol and water (4:1). The Compound B RS, and USP Misoprostol Related
solution does not exhibit a maximum near 280 nm, when Compound C RS in a mixture of water and iaopropyl
compared to a blank solution containing hydroxypropyl aloohol (<\:l)Diluent to obtain a solution having
methylcellulose. concentrations of about 0.1 mg per mL, 0.5 ug per mL,
Solution 2: 0.08 mg per mL, prepared from Solution 1. 0.5 ug per mL, and 0.3 ug per mL, respectively.
Medium: a 50% mixture of methanol and water (4:1) and Test solution—Use the Assay preparation.
methanol and 1 N potassium hydroxide (4:1). After 30 Chromatographic system—Prepare as directed in the
minutes, the solution exhibits a maximum near 280 nm, Assay. Chromatograph Standard solution I, and record the
when compared to a blank solution containing peak areas as directed for Procedure: the resolution, R,
Pharmacopeial Forum
between misoprostol and misoprostol related compound C 990 mL of water, adjust with phosphoric acid to a pH of
is not less than 0.9; and the relative standard deviation for 3.0, dilute with water to volume, and mix.
replicate injections is not less than 2.0%. Mobile phase—Prepare a filtered and degassed mixture of
Procedure—Separately inject equal volumes (about 100 Phosphate buffer and isopropyl alcohol (73:27). Make
uL) of Standard solution 1, Standard solution 2, the adjustments if necessary (see System Suitability under
System suitability solution, and the Test solution into the Chromatography (621)).
chromatograph, record the chromatograms, and measure Standard preparation—Dissolve an accurately weighed
the areas for the major peaks. Calculate the percentage of quantity of USP Misoprostol RS in a mixture of water and
the relevant related compound in the portion of Dispersion isopropyl alcohol (4:\)Diluent to obtain a solution having a
taken by the formula: known concentration of about 0.1 mg of misoprostol per
mL.
Assay preparation—Dissolve an accurately weighed
in which Cs is the concentration, in mg per mL, of the rele-
quantity of Misoprostol Dispersion in a mixture of water
vant USP Reference Standard in Standard solution 2; Cv is
and isopropyl alcohol (75:25)Diluent to obtain a solution
the concentration, in mg per mL, of Misoprostol Dispersion
having a concentration of about 10 mg per mL.
in the Test solution; and rv and rs are the peak areas obtained
from the Test solution and Standard solution 2, respectively:
(621))— The liquid chromatograph is equipped with a
not more than 0.3% of misoprostol related compound B is
found; not more than 0.5% of misoprostol related com-
contains packing L7. The flow rate is about 1.5 mL per
pound A is found; and not more than 0.5% of misoprostol
minute. Chromatograph the Standard preparation, and
related compound C is found. Calculate the percentage of
record the peak areas as directed for Procedure: the
any unknown impurities using the same formula, in which
relative retention time for misoprostol is about 12 minutes.
Cs is the concentration, in mg per mL, of USP Related Com-
pound C RS in Standard solution 2; rv is the peak response
fxL) of the Standard preparation and the Assay
of any unknown impurity obtained from the Test solution; rs
is the peak response of misoprostol related compound C ob-
tained from Standard solution 2; and the other term is as
peaks. Calculate the quantity, in mg, of misoprostol
defined therein: not more than 0.5% of any unknown indi-
(C22H3g05) in the portion of the Dispersion taken by the
vidual impurity is found; not more than 1.0% of total un-
formula:
known impurities is found; and not more than 2.3% of VC(rv/rs),
total impurities is found.
in which Fis the volume, in mL, of solution used to prepare
Assay—
the Assay preparation; C is the concentration, in mg per mL,
Diluent—Prepare a mixture of water and isopropyl
of USP Misoprostol RS in the Standard preparation; and rv
alcohol (73:27).
and rs are the peak areas obtained from the Assay prepara-
Phosphate buffer—Transfer 1.36 g of monobasic
tion and the Standard preparation, respectively.
potassium phosphate to a 1000-mL volumetric flask, add
Pharmacopeial Forum
of about 0.7 and two moderately intense purplish red spots at RF

values of about 0.5 and 0.4. The chromatogram of the Test solution
may exhibit other spots of varying intensities, including a spot at
BRIEFING the origin.
Myrrh, USP 25 page 1177 and page 2176 of PF27(2) [Mar- "D: Thin-Layer Chromatographic Identification Test
Apr. 2001]. The previous proposal to revise the Labeling require-
ment is now modified because, based on pharmacy compounding (201)-
experience, the term "topical use only" is considered to be too re-
strictive. Additional information provided to USP indicates that Test solution—Transfer 0.5 g of finely powdered Myrrh to
myrrh is used for compounding preparations for topical and oro-
pharyngeal applications (topical is defined as administration to a a test tube containing 5.0 mL of alcohol, and warm the
particular spot on the outer surface of the body; oropharyngeal is
defined as administration directly to the mouth and pharynx). mixture in a water bath for 2 to 3 minutes. Cool, and filter.
(NL: C. Barnstein; DSB: G. Giancaspro) RTS—35682-1 Standard solution—Dissolve accurately weighed
quantities of (Zs)-anethole and thymol in alcohol, and
Change to read: alcohol to obtain a solution having known concentrations

Labeling—Label it to indicate the species of Commiphora from
which the oleo-gum resin was obtained. Label it also to indicate; of about 4 ug of (£)-anethole per mL and about 1 mg of
that it ia intended for topical uoo only.
thymol per mL.
"Label it also to indicate that it is intended for topical and
Developing solvent system: a mixture of toluene and ethyl
oropharyngeal use only. B2
acetate (98:2).
Change to read: Procedure—Proceed as directed in the chapter. Allow the

Identification— plate to air-dry, and examine under UV light at 365 nm. The
A: Triturate 0.4 g of crushed Myrrh with 1 g of washed sand,
shake for a few minutes with 10 mL of ethyl ether, and filter. chromatogram of the Test solution shows no blue to violet
Evaporate the filtrate to dryness in a porcelain dish, and add a
few drops of nitric acid to the residue: a purplish violet color is fluorescent zones in the lower third of the chromatogram
produced instantly.
B: Transfer 0.1 g of powdered Myrrh to a test tube, and add 1 {absence of Commiphora mukul).m2
mL of nitric acid: a red color is produced. Upon addition of a
crystal of vanillin, the red color deepens. The red color does not
diminish when water is added.
C: Thin-Layer Chromatographic Identification Test (201)—
Test solution—Transfer 0.5 g of finely powdered Myrrh to a 10-
tnL centrifuge tube, add 2 mL of alcohol, shake for 1 minute,
centrifuge, andfilter.Apply 2 uL of the filtrate to the plate.
Standard solution—Dissolve accurately weighed quantities of
(£)-anethole, linalool, (-)-bornyl acetate, and (i?)-(-)-carvone in
toluene, and dilute quantitatively, and stepwise if necessary, with
toluene to obtain a solution having known concentrations of about
7 ug per mL of (£)-anethole, 8 ug per mL of linalool, and 10 ug per
mL each of (-)-bornyl acetate and (/?)-(-)-carvone. Apply 1 (xL to BRIEFING
the plate.
Developing solvent system: a mixture of toluene and ethyl Nifedipine Capsules, USP 25 page 1228. It is proposed to
acetate (93:7). add instructions to prepare a Standard solution in the test for Dis-
Spray reagent—Dissolve 0.5 mL of p-anisaldehyde in 10 mL of solution. Methanol, in a volume not exceeding 2% of the final so-
glacial acetic acid, add 85 mL of methanol, and mix. Carefully add lution volume, can be used in the first step of the solution
5 mL of sulfuric acid, and mix. [NOTE—Prepare fresh immediately preparation because nifedipine is not easily soluble in the Dissolu-
before use.] tion Medium.
Procedure—[NOTE—Wash the plate in Developing solvent
system, and air-dry prior to use.] Proceed as directed in the
chapter. Spray the plate with Spray reagent, heat in an oven at (BPC: M. Marques) RTS—35596-1
100° for 5 minutes, and examine in white light. The
chromatogram of the Standard solution exhibits four well-
resolved spots: an olive-brown spot due to (£)-anethole at an RF
value of about 0.6; an orange-brown spot due to (-)-bornyl
acetate at an RF value of about 0.5; a reddish brown spot due to
(/?)-(-)-carvone at an RF value of about 0.4; and a deep gray spot
due to linalool at an RF value of about 0.2. The chromatogram of
the Test solution exhibits an intense purplish red spot at an RF value
Pharmacopeia! Forum
Change to read: 7.5 and 9.5 minutes, respectively. In addition, it is proposed to

Dissolution (711)— modify the Tolerances in the test for Dissolution, to be in accor-
Medium: simulated gastric fluid TS (without pepsin); 900 mL. dance with the NDA.
(PA1: S. Salado; BPC: M. Marques) RTS—34883-1;
Time: 20 minutes. 33448-7
^Standard solution—Dissolve an accurately weighed
quantity of USP Nifedipine RS in an amount of methanol
Add the following:
not exceeding 2% of the final volume, and dilute
A
quantitatively and stepwise, if necessary, with Dissolution
Norgestimate and Ethinyl Estradiol
Tablets
Medium to obtain a solution having a known appropriate
concentration. A USP26
Procedure—Determine the amount of C 17 H 18 N 2 O 6 dissolved » Norgestimate and Ethinyl Estradiol Tablets
by employing UV absorption at the wavelength of maximum
absorbance at about 340 nm on filtered portions of the solution contain not less than 90.0 percent and not more
under test, suitably diluted with Dissolution Medium, if
necessary, in comparison with a
than 110.0 percent of the labeled amounts of nor-
Standard solution, having a known concentration of USP Nifodi gestimate (C23H31NO3) and ethinyl estradiol
pino RS in tho oamo Medium.
AUSP26
(C20H24O2).
[NOTE—Filters must be checked for absorptive loss of nifedipine.]
Tolerances—Not less than 80% ( 0 of the labeled amount of Packaging and storage—Preserve in well-closed
C 17 H lg N 2 O 6 is dissolved in 20 minutes.
containers.
USP Reference standards (11)—USP Ethinyl Estradiol
RS. USP Norgestimate RS.
Identification—The retention times of the major peaks in

the chromatogram of the Assay preparation correspond to
those in the chromatogram of the Standard preparation,
BRIEFING
as obtained in the Assay.
Norgestimate and Ethinyl Estradiol Tablets, page 1417 of
PF 26(5) [Sept.-Oct. 2000]. This new monograph, which pre- Disintegration (701): 15 minutes.
viously appeared in Pharmaceutical Previews, is now forwarded
with changes to In-Process Revision. It is proposed to modify
the chromatographic procedures in the tests for Dissolution and Dissolution (711)—
Chromatographic purity and in the Assay, to be in accordance with
that stated in the NDA. The liquid chromatographic procedures in NOTE—Exorciseoaro in filtering and handling solutions
the test for Chromatographic purity and in the Assay are based on
analyses performed with the IBM C18 brand of LI column. containing othinyl ostradiol to prevent adsorptivo loos of
[NOTE—The IBM C18 column is no longer manufactured. How-
ever, the Apex C18 column is a suitable alternative.] The retention the drug: Contrifugation may bo used instead of filtration
times for ethinyl estradiol, (Z)-norgestimate and (^-norgestimate
are about 3.7, 8.1, and 10 minutes, respectively. The liquid chro- with nonadsorptivo membrane filtora. Withdraw aliquots
matographic procedure in the test for Dissolution is based on ana-
lyses performed with the Zorbax CN brand of L10 column. The of solutions under tost with gla33 or polytef pipota or syr
retention times for ethinyl estradiol and norgestimate are about
ingos that havo boon ohookod for adsorptivo loos. Uso glass
dissolution vossols and polytof ooatod or solid polytof pad-
Pharmacopeial Forum
Medium: 0.05% polyaorbato 20; 600 mL. responses for the major peaks. Calculate tho quantities, in
—Apparatus 2: 75 rpm. mg, of norgostimato (Caatf^NQj.) and othinyl eatradiol
—Time: 20 minutes: s) dissolved by tho formula:
Determinetho amounts of norgostimato (C^SJ4J4O») and
ethinyl ofltradiol (CaoH^Qa) dissolved by employing tho fol
in which C is tho oonoontration, in mg per mL, of the appro
lowing-mothod.
priatc analyto in tho Standard solution; and v# and-f^ are tho
—Mobile phase—Prepare a filtered and degassed mixture of
peak responses obtained from the Test solution and the Stan
water and isopropyl aloohol (13:7). Make adjustments if
dard solution, respectively.
nooossary (see System Suitability under Ckromatography
Tolerances Not loss than 80% (Q) of tho labeled
amounts of CayB»4.NQj. and Cas-HÔ^ is dissolved in 30
—Standard solution—Dissolve aoourately weighed
quantities of USP Norgostimato RS and USP Ethinyl
NOTE—Exercise care in filtering and handling solutions
Estradiol RS in Dissolution Medium, and dilute
containing ethinyl estradiol to prevent adsorptive loss of
quantitatively, and stopwiso if necessary, with Dissolution
the drug. Centrifugation may be used instead of filtration
Medium to obtain a solution having known concentrations
with nonadsorptive membrane filters. Withdraw dissolution
similar-to those of tho Test solution: [NOTE—A volume of
aliquots with glass or polytef pipettes or syringes that have
mothanol not exceeding 4% of the total volume of tho
been checked for adsorptive loss. Use glass dissolution ves-
Standard solution may bo used.]
sels and polytef-coated or solid polytef paddles.
—Test solution—U30a filtered portion of the solution under
Medium: 0.05% polysorbate 20; 600 mL.
—Chromatographic system (sec Chmmatography-{€3A?))—
Time: 30 minutes.
The liquid ohromatograph is equipped with a 254 nm
Determine the amount of norgestimate (C23H31NO3) and
detector (for norgestimato analysis), a spoetrofluoromotric
ethinyl estradiol (C20H24O2) dissolved by employing the
dotootor (for othinyl ostradiol analysis) sot at an oxoitation
following method.
wavelength of 220 nm and an omission wavelength of 280
Mobile phase—Prepare a degassed mixture of water and
nm, and a 4:6 mm x 25 cm column that contains a 5 urn
isopropyl alcohol (13:7). Make adjustments if necessary
paoking L18. The flow rate is about 1 mL per minute.
(see System Suitability under Chromatography (621)).
Ghromatograph the 'Standard solution, and record the peak
Standard solution—Dissolve an accurately weighed
responses as directed for Procedure: tho relative retention
quantity of USP Norgestimate RS and USP Ethinyl
times are about 0:7 for othinyl estradiol and 1.0 for
Estradiol RS in Dissolution Medium, and dilute
norgostimato; and the relative standard deviation for
quantitatively, and stepwise if necessary, with Dissolution
Medium to obtain a solution having known concentrations
—Procedure—Separately inject equal volumes (about 200
similar to those expected in the Test solution. [NOTE—A
uL) of the Standard solution and tho Test solution into tho
volume of methanol not exceeding 4% of the total volume
ohromatograph, record the ohromatograms, and measure the
of the Standard solution may be used to bring the standards
Pharmacopeial Forum
into solution prior to dilution with Dissolution Medium.] of C23H31NO3 and C20H24O2 are dissolved in 30 minutes
Test solution—Use a filtered or centrifuged portion of the for Tablets labeled as containing 250 jig of C23H31NO3
solution under test. and 35 ug of C20H24O2.
Chromatographic system (see Chromatography (621))— Uniformity of dosage units (905): meet the requirements.
The liquid chromatograph is equipped with a 254-nm Chromatographic purity—
detector (for norgestimate analysis), a spectrofluorometric Mobile phase—Proceed as directed in the Assay.
detector (for ethinyl estradiol analysis) with an excitation Standard solution—Use the Standard preparation,
wavelength of 234 nm and an emission wavelength of 304 prepared as directed in the Assay.
nm, and a 4.6-mm x 25-cm column that contains packing Test solution—Use the Assay preparation, prepared as
L10. The flow rate is about 1.2 mL per minute. The column directed in the Assay.
temperature is maintained at 40°. Chromatograph the
Chromatographic system—The liquid chromatograph is
Standard solution, and record the peak responses as
equipped with a detector capable of detecting at 230 nm
directed for Procedure: the retention times are about 7.5
and 254 nm, simultaneously, and a 4.6-mm x 10-cm
minutes for ethinyl estradiol and 9.5 minutes for
column that contains 5-um packing LI. The flow rate is
norgestimate; and the relative standard deviation for
about 2 mL per minute. Chromatograph the Standard
replicate injections is not more than 3.0% for the ethinyl
solution, and record the peak areas as directed for
estradiol and norgestimate peaks.
Procedure: the relative retention times are about 0r4 0.5
Procedure—Separately inject equal volumes (about 200 for ethinyl estradiol, 1.0 for (Z)-norgestimate, and 1.2 for
uL) of the Standard solution and the Test solution into the (£)-norgestimate; the resolution, R, between (Z)-
chromatograph, record the chromatograms, and measure the norgestimate and (^-norgestimate is not less than 1.5;
responses for the major peaks. Calculate the quantity, in mg, and the relative standard deviation for replicate injections,
of each drug dissolved by the formula: dotorminod from tho arearatio of the ethinyl estradiol
poak to tho aum of and norgestimate peaks, is not more
than 3.0%.
in which C is the concentration, in mg per mL, of the appro-
Procedure—Inject a volume (about 3£ 50 uL) of the Test
priate analyte in the Standard solution; and ru and râre the
solution into the chromatograph, record the chromatograms,
peak responses obtained from the Test solution and the Stan-
and measure the areas for the major peaks. Calculate the
percentage of the impurity having a relative retention time
Tolerances—Not less than 80% (Q) of the labeled
of about 0.6, relative to the (Z)-norgestimate peak, and
amounts of C23H31NO3 and C20H24O2 are dissolved in 20
detected at 230 nm in the portion of Tablets taken by the
minutes for Tablets labeled as containing 180 ug of
formula:
C 23 H 31 NO 3 and 35 ug of C 20 H 24 O 2 , and for Tablets
labeled as containing 215 ug of C23H31NO3 and 35 }ig of
C20H24O2. Not less than 80% (Q) of the labeled amounts
Pharmacopeial Forum
in which 1.31 is the relative response factor of this impurity; glass beads. Add 5.0 mL of water, and shako vigorously.
rt is the peak response for the impurity; and rs is the sum of Add 20.0 mL of mothanol, insert the stopper, and mix on
the peak responses of (£)-norgestimate and (Z)-norgesti- a vortox mixor. Sonicate to dissolve; mix, and pass
mate: not more than 8:0% 7.5% is found. Calculate the per- through a filter having a 0.45 urn porosity.
centage of any impurity having a relative retention time of —Chmmatographic system (sco Chrontatography (62A-))—
about 0.2 or 0.4, relative to the (Z)-norgestimate peak, and Tho liquid ohromatograph is equipped with a 230 nm
detected at 254 nm in the portion of Tablets taken by the detector and a 4:6 mm x 10 cm column that contains a 5
formula: urn paoking LI. Tho flow rato is about 2 mL por minuto.
Chromatograph tho Standard preparation, and rooord tho
poak responses as directed for Procedure: tho relative
retention times are about 0.1 for othinyl ostradiol, 1.0 for
(Z) norgestimato, and-1.2 for (E) norgostimato; tho
in which 1.54 is the relative response factor of the impurity resolution, R, botwroon (Z) norgo3timato and (E)
peaks; C z and CE are the quantities, in mg, of (Z)-norgesti- norgostimato is not loss than1.5; and tho relative standard
mate and ethinyl estradiol, respectively, as determined in the deviation for roplioato injootions is not more than 3:0%.
Assay; r,- is the peak response for each impurity; and rz is the —Procedure—Separately injoot equal volumes (about 50
peak response for (Z)-norgestimate: the sum of the impuri- uL) of tho Standard-preparation and tho Assay
ties having relative retention times of about 0.2 and 0.4 is preparation into tho ohromatograph, rooord tho
not more than 4.0%. ohromatograms, and measure thoresponsesfor tho major
Assay— peaks. Caloulato tho quantity, in mg, of norgestimato
—Mobilcphasc—Prepare a filtered and dogassod mixture of ») in tho portion of Tablets taken by tho formula:
water,-totrahydrofumn, and acotonitrilo (60:15:25). Malco
adjuatmonto if noooooary (soo System Suitability undor
Chromatography (62A-)}?
in which C is tho concentration, in mg por mL, of USP Nor
gostimato RS in tho Standard preparation; Pg is tho fraction
—Standard preparation—Dissolve accurately weighed
of (E) norgostimato in USP Norgostimato RS; RÊ and RJZ
quantitioa of USP Norgostimato RS and USP Ethinyl
are tho poak responses of (E) norgostimato obtainod from
Estradiol RS in mothanol, and dilute quantitatively; and
tho Assay preparation and tho Standard preparation, ro
stopwiso if necessary, with mothanol to obtain a solution
spootivoly; P# is tho fraotion of (Z) norgostimato in USP
having known oonoontrationa of about 125 \xg of
Norgostimato RS; and RJZ and R#Z are tho poak responses
norgestimato and 17.5 ug of othinyl ostradiol per mL. Mix
of (Z) norgostimato obtainod from tho Assay preparation
2.0 mL of this solution with 1.0 mL of water and 2.0 mL of
and tho Standard preparation, respectively. Caloulato tho
mothaHol.
quantity, in mg, of othinyl-ostradiol (CseH^Qs) in tho portion
—Assay preparation—Weigh and finely powdor not fewer
of Tablot3 takon by tho formula:
than 20 Tablets. Transfer an accurately weighed quantity
of the powder, equivalent to about 0.175 mg of ethinyl
oatradiolj to-a 50 mL glass oontrifugo tube, and add two
Pharmacopeial Forum
in which C ia tho oonoontration, in mg por mL, of USP Ethi Chromatograph the Standard preparation, and record the
nyl Estradiol RS in tho Standard preparation; and R^ and Rs peak responses as directed for Procedure: the relative
aro tho peak roapon303 of othinyl ostradiol obtained from tho retention times are about 0.5 for ethinyl estradiol, 1.0 for
Assay preparation and tho Standard preparation, roopoo (Z)-norgestimate, 1.2 for (Zs)-norgestimate and 1.5 for
dibutyl phthalate; the resolution, R, between (Z)-
Mobile phase—Prepare a degassed mixture of water, norgestimate and (is)-norgestimate is not less than 1.5;
tetrahydrofuran, and methanol (13:5:2). Make adjustments and the relative standard deviation of the peak response
if necessary (see System Suitability under Chromato- ratio of ethinyl estradiol, (Z)-norgestimate and (E)-
graphy (621)). norgestimate to dibutyl phthalate from replicate injections
Internal standard solution—Dissolve an accurately is not more than 3.0%.
weighed quantity of dibutyl phthalate in methanol to Procedure—Separately inject equal volumes (about 25
obtain a solution having a known concentration of about uL) of the Standard preparation and the Assay
0.05 mg per mL. preparation into the chromatograph, record the
Standard preparation—Dissolve an accurately weighed chromatograms, and measure the responses for the major
quantity of USP Norgestimate RS and USP Ethinyl peaks. Calculate the quantity, in mg, of ethinyl estradiol
Estradiol RS in Internal standard solution, and dilute (C20H24O2) in the portion of Tablets taken by the formula:
quantitatively, and stepwise if necessary, with Internal
standard solution to obtain a solution having a known
in which C is the concentration, in mg per mL, of USP Ethi-
concentration of about 7 fig per mL of ethinyl estradiol
nyl Estradiol RS in the Standard preparation; and Rv and Rs
and a known concentration similar to that expected in the
are the ratios of the peak response of ethinyl estradiol to di-
Assay preparation. Mix, and pass through a filter having a
butyl phthalate obtained from the Assay preparation and the
0.2-um porosity.
Standard preparation, respectively. Calculate the quantity,
Assay preparation—Weigh and finely powder not fewer
in mg, of norgestimate (CÎ^jNC^) in the portion of Ta-
than 20 Tablets. Transfer an accurately weighed portion of
blets taken by the formula:
the powder, equivalent to about 0.175 mg of ethinyl
estradiol, to a 50-mL glass centrifuge tube, and add two 25C[PA(RUA/RSA) + PS(RUS/RSS)],
glass beads. Add 25.0 mL of Internal standard solution,
in which C is the concentration, in mg per mL, of USP Nor-
stopper, and mix on a vortex mixer for at least 15
gestimate RS in the Standard preparation; PA and Ps are the
minutes. Sonicate for at least 5 minutes to ensure
corresponding (E) and (Z) fractions of USP Norgestimate
complete dissolution of the drug substances, mix, and
RS; RUA and RSA are the ratios of the peak responses of
pass through a filter having a 0.2-um porosity.
(£)-norgestimate to dibutyl phthalate obtained from the As-
say preparation and the Standard preparation, respectively;
and Rus and Rss are the ratios of the peak responses of (Z)-
detector and a 4.6-mm x 5-cm column that contains 5-um
Pharmacopeial Forum
A
norgestimate to dibutyl phthalate obtained from the Assay Prepare a filtered and degassed mixture by dissolving 675
preparation and the Standard preparation, respective- mg of sodium 1-octanesulfonate and 426 mg of anhydrous
dibasic sodium phosphate in 625 mL of water, and mix. Add
475 mL of methanol and 10 mL of phosphoric acid.Aas.P2(j
Make adjustments if necessary (see System Suitability under Chro-

matography (621)).
Strong anion-exchange resin—Transfer about 30 g of strong
anion-exchange resin to a 250-mL beaker. Wash the resin with
two 200-mL portions of water, decanting the water after each
wash. Wash with two 200-mL portions of dilute glacial acetic
acid (1 in 20), decanting the first wash, and filter with the aid of
suction.
BRIEFING Standard stock solution—Transfer about 20 mg of USP
Naloxone RS, accurately weighed, to a 100-mL volumetric flask.
Oxycodone Hydrochloride, USP 25 page 1281. Dissolve in and dilute with Solvent mixture to volume, and mix.
Standard solution—Transfer about 100 mg of USP Pentazocine
RS, accurately weighed, to a 50-mL volumetric flask. Dissolve in
(PA2: J.Kelly) RTS—35136-1 about 30 mL of Solvent mixture. Add 5.0 mL of the Standard stock
solution, dilute with Solvent mixture to volume, and mix.
Test solution—Transfer 1 Tablet to a 25-mL glass-stoppered
cylinder. Add 25.0 mL of Solvent mixture. Sonicate for 10
Erratum: minutes, and shake intermittently for 15 minutes. Filter into a
Limit of alcohol, line 3 under Chromatographic system: Change glass-stoppered conical flask. Add about 125 mg of Strong
"100- to 120-mesh" to: 80- to 100-mesh anion-exchange resin, and shake for 30 minutes.
4.6-mm x 25-cm column that contains packing LI. The flow
rate is about 1.5 mL per minute. Chromatograph the Standard
solution, and record the peak responses as directed for
Procedure: the relative retention times are about 0.3 for
naloxone and 1.0 for pentazocine; the resolution, R, between
pentazocine and naloxone is not less than 6; and the relative
standard deviation for replicate injections is not more than 2.0%.
the Standard solution and the Test solution into the
BRIEFING chromatograph, adjusting the operating parameters such that
satisfactory chromatography and peak responses are obtained
Pentazocine and Naloxone Hydrochlorides Tablets, USP with the Standard solution. Record the chromatograms, and
25 page 1337 and page 3321 of PF 27(6) [Nov.-Dec. 2001]. It measure the areas for the major peaks. Calculate the quantities,
is proposed to revise the composition of the Mobile phase in the in mg, of pentazocine (C 19H27NO) and naloxone (C 19 H 21 NO 4 )
test for Uniformity of dosage units to improve chromatographic re- in the Tablet taken by the same formula:
sults and to facilitate achievement of system suitability require-
ments. Typical retention times for naloxone and pentazocine are
4 minutes and 14 minutes, respectively. in which C is the concentration, in mg per mL, of the appropriate
Reference Standard in the Standard solution; and rv and rs are the
(PA2: J.Kelly) RTS—34849-1; 34940-1 peak responses for the corresponding analyte obtained from the
Test solution and the Standard solution, respectively.
Change to read:
Uniformity of dosage units (905): meet the requirements.
PROCEDURE FOR CONTENT UNIFORMITY FOR PENTAZOCINE AND
NALOXONE—
Solvent mixture—Use a mixture containing methanol, water, and
phosphoric acid (500:500:1).
Mobile phase—Disoolvo 675 mg of aodium 1 ootanoaulfonato
and 426 mg of anhydrouo dibasio oodium phosphate in a mixturo BRIEFING
of 625 mL of water, 375 mL of mothanol and 10 mL of phoaphorio
Praziquantel, USP 25 page 1423.
(PA7: B.Gilbert) RTS—35496-1
Pharmacopeia] Forum
Erratum:
Assay, line 6 under Procedure: Change "200C(rj//rs)," to: Calculate the amount of C10H15NO • HC1 dissolved per Tab-
0C(V)
let.
Times and Tolerances:
Time (hours) Amount dissolved
1 between 25% and 45%

BRIEFING
Pseudoephedrine Hydrochloride Extended-Release Tab-
lets, USP 25 page 1487 and page 3325 of PF 27(6) [Nov.-Dec. 6 not less than 75% _0
2001]. It is proposed to modify the Assay preparation in the Assay
to include a filtration of a portion of the solution using a 0.45-um
filter prior to injection, due to a cloudy solution being previously
obtained. The change to the Definition is editorial. Change to read:
Assay—
(PA2: J. Kelly) RTS—35236-6 Mobile phase—Prepare a filtered and degassed mixture of
alcohol and ammonium acetate solution (1 in 250) (17:3).
Standard preparation—Dissolve an accurately weighed quantity
of USP Pseudoephedrine Hydrochloride RS in alcohol to obtain a
solution having a known concentration of about 1.2 mg per mL.
Change to read: Assay preparation—Transfer not fewer than 20 Tablets to a
» Pseudoephedrine Hydrochloride Extended-Release suitable container, add 500 mL of alcohol, and homogenize until
the Tablets are dispersed. Quantitatively transfer the contents of the
Tablets contain not less than 90.0 percent and not more container to a 1000-mL volumetric flask, dilute with alcohol to
than 110.0 percent of the labeled amount of volume, mix, and allow to stand for solids to settle. Transfer
^pseudoephedrine hydrochloride^,^ 25.0 mL of the supernatant into a 50-mL volumetric flask, dilute
with alcohol to volume, and mix.
(C10H15NO-HC1).
A
Pass a portion of this solution through a 0.45-(im filter be-
Add the following: fore injection.A(75p26

Chromatographic system (see Chromatography (621))^The
"Drug release (724)— liquid chromatograph is equipped with a 254-nm detector and a
4.6-mm x 15-cm column that contains packing L3. The flow
Medium: water; 900 mL. rate is about 0.7 mL per minute. Chromatograph the Standard
preparation, and record the peak responses as directed for
Apparatus 2: 50 rpm Procedure: the tailing factor is not more than 2.5; and the
relative standard deviation for replicate injections is not more
Times: 1,3, and 6 hours. than 2.0%.
Standard solution—Dissolve an accurately weighed the Standard preparation and the Assay preparation into the
quantity of USP Pseudoephedrine Hydrochloride RS in responses for the major peaks. Calculate the quantity, in mg, of
pseudoephedrine hydrochloride (C10 H 15 NO • HC1) in the portion
water, and dilute quantitatively, and stepwise if necessary, of Tablets taken by the formula:
with water to obtain a solution having a known
concentration of about 0.13 mg per mL. in which C is the concentration, in mg per mL, of USP Pseudo-
ephedrine Hydrochloride RS in the Standard preparation; and rv
Procedure—Determine the amount of Ci0Hi5NO -HC1 and rs are the peak responses obtained from the Assay preparation
and the Standard preparation, respectively.
dissolved by employing the procedure set forth in the
Assay. Separately inject equal volumes (about 50 uL) of
the Standard solution and the filtered solution under test.
Pharmacopeial Forum
BRIEFING BRIEFING
Streptomycin Injection, USP 25 page 1602—See briefing Streptomycin for Injection, USP 25 page 1603—See brief-
under Streptomycin Sulfate. ing under Streptomycin Sulfate.
(PA7: W. Wright) RTS—35165-2 (PA7: W.Wright) RTS—35165-3

Assay— Assay—
—Assay preparation 1 (whoro it is represented a3 being in a single —Assay preparation 1 (whoro it is represented as being in a
dooo container)—Withdraw all of the withdrawable oontonta of single dose container)—Constitute Streptomycin for Injootion in
Injootion, uaing a suitable hypodermic noodle and ayringo, and a volume of water, accurately measured, corresponding to tho
dilute quantitatively with water to obtain a solution containing a volume of solvent specified in tho labeling. Withdraw all of the
oonvoniont quantity of streptomycin per mL. withdrawable oontonts, using a suitable hypodormio noodle and
—Assay preparation 2 (whore the label 3tatoa the quantity of syringe, and dilute quantitatively with water to obtain a solution
streptomycin in a given volume of solution) Dilute an containing a convenient quantity of streptomycin per mL.
aoourately measured volume of Injection quantitatively with —Assay preparation 2 (whore the label states tho quantity of
water to obtain a solution containing a convenient quantity of streptomycin in a given volume of constituted solution)—
streptomycin por mL. Constitute Stroptomyoin for Injootion in a volume of water,
—Procedure—Proceed as directed under Antibiotics—Microbiai accurately measured, corresponding to the volume of solvent
Assays (•84-), using an aoourately measured volume of Assay specified in tho labeling. Diluto an aoouratoly measured volume
preparation diluted quantitatively with water to yield a Test of tho constituted solution quantitatively with water to obtain a
Dilution having a concentration assumed to be equal to the solution containing a convenient quantity' of streptomycin por mL.
modian dose level of the Standard. —Procedure—Proceed as dirootod under Antibiotics—Microbiai
Assays (84-), using an aoouratoly measured volume of tho
*Mobile phase, Standard preparation, System suitability appropriate Assay preparation diluted quantitatively with wator
to yield a Test Dilution having a concentration assumed to bo
solution, and Chromatographic system—Proceed as equal to tho modian doso level of tho Standard.
directed in the Assay under Streptomycin Sulfate. ^Mobile phase, Standard preparation, System suitability
Assay preparation—Transfer an accurately measured solution, and Chromatographic system—Proceed as
volume of Injection, equivalent to about 500 mg of directed in the Assay under Streptomycin Sulfate.
streptomycin, to a 500-mL volumetric flask, dilute with Assay preparation 1 (where it is represented as being in a
water to volume, and mix. Transfer 5.0 mL of this single-dose container)—Constitute Streptomycin for
solution to a 200-mL volumetric flask, dilute with water Injection in a volume of water, accurately measured,
to volume, and mix. corresponding to the volume of solvent specified in the
Procedure—Proceed as directed in the Assay under labeling. Withdraw all of the withdrawable contents, using
Streptomycin Sulfate. Calculate the quantity, in mg, of a suitable hypodermic needle and syringe, and dilute
streptomycin (C21H39N7O12) in each mL of the Injection quantitatively, and stepwise if necessary, with water to
taken by the formula: obtain a solution containing about 0.025 mg of

streptomycin per mL.
20(CP/V)(ru/rs),
Assay preparation 2 (where the label states the quantity
in which Fis the volume, in mL, of Injection taken to pre-
of streptomycin in a given volume of constituted
pare the Assay preparation; and the other terms are as de-
solution)—Constitute Streptomycin for Injection in a
fined therein. AUSP26
volume of water, accurately measured, corresponding to
the volume of solvent specified in the labeling. Dilute an
accurately measured volume of the constituted solution
Pharmacopeia! Forum
quantitatively, and stepwise if necessary, with water to Change to read:

obtain a solution containing about 0.025 mg of Assay—
—Assay preparation—Diooolvo a ouitablo quantity of
streptomycin per mL. Streptomycin Sulfate, accurately weighed, in water, and dilute
quantitatively with water to obtain a oolution containing a
convenient quantity of otroptomyoin por mfe.
Procedure—Proceed as directed in the Assay under —Procedure—Prooood ao directed under Antibiotics—Micwbial
Assays (8-1-), uaing an accurately moaourod volume of the Assay
Streptomycin Sulfate. Calculate the quantity, in mg, of preparation diluted quantitatively with water to yield a Test
Dilution having a oonoontration aooumed to bo equal to the
streptomycin (C 2 iH 3 9 N 7 O 1 2 ) withdrawn from the median dooo level of the- Standard.
container, or in the portion of constituted solution taken ^Mobile phase—Use 70 mM sodium hydroxide. During
by the formula: use store in a plastic bottle flushed with a blanket of
(CPn000)(L/D)(ru/rs), helium above the liquid surface. Make adjustments if
in which L is the labeled quantity, in mg, of streptomycin
(621)).
(C21H39N7O12) in the container, or in the volume of consti-
tuted solution taken; D is the concentration, in mg of strep-
quantity of USP Streptomycin Sulfate RS in water, and
tomycin per mL, of Assay preparation 1 or Assay
quantitatively dilute with water to obtain a solution having
preparation 2, based on the labeled quantity in the contain-
a known concentration of about 0.03 mg per mL. Sonicate
er, or in the volume of constituted solution taken, respec-
for 1 minute, and mix.
tively; and the other terms are as defined therein.AUSP26
Streptomycin Sulfate, accurately weighed, to a 100-mL
volumetric flask, dilute with water to volume, sonicate for
1 minute, and mix. Transfer 10.0 mL of this solution to a
second 100-mL volumetric flask, dilute with water to
volume, and mix.
BRIEFING
System suitability solution—Heat about 10 mL of the
Streptomycin Sulfate, USP25page 1602; Streptomycin In- Standard preparation at 75° for 1 hour. Allow to cool.
jection, USP 25 page 1602; Streptomycin for Injection, USP 25
page 1603. A new specific liquid chromatographic Assay for strep- Chromatographic system (see Chromatography (621))—
tomycin is proposed as a replacement for the microbial Assay in
these monographs. The liquid chromatographic procedure is based The liquid chromatograph is equipped with an
on analyses performed with the CarboPac PA1 brand of L48 col-
umn using an ED40 brand of electrochemical detector in the inte- electrochemical detector, a gold working electrode, a pH
grated amperometric mode. Amikacin, dihydrostreptomycin,
gentamicin, kanamycin, neomycin, netilmicin, paromomycin, siso- silver-silver chloride reference electrode, a 4-mm x 5-cm
micin, and tobramycin do not interfere with the analysis of strep-
tomycin using the proposed procedure. Typical retention times guard column that contains packing L48, and a 4-mm x
were about 9 minutes for the major streptomycin degradation pro-
duct, obtained by heating streptomycin solution at 75° for 1 hour, 25-cm analytical column that contains packing L48. The
and 18 minutes for streptomycin.
electrochemical detector is used in the integrated
amperometric mode with a range of 300 nC, an output of
1 V full scale, and a rise time of 0.5 second, positive
polarity. The potential is programmed as follows.
Pharmacopeial Forum
Step Time Potential Integration

(seconds) (V) BRIEFING
1 0.00 +0.1
2 0.20 +0.1 begins Thyroid Tablets, USP 25 page 1711. It is proposed to delete
3 0.40 +0.1 ends the test for Limit of inorganic iodides, because the test cannot be
4 0.41 -2.0 performed in its current format. The USP Expert Committee on
5 0.42 -2.0 Biotechnology and Natural Therapeutics encourages interested
6 0.43 +0.6 parties to submit a new method for the determination of inorganic
7 0.44 -0.1 iodides in this monograph, preferably based on the potentiometric
8 0.50 -0.1 Assay specified under Thyroid. Submissions may be addressed to
the attention of the Expert Committee.
The flow rate is about 0.5 mL per minute. Chromatograph
(BNT: I. DeVeau) RTS—35396-1
the System suitability solution, and measure the peak areas
as directed for Procedure: the relative retention times are
about 0.5 for the main degradation product and 1.0 for strep-
A
tomycin; and the resolution, R, between the two peaks is not Limit of inorganic iodides—Plaoo a quantity of finely powdorod
Tablota, equivalent to 1.00 g of thyroid, in a dry toot tubo and pro
less than 3. Chromatograph the Standard preparation, and oood ao dirootod in tho tost for Limit of inorganic iodides under
Thyroid, beginning with "To a oooond tube add 10.0 mL." Tho
measure the peak areas as directed for Procedure: the tailing limit of inorganio iodido ia 0.08%.AUSP26
factor is not more than 2; the column efficiency is not less
than 1000 theoretical plates; and the relative standard devia-
tion for replicate injections is not more than 5%. [NOTE—If GENERAL NOTICES AND
variation of retention time or increase of tailing occurs, REQUIREMENTS
clean the columns with 0.2 M sodium hydroxide. Carefully
maintain the working and reference electrodes.]
BRIEFING
uL) of the Standard preparation and the Assay preparation
General Notices and Requirements, NF 20 page 2500. It is
into the chromatograph, record the chromatograms, and proposed to revise the General Notices and Requirements in order
to clarify that an article must comply with all standards in its cor-
measure the areas for the major peaks. Calculate the quan- responding monograph in order to be labeled as USP, NF, or USP-
NF in conjunction with the official title or labeling.
tity, in jag, of streptomycin (C21H39N7O12)in each mg of
(DSB: G. Giancaspro) RTS—35644-1
Streptomycin Sulfate taken by the formula:
Change to read:
in which C is the concentration, in mg per mL, of USP
Streptomycin Sulfate RS in the Standard preparation; P is "OFFICIAL" AND "OFFICIAL ARTICLES"
the designated streptomycin content, in ug per mg, of strep- The word "official", as used in this National Formulary or
with reference hereto, is synonymous with "National Formulary",
tomycin (C21H39N7O12) in USP Streptomycin Sulfate RS; with "NF", and with "compendial".
The designation "NF" in conjunction with the official title or
Wv is the weight, in mg, of Streptomycin Sulfate taken to elsewhere on the label of an article is a reminder that the artiolo
prepare the Assay preparation; and rv and rs are the strep- Represents that a monograph is included in the NF, and that
tomycin peak areas obtained from the Assay preparation the articleAA,F2;
and the Standard preparation, respectively. AUSP26 purports to comply with
Pharmacopeial Forum
NF standards.
A
Any language modifying or limiting this representation MONOGRAPHS (NF)
shall be accompanied by a statement that the article is
"not NF\ ANF21
such specific
A
Thp
designation
BRIEFING
on the label
Garlic Delayed-Release Tablets, page 2224 of PF 27(2)
A [Mar-Apr. 2001]. For further clarification, it is proposed to include
may not a
additional instructions in Identification test A. Changes are pro-
does not constitute a representation, endorsement, or incorporation posed in the test for Content of potential allicin to obtain similar
by the manufacturer's labeling of the informational material con- concentrations in the Test solution and the Standard solution. It is
tained in the NF monograph, nor does it constitute assurance by NF also proposed to include the appropriate time for storage of the
that the article is known to comply with NF standards. An article Crude alliinase solution.
may only purport to comply with an NF standard
A (DSB: G. Giancaspro) RTS—35542-8
or other requirements ANF21
when the article is recognized in the NF. The standards apply
equally to articles bearing the official titles or names derived by
transposition of the definitive words of official titles or transposi- Add the following:
tion in the order of the names of two or more ingredients in official
titles, whether or not the added designation "NF" is used. Names A
considered to be synonyms of the official titles may not be used for Garlic Delayed-Release Tablets
official titles.
Although both compendia, the United States Pharmacopeia
and the National Formulary, currently are published under one
cover, they remain separate compendia. The designation USP— » Garlic Delayed-Release Tablets are prepared
NF or similar combination may be used on the label of an article,
provided the label also bears a statement such as, "Meets NF stan- from Powdered Garlic or Powdered Garlic Extract
dards as published by the USP", indicating the particular compen-
dium to which the article purports to apply. and contain not less than 90.0 percent and not
Where an article differs from the standards of strength, qual-
ity, and purity as determined by the application of the assays and
tests, set forth for it in the National Formulary, its difference shall more than 140.0 percent of the labeled amount
be plainly stated on its label. Where an article fails to comply in
identity with the identity prescribed in the NF, or contains an added of alliin (C6HnNO3S) and not less than 90.0 per-
substance that interferes with the prescribed assays and tests, such
article shall be designated by a name that is clearly distinguishing cent and not more than 140.0 percent of the la-
and differentiating from any name recognized in the National For-
mulary. beled amount of available potential allicin
Articles listed herein are official, and the standards set forth in
the monographs apply to them only when the articles are intended
or labeled for use as drugs, as nutritional or dietary supplements, or (C6H10OS2).
as medical devices and when bought, sold, or dispensed for these
purposes or when labeled as conforming to this National Formu-
lary. Packaging and storage—Preserve in tight containers.
An article is deemed to be recognized in this National Formu- Labeling—The label states the Latin binomial name and,
lary when a monograph for the article is published in it, including
its supplements, addenda, or other interim revisions, and an official
date is generally or specifically assigned to it. following the official name, the article from which the
Because of differing characteristics not standardized by this
Formulary, all sources or types of some excipients may not have Tablets were prepared. Label it to indicate the amount of
identical properties with respect to use in a specific preparation. To
assure interchangeability in such instances, users may wish to as- total alliin, in u,g per Tablet, and the amount of available
certain final performance equivalency or determine such character-
istics prior to use. potential allicin, in |j.g per Tablet.
USP Reference standards (11)—USP Alliin RS. USP L-

Methionine RS.
Pharmacopeial Forum
Identification— carboxymethoxylamine hemihydrochloride. [NOTE—The

A: Transfer an aooumtoly oountod number of Tablets; solution must be transferred immediately upon removal
amount of pulverized Tablets, equivalent to about 30 mg from the dissolution vessel in order to inhibit the alliinase
of alliin, to a 110 mL homogenizing oup. 100-mL enzyme.]
volumetric flask. Add 70 mL of a mixture of methanol Procedure—[NOTE—Do not perform the allicin
and water (1:1), and blond at the higher speed for 30 determination in the Acid stage.] Determine the amount of
seconds: centrifuge, and decant the supernatant into a allicin released by injecting equal volumes (about 100 uL)
round bottom flask: shake, and centrifuge. Concentrate to of the Standard solution and the Test solution into the
a small volume (about 5 mL), using a rotary evaporator. chromatograph, record the chromatograms, and measure
Continue as directed in Identification test A under Garlic. the responses for the allicin peaks. Calculate the amount,
B: The retention times of the alliin diastereomer peaks in |ig, of allicin released in the Buffer stage by the formula:
in the chromatogram of the Test solution correspond to those
1050C(162.26/354.42)(rl,/rs)>
in the chromatogram of the Standard solution, as obtained
in which C is the concentration, in |ig per mL, of USP Alliin
in the test for Content of alliin.
RS in the Standard solution; 162.26 is the molecular weight
Allicin release—Proceed as directed for Delayed-Release
of allicin; 354.42 is twice the molecular weight of alliin; and
{Enteric-Coated) Articles, Method A under Drug Release
rv and rs are the peak responses for allicin obtained from the
(724). Place a number of Tablets, equivalent to about 5
mg of available potential allicin, in each vessel.
[NOTE—Q is the percentage of the labeled amount of avail -
able potential allicin released only in the Buffer stage.]
Time: 60 minutes for the Buffer stage.
Weight variation (2091): meet the requirements.
Mobile phase, Crude alliinase solution, Blank solution,
Content of alliin—
and Chromatographic system—Proceed as directed in the
test for Content of available potential allicin. 0.045 MPhosphate buffer, 0.05 MPhosphate buffer, 0.01
Standard solution—Dissolve an accurately weighed M Carboxymethoxylamine hemihydrochloride solution,
quantity of USP Alliin RS in water, and dilute Derivatization reagent, Mobile phase, Standard solution,
quantitatively, and stepwise if necessary, with water to and Chromatographic system—Proceed as directed in the
obtain a solution having a known concentration of about test for Content of alliin under Garlic.
50 ug per mL. Transfer 1.0 mL of this solution to a 5-mL Test solution—Transfer Pulverize an accurately counted
volumetric flask containing 100 uL of Crude alliinase number of Tablets, equivalent to about & 50 mg of alliin,
solution, mix, and allow to stand for 5 minutes at room with a mortar and pestle. Transfer an accurately weighed
temperature. Dilute with water to volume, and pass amount of the powder, equivalent to 5 mg of alliin, te-ft
through a membrane filter having a 0.45-um or finer 110 mL homogenizing cup, add 70 mL of 0.01 M
porosity. Carboxymethoxylamine hemihydrochloride solution, and
Test solution—Transfer 1.0 mL of the solution under test blond at the higher speed for 30 seconds: Centrifuge;and
to a t e s t t u b e c o n t a i n i n g 50 uL of 0 . 2 1 M dooant the supernatant into a 100-mL volumetric flask,

Mix the remaining solida in the oup with 20 mL of 0.01
Pharmacopeial Forum
M Carboxymcthoxylaminc hemihydrochloride solution, This solution is stable for 6 months when stored as
oentrifugo, and add tho supernatant to tho volumetrio directed.] Thaw at room temperature just before use.
flask.add about 70 mL of 0.01 M Carboxymethoxylamine Blank solution—Dilute 100 uL of Crude alliinase
hemihydrochloride solution, and shake for 1 minute. solution with water to 1 mL.
D i l u t e w i t h 0.01 M Carboxymethoxylamine Standard solution—Dissolve an accurately weighed
hemihydro chloride solution to volume, and mix. Using a quantity of USP Alliin RS in water, and dilute
volumetric syringe, transfer 0.1 mL of this solution to a quantitatively, and stepwise if necessary, with water to
septum-capped vial, add 0.5 mL of the Derivatization obtain a solution having a known concentration of about
reagent, and mix. Allow a reaction time of not less than 2 50 ug per mL. Add 100 uL of Crude alliinase solution to
minutes before injection into the chromatograph. 900 uL of this solution, mix, allow to stand for 5 minutes,
Procedure—Proceed as directed in the test for Content of and pass through a mombrano filter having a 0.45 urn or
alliin under Garlic. Calculate the quantity, in ug, of alliin in finer porosity: Transfer 1.0 mL of this solution to a 5-mL
each Tablet the portion of Tablets taken by the formula: volumetric flask containing 100 uL of Crude alliinase
solution, mix, and allow to stand for 5 minutes at room
600C/(r a /r,), temperature. Dilute to volume with water, and pass

through a filter having a 0.45-um or finer porosity.
Test solution—Weigh and finely powder not fewer than
in which C is the concentration, in jig per mL, of USP Alliin
20 Tablets. Transfer an accurately weighed quantity of the
RS in the Standard solution;N is the number of Tablets taken
powder, equivalent to about 5 mg of available potential
to pi«cparc the Test solution; and rv and rs are the sums of
allicin, to a 200-mL volumetric flask, add 25 mL of water,
the peak responses for the alliin diastereomers obtained
and mix. Incubate at room temperature for exactly 30
from the Test solution and the Standard solution, respec-
minutes. Stop the enzymatic reaction by diluting with 0.01
tively.
M Carboxymethoxylamine hemihydrochloride solution to
Content of available potential allicin—
volume, and mix. Centrifuge a portion of this solution,
0.01 M Carboxymethoxylamine hemihydrochloride
transfer 1.0 mL of the supernatant to a 2S- 5-mL
solution—Prepare as directed in the test for Content of
volumetric flask, dilute with water to volume, and mix.
alliin under Garlic.
methanol and water (60:40). Make adjustments if necessary
contains packing LI. The flow rate is about 1.0 mL per
Crude alliinase solution—Homogenize about 5 g of raw
minute. Chromatograph the Standard solution and the
garlic cloves with 25 mL of water. Filter, and extract three
Blank solution, and record the peak responses as directed
times with 50 mL of fert-butyl methyl ether. Discard the
for Procedure: the allicin peak is identified by comparing
organic phase, and remove the residual solvent from the
the chromatograms of the Blank solution and the Standard
aqueous phase by rotary evaporation in vacuum for 5
solution; and the relative standard deviation for replicate
minutes. Filter, and store frozen in small vials. [NOTE—
Pharmacopeial Forum
injections is not more than 2.0%. Chromatograph the Test supernatant to a septum-capped vial. Add 0.5 mL of the
solution: and record the peak responses as directed for Derivatization reagent, and mix. Allow a reaction time of
Procedure: the resolution, R, between the allicin peak and not less than 2 minutes before injection into the
the preceding peak at a relative retention time of 0.80 chromatograph.
(allyl methyl thiosulfinates) is not less than 2.0. Procedure—Proceed as directed in the test for Content of
Procedure—Inject equal volumes (about 100 uL) of the alliin under Garlic. The area of the alliin peak obtained from
Standard solution, the Blank solution, and the Test the Test solution is not more than 1% of the area of the alliin
solution into the c h r o m a t o g r a p h , r e c o r d the peak obtained from the Standard solution. ANF2I
chromatograms, and measure the peak responses for

allicin. Calculate the amount of available potential allicin,
in ug, in the portion of Tablets taken by the formula:
1000C(162.26/354.42)(rl//rJ),
BRIEFING
Glucosamine Hydrochloride, page 1449 of PF 26(5) [Sept-

in which C is the concentration, in ug per mL, of USP Alliin Oct. 2000]; Glucosamine Tablets, page 1451 of PF 26(5) [Sept.-
Oct. 2000]; Glucosamine Potassium Sulfate, page 1452 of P F
RS in the Standard solution; 162.26 is the molecular weight 26(5) [Sept.-Oct. 2000]; Glucosamine Sodium Sulfate, page
1453 of P F 26(5) [Sept.-Oct. 2000]. These monographs, which
of allicin; 354.42 is twice the molecular weight of alliin; and previously appeared in Pharmacopeial Previews, are now for-
warded to In-Process Revision. The liquid chromatographic proce-
rv and rs are the responses for the allicin peaks, corrected by dures in the Assays are based on analyses performed with the
Symmetry brand of L7 column. The typical retention time for glu-
the response of the blank, obtained from the Test solution cosamine is about 6 minutes.
(DSN: G. Giancaspro) RTS— 30148-1
Alliinase activity—
0.045 MPhosphate buffer, 0.05 MPhosphate buffer, 0.01
Add the following:
M Carboxymethoxylamine hemihydrochloride solution,
A
Derivatization reagent, Mobile phase, Standard solution, Glucosamine Hydrochloride
test for Content of alliin under Garlic.
C 6 H 13 NO 5 -HC1 215.63
D-Glucose, 2-amino-2-deoxy-, hydrochloride.
20 Tablets. Transfer an accurately weighed quantity of the
2-Amino-2-deoxy-/5-D-glucopyranose hydrochloride
powder, equivalent to about 5 mg of alliin, to a 100-mL
[66-84-2]
volumetric flask, add 25 mL of water, and mix. Incubate
at room temperature for exactly 5 minutes. Stop the
» Glucosamine Hydrochloride contains not less
e n z y m a t i c r e a c t i o n by d i l u t i n g with 0.01 M
Carboxymethoxylamine hemihydrochloride solution to
volume, and mix. Centrifuge a portion of this solution,
of C6H13NO5 • HC1, calculated on the dried basis.
and, using a volumetric syringe, transfer 0.1 mL of the
Pharmacopeial Forum
Packaging and storage—Preserve in tight, light-resistant adjustments if necessary (see System Suitability under
containers. Chromatography (621)).
USP Reference standards (11)—USP Glucosamine Standard preparation—Dissolve an accurately weighed

Hydmchloride RS. quantity of USP Glucosamine Hydrochloride RS in water
Identification— to obtain a solution having a known concentration of
A: Infrared Absorption (197K). about 1.0 mg per mL.
B: It meets the requirements of the tests for Chloride Assay preparation—Transfer about 100 mg of
(191). Glucosamine Hydrochloride, accurately weighed, to a
C: The retention time of the major peak in the 100-mL volumetric flask. Dissolve in 30 mL of water,
shake by mechanical means, dilute with water to volume,
and mix.
obtained in the Assay. Chromatographic system (see Chromatography
Specific rotation (781S): between +70.0° and +73.0°. (621))— The liquid chromatograph is equipped with a
Test solution: 25 mg per mL.
contains packing L7. The flow rate is about 0.6 mL per
pH (791): between 3.0 and 5.0, in a solution containing 20
minute. Chromatograph the Standard preparation, and
mg per mL.
record the responses as directed for Procedure: the tailing
Loss on drying (731)—Dry it at 105° for 2 hours: it loses
factor for the glucosamine peak is not more than 2.0; and
not more than 1.0% of its weight.
the relative standard deviation for replicate injections is
not more than 2.0%.
Sulfate(221)—A 0.10-g portion shows no more sulfate than
corresponds to 0.25 mL of 0.020 N sulfuric acid: not more uL) of the Standard preparation and the Assay pre-
than 0.24% is found. paration into the chromatograph, record the chroma-
Arsenic, MethodII (211): 3 ug per g. tograms, and measure the areas for the glucosamine
Heavy metals, Method II (231): 0.001%. peaks. Calculate the percentage of C6H13NO5 -HC1 in the
Organic volatile impurities, Method I (467): meets the portion of Glucosamine Hydrochloride taken by the
requirements. formula:
Assay—
Phosphate buffer—Mix 1.0 mL of phosphoric acid with 2
in which C is the concentration, in mg per mL, of USP Glu-
liters of water, and adjust with potassium hydroxide to a pH
cosamine Hydrochloride RS in the Standard preparation; W
of 3.0.
is the weight, in mg, of Glucosamine Hydrochloride used to
Mobile phase—Prepare a mixture of Phosphate buffer
prepare the Assay preparation; and rv and rs are the peak
and acetonitrile (3:2). Sonicate for 15 minutes, and pass
responses obtained from the Assay preparation and the
through a filter having a 0.5-(im or finer porosity. Make
Standard preparation, respectively. ANF2I
Pharmacopeial Forum
Identification—
BRIEFING
A: Infrared Absorption (197K).
Test solution—Transfer about 50 mg of Glucosamine
Glucosamine Potassium Sulfate, page 1452 of PF 26(5)
[Sept.-Oct. 2000]—See briefing under Glucosamine Hydrochlor- Sulfate Potassium Chloride to a centrifuge tube, and
ide. On the basis of comments and data received, it has been
learned that a physical mixture of glucosamine hydrochloride dissolve in 2 mL of water. Add about 0.5 mL of barium
and sodium sulfate is being marketed as "glucosamine sulfate".
The present monograph is intended for a chemical substance with chloride TS, and centrifuge. Evaporate the supernatant,
a crystal lattice constituted by the cations potassium and protonated
glucosamine and the anions chloride and sulfate. Changes in the and dry the residue at 105° for 2 hours. The IR spectrum
Definition, molecular formula, and chemical names are made to
describe more accurately the chemical substance, to avoid confu- corresponds to a similar preparation of USP Glucosamine
sion with the physical mixture. In addition, a test for Content of
sulfate has been added. Hydrochloride RS, with the addition of barium chloride
(DSN: G. Giancaspro) RTS—31642-1; 31643-1; 32038-1 TS being omitted.
B: It meets the requirements of the tests for Chloride
(191), Sulfate (191), sad Potassium (191).
Add the following:
C: The retention time of the major peak in the
A
Glueosamine Sulfate Potassium chromatogram of the Assay preparation corresponds to
Chloride
• 2KC1 obtained in the Assay.
605.52 Specific rotation (781S): between +50.0° and +52.0°.
Test solution: 35 mg per mL.
Bis(D-Glucose, 2-amino-2-deoxy-), hydroohlorido sulfate
potassium chloride complex. pH (791): between 3.0 and 5.0, in a solution containing 20
mg per mL.
Bis(2-Amino-2-deoxy-/?-D-glucopyranose) hydroohlorido
sulfate potassium chloride complex(-,-) [38899-
05-7]
Residue on ignition (281): between 27.0% and 29.0%.
Sodium—A solution (1 in 10), tested on a platinum wire,
» Glucosamine Sulfate Potassium Chloride con-
does not impart a pronounced yellow color to a non-
tains not less than €9S 98.0 percent and not more
luminous flame.
than 2 3 T £ 102.0 percent of G ^ H ^ N O ^ - H G I T
Arsenic, Method II (211): 3 jig per g.
(C6Hi4NO5)2SO4 • 2KC1, calculated on the dried
Heavy metals, Method II (231): 0.001%.
basis.
Organic volatile impurities, Method I (467): meets the
Packaging and storage—Preserve in tight, light-resistant requirements.
containers. Content of sulfate—Transfer about 1 g of Glucosamine
USP Reference standards (11)—USP Glucosamine Sulfate Potassium Chloride, accurately weighed, to a 250-
Hydrochloride RS. mL beaker, and dissolve in about 100 mL of water. Add 4
mL of 6 N hydrochloric acid. Heat the solution to boiling,
Pharmacopeial Forum
and add, with constant stirring, sufficient boiling barium Glucosamine Sulfate Potassium Chloride used to prepare
chloride TS to completely precipitate the sulfate. Add an the Assay preparation; and the other terms are as defined
additional 2 mL of barium chloride TS, and digest on a therein.,•A.NF21
steam bath for 1 hour. Pass the mixture through ashless
filter paper, transferring the residue quantitatively to the
filter, and wash the residue with hot water until no
precipitate is obtained when 1 mL of silver nitrate TS is
added to 5 mL of washing. Transfer the paper containing
the residue to a tared crucible. Char the paper, without BRIEFING
burning, and ignite the crucible and its contents to Glucosamine Sodium Sulfate page 1453 of PF26(5) [Sept-
Oct. 2000]—See briefing under Glucosamine Hydrochloride. On
constant weight. Calculate the content of sulfate by the basis of comments and data received, it has been learned that
a physical mixture of glucosamine hydrochloride and sodium sul-
multiplying the weight obtained by 0.4116. The content of fate is being marketed as "glucosamine sulfate". The present
monograph is intended for a chemical substance and not the phy-
sulfate is between 15.5% and 16.5%. sical mixture. Changes in the Definition, molecular formula, and
chemical names are made to describe more accurately the chemical
Assay— substance, to avoid confusion with the physical mixture. In addi-
tion, a test for Content of sulfate has been added.
Phosphate buffer, Mobile phase, Standard preparation,
Assay under Glucosamine Hydrochloride.
Assay preparation—Transfer about 125 mg of Add the following:
Glucosamine Sulfate Potassium Chloride, accurately A

Glucosamine Sulfate Sodium Chloride
weighed, to a 100-mL volumetric flask. Dissolve in 30
(C6H14NO5)2SO4 • 2NaCl
mL of water, shake by mechanical means, dilute with
5^3-573.31
water to volume, and mix.
Bis(D-Glucose, 2-amino-2-deoxy-), hydroohlorido sulfate
Procedure—Proceed as directed in the Assay under
sodium chloride complex.
Glucosamine Hydrochloride. Calculate the percentage of
Bis(2-Amino-2-deoxy-/3-D-glucopyranose) hydroohlorido
G«H«N©«r"H€i (C6H14NO5)2SO4 • 2KC1 in the portion of
sulfate sodium chloride complex (-,-). [38899-
Glucosamine Sulfate Potassium Chloride taken by the
05-7]
formula:
» Glucosamine Sulfate Sodium Chloride con-

(605.52/431.26)(10,000 Cl W){rulrs),
tains not less than 7 3 ^ 98.0 percent and not more
than 76T7- 102.0 percent of G^H^NO^-HGir
in which 605.52 is the molecular weight of Glucosamine
(C6Hi4NO5)2SO4 • 2NaCl calculated on the dried
Sulfate Potassium Chloride and 431.26 is twice the molec-
basis.
ular weight of Glucosamine HC1; W\s the weight, in mg, of
Packaging and storage—Preserve in tight, light-resistant
containers.
Pharmacopeial Forum
USP Reference standards (11)—USP Glucosamine Content of sulfate—Transfer about 1 g of Glucosamine

Hydrochloride RS. Sulfate Sodium Chloride, accurately weighed, to a 250-
Identification— mL beaker, and dissolve in about 100 mL of water. Add 4
A: Infrared Absorption (197K). mL of 6 N hydrochloric acid. Heat the solution to boiling,
Test solution—Transfer about 50 mg of Glucosamine and add, with constant stirring, sufficient boiling barium
Sulfate Sodium Chloride to a centrifuge tube, and dissolve chloride TS to completely precipitate the sulfate. Add an
in 2 mL of water. Add about 0.5 mL of barium chloride TS, additional 2 mL of barium chloride TS, and digest on a
and centrifuge. Evaporate the supernatant, and dry the steam bath for 1 hour. Pass the mixture through ashless
residue at 105° for 2 hours. The IR spectrum corresponds filter paper, transferring the residue quantitatively to the
to a s i m i l a r p r e p a r a t i o n of USP G l u c o s a m i n e filter, and wash the residue with hot water until no
Hydrochloride RS, with the addition of barium chloride precipitate is obtained when 1 mL of silver nitrate TS is
TS being omitted. added to 5 mL of washing. Transfer the paper containing
B: It meets the requirements of the tests for Chloride the residue to a tared crucible. Char the paper, without
(191), Sulfate (191), and Sodium (191). burning, and ignite the crucible and its contents to
C: The retention time of the major peak in the constant weight. Calculate the content of sulfate by
chromatogram of the Assay preparation corresponds to multiplying the weight obtained by 0.4116. The content of
that in the chromatogram of the Standard preparation, as sulfate is between 16.3% and 17.3%.
Assay—
Specific rotation (78IS): between +52.0° and +54.0°. Phosphate buffer, Mobile phase, Standard preparation,
Test solution: 35 mg per mL. and Chromatographic system—Proceed as directed in the
pH (791): between 3.0 and 5.0, in a solution containing 20 Assay under Glucosamine Hydrochloride.
mg per mL. Assay preparation—Transfer about 100 mg of

Glucosamine Sulfate Sodium Chloride, accurately
weighed, to a 100-mL volumetric flask. Dissolve in 30
mL of water, shake by mechanical means, dilute with
Residue on ignition (281): between 23.5% and 25.0%.
water to volume, and mix.
Potassium—Acidify 5 mL of a solution (1 in 20) with 6 N
acetic acid, and add 5 drops of sodium cobalt nitrite TS: no
Glucosamine Hydrochloride. Calculate the percentage of
precipitate is formed.
€<H»NQ*-tt€i (C6Hi4NO5)2SO4 • 2NaCl in the portion of
Arsenic, Method II (211): 3 jxg per g.
Glucosamine Sulfate Sodium Chloride taken by the
Heavy metals, MethodII (231): 0.001%. formula:
Organic volatile impurities, Method I (467): meets the
requirements.
10,000(573.31/431.26)(C/r)(rc;/r-y),
Pharmacopeial Forum
in which 573.31 is the molecular weight of the Glucosa- Identification—

mine Sulfate Sodium Chloride and 431.26 is twice the mo- A: The retention time of the major peak in the
lecular weight of Glucosamine HC1; Wis the weight, in mg, chromatogram of the Assay preparation corresponds to
of Glucosamine Sulfate Sodium Chloride used to prepare that in the chromatogram of the Standard preparation, as
the Assay preparation; and the others terms are as defined obtained in the Assay.
therein. B: It meets the requirements of the tests for Chloride
(191).
C: It meets the requirements of the tests for Sulfate
(191) (only for Tablets labeled as containing glucosamine
sodium sulfate or glucosamine potassium sulfate).
Disintegration and dissolution (2040): meet the
BRIEFING requirements for Dissolution.
Glucosamine Tablets, page 1451 of PF 26(5) [Sept.-Oct. Medium: water; 900 mL.
2000]—See briefing under Glucosamine Hydrochloride. Changes
in the Definition are made to be consistent with those made under Apparatus 2: 50 rpm.
Glucosamine Potassium Sulfate and Glucosamine Sodium Sulfate,
both monographs that are proposed elsewhere in this number of Time: 45 minutes.
PF.
Phosphate buffer, Mobile phase, and Chromatographic
(DSN: G. Giancaspro) RTS—30148-2
system—Proceed as directed in the Assay under
Glucosamine Hydrochloride.
Add the following: Standard solution—Dissolve an accurately weighed
A quantity of USP Glucosamine Hydrochloride RS in water
Glucosamine Tablets
to obtain a solution having a known concentration of
about 1.0 mg per mL. Dilute with a suitable quantity of
» Glucosamine Tablets are prepared from Glu-
water, if necessary.
cosamine Hydrochloride, Glucosamine Sulfate
Test solution—Use the solution under test.
Sodium Chloride, Glucosamine Sulfate Potassium
Chloride, or a mixture of any of them. Tablets uL) of the Standard solution and the Test solution into the
contain not less than 90.0 percent and not more chromatograph, record the chromatograms, and measure the
than 110.0 percent of the labeled amount of gluco- areas for the glucosamine peaks. Calculate the amount, in
samine (C6H13NO5). mg, of glucosamine (C6H13NO5) dissolved by the formula:
Packaging and storage—Preserve in tight, light-resistant (179.17/2 \5.6)
containers.
Labeling—The label indicates the type of glucosamine salt (l79.n/2l5.63)(900C)(ru/rs),

contained in the article. in which 179.17 and 215.6215.63 are the molecular weights
USP Reference standards (11)—USP Glucosamine of glucosamine and glucosamine hydrochloride, respec-
Hydrochloride RS. tively; C is the concentration, in mg per mL, of USP Gluco-
Pharmacopeial Forum
samine Hydrochloride RS in the Standard solution; and rv
and rs are the peak responses obtained from the Test solution
BRIEFING
and Standard solution, respectively.
Glucosamine and Chondroitin Sulfate Tablets, page 1454
Tolerances—Not less than 7 5 % of the labeled amount of of PF 26(5) [Sept.-Oct. 2000]. This monograph, which previously
appeared in Pharmacopeial Previews, is now forwarded with min-
C 6 Hi3NO 5 is dissolved in 45 minutes. or editorial style changes to In-Process Revision. Changes in the
Definition are made to be consistent with those made in Glucosa-
mine Potassium Sulfate and Glucosamine Sodium Sulfate, both
Weight variation (2091): meet the requirements. monographs being proposed elsewhere in this number of PF.
Assay—
Phosphate buffer, Mobile phase, Standard preparation,
Add the following:
Assay under Glucosamine Hydrochloride.
A
Assay preparation—Weigh and finely powder not fewer Glucosamine and Chondroitin Sulfate
than 20 Tablets. Transfer an accurately weighed portion of Tablets
the finely powdered material, equivalent to about 80 mg of
glucosamine, to a 100-mL volumetric flask, add 60 mL of » Glucosamine and Chondroitin Sulfate Tablets
water, and sonicate for 10 minutes. Shake by mechanical are prepared from Chondroitin Sulfate Sodium,
means for 15 minutes. Dilute with water to volume, and Glucosamine Hydrochloride, Glucosamine Sul-
mix. Pass a portion of this solution through a membrane
fate Sodium Chloride, Glucosamine Sulfate Po-
filter having a 0.45-um or finer porosity.
tassium Chloride, or a mixture of any of them.
Tablets contain not less than 90.0 percent and
not more than 120.0 percent of the labeled
amounts of chondroitin sulfate sodium and gluco-
peaks. Calculate the quantity, in mg, of glucosamine samine (C6H13NO5).
(C6H13NO5) in the portion of Tablets taken by the formula:

(179.17/215. containers.
Labeling—The label indicates the types of glucosamine
(179.17/215.63)(100Q(Vrs), salts contained in the article, and the species source from
which chondroitin was derived.

in which 179.17 and 215.6 215.63 are the molecular weights
USP Reference standards (11)—USP Chondroitin Sulfate
of glucosamine and glucosamine hydrochloride, respec-
Sodium RS. USP Glucosamine Hydrochloride RS.
tively; C is the concentration, in mg per mL, of USP Gluco-
samine Hydrochloride RS in the Standard preparation; and Identification—
ru and rs are the peak responses obtained from the Assay A: The retention times of the major peaks in the
chromatogram of the Test solution correspond to those in
preparation and the Standard preparation, respective-
the chromatogram of the Standard solution, as obtained in
ly- A.NF21
the test for Content of glucosamine (presence of
Pharmacopeial Forum
glucosamine). chondroitin sulfate sodium.

B: Standard solution and Test solution—Prepare as Procedure—Proceed as directed in the test for Content of
directed in the test for Content of chondroitin sulfate chondroitin sulfate sodium, adjusting the volume of the
sodium under Chondroitin Sulfate Tablets. sample, if necessary. Calculate the quantity, in mg, of
Procedure (see Electrophoresis (726))—Proceed as chondroitin sulfate sodium dissolved by the formula:
directed for Identification under Chondroitin Sulfate
900C,
Tablets {presence of chondroitin sulfate).
in which C is the concentration, in mg per mL, of chondroi-
tin sulfate sodium in the solution under test.
requirements for Dissolution.
Tolerances—Not less than 75% of the labeled amount of
chondroitin sulfate sodium is dissolved in 60 minutes.
Time: 60 minutes. Weight variation (2091): meet the requirements.
Determine the amount of glucosamine (C6H13NO5) dis- Content of glucosamine—
solved by employing the following method. Diluent—Transfer 29 uL of acetic acid and 5 mL of
Diluent, 0.2 M Borate buffer, Derivatizing reagent, acetonitrile to a 100-mL volumetric flask containing about
Mobile phase, and Chromatographic system—Proceed as 50 mL of water, and dilute with water to volume.
directed in the test for Content of glucosamine. 0.2 M Borate buffer—Dissolve 7.63 g of sodium borate in
Standard solution—Prepare as directed in the test for 80 mL water, and adjust with hydrochloric acid TS to a pH
Content of glucosamine. Dilute with a suitable quantity of of 9.5. Transfer to a 100-mL volumetric flask, dilute with
water, if necessary. water to volume, and mix. [NOTE—Buffer must be stored
Test solution—Use the solution under test. at room temperature and can be used indefinitely, but must
be warmed to dissolve if crystallization occurs.]
Procedure—Proceed as directed in the test for Content of
Derivatizing reagent—In a 14-mL polypropylene culture
glucosamine. Calculate the quantity, in mg, of glucosamine
tube, dissolve 50 mg of o-phthalaldehyde in 1.25 mL of
(C6H13NO5) dissolved by the formula:
anhydrous methanol, add 50 uL of 3-mercaptopropionic
acid and 11.2 mL of 0.2 M Borate buffer, and mix gently.
Allow to stand in the dark for 30 minutes before use.
(179.17/215.63)(900Q(rl//rs), [NOTE—Reagent strength is maintained by adding 10 uL

of 3-mercaptopropionic acid every two days. Storage
in which the terms are as defined therein.
should be in the dark, at room temperature, and can be
used for not more than two weeks.]
C6Hi3NO5 is dissolved in 60 minutes.
Mobile phase—In a 1000-mL volumetric flask dissolve
Determine the amount of chondroitin sulfate dissolved by
6.80 g of sodium acetate trihydrate in 700 mL water.
Adjust with dilute acetic acid to a pH of 5.9, dilute with
Cetyl pyridinium solution, Standard solution, and Test
water to volume, and mix. Combine 100 mL of methanol
solution—Prepare as directed in the test for Content of
with 900 mL of acetate buffer, and mix thoroughly. Pass
Pharmacopeial Forum
through a nylon membrane filter having a 0.45-um or finer the major peaks. Calculate the quantity, in mg, of
porosity, and degas. Make adjustments if necessary (see glucosamine (C6HI3NO5) in the portion of Tablets taken
System Suitability under Chromatography (621)). by the formula:
179.17/215.6(100C)(?v^
quantity of USP Glucosamine Hydrochloride RS in water,
and dilute quantitatively, and stepwise if necessary, with
water to obtain a solution having a known concentration (179.17/215.63)(100Q(ra/r5),
of about 1.0 mg per mL. Allow to stand at room
in which 179.17 and 215.6 215.63 are the molecular weights
temperature for 1 hour.
of glucosamine and glucosamine hydrochloride, respec-
tively; C is the concentration, in mg per mL, of USP Gluco-
20 Tablets. Transfer an accurately weighed portion of the
samine Hydrochloride RS in the Standard solution; and rv
powder, equivalent to about 25 mg of glucosamine, to a
and rs are the peak responses for the /?-anomer obtained
25-mL volumetric flask, and dilute with Diluent to
from the Test solution and the Standard solution, respec-
volume. Mix on a vortex mixer to suspend the powder in
tively.
solution. Sonicate in a 65° water bath for 20 minutes.
Content of chondroitin sulfate sodium—
Remove from the bath, stir for 5 minutes with the aid of a
Cetyl pyridinium chloride solution, Standard solution,
magnetic stirrer, and centrifuge.
Test solution, and Procedure—Proceed as directed in the
test for Content of chondroitin sulfate sodium under
equipped with a 340-nm detector and a 3.0-mm x 5-cm
Chondroitin Sulfate Tablets.ANF2I
column that contains packing LI. The flow rate is about
1.0 mL per minute. Chromatograph the Standard solution,
and record the peak responses as directed for Procedure: the
relative retention times are 1.0 for the /?-anomer and 1.8 for
the o:-anomer; the typical retention time of the /3-anomer is
not less than 4 minutes; and the relative standard deviation
BRIEFING
for replicate injections is not more than 2.0%.
Kava, page 779 of PF 26(3) [May-June 2000]. This pro-
Procedure—Transfer 100 uL of the Derivatizing reagent posed new monograph is presented again with changes in the De-
finition, in Botanic characteristics, in Microbial limits, and in
and 100 uL of the Standard solution or the Test solution to a Content of kavalactones. The Definition is revised to include the
roots as part of this pharmacopeial article. The term rhizome is
vial containing 400 uL of 0.2 M Borate buffer, mix, allow changed to the term rootstock, which is a more accurate botanical
term. It has been shown that the roots of kava contain more kava-
the derivatization to proceed for 1 minute, and inject the lactones than the rhizome and that they may be used together with
the rootstock (rhizome). A description of the roots is also added.
derivatized solution into the chromatograph. Separately The revisions in the test for Microbial limits are based on the re-
commendations of the USP Microbiology Expert Committee for
inject equal volumes (about 10 uL) of the Standard botanical articles. It is reported that interfering peaks are separated
with the proposed revisions in the Mobile phase and Chromato-
solution and the Test solution into the chromatograph, graphic system in the test for Content of kavalactones. Validation
data were obtained using YMC basic C8 or YMC J'Sphere H80
record the chromatograms, and measure the responses for brand columns. Typical retention times for methysticin, dihydro-
Pharmacopeial Forum
methysticin, kawain, dihydrokawain, yangonin, and desmethox- rhizomes, rootstocks, numerous splits and cavities,
yyangonin are 14, 15, 18.6, 20.7, 24.3, and 27.1 minutes, respec-
tively. Other changes are editorial. resulting from the loss of parenchyma from the central
(DSB: G. Giancaspro) RTS—31952-1; 34457-1 region, are visible. The unpeeled rhizomo rootstock has a
gray to grayish brown, longitudinally wrinkled outer layer
of cork with circular root scars. If not removed, a fringe
Add the following:
of long lateral roots that are filiform at the end extends
A
Kava from the pithy rootstock. The roots are often intertwined
in a braid-like formation. The roots comprise a multitude
» Kava is the dried rhizome rootstock (rhizome) of fibers that are rich in starch.
of Piper methysticum G. Forster Forst. (Fam. Pi- Histology—The entire medullary parenchyma, the
peraceae), usually peeled and cut in pieces with or medullary rays, and the central cortex are very rich in
starch; the parenchyma also contains a fine-grained brown
without the roots removed. It contains not less
material and some resinous masses. The starch granules
than 4.5% of kavalactones, calculated as the
are spherical to slightly ovoid, 10 to 30 urn in diameter,
sum of methysticin, dihydromethysticin, kawain,
with a central hilum in the form of a cleft or deep split.
dihydrokawain, desmethoxyyangonin, and yan-
The primary cortex contains strips of collenchyma, and
gonin, on the dried basis. frequently contains oleoresin excretory cells with greenish
Packaging and storage—Preserve in well-closed, light- yellow, resinous contents, and contains stone cells
resistant containers. covering the phloem. The stone cells have uniform, non-
pitted wall thickenings, and are approximately polygonal
Labeling—The label states the Latin binomial name and,
in shape, with a diameter of about 50 urn. The unpeeled
following the official name, the part of the plant contained
rhizome has a thin-walled cork layer.
in the article.
The center of a transverse section of the rhizome contains
USP Reference standards (11)—USP Powdered Kava
primary xylem elements in narrow strips formed mainly by
Extract RS. USP Kawain RS.
tracheid-like elements, and secondary xylem elements with
Botanic characteristics—
strands of lignified vascular tissue that extend evenly around
Macroscopic—Kava occurs in irregular longitudinal and
the medulla and alternate with broad secondary medullary
transverse cut pieces of various shapes and thicknesses. The
rays. The secondary vascular elements consist of large xy-
rhizomco rootstocks are 3 to 20 cm long and 1 to 10 cm
lem vessels with scalariform thickening, groups of thicker-
thick. The outer surface of the peeled rhizome rootstock is
walled fibers with bluntly narrowing ends, and abundant
whitish or pale grayish brown; the inner surface is white to
parenchymatous cells with moderately thickened walls
yellowish white with light and dark brown areas. The
and numerous pits. Additional vascular bundles are scat-
fracture is coarsely fibrous and starchy. In a transverse
tered throughout the medulla. The phloem contains extre-
section, the lighter colored sunken pith, surrounded by a
mely delicate, thin-walled cells. A transverse section
radiate xylem crossed by fans of rays, is visible; and in
through the radicles occasionally reveals a macrocellular,
some cases, a thin layer of cork may be present. In older
Pharmacopeial Forum
slightly suberose primary cortex composed of thin-walled appear above the main zone and two others below it.
polygonal cells; a narrow strip of secondary cortex clearly Spray the plate with the Spray reagent, heat at 100° to
separated from the primary cortex by a dark brown endoder- 105°, and examine the plate in visible light: a zone in the
mis; broad medullary rays; and a macrocellular, parenchy- chromatogram of the Standard solution and the
matous medulla. There are no calcium oxalate crystals corresponding zone in the chromatogram of the Test
present. solution turns red (kawain). In the chromatogram of the
Identification— Test solution, two brownish zones appear above the main
A: Thin-Layer Chromatographic Identification Test zone (dihydroyangonin and dihydrokawain), and two grey
(201)- zones below it (dihydromethysticin and methysticin); a
Adsorbent: 0.25-mm layer of chromatographic alumina faint greenish zone may also be discernible directly above
with fluorescence indicator at 254 nm (see Chromato- the main zone (yangonin).
graphy (621)). B: The retention times of the relevant analytes in the
Test solution—Pulverize about 5 g of Kava. To about 0.6 chromatogram of the Test solution correspond to those in
g of the pulverized Kava add 10 mL of methylene chloride, the chromatogram of Standard solution 2, as obtained in
and heat under reflux in a water bath for 10 minutes. Filter the test for Content ofkavalactones.
into a 10-mL volumetric flask, dilute with methylene Microbial limits (2021)—The total bacterial count does
chloride to volume, and mix. not exceed 40* 106 per g, the total combined molds and
Standard solution—Prepare a solution containing about 1 yeasts count does not exceed 40* 104 per g, tho count for
mg of USP Kawain RS per mL of methylene chloride. ooliforms doca not exceed 10 4 per g, the count for
Developing solvent system: a mixture of ether and solvent enterobacteria does not exceed 404 103per g, and it meets
hexane (7:3). the requirements of the tests for absence of Salmonella
Spray reagent—Mix, in the following order, 0.5 mL of species and Escherichia coli.
anisaldehyde, 10 mL of glacial acetic acid, 85 mL of Loss on drying (731): not more than 12.0%.
methanol, and 5 mL of sulfuric acid. Total ash (561): not more than 8.0%.
Procedure—Develop the chromatogram until the solvent Extractable matter—Transfer 2.00 g of coarsely powdered
front has moved 15 cm from the origin. Remove the plate Kava to a round-bottom flask fitted with a condenser. Add
from the developing chamber, mark the solvent front, and 25 mL of acetone, and reflux for 30 minutes. Cool, and filter
allow the solvent to evaporate. Develop again until the through a sintered-glass crucible. Repeat the extraction
solvent front has moved 15 cm from the origin. Remove twice, in each case using the residue. Combine the
the plate from the developing chamber, mark the solvent filtrates, and transfer to a 100-mL volumetric flask. Dilute
front, and dry the plate. Examine the plate under UV light with acetone to volume, and evaporate 50 mL of this
at 254 nm: the RF of the zone in the middle third of the solution to dryness. Dry at 105° for 2 hours, cool in a
chromatogram of the Test solution corresponds to that in desiccator, and weigh immediately: not less than 5% is
the chromatogram of the Standard solution. On the found.
chromatogram of the Test solution, two secondary zones Foreign organic matter (561): not more than 2.0%.
Pharmacopeia! Forum
Pesticide residues (561): meets the requirements. replicate injections is not more than 2.0%. Chromatograph
Content of kavalactones— Standard solution 2, and record the peak responses as
Mobile phase—Prepare a filtered and degassed mixture of directed for Procedure: the chromatogram obtained from
water, aootonitrilo;mothanol, and aoctio aoid (60:20:20:0:1) Standard solution 2 is similar to the Reference
phosphoric acid 0.1%, acetonitrile, and isopropyl alcohol Chromatogram provided with USP Powdered Kava
(64:20:16). Make adjustments if necessary (see System Extract RS; and the resolution, R, between desmethoxy-
Suitability under Chromatography (621)). yangonin and yangonin is not less than 1.8.
Extraction solvent—Prepare a mixture of methanol and Procedure—Separately inject equal volumes (about 5 uL)
water (70:30). of Standard solution 1, Standard solution 2, and the Test
Standard solution 1—Dissolve an accurately weighed solution into the chromatograph, and allow the Test
quantity of USP Kawain RS in methanol, and dilute solution to elute for not less than 1.5 times the retention
quantitatively, and stepwise if necessary, to obtain a time of kawain. Record the chromatograms, and measure
solution having a known concentration of about 0.20 mg all of the peak responses. Identify the relevant peaks in
per mL. Prepare this solution fresh daily. the chromatogram of the Test solution by comparison with
Standard solution 2—Transfer a quantity of USP the peaks obtained from the chromatograms of Standard
Powdered Kava Extract RS, accurately weighed, to a solution 1 and Standard solution 2. Separately calculate
suitable volumetric flask, and dilute with Extraction the percentage of methysticin, dihydromethysticin,
solvent to volume to obtain a solution having a known kawain, dihydrokawain, desmethoxyyangonin, and
concentration of about 0.2 mg of kawain per mL. Shake yangonin in the portion of Kava taken by the formula:
by mechanical means for 10 minutes, and then sonicate 5000F(OW)(r [/ /r 5 ),

for 10 minutes at room temperature. Decant, and pass
in which F is the relative- rosponoo conversion factor (see
through a membrane filter having a 0.45-um or finer
NOTE below for values); C is the concentration, in mg per
porosity. Prepare this solution fresh daily.
mL, of USP Kawain RS in Standard solution 1; W is the
Test solution—Transfer about 750 mg of finely ground
quantity, in mg, of Kava in the portion taken; rv is the peak
Kava, accurately weighed, to a 50-mL volumetric flask,
response obtained from the relevant analyte; and rs is the
dilute with Extraction solvent to volume, and sonicate for
peak response for kawain obtained from Standard solution
60 minutes at room temperature. Decant, and pass through
1. Calculate the percentage of kavalactones in the portion of
a membrane filter having a 0.45-um or finer porosity.
Kava taken by adding the individual quantities calculated.
[NOTE—The relative response conversion factor, F, is
0.66 for methysticin, 0.88 for yangonin, 0.90 for des-
methoxyyangonin, 1.00 for kawain, 1.65 for dihydro-
contains highly deactivated 5-um packing L7. The flow
methysticin, and 1.70 for dihydrokawain. ]ANF2i
rate is about 4-rO- 0.6 mL per minute. Chromatograph
Standard solution 1, and record the peak responses as
directed for Procedure: the relative standard deviation for
Pharmacopeia! Forum
granules, simple or compounded, of 2 to 3 lenticular to

BRIEFING
obconic components. Crystals of methysticin that polarize
Powdered Kava, page 782 of PF 26(3) [May-June 2000].
The revision in the test for Water is made to reflect the quality of light in the red to violet range are observed; calcium
the material commercially available. The revision in the test for
Microbial limits is based on the recommendations of the USP Mi- oxalate crystals are absent.
crobiology Expert Committee for botanical articles.
MierobinI limits (2021)—Tho total baotorial oount dooo
not cxoood 10,000 por g, the total combined moldo and
yoasts count doo9 not oxoood 1000 por g, tho ooliform
Add the following: oount dooa not oxocod 100 por g^ tho count for
A cntorobaotcria doog not cxoood 100 per g, and it moots tho
Powdered Kava
requirements of tho toota for absonoo of Salmonella opooiog,
Eschcrichia coli, and Staphylococcus aumus:
» Powdered Kava is Kava reduced to a powder
Water, Method la (921): not more than 5.0% 12.0%.
or very fine powder. It contains not less than 4.5
Heavy metals, Method III (231): not more than 0.005%.
percent of kavalactones, calculated as the sum of
Content of kavalactones—Proceed as directed for Content
methysticin, dihydromethysticin, kawain, dihy- of kavalactones under Kava, except to use Powdered Kava
drokawain, desmethoxyyangonin, and yangonin, to prepare the Test solution, and to calculate the percentage
on the dried basis. of m e t h y s t i c i n , d i h y d r o m e t h y s t i c i n , k a w a i n ,
dihydrokawain, desmethoxyyangonin, and yangonin in the
Packaging and storage—Preserve in well-closed, light-
portion of Powdered Kava taken by the formula:
resistant containers.
following the official name, the part of the plant from
in which W\s the weight, in mg, of the portion of Powdered
which the article was derived.
Kava taken; and the other terms are as defined therein: not
USP Reference standards (11)—USP Powdered Kava less than 4.5% is found.
Extract RS. USP Kawain RS.
Other requirements: meets the requirements of the tests
Botanic characteristics—The pale yellowish brown for Identification, Total ash, Loss on drying, Extractable
powder has a slight, agreeable odor and a bitter, pungent matter, Microbial limits, and Pesticide residues under
taste. Under a microscope, the following characteristics Kava.ANF21
are observed: fragments of parenchyma cells containing
reddish or yellowish brown oleoresin; elongated, lignified,
and pitted parenchyma of the xylem and medullary rays;
fragments of vessels with scalariform thickening; groups
of moderately thickened, slightly lignified fibers; large,
thin-walled parenchymatous cells of the pith; occasional
fragments of thin-walled cork; and numerous starch
Pharmacopeial Forum
USP Reference standards (11)—USP Aspartic Acid RS.

BRIEFING
USP Glutamic Acid RS. USP Scopoletin RS. USP (3-
Nettle, Powdered Nettle, and Powdered Nettle Extract,
page 636, 640, and 641 of PF 26(3) [May-June 2000]. These Sitosterol RS.
monographs, which previously appeared in Pharmacopeial Pre-
views, are now forwarded to In-Process Revision. A revision, to Botanic characteristics—
change the title of this monograph to Nettles, is proposed. The pro-
posed title reflects the two species recognized in the monograph. Macroscopic—The rhizome is irregularly bent, about 3 to
According to the resolution of the Nomenclature Committee, the
standard common names recognized in Herbs of Commerce are 10 mm thick, and light gray-brown on the outside; thin roots
also included in the Definition. It is proposed to revise Microbial
limits based on the recommendations of the Microbiology Expert spring from the knotty bulges of a lengthwise furrow. A
Committee for botanical articles.
Total amino acid is determined via a spectrophometric proce- transverse cut of the rhizome shows it is fibrous, light
dure using glutamic and aspartic acids as reference standards.
The gas chromatographic procedures for the Content of p-sitoster- yellowish white, and usually has a small medulla cave.
ol test are based on analyses performed with the HP-1 brand of G2
column. Typical retention times for cholesterol and /3-sitosterol are The roots are often very long, usually 0.5 to 2 mm thick,
about 14 and 20 minutes, respectively. The gradient liquid chroma-
tographic procedure for the Content of scopoletin test is based on light yellow-brown on the outside, and contain some deep
analyses performed with the Kromasil C18 brand of LI column.
Typical retention times for scopoletin, cholesterol, and /3-sitosterol longitudinal furrows; a transverse cut shows a pale and
are 12, 14, and 20 minutes, respectively.
almost pure-white color.
Histology—The transverse section of the rhizome and
root shows the following characteristics. The rhizome has
Add the following: a narrow cork composed of brown, thin-walled cells, a
A few rows of tangentially-elongated cortical parenchyma,
Nettie Nettles
and a pericyclic region with numerous fibers occurring
singly or, more frequently, in small groups. Fibers are
» Nottlo Nettles consists of dried roots and rhi-
much elongated with very thick and lignified walls. Some
zomes of Urtica dioica(Linn6QQ) L. ssp dioica. cells of the pericycle and outer part of secondary phloem
(Fam. Urticaceae), known in commerce as sting- contain large globular compound crystals of calcium
ing nettle,Urtica urens{LirmoQ,Q), L., known in oxalate. The vascular cambial region is distinct and
commerce as dwarf nettle, their hybrids, or mix- continuous with narrow radial groups of vascular tissue
tures of them. It contains not less than 0.8 percent separated by wide medullary rays. The secondary phloem
of total amino acids, not less than 0.05 percent of is mainly parenchymatous with groups of thin-walled
sieve tissue. The xylem is dense and completely lignified,
/3-sitosterol (C29H50O), and not less than 3 jig per
containing scattered vessels, isolated or in small groups,
g of scopoletin (CioHgCU), calculated on the dried
associated with moderately thickened xylem parenchyma
basis.
cells and numerous thicker-walled xylem fibers with slit-
Packaging and storage—Store in tight containers, shaped pits. Individual vessels have fairly large, closely
protected from light, moisture, and heat. arranged, bordered pits, while the adjacent parenchyma
Labeling—The label states the Latin binomial and, has simple or bordered pits. Medullary rays indicate
following the official name, the parts of the plant alternating areas of lignified and unlignified cells,
contained in the article. appearing as tangential bands between the vascular
Pharmacopeial Forum
bundles, each composed of five or six layers of cells; the Standard solution. Weakly violet-red zones above and
lignified cells have moderately thickened walls with below /3-sitosterol, corresponding to /3-sitosterol-
simple pits. The pith is composed of rounded, unlignified glucoside, are visible.
parenchyma, collapsed in the central part to form a cavity. Microbial limits (2021)—The total aerobic microbial
Mature roots show a thin cork, narrow phelloderm, and count does not exceed 4-0-*" 106 cfu per g, the total
secondary phloem and xylem with alternating areas of combined molds and yeasts count does not exceed 4-0* 104
lignified and unlignified parenchyma in the wide cfu per g, tho ooliform count does not cxcood 104 ofu per g;
medullary rays, similar to that found in the rhizome. and the enterobacterial count does not exceed 4-04 103 cfu
Identification, Thin-Layer Chromatographic Identification per g. It meets the requirements of the tests for absence of
Test (201)— Salmonella species and Escherichia coli.and Staphylo-
Adsorbent: 0.50-mm layer of chromatographic silica gel coccus awviis.
mixture. Loss on drying (731)—Dry 1.0 g of Nottlo Nettles, finely
Test solution—Extract 1 g of powder by refluxing with 10 powdered, at 105° for 2 hours: it loses not more than 12.0%
mL of a solution containing toluene, ethyl acetate, and of its weight.
methanol (7:2:1) for 15 minutes, cool, and filter. Foreign organic matter (561): not more than 2.0%.
Evaporate the filtrate to dryness under reduced pressure at
Total ash (561): not more than 10%.
less than 40°, and dissolve the residue in 2 mL of the
Pesticide residues (561): meets the requirements.
toluene, ethyl acetate, methanol solution.
Content of total amino acids—
pH 5.5 Acetate buffer—Mix 5.40 g of anhydrous sodium
quantity of USP Scopoletin RS and USP 0-Sitosterol RS
acetate, 0.3 mL of glacial acetic acid, and water to a final
in methanol to obtain a solution having a known
volume of 100 mL.
concentration of 0.05 and 0.5 mg per mL, respectively.
Reagent solution—Prepare a solution containing about
Application volume: 20 uL for the Test solution; 10 uL
1.00 g of ninhydrin, 1.50 g of hydrindantin, and 37.5 mL
for the Standard solution.
of propylene glycol, and adjust with/?//5.5 Acetate buffer
Developing solvent system: diethyl ether and methanol
to 50.0 mL. [NOTE—Prepare the Reagent solution daily.]
(9:1).
Standard solution—Dissolve accurately weighed
Procedure—Proceed as directed in the chapter. Examine
quantities of USP Glutamic Acid RS and USP Aspartic
the plates under UV light at 365 nm. Spray the plate with
Acid RS in water to obtain a solution having a known
about 10 mL of a mixture of water, 85% phosphoric acid,
concentration of about 0.1 mg of each per mL.
and 10% vanillin in 96% ethanol (4.5:4.5:1); heat between
Test solution—Finely powder an amount of Nottlo
100° and 105° for 10 minutes; and examine under daylight.
Nettles, and transfer about 1.0 g, accurately weighed, to
The chromatogram of the Test solution exhibits a violet-red
80 mL of water. Place in an ultrasonic bath for 25
zone corresponding to the /?-sitosterol peak at the same RF
minutes, and centrifuge. Transfer the supernatant to a 100-
value as the /?-sitosterol peak in the chromatogram of the
mL volumetric flask, dilute with water to volume, and filter.
Procedure—Transfer 5.0 mL of the Test solution and 1.0
Pharmacopeial Forum
mL of the Standard solution to two separate, appropriately 5 mL. Transfer 0.5 mL of this solution to a 10-mL round-
labeled, 50-mL volumetric flasks. Add 4.0 mL of water to bottomed flask, dry the solvent under reduced pressure, add
the Standard solution and 5.0 mL of Reagent solution to 1 mL of Derivatizing reagent, and mix.
both the Test solution and the Standard solution. Heat in a Test solution—Finely powder an amount of Nottlo
boiling water bath for 30 minutes, cool, and adjust with a Nettles, transfer 50.0 g to a Soxhlet apparatus, treat with
mixture of ethanol and water (1:1) to volume. chloroform, and extract for 6 hours. The volume of
Concomitantly determine the absorbances of the Standard chloroform used is at least twice the volume of the
solution and the Test solution in 1-cm cells at the thimble with an appropriate-size flask. Dry the solvent
wavelength of maximum absorbance at about 570 nm under reduced pressure, add 1.0 mL of Internal standard
with a suitable spectrophotometer. Prepare a blank using solution, and dilute with chloroform to 10 mL. Transfer
5.0 mL of water, and treat similarly to the Test solution. 0.5 mL of this solution to a 10-mL round-bottomed flask,
Calculate the percentage of total amino acids in the dry the solvent under reduced pressure, and add 0.5 mL of
portion of Nottlo Nettles taken by the formula: Derivatizing reagent.
(621))— The gas chromatograph is equipped with a
in which Av and As are the absorbances of the Test solution
flame-ionization detector and a 0.20-mm x 25-m fused-
and the Standard solution, respectively; Ws is the sum of the
silica capillary column coated with a 0.35-|xm film of
weights, in mg, of USP Glutamic Acid RS and USP Aspartic
phase G2. The carrier gas is helium, flowing at a rate of
Acid RS, calculated on the dried basis, in the Standard solu-
about 0.5 mL per minute. The injection port and detector
tion; and WJJ is the weight, in mg, of dried Nottlo Nettles in
temperatures are maintained at 325°. The column
the Test solution: not less than 0.8% of total amino acids is
temperature is initially held at 300°, and maintained at this
found.
temperature for 60 minutes. Chromatograph the Standard
Content of /?-sitosterol—
Derivatizing reagent—Prepare a solution containing Procedure: the tailing factor for each sterol peak is not
equal volumes (1:1:1) of BSTFA [iV,0-bis(trimethylsilyl)- more than 2.0; and the relative standard deviation for
trifluoroacetamide], anhydrous pyridine, and a mixture of replicate injections determined from each sterol peak is
BSA [tf,0-(trimethylsilyl)acetamide], TMSI (N- not more than 5.0%.
trimethylsiryimidazole), and TMCS (trimethylchlorosilane) Procedure—Separately inject equal volumes (about 1 uL)
(3:3:2). of the Standard solution and the Test solution into the
Internal standard solution—Dissolve an accurately chromatograph, record the chromatograms, and measure
weighed quantity of cholesterol in chloroform to obtain a the peak responses of the sterols. Calculate the percentage
solution having a known concentration of about 10 mg of /?-sitosterol in the portion of Nottlo Nettles taken by the
per mL. formula:
Standard solution—Dissolve 50 mg of USP /?-Sitosterol
RS, accurately weighed, in 2.0 mL of chloroform, add 1 mL
of Internal standard solution, and dilute with chloroform to
Pharmacopeial Forum
in which Rv and Rs are the peak response ratios of /?-sitos- Chromatograph about 10 uL of the Standard solution, and
terol to the internal standard obtained from the Standard so- record the peak responses as directed for Procedure: the ca-
lution and the Test solution, respectively; Cs is the pacity factor (K) determined from the scopoletin peak is not
concentration, in mg per mL, of USP /?-Sitosterol RS in less than 5; the tailing factor for the scopoletin peak is not
the Standard solution; and Cv is the concentration, in mg more than 2.0; and the relative standard deviation for repli-
per mL, of Nottlo Nettles in the Test solution: not less than cate injections is not more than 5.0%.
0.05% of /3-sitosterol is found. Procedure—Separately inject equal volumes (about 10
Content of scopoletin— uL) of the Standard solution and the Test solution into the
Solution A—Use water. chromatograph, record the chromatograms, and measure the
Solution B—Use methanol. peak responses for scopoletin. Calculate the content of
Mobile phase—Use variable mixtures of Solution A and scopoletin (C10H8O4), in jig per g, in the portion of Nottle
Solution B as directed for Chromatographic system. Make Nettles taken by the formula:

in which rv and rs are the peak responses of scopoletin in the
Test solution and the Standard solution, respectively; Cs is
quantity of USP Scopoletin RS in methanol to obtain a
the concentration, in mg per mL, of USP Scopoletin RS in
solution having a known concentration of about 0.02 ug
the Standard solution; and Cv is the concentration, in mg
per mL.
per mL, of Nottlc Nettles in the Test solution: not less than
Test solution—Finely powder a suitable quantity ofNcttlo
3 ug per g of scopoletin is found.ANF21
Nettles, and mix 4.000 g, accurately weighed, with 25 mL of
methanol. Place in an ultrasonic bath for 25 minutes, and
centrifuge. Transfer 0.5 mL of the solution to a 10-mL
volumetric flask, and dilute with methanol to volume.
BRIEFING
fluorescence detector set at an excitation wavelength of
Powdered Nettle, page 640 of PF 26(3) [May-June 2000]—
366 nm and an emission wavelength of 420 nm and a 4.6- See briefing under Nettle.
mm x 25-cm column that contains packing LI. The flow (DSB: G. Giancaspro) RTS—30187-2
rate is about 1 mL per minute. The chromatograph is
programmed as follows.
Add the following:
(minutes) (%) (%) Elution A
0 75 25 equilibration Powdered Nettle Nettles
0-2 75->60 25^40 linear gradient
2-8 60 40 isocratic
8-10 60-+0 40-* 100 linear gradient
10-15 0 100 isocratic » Powdered Nettle Nettles is Nottlo Nettles re-
15-20 0-»75 100->25 linear gradient
20-30 75 25 isocratic duced to a fine or very fine powder.
Pharmacopeial Forum
Packaging and storage—Store in tight containers,

BRIEFING
protected from light and moisture.
Powdered Nettle Extract, page 641 of PF 26(3) [May-June
Labeling—The label states the Latin binomial and, 2000]—See briefing under Nettle.
following the official name, the parts of the plant (DSB: G. Giancaspro) RTS—30187-3
contained in the article.
USP Reference standards (11)—C/SP Aspartic Acid RS.

Add the following:
USP Glutamic Acid RS. USP Scopoletin RS. USP (3-
A
Sitosterol RS. Powdered Nettle Nettles Extract
Botanic characteristics— [NOTE—The test is carried out
under a microscope using chloral hydrate solution.] The » Powdered Nottlo Nettles Extract is prepared
powder is yellowish to brownish gray, and shows several from comminuted Nettle with 60 percent alcohol
fragments of net and dot vessels with a strongly varying or other suitable solvents. It contains not less than
diameter, usually between 50 and 150 jam. Few, if any, 5.0 percent of total amino acids, not less than 0.1
dotted bast fibers are present. Clearly dotted wood fibers, percent of /3-sitosterol (C29H50O) and not less than
about 200 to 800 urn in length, thin-walled parenchyma
30 ug per g of scopoletin (CioHsCU). The ratio of
cells, sometimes with calcium oxalate glands and
the starting crude plant material to Powdered Ex-
occasionally with single crystals and fragments of cork
tract is 10:1.
consisting of flat-shaped, thin-walled cells are also present.
Other requirements—It meets the requirements of the tests Packaging and storage—Store in tight containers,
for Identification, Microbial limits, Foreign organic matter, protected from light and moisture.
Total ash, Pesticide residues, Content of total amino acids, Labeling—The label states the official name of the article,
Content of (3-sitosterol, and Content of scopoletin under the Latin binomial, and, following the official name, the part
Nettle Nettles.ANF21 of the plant from which the article was prepared. Label it to
indicate the content of total amino acids, /?-sitosterol,
scopoletin, the extracting solvent used for preparation, and
the ratio of the starting crude plant material to Powdered
Extract.
USP Reference standards (11)—USP Aspartic Acid RS.

USP Glutamic Acid RS. USP Scopoletin RS. USP j3-
Sitosterol RS.
Identification—
(201)-
Adsorbent, Standard solution, Application volume,
Developing solvent system, and Procedure—Proceed as
Pharmacopeia! Forum
directed for the test for Identification under Nettle Netties. acids under Nettle Nettles.
Test solution—Dissolve 0.6 g of Powdered Extract, Test solution—Dissolve 50 mg of Powdered Extract,
accurately weighed, in a mixture of toluene, ethyl acetate, accurately weighed, in 80 mL of water, shake for 10
and methanol (7:2:1), filter, and dry under reduced minutes, dilute with water to 100 mL, and filter.
pressure at a temperature below 40°. Dissolve the residue Procedure—Proceed as directed for Content of total
in 2.0 mL of the toluene, ethyl acetate, and methanol amino acids under Nettle Nettles, except to calculate the
mixture. percentage of total amino acids taken by the formula:
B: The retention time of /?-sitosterol in the
2000(4^ A^Ws/Wy),
chromatogram of the Test solution corresponds to that in
in which Wv is the weight, in mg, of the Powdered Extract in
the Test solution; and the other terms are as defined therein:
the test for Content o/0-sitosterol.
not less than 5.0% of total amino acids is found.
C: The r e t e n t i o n time of s c o p o l e t i n in the
Content of /?-sitosteroI—
the chromatogram of the Standard solution, as obtained in Derivatizing reagent, Internal standard solution,
the test for Content of scopoletin. Standard solution, and Chromatographic system—Proceed
as directed for Content of /3-sitosterol under Nettle Nettles.
Microbial limits (2021)—The total aerobic microbial
Test solution—Transfer 20.0 g of Powdered Extract,
count does not exceed 4-0-4" 103 cfu per g, the total
accurately weighed, to a Soxhlet apparatus, treat with
combined molds and yeasts count does not exceed 4-Q* 102
chloroform, and extract for 6 hours. The volume of
cfu per g, tho ooliform count does not oxoood 10*-efe; and
chloroform used is at least twice the volume of the
the enterobacterial count does not exceed 40* 102 cfu per g.
thimble with an appropriate-size flask. Dry the solvent
It meets the requirements of the tests for absence of
under reduced pressure, add 1.0 mL of Internal standard
Salmonella species and Escherichia coli. Staphylococcus
solution, and dilute with chloroform to 10 mL. Transfer
0.5 mL of this solution to a 10-mL round-bottomed flask,
Loss on drying (731)—Dry about 1.0 g of Powdered
dry the solvent under reduced pressure, and add 0.5 mL of
Extract, accurately weighed, at 105° for 2 hours: it loses
Derivatizing reagent.
Procedure—Proceed as directed for Content of 0-
Total ash (561): not more than 20.0%.
sitosterol under Nettle Nettles, except to calculate the
percentage of /3-sitosterol in the portion of Powdered
Organic volatile impurities, Method I (467): meets the Extract taken by the formula:
requirements.
Alcohol content, Method II {611) (if present): not more
than 1.0%. in which Cv is the concentration, in mg per mL, of Pow-

dered Extract in the Test solution; and the other terms are
Content of total amino acids—
as defined therein: not less than 0.1% of/3-sitosterol is
pH 5.5 Acetate buffer, Reagent solution, and Standard
found.
solution—Proceed as directed for Content of total amino
Pharmacopeial Forum
Content of scopoletin— 2000], page 471 of PF 26(2) [Mar.-Apr. 2000], page 793 of PF
26(3) [May-June 2000], page 1101 of P F 26(4) [July-Aug.
Solution A, Solution B, Mobile phase, Standard solution, 2000], page 1369 of P F 26(5) [Sept.-Oct. 2000], page 1606 of
PF 26(6) [Nov.-Dec. 2000], page 1832 of P F 27(1) [Jan.-Feb.
and Chromatographic system—Proceed as directed for 2001], page 2268 of PF 27(2) [Mar.-Apr. 2001], page 2594 of
PF 27(3) [May-June 2001], page 2806 of PF 27(4) [July-Aug.
Content of scopoletin under Nettle Nettles. 2001], page 3071 of P F 27(5) [Sept.-Oct. 2001], and page 3348
of PF 27(6) [Nov.-Dec. 2001].
Test solution—Dissolve 200 mg of Powdered Extract,
(HDQ) RTS—30148-1; 30187-1; 34780-1; 35659-1; 35123-
accurately weighed, in 25 mL of methanol, place in an 1; 35353-1; 35416-01; 35504-1; 35617-1
ultrasonic bath for 25 minutes, and centrifuge. Transfer
0.5 mL of this solution to a 10-mL volumetric flask, and
dilute with methanol to volume. Add the following:
A
Procedure—Proceed as directed for Content ofscopoletin USP Aspartic Acid RS—Do not dry. Store at room tem-
under Nettle Nettles, except to calculate the content of perature.^,^
scopoletin (Ci0HgO4) in the portion of Powdered Extract Change to read:
USP Betaine Hydrochloride RS.
taken by the formula: A
—Do not dry. Keep container tightly closed.AUS7,2<5
10,000(^1 r.XCs/Cy),
Add the following:
A
in which Cv is the concentration, in mg per mL of Powdered USP Glucosamine Hydrochloride RS—Dry portion at
Extract in the Test solution; and the other terms are as de- 105° for 2 hours. Keep container tightly closed. Protect from
fined therein: not less than 30 ug per g of scopoletin is
found. ANF21
Add the following:
A
USP Glutamic Acid RS—Do not dry. Store at room
GENERAL CHAPTERS Add the following:

A
USP Hydrocodone Bitrartrate Related Compound A
General Tests and Assays RS—[To come.]AUSP26
Add the following:
General Requirements for A
USP Insulin Lispro—[To comQ.]AUSP26
Tests and Assays Change to read:

USP Quininone RS (G^H^Qg-O 322.11)
B
(C 2 0 H 2 2 O 2 <> 322.41) H2
—Do not dry. Keep container tightly closed and protected from
light.
BRIEFING
Add the following:

(11 ) Reference Standards, USP 25 page 1836, page 8060 of A
P F 20(5) [Sept.-Oct. 1994], page 3212 of P F 22(6) [Nov.-Dec. USP Scopoletin RS—Do not dry. Store at - 20°.AUSP26
1996], page 4500 of P F 23(4) [July-Aug. 1997], page 4849 of
PF 23(5) [Sept.-Oct. 1997], page 5180 of PF 23(6) [Nov.-Dec. Add the following:
1997], page 5965 of P F 24(2) [Mar.-Apr. 1998], page 6925 of
PF 24(5) [Aug.-Sept. 1998], page 7511 of P F 25(1) [Jan.-Feb. A
USP P-Sitosterol RS—Do not dry. Store at room tem-
1999], page 7876 of PF 25(2) [Mar.-Apr. 1999], page 8222 of
PF 25(3) [May-June 1999], page 8561 of PF 25(4) [July-Aug. perature. AUSP26
1999], page 8893 of PF 25(5) [Sept.-Oct. 1999], page 9222 of
PF 25(6) [Nov.-Dec. 1999], page 218 of PF 26(1) [Jan.-Feb.
© 2002 The United States Pharmacopeial Convention, Inc. AH Rights Reserved.

Pharmacopeial Forum
Chemical Tests and Assays Pharmacists must avoid ingredients and conditions that could
result in excessive physical deterioration or chemical decomposi-
tion of drug preparations, especially when compounding
Phamnacy C d ( 9 ) ^
A
(see Pharmaceutical Compounding—Nonsterile Prepara-
LIMIT TESTS
tions (195)).AUSP26
The stability and clinical effect of manufactured dosage forms

can be greatly compromised by seemingly negligible alterations
or inappropriate prescription compounding. Pharmacists must es-
tablish and maintain compounding conditions that include the en-
surance of drug stability to help prevent therapeutic failure and
adverse responses.
BRIEFING STABILITY is defined as the extent to which a product retains,
within specified limits, and throughout its period of storage and use
(i.e., its shelf life), the same properties and characteristics that it
(281) Residue on Ignition, USP 25 page 1927 and page 2325 of possessed at the time of its manufacture. Five types of stability gen-
PF 27(2) [Mar.-Apr. 2001]. The revision proposals for this mono- erally recognized are shown in the accompanying table.
graph appear in the Harmonization section of this PF.
Criteria for Acceptable Levels of Stability
(PA6: W.L.Paul) RTS—32552-1
Conditions Maintained
Throughout the Shelf Life of the
Type of Stability Drug Product
Chemical Each active ingredient retains its
chemical integrity and labeled
potency, within the specified
limits.
General Information Physical The original physical properties,
including appearance, palatabil-
ity, uniformity, dissolution, and
suspendability are retained.
Microbiological Sterility or resistance to micro-
bial growth is retained according
to the specified requirements.
BRIEFING Antimicrobial agents that are
present retain effectiveness
(1191) Stability Considerations in Dispensing Practice, USP within the specified limits.
25 page 2231 and page 1378 of P F 26(5) [Sept.-Oct. 2000]. It is Therapeutic The therapeutic effect remains
proposed to revise the title of Pharmacy Compounding (795) that unchanged.
is referenced in this chapter to agree with the newly proposed Toxicological No significant increase in toxi-
change in title to Pharmaceutical Compounding—Nonsterile Pre- city occurs.
parations (795). In addition, it is proposed to update this chapter
by deleting the reference to Stability Testing of New Drug Sub-
stances and Products—The Tripartite Guideline (1196) in the sec- Change to read:
tion Stability Studies in Manufacturing. Stability Studies in Manufacturing
The scope and design of a stability study vary according to
(PSD: C. Okeke) RTS—35351-1 the product and the manufacturer concerned. Ordinarily, the formu-
lator of a product first determines the effects of temperature, light,
air, pH, moisture, trace metals, and commonly used excipients or
solvents on the active ingredients. From this information, one or
more formulations of each dosage form are prepared, packaged
Change to read: in suitable containers, and stored under a variety of environmental
conditions, both exaggerated and normal. See Stability under Phar-
maceutical Dosage Forms(1 151). and tho Stability Testing of New
Drug Substances and Products TIic Tripartite Guidclinc{U9£)7
NOTE—Inasmuch as this chapter is for purposes of general in-
A
formation only, no statement in the chapter is intended to modify or a n d Shipping and Storage of Labile Preparations
supplant any of the specific requirements pertinent to Pharmaco-
peial articles, which are given elsewhere in this Pharmacopeia.
Aspects of drug product stability that are of primary concern to
the pharmacist in the dispensing of medications are discussed here-
in At appropriate time intervals, samples of the product are assayed
A
for potency by use of a stability-indicating method, observed for
(see Packaging, Storage, and Distribution of Pharmaco- physical changes, and, where applicable, tested for sterility and/
or resistance to microbial growth and for toxicity and bioavailabil-
peial Articles (1141 )).AUSP26 ity. Such a study, in combination with clinical and toxicological
Pharmacopeial Forum
results, enables the manufacturer to select the optimum formulation surface of the container-closure system. An apparent gain in po-
and container and to assign recommended storage conditions and tency usually is caused by solvent evaporation or by leaching of
an expiration date for each dosage form in its package. The be- materials from the container-closure system.
yond-use date is stated on the container label. The chemical potency of the active ingredient(s) is required
to remain within the limits specified in the monograph definition.
Change to read: Potency is determined by means of an assay procedure that differ-
entiates between the intact molecule and its degradation products.
Chemical stability data should be available from the manufacturer.
Although chemical degradation ordinarily cannot be detected by
Responsibility of the Pharmacist the pharmacist, excessive chemical degradation sometimes is ac-
companied by observable physical changes. In addition, some phy-
The pharmacist helps to ensure that the products under his sical changes not necessarily related to chemical potency, such as
supervision meet acceptable criteria of stability by (1) dispensing change in color and odor, or formation of a precipitate, or clouding
oldest stock first and observing expiration dates; (2) storing proof solution, may serve to alert the pharmacist to the possibility of a
ducts under the environmental conditions stated in the individual stability problem. It should be assumed that a product that has un-
monographs and/or in the labeling; (3) observing products for evi- dergone a physical change not explained in the labeling may also
dence of instability; (4) properly treating and labeling products that have undergone a chemical change and such a product is never to
are repackaged, diluted, or mixed with other products; (5) dispen- be dispensed. Excessive microbial growth and/or contamination
sing in the proper container with the proper closure; and (6) in- also may appear asa physical change. A gross change in a physical
forming and educating patients concerning the proper storage characteristic such as color or odor is a sign of instability in any
and use of the products, including the disposition of outdated or product. Other common physical signs of deterioration of dosage
excessively aged prescriptions. forms include the following.
Rotating Stock and Observance of Expiration Dates—Proper Solid Dosage Forms—Many solid dosage forms are designed
rotation of stock is necessary to ensure the dispensing of suitable for storage under low-moisture conditions. They require protection
products. A product that is dispensed on an infrequent basis should from environmental water, and therefore should be stored in tight
be closely monitored so that old stocks are given special attention, containers (see Containers in the General Notices) or in the con-
particularly with regard to expiration dates. The manufacturer can tainer supplied by the manufacturer. The appearance of fog or li-
guarantee the quality of a product up to the time designated as its quid droplets, or clumping of the product, inside the container
expiration date only if the product has been stored in the original signifies improper conditions. The presence of a desiccant inside
container under recommended storage conditions. the manufacturer's container indicates that special care should be
taken in dispensing. Some degradation products, for example, sal-
Storage under Recommended Environmental Conditions— icylic acid from aspirin, may sublime and be deposited as crystals
In most instances, the recommended storage conditions are stated on the outside of the dosage form or on the walls of the container.
on the label, in which case it is imperative to adhere to those con-
ditions. They may include a specified temperature range or a desig- HARD AND SOFT GELATIN CAPSULES—Since the capsule for-
nated storage place or condition (e.g., "refrigerator," or mulation is encased in a gelatin shell, a change in gross physical
"controlled room temperature") as defined in the General Notices. appearance or consistency, including hardening or softening of the
Supplemental instructions, such as a direction to protect the pro- shell, is the primary evidence of instability. Evidence of release of
duct from light, also should be followed carefully. Where a product gas, such as a distended paper seal, is another sign of instability.
is required to be protected from light and is in a clear or translucent
container enclosed in an opaque outer covering, such outer cover- UNCOATED TABLETS—Evidence of physical instability in un-
ing is not to be removed and discarded until the contents have been coated tablets may be shown by excessive powder and/or pieces
used. In the absence of specific instructions, the product should be (i.e., crumbling as distinct from breakage) of tablet at the bottom
stored at controlled room temperature (see Storage Temperature in of the container (from abraded, crushed, or broken tablets); cracks
the General Notices). The product should be stored away from lo- or chips in tablet surfaces; swelling; mottling; discoloration; fusion
cations where excessive or variable heat, cold, or light prevails, between tablets; or the appearance of crystals that obviously are not
such as near heating pipes or fluorescent lighting. part of the tablet itself on the container walls or on the tablets.
COATED TABLETS—Evidence of physical instability in coated

A tablets is shown by cracks, mottling, or tackiness in the coating and
Labile Preparations—Dispense and ship products labled the clumping of tablets.
as Labile Preparations a) according to manufacturer's re- DRY POWDERS AND GRANULES—Dry powders and granules
that are not intended for constitution into a liquid form in the ori-
commendation or b) if not advised by the manufacturer, ac- ginal container may cake into hard masses or change color, which
may render them unacceptable.
cording to Shipping and Storage of Labile Preparations
POWDERS AND GRANULES INTENDED FOR CONSTITUTION AS
SUSPENSIONS—Dry powders and granules intended for constitu-
tion into solutions or suspensions require special attention. Usually
such forms are those antibiotics or vitamins that are particularly
Observing Products for Evidence of Instability—Loss of po- sensitive to moisture. Since they are always dispensed in the origi-
tency usually results from a chemical change, the most common nal container, they generally are not subject to contamination by
reactions being hydrolysis, oxidation-reduction, and photolysis. moisture. However, an unusual caked appearance necessitates
Chemical changes may occur also through interaction between in- careful evaluation, and the presence of a fog or liquid droplets in-
gredients within a product, or rarely between product and contain- side the container generally renders the preparation unfit for use.
er. An apparent loss of potency in the active ingredient(s) may Presence of an objectionable odor also may be evidence of instabil-
result from diffusion of the drug into or its combination with the ity.
Pharmacopeial Forum
should be stored in a refrigerator (see Storage Temperature in

EFFERVESCENT TABLETS, GRANULES, AND POWDERS—Effer- the General Notices).
vescent products are particularly sensitive to moisture. Swelling
of the mass or development of gas pressure is a specific sign of Proper Treatment of Products Subjected to Additional Ma-
instability, indicating that some of the effervescent action has oc- nipulations—In repackaging, diluting, or mixing a product with
curred prematurely. another product, the pharmacist may become responsible for its
stability.
Liquid Dosage Forms—Of primary concern with respect to li-
quid dosage forms are homogeneity and freedom from excessive Repackaging—In general, repackaging is inadvisable. However,
microbial contamination and growth. Instability may be indicated if repackaging is necessary, the manufacturer should be consulted
by cloudiness or precipitation in a solution, breaking of an emul- concerning potential problems. In the filling of prescriptions, it is
sion, nonresuspendable caking of a suspension, or organoleptic essential that suitable containers be used. Appropriate storage con-
changes. Microbial growth may be accompanied by discoloration, ditions and, where appropriate, an expiration date and beyond-use
turbidity, or gas formation. date should be indicated on the label of the prescription container.
Single-unit packaging calls for care and judgment, and for strict
SOLUTIONS, ELIXIRS, AND SYRUPS—Precipitation and evi- observance of the following guidelines: (1) use appropriate packa-
dence of microbial or chemical gas formation are the two major ging materials; (2) where stability data on the new package are not
signs of instability. available, repackage at any one time only sufficient stock for a lim-
ited time; (3) include on the unit-dose label a lot number and an
EMULSIONS—The breaking of an emulsion (i.e., separation of appropriate beyond-use date; (4) where a sterile product is repack-
an oil phase that is not easily dispersed) is a characteristic sign of aged from a multiple-dose vial into unit-dose (disposable) syr-
instability; this is not to be confused with creaming, an easily re- inges, discard the latter if not used within 24 hours, unless data
dispersible separation of the oil phase that is a common occurrence are available to support longer storage; (5) where quantities are re-
with stable emulsions. packaged in advance of immediate needs, maintain suitable re-
packaging records showing name of manufacturer, lot number,
SUSPENSIONS—A caked solid phase that cannot be resus- date, and designation of persons responsible for repackaging and
pended by a reasonable amount of shaking is a primary indication for checking; (6) where safety closures are required, use container
of instability in a suspension. The presence of relatively large par- closure systems that ensure compliance with compendial and reg-
ticles may mean that excessive crystal growth has occurred. ulatory standards for storage.
TINCTURES AND FLUIDEXTRACTS—Tinctures, fluidextracts, Dilution or Mixing—Where a product is diluted, or where two
and similar preparations usually are dark in color because they products are mixed, the pharmacist should observe good profes-
are concentrated, and thus they should be scrutinized carefully sional and scientific procedures to guard against incompatibility
for evidence of precipitation. and instability. For example, tinctures such as those of belladonna
and digitalis contain high concentrations of alcohol to dissolve the
STERILE LIQUIDS—Maintenance of sterility is of course criti- active ingredient(s), and they may develop a precipitate if they are
cal for sterile liquids. The presence of microbial contamination in diluted or mixed with aqueous systems. Pertinent technical litera-
sterile liquids usually cannot be detected visually, but any haze, ture and labeling should be consulted routinely; it should be current
color change, cloudiness, surface film, particulate or flocculent literature, because at times formulas are changed by the manufac-
matter, or gas formation is sufficient reason to suspect possible turer. If a particular combination is commonly used, consultation
contamination. Clarity of sterile solutions intended for ophthalmic with the manufacturers) is advisable. Since the chemical stability
or parenteral use is of utmost importance. Evidence that the integ- of extemporaneously prepared mixtures is unknown, the use of
rity of the seal has been violated on such products should make such combinations should be discouraged; if such a mixture in-
them suspect. volved an incompatibility, the pharmacist might be responsible.
Oral antibiotic preparations constituted from powder into liquid
Semisolids {Creams, Ointments, and Suppositories)—For form should never be mixed with other products.
creams, ointments, and suppositories, the primary indication of in- Combining parenteral products necessitates special care,
stability is often either discoloration or a noticeable change in con- particularly in the case of intravenous solutions, primarily because
sistency or odor. of the route of administration. This area of practice demands the
utmost in care, aseptic technique, judgment, and diligence. Be-
CREAMS—Unlike ointments, creams usually are emulsions cause of potential unobservable problems with respect to sterility
containing water and oil. Indications of instability in creams are and chemical stability, all extemporaneous parenteral preparations
emulsion breakage, crystal growth, shrinking due to evaporation should be used within 24 hours unless data are available to support
of water, and gross microbial contamination. longer storage.
OINTMENTS—Common signs of instability in ointments are a Informing and Educating the Patient—As a final step in meet-
change in consistency and excessive "bleeding" (i.e., separation of ing responsibility for the stability of drugs dispensed, the pharma-
excessive amounts of liquid) and formation of granules or gritti- cist is obligated to inform the patient regarding the proper storage
ness. conditions (for example, in a cool, dry place—not in the bath-
room), for both prescription and nonprescription products, and to
SUPPOSITORIES—Excessive softening is the major indication suggest a reasonable estimate of the time after which the medica-
of instability in suppositories, although some suppositories may tion should be discarded. Where beyond-use dates are applied, the
dry out and harden or shrivel. Evidence of oil stains on packaging pharmacist should emphasize to the patient that the dates are ap-
material should warn the pharmacist to examine individual suppo- plicable only when proper storage conditions are used. Patients
sitories more closely by removing any foil covering if necessary. should be encouraged to clean out their drug storage cabinets per-
As a general rule (although there are exceptions), suppositories iodically.
Pharmacopeia! Forum
REAGENTS, INDICATORS, REFERENCE TABLES

AND SOLUTIONS
Reagent Specifications
BRIEFING
Container Specifications for Capsules and Tablets, USP 25

page 2357, page 5856 of PF 24(2) [Mar.-Apr. 1998], page 8853
of PF 25(5) [Sept.-Oct. 1999], page 9176 of PF 25(6) [Nov.-Dec.
1999], page 250 of PF 26(1) [Jan.-Feb. 2000], page 836 of PF
26(3) [May-June 2000], page 1133 of P F 26(4) [July-Aug.
BRIEFING 2000], page 1383 of P F 26(5) [Sept.-Oct. 2000], page 1906 of
PF 27(1) [Jan.-Feb. 2001], page 2280 of PF 27(2) [Mar.-Apr.
FD&C Blue No. 1. It is proposed to add this new reagent which 2001], page 2597 of PF 27(3) [May-June 2001], page 2838 of
is used in the test for Defoaming activity in the monographs for PF 27(4) [July-Aug. 2001], page 3118 of PF 27(5) [Sept.-Oct.
Alumina, Magnesia, and Simethicone Oral Suspension; Alumina, 2001], and page 3374 of P F 27(6) [Nov.-Dec. 2001].
Magnesia, and Simethicone Tablets; Calcium Carbonate, Magne-
sia, and Simethicone Tablets; Magaldrate and Simethicone Oral (HDQ) RTS—30418-1; 33295-3; 33448-7; 34883-1
Suspension; Simethicone Oral Suspension; and Simethicone Ta-
blets.
(HDQ: M. Marques) RTS—35539-1

Containers for Dispensing Capsules and Tablets
The following table is provided as a reminder for the pharmacist
engaged in the typical dispensing situation who already is ac-
Add the following: quainted with the Packaging and storage requirements set forth
in the individual monographs. It lists the capsules and tablets that
A
FD&C Blue No. 1 (Brilliant Blue), C 37 H 34 N 2 O 9 S3 are official in the United States Pharmacopeia and indicates the re-
levant tight (T), well-closed (W), and light-resistant (LR) specifi-
j—792.86 [3844-45-9]—Use a suitable grade.A(;5p2(5 cations applicable to containers in which the drug that is
repackaged should be dispensed.
This table is not intended to replace, nor should it be interpreted
as replacing, the definitive requirements stated in the individual
monographs.
BRIEFING Container Specifications for Capsules and Tablets

Water, HPLC Grade, USP 25 page 2337. It is proposed to de- Container
lete this reagent. See briefing under Insulin Human, appearing else- Monograph Title Specification
where in this number of PF.
Add the following:
A
(HDQ: M. Marques) RTS—35362-1 GIucosamine Tablets T,
Add the following:
A
Glucosamine and Chondroitin Sulfate Tablets T, LRAUSP26
Delete the following: Add the following:
A
Water, HPLC Grade, II 3 » 18.02—Colorlooo liquid. A
Norgestrel and Ethinyl Estradiol Tablets W AUSP26
Absorption characteristics—Dotormino tho ultraviolet ab

florbaneoo in a 1 om ooll, uoing wator-aa tho blank. The maximum
aboorbanooa aro 0.005, 0.01, and 0.01 at 100 to 250 nm, 200 nm,
and 190 nm, roapoctivoly.
Residue on evaporation—Evaporate an aoouratoly moa

gurod volume on a gtoam bath to drynooa, and dry tho roaiduc at
105° for 1 hour: tho limit is 3 ppm.AUSP26
Pharmacopeial Forum
(HDQ) RTS—33936-1; 35100-02

BRIEFING
Description and Relative Solubility of USP and NF Articles,

USP 25 page 2363, page 3037 of PF18(2) [Mar.-Apr. 1992], page Add the following:
6597 of P F 19(6) [Nov.-Dec. 1993], page 1250 of P F 21(5)
[Sept-Oct. 1995], page 4533 of PF 23(4) [July-Aug 1997, page
4874 of P F 23(5) [Sept.-Oct. 1997], page 5310 of P F 23(6) [Nov.- A
Carboprost Tromethamine: White to off-white
Dec. 1997], page 7017 of P F 24(5) [Nov.-Sept.-Oct. 1998], page
7930 of P F 25(2) [Mar.-Apr. 1999], page 8282 of PF 25(3) [May- powder. Soluble in water.AUSP26
June 1999], page 8589 of P F 25(4) [July-Aug. 1999], page 8917
of PF 25(5) [Sept.-Oct. 1999], page 9254 of PF 25(6) [Nov.-Dec.
1999], page 250 of P F 26(1) [Jan.-Feb. 2000], page 504 of P F
26(2) [Mar.-Apr. 2000], page 837 of P F 26(3) [May-June Add the following:
P F 26(5) [Sept-Oct. 2000], page 1623 of PF 26(6) [Nov.-Dec.
2000], page 1907 of P F 27(1) [Jan.-Feb. 2001], page 2281 of A
Insulin Lispro: White or practically white crystals.
PF 27(2) [Mar.-Apr. 2001], page 2601 of P F 27(3) [May-June
2001], page 2839 of PF 27(4) [July-Aug. 2001], page 3120 of Soluble in solutions of dilute acids and alkalies.A[/iSW5
PF 27(5) [Sept-Oct. 2001], and page 3374 of PF 27(6) [Nov.-
Dec. 2001]
Pharmacopeia! Forum
Items from Earlier Numbers of PF that Have Not Yet Ap- Acetic Acid Otic Solution—See PF Vol. 27, No. 3, page 2501.
peared in a Supplement, and are Therefore Candidates for Acetohexamide—See PF Vol. 27, No. 3, page 2501.
Subsequent Supplements. Acetohexamide Tablets—See PF Vol. 27, No. 3, page 2501.
Acetohydroxamic Acid—See PF Vol. 27, No. 2, page 2115.
GENERAL NOTICES AND REQUIREMENTS Acetohydroxamic Acid Tablets—See PF Vol. 27, No. 3, page
2502.
"Official" and "Official Articles"—See PF Vol. 27, No. 4, page Acetylcholine Chloride—See PF Vol. 27, No. 3, page 2502.
2687. Acetylcholine Chloride for Ophthalmic Solution—See PF Vol. 27,
Preservation, Packaging, Storage, and Labeling—See PF Vol. 26, No. 3, page 2502.
No. 3, page 653. Acetylcysteine—See PF Vol. 27, No. 3, page 2503.
USP MONOGRAPHS Acetylcysteine Solution—See PF Vol. 27, No. 3, page 2503.
Acetylcysteine and Isoproterenol Hydrochloride Inhalation Solu-
Acebutolol Hydrochloride—See PF Vol. 27, No. 3, page 2493 . tion—See PF Vol. 27, No. 3, page 2503.
Acebutolol Hydrochloride Capsules—See PF Vol. 27, No. 1, page Acyclovir—See PF Vol. 27, No. 3, page 2503.
1743. Acyclovir Capsules—See PF Vol. 27, No. 3, page 2503.
Acepromazine Maleate—See PF Vol. 27, No. 3, page 2493. Acyclovir for Injection—See PF Vol. 27, No. 3, page 2503.
Acepromazine Maleate Injection—See PF Vol. 27, No. 3, page Acyclovir Ointment—See PF Vol. 27, No. 3, page 2504.
2494. Acyclovir Oral Suspension—See PF Vol. 27, No. 3, page 2504.
Acepromazine Maleate Tablets—See PF Vol. 27, No. 3, page 2494. Acyclovir Tablets—See PF Vol. 27, No. 3, page 2504.
Acetaminophen—See PF Vol. 27, No. 3, page 2494. Adenine—See PF Vol. 27, No. 3, page 2504.
Acetaminophen Capsules—See PF Vol. 27, No. 3, page 2494. Adenosine—See PF Vol. 27, No. 3, page 2504.
Acetaminophen Oral Solution—See PF Vol. 27, No. 3, page 2494. Adenosine Injection—See PF Vol. 27, No. 3, page 2504.
Acetaminophen for Effervescent Oral Solution—See PF Vol. 27, Medical Air—See PF Vol. 27, No. 5, page 2973.
No. 3, page 2495. Alanine—See PF Vol. 27, No. 5, page 2973.
Acetaminophen Oral Suspension—See PF Vol. 27, No. 3, page Albendazole—See PF Vol. 27, No. 3, page 2505.
2495. Albendazole Oral Suspension—See PF Vol. 27, No. 3, page 2505.
Acetaminophen Suppositories—See PF Vol. 27, No. 3, page 2495. Albendazole Tablets—See PF Vol. 27, No. 3, page 2505.
Acetaminophen Tablets—See PF Vol. 27, No. 3, page 2495. Albumin Encapsulated Octafluoropropane Microspheres for Injec-
Acetaminophen and Aspirin Tablets—See PF Vol. 27, No. 3, page tion—See PF Vol. 27, No. 4, page 2688.
2495. Albumin Human—See PF Vol. 27, No. 3, page 2505.
Acetaminophen, Aspirin, and Caffeine Tablets—See PF Vol. 27, Albuterol—See PF Vol. 27, No. 3, page 2505.
No. 3, page 2495. Albuterol Sulfate—See PF Vol. 27, No. 3, page 2506.
Acetaminophen and Caffeine Tablets—See PF Vol. 27, No. 3, page Albuterol Tablets—See PF Vol. 27, No. 3, page 2506.
2496. Alclometasone Dipropionate—See PF Vol. 27, No. 3, page 2506.
Capsules Containing at Least Three of the Following— Acetami- Alclometasone Dipropionate Cream—See PF Vol. 27, No. 3, page
nophen and Salts of Chlorpheniramine, Dextromethorphan, 2507.
and Pseudoephedrine—See PF Vol. 27, No. 3, page 2496. Alclometasone Dipropionate Ointment—See PF Vol. 27, No. 3,
Oral Powder Containing at Least Three of the Following—Aceta- page 2507.
minophen and Salts of Chlorpheniramine, Dextromethor- Alcohol—See PF Vol. 27, No. 3, page 2507.
phan, and Pseudoephedrine—See PF Vol. 27, No. 3, page Dehydrated Alcohol—See PF Vol. 27, No. 3, page 2507.
2496. Dehydrated Alcohol Injection—See PF Vol. 27, No. 3, page 2507.
Oral Solution Containing at Least Three of the Following—Acet- Rubbing Alcohol—See PF Vol. 27, No. 3, page 2507.
aminophen and Salts of Chlorpheniramine, Dextromethor- Alcohol in Dextrose Injection—See PF Vol. 27, No. 3, page 2508.
phan, and Pseudoephedrine—See PF Vol. 27, No. 6, page Alendronate Sodium—See PF Vol. 27, No. 4, page 2688.
3241. Alendronate Sodium Tablets—See PF Vol. 26, No. 2, page 398.
Tablets Containing at Least Three of the Following—Acetamino- Alfentanil Hydrochloride—See PF Vol. 27, No. 3, page 2508.
phen and Salts of Chlorpheniramine, Dextromethorphan, and Alfentanil Injection—See PF Vol. 27, No. 3, page 2508.
Pseudoephedrine—See PF Vol. 27, No. 3, page 2496. Allantoin—See PF Vol. 27, No. 5, page 2973.
Acetaminophen and Codeine Phosphate Capsules—See PF Vol. Allopurinol—See PF Vol. 27, No. 3, page 2508.
27, No. 3, page 2496. Allopurinol Tablets—See PF Vol. 27, No. 3, page 2508.
Acetaminophen and Codeine Phosphate Oral Solution—See PF Allyl Isothiocyanate—See PFVol. 27, No. 3, page 2509.
Vol. 27, No. 3, page 2497. Alprazolam—See PF Vol. 27, No. 3, page 2509.
Acetaminophen and Codeine Phosphate Oral Suspension— See PF Alprazolam Tablets—See PF Vol. 27, No. 3, page 2509.
Vol. 27, No. 3, page 2497. Alprostadil—See PF Vol. 27, No. 3, page 2509.
Acetaminophen and Codeine Phosphate Tablets—See PF Vol. 27, Alprostadil Injection—See PF Vol. 27, No. 3, page 2514.
No. 5, page 2973. Alteplase—See PF Vol. 27, No. 3, page 2514.
Acetaminophen, Dextromethorphan Hydrobromide, Doxylamine Alteplase for Injection—See PF Vol. 27, No. 3, page 2514.
Succinate, and Pseudoephedrine Hydrochloride Oral Solu- Altretamine—See PF Vol. 27, No. 3, page 2514.
tion—See PF Vol. 27, No. 3, page 2499. Altretamine Capsules—See PF Vol. 27, No. 3, page 2514.
Acetaminophen and Diphenhydramine Citrate Tablets—See PF Potassium Alum—See PF Vol. 27, No. 3, page 2515.
Vol. 27, No. 3, page 2499. Alumina and Magnesia Oral Suspension—See PF Vol. 27, No. 3,
Acetaminophen, Diphenhydramine Hydrochloride, and Pseudo- page 2515.
ephedrine Hydrochloride Tablets—See PF Vol. 27, No. 3, Alumina and Magnesia Tablets—See PF Vol. 27, No. 3, page
page 2499. 2515.
Acetaminophen and Pseudoephedrine Hydrochloride Tablets— Alumina, Magnesia, and Calcium Carbonate Oral Suspension—
See PF Vol. 27, No. 3, page 2500. See PF Vol. 27, No. 6, page 3241.
Acetazolamide—See PF Vol. 27, No. 3, page 2500. Alumina, Magnesia, and Calcium Carbonate Tablets—See PF Vol.
Acetazolamide for Injection—See PF Vol. 27, No. 3, page 2500. 27, No. 3, page 2515.
Acetazolamide Tablets—See PF Vol.27, No. 3, page 2501. Alumina, Magnesia, Calcium Carbonate, and Simethicone Ta-
Glacial Acetic Acid—See PF Vol. 27, No. 3, page 2501. blets—See PF Vol. 27, No. 6, page 3241.
Acetic Acid Irrigation—See PF Vol. 27, No. 3, page 2501.
Pharmacopeial Forum
Alumina and Magnesium Carbonate Oral Suspension—See PF Benazepril Hydrochloride—See PF Vol. 27, No. 6, page 3246.
Vol. 27, No. 6, page 3242. Benazepril Tablets—See PF Vol. 27, No. 6, page 3250.
Aluminum Phosphate Gel—See PF Vol. 27, No. 6, page 3242. Benzethonium Chloride Concentrate—See PF Vol. 27, No. 5, page
Aluminum Zirconium Octachlorohydrate—See PF Vol. 27, No. 4, 2979.
page 2691. Benzethonium Chloride Topical Solution—See PF Vol. 27, No. 5,
Aluminum Zirconium Octachlorohydrate Solution—See PF Vol. page 2979.
27, No. 4, page 2692. Betamethasone Valerate—See PF Vol. 27, No. 5, page 2980.
Aluminum Zirconium Octachlorohydrex Gly—See PF Vol. 27, Betaxolol Tablets—See PF Vol. 27, No. 4, page 2703.
No. 4, page 2692. Bethanechol Chloride Injection—See PF Vol. 27, No. 1, page
Aluminum Zirconium Octachlorohydrex Gly Solution—See PF 1754.
Vol. 27, No. 4, page 2693. Bethanechol Chloride Tablets—See PF Vol. 27, No. 1, page 1755.
Aluminum Zirconium Pentachlorohydrate—See PF Vol. 27, No. 4, Bismuth Citrate—See PF Vol. 27, No. 2, page 2118.
page 2693. Bismuth Subsalicylate Magma—See PF Vol. 26, No. 4, page 981.
Aluminum Zirconium Pentachlorohydrate Solution—See PF Vol. Bisoprolol Fumarate—See PF Vol. 26, No. 4, page 982.
27, No. 4, page 2694. Bisoprolol Fumarate Tablets—See PF Vol. 26, No. 4, page 983.
Aluminum Zirconium Pentachlorohydrex Gly—See PF Vol. 27, Bisoprolol Fumarate and Hydrochlorothiazide Tablets—See PF
No. 4, page 2695. Vol. 26, No. 4, page 985.
Aluminum Zirconium Pentachlorohydrex Gly Solution—See PF Brinzolamide—See PF Vol. 27, No. 4, page 2703.
Vol. 27, No. 4, page 2695. Brinzolamide Ophthalmic Suspension—See PF Vol. 27, No. 4,
Aluminum Zirconium Tetrachlorohydrate—See PF Vol. 27, No. 4, page 2705.
page 2696. Bromocriptine Mesylate—See PF Vol. 27, No. 4, page 2707.
Aluminum Zirconium Tetrachlorohydrate Solution—See PF Vol. Bromodiphenhydramine Hydrochloride and Codeine Phosphate
27, No. 4, page 2697. Syrup—See PF Vol. 27, No. 5, page 2980.
Aluminum Zirconium Tetrachlorohydrex Gly—See PF Vol. 27, Bumetanide—See PF Vol. 27, No. 5, page 2982.
No. 4, page 2697. Bupropion Hydrochloride—See PF Vol. 27, No. 4, page 2708.
Aluminum Zirconium Tetrachlorohydrex Gly Solution—See PF Bupropion Hydrochloride Tablets—See PF Vol. 27, No. 3, page
Vol. 27, No. 4, page 2698. 2521.
Aluminum Zirconium Trichlorohydrate—See PF Vol. 27, No. 4, Bupropion Hydrochloride Extended-Release Tablets—See PF Vol.
page 2698. 27, No. 5, page 2982.
Aluminum Zirconium Trichlorohydrate Solution—See PF Vol. 27, Butabarbital Sodium—See PF Vol. 27, No. 6, page 3253.
No. 4, page 2699. Butalbital, Aspirin, and Caffeine Capsules—See PF Vol. 27, No. 6,
Aluminum Zirconium Trichlorohydrex Gly—See PF Vol. 27, No. page 3254.
4, page 2700. Calcium Acetate—See PF Vol. 27, No. 6, page 3254.
Aluminum Zirconium Trichlorohydrex Gly Solution—See PF Vol. Calcium Acetate Tablets—See PF Vol. 27, No. 6, page 3254.
27, No. 4, page 2700. Calcium Ascorbate—See PF Vol. 27, No. 6, page 3255.
Amiloxate—See PF Vol. 27, No. 5, page 2975. Calcium Carbonate—See PF Vol. 27, No. 6, page 3255.
7-Aminodesacetoxycephalosporanic Acid—See PF Vol. 26, No. 6, Calcium Carbonate Oral Suspension—See PF Vol. 27, No. 6, page
page 1534. 3255.
6-Aminopenicillanic Acid—See PF Vol. 27, No. 1, page 1745. Calcium Carbonate Tablets—See PF Vol. 27, No. 6, page 3255.
Aminopentamide Sulfate—See PF Vol. 27, No. 1, page 1748. Calcium Carbonate and Magnesia Tablets—See PF Vol. 27, No. 6,
Aminopentamide Sulfate Injection—See PF Vol. 27, No. 1, page page 3256.
1748. Calcium and Magnesium Carbonates Tablets—See PF Vol. 27, No.
Aminopentamide Sulfate Tablets—See PF Vol. 27, No. 1, page 6, page 3256.
1748. Calcium Chloride—See PF Vol. 27, No. 6, page 3256.
Aminophylline Rectal Solution—See PF Vol. 27, No. 1, page Calcium Citrate—See PF Vol. 27, No. 6, page 3257.
1748. Calcium Glubionate Syrup—See PF Vol. 27, No. 6, page 3257.
Aminophylline Tablets—See PF Vol. 27, No. 4, page 2701. Calcium Gluceptate—See PF Vol. 27, No. 6, page 3257.
Ferric Ammonium Citrate—See PF Vol. 27, No. 2, page 2117. Calcium Gluceptate Injection—See PF Vol. 27, No. 6, page 3257.
Ferric Ammonium Citrate for Oral Solution—See PF Vol. 27, No. Calcium Gluconate—See PF Vol. 27, No. 6, page 3258.
2, page 2118. Calcium Gluconate Injection—See PF Vol. 27, No. 6, page 3258.
Amoxicillin and Clavulanate Potassium for Oral Suspension—See Calcium Gluconate Tablets—See PF Vol. 27, No. 6, page 3258.
PF Vol. 27, No. 4, page 2701. Calcium Hydroxide—See PF Vol. 27, No. 6, page 3258.
Amoxicillin and Clavulanate Potassium Tablets—See PF Vol. 27, Calcium Hydroxide Topical Solution—See PF Vol. 27, No. 6, page
No. 6, page 3243. 3259.
Amoxicillin for Oral Suspension—See PF Vol. 27, No. 6, page Calcium Lactate—See PF Vol. 27, No. 6, page 3259.
3243. Calcium Lactate Tablets—See PF Vol. 27, No. 6, page 3259.
Amphetamine Sulfate—See PF Vol. 27, No. 3, page 2518. Calcium Lactobionate—See PF Vol. 27, No. 6, page 3260.
Ampicillin Tablets—See PF Vol. 27, No. 2, page 2118. Calcium Levulinate—See PF Vol. 27, No. 6, page 3260.
Arginine Hydrochloride—See PF Vol. 27, No. 6, page 3244. Calcium Pantothenate—See PF Vol. 27, No. 6, page 3260.
Arginine Hydrochloride Injection—See PF Vol. 27, No. 6, page Calcium Pantothenate Tablets—See PF Vol. 27, No. 6, page 3260.
3244. Dibasic Calcium Phosphate—See PF Vol. 27, No. 6, page 3261.
Aspartic Acid—See PF Vol. 26, No. 5, page 1269. Calcium Polycarbophil—See PF Vol. 27, No. 6, page 3261.
Atenolol and Chlorthalidone Tablets—See PF Vol. 27, No. 6, page Calcium Saccharate—See PF Vol. 27, No. 6, page 3261.
3244. Carbamazepine Extended-Release Tablets—See PF Vol. 27, No. 6,
Atovaquone—See PF Vol. 26, No. 1, page 134. page 3261.
Atovaquone Oral Suspension—See PF Vol. 26, No. 1, page 137. Carbamazepine Oral Suspension—See PF Vol. 27, No. 4, page
Atracurium Besylate—See PF Vol. 27, No. 5, page 2975. 2711.
Atracurium Besylate Injection—See PF Vol. 26, No. 2, page 403. Carboprost Tromethamine—See PF Vol. 27, No. 5, page 2988.
Azithromycin—See PF Vol. 27, No. 6, page 3245. Carboprost Tromethamine Injection—See PF Vol. 27, No. 5, page
Barium Sulfate Paste—See PF Vol. 25, No. 4, page 8479. 2990.
Barium Sulfate for Suspension—See PF Vol. 27, No. 6, page 3246. Urea C 13—See PF Vol. 26, No. 2, page 410.
Pharmacopeial Forum
Urea C 13 for Oral Solution—See PF Vol. 26, No. 2, page 412. Diatrizoate Meglumine and Diatrizoate Sodium Solution—See PF
Urea C 14 Capsules—See PF Vol. 27, No. 2, page 2126. Vol. 27, No. 6, page 3273.
Cefaclor—See PF Vol. 27, No. 3, page 2523. Diethylcarbamazine Citrate—See PF Vol. 27, No. 1, page 1775.
Cefaclor Extended-Release Tablets—See PF Vol. 27, No. 2, page Diethylcarbamazine Citrate Tablets—See PF Vol. 27, No. 1, page
2126. 1777.
Cefazolin Ophthalmic Solution—See PF Vol. 27, No. 6, page Diflorasone Diacetate—See PF Vol. 27, No. 5, page 3003.
3262. Digoxin—See PF Vol. 27, No. 2, page 2138.
Cefepime Hydrochloride—See PF Vol. 27, No. 5, page 2991. Digoxin Tablets—See PF Vol. 27, No. 3, page 2537.
Cefepime for Injection—See PF Vol. 27, No. 5, page 2994. Dihydroergotamine Mesylate—See PF Vol. 24, No. 1, page 5562.
Cefixime—See PF Vol. 27, No. 4, page 2711. Dihydroergotamine Mesylate Injection—See PF Vol. 24, No. 1,
Cefpodoxime Proxetil—See PF Vol. 24, No. 2, page 5853. page 5564.
Cefpodoxime Proxetil for Oral Suspension—See PF Vol. 24, No. Diloxanide Furoate—See PF Vol. 27, No. 1, page 1778.
2, page 5855. Diltiazem Hydrochloride Extended-Release Capsules—See PF
Cefpodoxime Proxetil Tablets—See PF Vol. 24, No. 2, page 5856. Vol. 27, No. 3, page 2535.
Cefuroxime Axetil Tablets—See PF Vol. 27, No. 5, page 2996. Dinoprost Tromethamine—See PF Vol. 27, No. 3, page 2537.
Cellulose Sodium Phosphate—See PF Vol. 27, No. 6, page 3263. Dinoprostone—See PF Vol. 27, No. 6, page 3273.
Chlordiazepoxide and Amitriptyline Hydrochloride Tablets—See Divalproex Sodium Delayed-Release Tablets—See PF Vol. 27,
PF Vol. 27, No. 6, page 3263. No. l,page 1781.
Chlordiazepoxide Hydrochloride and Clidinium Bromide Cap- Dobutamine in Dextrose Injection—See PF Vol. 27, No. 2, page
sules—See PF Vol. 27, No. 4, page 2712. 2140.
Chlorhexidine Gluconate Oral Rinse—See PF Vol. 27, No. 1, page Dolasetron Mesylate—See PF Vol. 26, No. 4, page 1017.
1765. Dolasetron Mesylate Injection—See PF Vol. 25, No. 4, page 8493.
Chlorhexidine Gluconate Solution—See PF Vol. 27, No. 5, page Dolasetron Mesylate Tablets—See PF Vol. 26, No. 1, page 145.
2996. Doxazosin Mesylate Tablets—See PF Vol. 27, No. 6, page 3275.
Chloroxylenol—See PF Vol. 27, No. 6, page 3264. Doxepin Hydrochloride—See PF Vol. 27, No. 4, page 2730.
Chlorpheniramine Maleate Tablets—See PF Vol. 27, No. 6, page Doxycycline Hyclate Capsules—See PF Vol. 27, No. 4, page 2731.
3265. Edetate Disodium—See PF Vol. 27, No. 6, page 3277.
Chlorpheniramine Maleate and Pseudoephedrine Hydrochloride Multiple Electrolytes Injection Type 1—See PF Vol. 27, No. 4,
Extended-Release Capsules—See PF Vol. 27, No. 3, page page 2731.
2525. Emedastine Difumarate—See PF Vol. 27, No. 1, page 1782.
Choline Bitartrate—See PF Vol. 27, No. 4, page 2715. Emedastine Ophthalmic Solution—See PF Vol. 27, No. 1, page
Choline Chloride—See PF Vol. 27, No. 4, page 2717. 1782.
Sodium Chromate Cr 51 Injection—See PF Vol. 27, No. 3, page Enalapril Maleate Tablets—See PF Vol. 27, No. 3, page 2541.
2526. Enalapril Maleate and Hydrochlorothiazide Tablets—See PF Vol.
Cinoxate—See PF Vol. 27, No. 3, page 2526. 27, No. 3, page 2541.
Cinoxate Lotion—See PF Vol. 27, No. 3, page 2527. Erythromycin Estolate Oral Suspension—See PF Vol. 27, No. 4,
Ciprofloxacin Ophthalmic Ointment—See PF Vol. 27, No. 6, page page 2731.
3266. Erythromycin Ointment—See PF Vol. 27, No. 6, page 3278.
Citric Acid—See PF Vol. 25, No. 3, page 8114. Estradiol—See PF Vol. 27, No. 2, page 2141.
Clidinium Bromide—See PF Vol. 27, No. 4, page 2720. Estropipate Tablets—See PF Vol. 27, No. 6, page 3280.
Clindamycin Hydrochloride Capsules—See PF Vol. 27, No. 4, Ethacrynate Sodium for Injection—See PF Vol. 27, No. 4, page
page 2720. 2731.
Clindamycin Phosphate—See PF Vol. 27, No. 6, page 3267. Ethosuximide Capsules—See PF Vol. 27, No. 4, page 2732.
Clomiphene Citrate—See PF Vol. 27, No. 5, page 2997. Etodolac Capsules—See PF Vol. 27, No. 2, page 2143.
Clomipramine Hydrochloride—See PF Vol. 27, No. 3, page 2529. Etoposide—See PF Vol. 27, No. 5, page 3004.
Clomipramine Hydrochloride Capsules—See PF Vol. 27, No. 3, Etoposide Capsules—See PF Vol. 27, No. 5, page 3004.
page 2531. Felodipine—See PF Vol. 27, No. 2, page 2144.
Clonazepam—See PF Vol. 25, No. 3, page 8120. Felodipine Extended-Release Tablets—See PF Vol. 27, No. 1, page
Clonidine Transdermal System—See PF Vol. 27, No. 1, page 1766. 1782.
Clozapine—See PF Vol. 25, No. 6, page 9129. Fenoldopam Mesylate Injection—See PF Vol. 27, No. 1, page
Clozapine Tablets—See PF Vol. 25, No. 6, page 9130. 1785.
Cocaine and Tetracaine Hydrochlorides and Epinephrine Topical Fenoprofen Calcium—See PF Vol. 27, No. 6, page 3280.
Solution—See PF Vol. 27, No. 6, page 3269. Ferric Subsulfate Solution—See PF Vol. 27, No. 3, page 2543.
Cromolyn Sodium Inhalation Powder—See PF Vol. 27, No. 1, Ferric Sulfate—See PF Vol. 27, No. 2, page 2144.
page 1769. Ferumoxides Injection—See PF Vol. 27, No. 3, page 2543.
Cycloserine—See PF Vol. 27, No. 5, page 2998. Ferumoxsil Oral Suspension—See PF Vol. 27, No. 6, page 3281.
Cycloserine Capsules—See PF Vol. 27, No. 5, page 2998. Finasteride—See PF Vol. 27, No. 2, page 2144.
Cyclosporine Capsules—See PF Vol. 27, No. 4, page 2721. Finasteride Tablets—See PF Vol. 27, No. 2, page 2144.
Cyclosporine Oral Solution—See PF Vol. 27, No. 4, page 2727. Fluorodopa F 18 Injection—See PF Vol. 26, No. 1, page 155.
Cysteine Hydrochloride—See PF Vol. 27, No. 4, page 2728. Fluoxetine Capsules—See PF Vol. 27, No. 2, page 2150.
Danazol—See PF Vol. 27, No. 6, page 3269. Fluoxetine Tablets—See PF Vol. 27, No. 6, page 3283.
Desogestrel—See PF Vol. 27, No. 4, page 2728. Flurandrenolide Cream—See PF Vol. 27, No. 2, page 2152.
Desogestrel and Ethinyl Estradiol Tablets—See PF Vol. 27, No. 6, Flurandrenolide Ointment—See PF Vol. 27, No. 2, page 2154.
page 3270. Fosphenytoin Sodium—See PF Vol. 27, No. 6, page 3285.
Dextran 40—See PF Vol. 27, No. 3, page 2533. Fosphenytoin Sodium Injection—See PF Vol. 27, No. 6, page
Dextran 70—See PF Vol. 27, No. 3, page 2533. 3287.
Dextroamphetamine Sulfate—See PF Vol. 27, No. 3, page 2533. Furosemide Oral Solution—See PF Vol. 27, No. 2, page 2159.
Dextroamphetamine Sulfate Tablets—See PF Vol. 27, No. 5, page Gabapentin—See PF Vol. 27, No. 5, page 3004.
3003. Gabapentin Capsules—See PF Vol. 27, No. 2, page 2160.
Dextrose and Sodium Chloride Injection—See PF Vol. 27, No. 3, Gadodiamide—See PF Vol. 27, No. 2, page 2163.
page 2534. Gadodiamide Injection—See PF Vol. 27, No. 2, page 2163.
Pharmacopeial Forum
Gadoteridol—See PF Vol. 27, No. 2, page 2163. Levodopa—See PF Vol. 27, No. 4, page 2753.
Gadoteridol Injection—See PF Vol. 27, No. 2, page 2164. Levodopa Capsules—See PF Vol. 27, No. 4, page 2754.
Ganciclovir for Injection—See PF Vol. 27, No. 5, page 3009. Levodopa Tablets—See PF Vol. 27, No. 4, page 2754.
Gemfibrozil—See PF Vol. 27, No. 6, page 3289. Levonorgestrel—See PF Vol. 27, No. 3, page 2565.
Glyburide—See PF Vol. 27, No. 4, page 2735. Levothyroxine Sodium Oral Powder—See PF Vol. 27, No. 6, page
Glycerin—See PF Vol. 27, No. 5, page 3010. 3313.
Gonadorelin Hydrochloride—See PF Vol. 27, No. 3, page 2552. Lorazepam Oral Concentrate—See PF Vol. 27, No. 4, page 2754.
Graftskin—See PF Vol. 27, No. 6, page 3290. Lorazepam Tablets—See PF Vol. 27, No. 4, page 2756.
Guaifenesin—See PF Vol. 27, No. 4, page 2735. Lovastatin—See PF Vol. 27, No. 3, page 2566.
Guanfacine Tablets—See PF Vol. 27, No. 4, page 2736. Mafenide Acetate for Topical Solution—See PF Vol. 27, No. 1
Haloperidol—See PF Vol. 27, No. 6, page 3300. page 1800.
Heparin Sodium—See PF Vol. 25, No. 6, page 9153. Magnesium Carbonate, Citric Acid, and Potassium Citrate for Oral
Hydralazine Hydrochloride Oral Solution—See PF Vol. 27, No. 6, Solution—See PF Vol. 26, No. 4, page 1050.
page 3301. Magnesium Sulfate—See PF Vol. 27, No. 4, page 2758.
Hydrochlorothiazide—See PF Vol. 27, No. 4, page 2736. Manganese Chloride for Oral Solution—See PF Vol. 27, No. 2,
Hydrochlorothiazide Tablets—See PF Vol. 27, No. 4, page 2739. page 2171.
Hydrocodone Bitartrate—See PF Vol. 27, No. 5, page 3012. Mannitol—See PF Vol. 27, No. 5, page 3017.
Hydrocodone Bitartrate and Acetaminophen Tablets—See PF Vol. Mannitol Injection—See PF Vol. 27, No. 5, page 3020.
27, No. 6, page 3301. Medroxyprogesterone Acetate—See PF Vol. 27, No. 2, page 2172.
Hydrocortisone Acetate Ophthalmic Suspension—See PF Vol. 27, Medroxyprogesterone Acetate Tablets—See PF Vol. 27, No. 1
No. 6, page 3302. page 1800.
Hydrocortisone Valerate Ointment—See PF Vol. 27, No. 2, page Megestrol Acetate Oral Suspension—See PF Vol. 27, No. 6, page
2165. 3314.
Hydromorphone Hydrochloride Tablets—See PF Vol. 26, No. 5, Menthyl Anthranilate—See PF Vol. 27, No. 5, page 3021.
page 1291. Mephenytoin—See PF Vol. 27, No. 2, page 2174.
Hydroxyzine Hydrochloride Tablets—See PF Vol. 27, No. 6, page Mephenytoin Tablets—See PF Vol. 27, No. 2, page 2174.
3302. Mephobarbital Tablets—See PF Vol. 26, No. 1, page 178.
Ibuprofen—See PF Vol. 27, No. 4, page 2740. Meradimate—See PF Vol. 27, No. 5, page 3021.
Idarubicin Hydrochloride—See PF Vol. 27, No. 6, page 3302. Meropenem—See PF Vol. 27, No. 1, page 1801.
Indinavir Sulfate—See PF Vol. 27, No. 2, page 2165. Meropenem for Injection—See PF Vol. 27, No. 1, page 1801.
Insulin—See PF Vol. 27, No. 3, page 2553. Mesalamine Rectal Suspension—See PF Vol. 27, No. 6, page
Insulin Injection—See PF Vol. 27, No. 2, page 2168. 3315.
Isophane Insulin Suspension—See PF Vol. 27, No. 2, page 2169. Methohexital Sodium for Injection—See PF Vol. 27, No. 1, page
Isophane Insulin Human Suspension—See PF Vol. 27, No. 2, page 1801.
2169. Methylprednisolone Acetate for Rectal Suspension—See PF Vol.
Insulin Zinc Suspension—See PF Vol. 27, No. 2, page 2169. 27, No. 5, page 3022.
Extended Insulin Zinc Suspension—See PF Vol. 27, No. 2, page Methyltestosterone—See PF Vol. 27, No. 3, page 2568.
2169. Metoprolol Succinate—See PF Vol. 27, No. 6, page 3316.
Prompt Insulin Zinc Suspension—See PF Vol. 27, No. 2, page Metoprolol Succinate Extended-Release Tablets—See PF Vol. 27,
2170. No. l,page 1803.
Insulin Human Zinc Suspension—See PF Vol. 27, No. 2, page Miconazole Nitrate—See PF Vol. 25, No. 2, page 7838.
2170. Miconazole Nitrate Cream—See PF Vol. 26, No. 5, page 1302.
Extended Insulin Human Zinc Suspension—See PF Vol. 27, No. 2, Milrinone—See PF Vol. 27, No. 2, page 2175.
page 2170. Minocycline Hydrochloride—See PF Vol. 27, No. 5, page 3022.
Inulin—See PF Vol. 27, No. 6, page 3303. Misoprostol—See PF Vol. 26, No. 5, page 1304.
Iodixanol—See PF Vol. 27, No. 6, page 3303. Misoprostol Dispersion—See PF Vol. 26, No. 5, page 1308.
Iodixanol Injection—See PF Vol. 27, No. 6, page 3311. Misoprostol Tablets—See PF Vol. 26, No. 5, page 1310.
Iodoform—See PF Vol. 27, No. 2, page 2170. Morphine Sulfate Suppositories—See PF Vol. 27, No. 6, page
Iohexol—See PF Vol. 27, No. 4, page 2748. 3318.
Iopromide Injection—See PF Vol. 27, No. 2, page 2170. Myrrh—See PF Vol. 27, No. 2, page 2176.
Ioxaglic Acid—See PF Vol. 27, No. 6, page 3312. Nabumetone—See PF Vol. 27, No. 5, page 3024.
Iron Sucrose Injection—See PF Vol. 27, No. 5, page 3012. Nabumetone Tablets—See PF Vol. 26, No. 5, page 1315.
Isoamyl Methoxycinnamate—See PF Vol. 27, No. 5, page 3017. Neomycin Sulfate, Isoflupredone Acetate, and Tetracaine Hydro-
Isoflupredone Acetate—See PF Vol. 27, No. 4, page 2749. chloride Ointment—See PF Vol. 27, No. 4, page 2758.
Isoflupredone Acetate Injectable Suspension—See PF Vol. 27, No. Neomycin Sulfate, Isoflupredone Acetate, and Tetracaine Hydro-
4, page 2751. chloride Topical Powder—See PF Vol. 27, No. 4, page 2760.
Isoflurane—See PF Vol. 26, No. 1, pagel72. Nifedipine—See PF Vol. 27, No. 3, page 2569.
Diluted Isosorbide Dinitrate—See PF Vol. 27, No. 3, page 2564. Nifedipine Capsules—See PF Vol. 27, No. 3, page 2570.
Isotretinoin Capsules—See PF Vol. 27, No. 1, page 1790. Nifedipine Extended-Release Tablets—See PF Vol. 27, No. 3, page
Ivermectin—See PF Vol. 27, No. 1, page 1790. 2570.
Kanamycin Sulfate—See PF Vol. 27, No. 6, page 3312. Nizatidine—See PF Vol. 27, No. 6, page 3319.
Ketamine Hydrochloride—See PF Vol. 27, No. 4, page 2752. Norethindrone Acetate—See PF Vol. 27, No. 4, page 2762.
Ketoconazole Oral Suspension—See PF Vol. 27, No. 6, page 3313. Norethindrone Acetate and Ethinyl Estradiol Tablets—See PF Vol.
Ketorolac Tromethamine—See PF Vol. 27, No. 6, page 3313. • 27, No. 6, page 3320.
Lansoprazole—See PF Vol. 26, No. 5, page 1293. Octisalate—See PF Vol. 27, No. 5, page 3027.
Lansoprazole Delayed-Release Capsules—See PF Vol. 26, No. 5, Octocrylene—See PF Vol. 27, No. 5, page 3028.
page 1295. Octyl Salicylate—See PF Vol. 27, No. 5, page 3028.
Lamivudine—See PF Vol. 27, No. 1, page 1796. Ofloxacin—See PF Vol. 27, No. 4, page 2763.
Letrozole—See PF Vol. 27, No. 6, page 3313. Oxybenzone—See PF Vol. 27, No. 3, page 2572.
Letrozole Tablets—See PF Vol. 27, No. 1, page 1800. Oxybutynin Chloride—See PF Vol. 26, No. 6, page 1561.
Levocarnitine—See PF Vol. 27, No. 3, page 2565.
Pharmacopeial Forum
Oxycodone Hydrochloride Oral Solution—See PF Vol. 27, No. 4, Saquinavir Capsules—See PF Vol. 27, No. 2, page 2197.
page 2763. Saquinavir Mesylate—See PF Vol. 27, No. 2, page 2196.
Oxycodone and Acetaminophen Capsules—See PF Vol. 27, No. 6, Saw Palmetto Capsules—See PF Vol. 26, No. 6, page 1571.
page 3320. Saw Palmetto Extract—See PF Vol. 26, No. 6, page 1567.
Water O 15 Injection—See PF Vol..27, No. 2, page 2182. Scopolamine Hydrobromide Injection—See PF Vol. 27, No. 6,
Paclitaxel—See PF Vol. 27, No. 2, page 2183. page 3328.
Paclitaxel Injection—See PF Vol. 27, No. 3, page 2572. Sevoflurane—See PF Vol. 27, No. 3, page 2577.
Paroxetine Hydrochloride—See PF Vol. 27, No. 4, page 2763. Shark Liver Oil—See PF Vol. 26, No. 6, page 1643.
Paroxetine Tablets—See PF Vol. 27, No. 5, page 3029. Sodium Acetate—See PF Vol. 27, No. 6, page 3328.
Penicillamine Capsules—See PF Vol. 27, No. 5, page 3031. Sodium Butyrate—See PF Vol. 27, No. 2, page 2197.
Penicillin G Sodium for Injection—See PF Vol. 27, No. 3, page Sodium Chloride—See PF Vol. 27, No. 4, page 2777.
2574. Sodium Chloride Injection—See PF Vol. 27, No. 4, page 2777.
Pentazocine and Naloxone Hydrochlorides Tablets—See PF Vol. Sodium Chloride Ophthalmic Ointment—See PF Vol. 27, No. 6,
27, No. 6, page 3321. page 3329.
Pentoxifylline—See PF Vol. 26, No. 2, page 432. Sodium Hypochlorite Topical Solution—See PF Vol. 27, No. 6,
Pentoxifylline Extended-Release Tablets—See PF Vol. 27, No. 2, page 3329.
page 2188. Sodium Phosphates Rectal Solution—See PF Vol. 27, No. 1, page
Perflutren Protein-Type A Microspheres for Injection—See PF 1816.
Vol. 27, No. 4, page 2769. Sodium Sulfide—See PF Vol. 27, No. 1, page 1816.
Pergolide Mesylate—See PF Vol. 26, No. 4, page 1060. Sodium Sulfide Topical Gel—See PF Vol. 27, No. 1, page 1816.
Pergolide Tablets—See PF Vol. 25, No. 2, page 7845. Somatropin—See PF Vol. 25, No. 4, page 8540.
Phenylpropanolamine Hydrochloride—See PF Vol. 26, No. 6, Somatropin for Injection—See PF Vol. 25, No. 4, page 8551.
page 1562. Sorbitol Solution—See PF Vol. 27, No. 6, page 3329.
Phenyltoloxamine Dihydrogen Citrate—See PF Vol. 27, No. 6, Sotalol Hydrochloride—See PF Vol. 26, No. 4, page 1068.
page 3321. Sotalol Hydrochloride Tablets—See PF Vol. 27, No. 1, page 1816.
Phenytoin Sodium—See PF Vol. 27, No. 5, page 3031. Spironolactone—See PF Vol. 27, No. 3, page 2581.
Extended Phenytoin Sodium Capsules—See PF Vol. 27, No. 5, Stanozolol Tablets—See PF Vol. 27, No. 6, page 3331.
page 3034. Sulfadimethoxine— See PF Vol. 27, No. 4, page 2778.
Chromic Phosphate P 32 Suspension—See PF Vol. 27, No. 6, page Sulfadimethoxine Oral Suspension—See PF Vol. 27, No. 2, page
3323. 2198.
Polymyxin B Sulfate and Trimethoprim Ophthalmic Solution— Sulfadimethoxine Sodium—See PF Vol. 27, No. 4, page 2778.
See PF Vol. 27, No. 2, page 2196. Sulfadimethoxine Soluble Powder—See PF Vol. 27, No. 2, page
Potassium Chloride—See PF Vol. 27, No. 4, page 2773. 2198.
Potassium Chloride in Dextrose Injection—See PF Vol. 27, No. 4, Sulfadimethoxine Tablets—See PF Vol. 27, No. 2, page 2198.
page 2774. Sulindac—See PF Vol. 25, No. 5, page 8879.
Potassium Chloride in Dextrose and Sodium Chloride Injection— Sulindac Tablets—See PF Vol. 25, No. 5, page 8880.
See PF Vol. 27, No. 4, page 2774. Sulisobenzone—See PF Vol. 27, No. 5, page 3044.
Potassium Chloride in Sodium Chloride Injection—See PF Vol. Sunflower Oil—See PF Vol. 27, No. 4, page 2779.
27, No. 4, page 2774. Sutilains—See PF Vol. 27, No. 2, page 2199.
Potassium Chloride Extended-Release Tablets—See PF Vol. 27, Sutilains Ointment—See PF Vol. 27, No. 2, page 2201.
No. 3, page 2575. Tacrine Capsules—See PF Vol. 26, No. 2, page 444.
Povidone—See PF Vol. 22, No. 6, page 3163. Tacrine Hydrochloride—See PF Vol. 26, No. 5, page 1337.
Prednisolone—See PF Vol. 27, No. 5, page 3036. Tamoxifen Citrate Tablets—See PF Vol. 27, No. 4, page 2779.
Prednisolone Acetate—See PF Vol. 27, No. 5, page 3037. Taurine—See PF Vol. 27, No. 6, page 3331.
Primidone—See PF Vol. 27, No. 4, page 2774. Technetium Tc 99m Arcitumomab Injection—See PF Vol. 27, No.
Progesterone Injection—See PF Vol. 27, No. 5, page 3038. 2, page 2202.
Progesterone Vaginal Suppositories—See PF Vol. 27, No. 6, page Technetium Tc 99m Depreotide Injection—See PF Vol. 27, No. 3,
3323. page 2583.
Propofol—See PF Vol. 27, No. 4, page 2774. Terazosin Hydrochloride—See PF Vol. 27, No. 2, page 2202.
Pseudoephedrine Hydrochloride Extended-Release Capsules—See Terbutaline Sulfate—See PF Vol. 26, No. 3, page 752.
PF Vol. 27, No. 6, page 3323. Terbutaline Sulfate Inhalation Aerosol—See PF Vol. 26, No. 3,
Pseudoephedrine Hydrochloride Extended-Release Tablets—See page 753.
PF Vol. 27, No. 6, page 3325. Terbutaline Sulfate Injection—See PF Vol. 26, No. 3, page 756.
Pseudoephedrine Hydrochloride, Carbinoxamine Maleate, and Terbutaline Sulfate Tablets—See PF Vol. 26, No. 3, page 757.
Dextromethorphan Hydrobromide Oral Solution—See PF Testolactone Tablets—See PF Vol. 27, No. 6, page 3332.
Vol. 27, No. 2, page 2196. Tetracycline Hydrochloride Oral Suspension—See PF Vol. 27, No.
Pyrantel Pamoate—See PF Vol. 27, No. 3, page 2576. 6, page 3333.
Pyrantel Pamoate Oral Suspension—See PF Vol. 27, No. 6, page Thalidomide—See PF Vol. 27, No. 1, page 1818.
3325. Thalidomide Capsules—See PF Vol. 27, No. 1, page 1818.
Pyrethrum Extract—See PF Vol. 26, No. 1, page 202. Theophylline Oral Solution—See PF Vol. 27, No. 5, page 3044.
Ramipril—See PF Vol. 27, No. 5, page 3039. Theophylline Syrup—See PF Vol. 27, No. 1, page 1819.
Repaglinide—See PF Vol. 27, No. 6, page 3325. Tiagabine Hydrochloride—See PF Vol. 26, No. 4, page 1076.
Repaglinide Tablets—See PF Vol. 26, No. 5, page 1333. Tinidazole—See PF Vol. 27, No. 1, page 1820.
Ribavirin—See PF Vol. 27, No. 3, page 2577. Tobramycin Inhalation Solution—See PF Vol. 26, No. 5, page
Rifampin Oral Suspension—See PF Vol. 27, No. 6, page 3327. 1340.
Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Hydrochlor- Tolazamide—See PF Vol. 27, No. 6, page 3333.
ide Tablets—See PF Vol. 27, No. 5, page 3041. Tolnaftate Topical Aerosol—See PF Vol. 27, No. 1, page 1821.
Rimantadine Hydrochloride—See PF Vol. 24, No. 2, page 5927. Torsemide—See PF Vol. 27, No. 1, page 1821.
Rimantadine Hydrochloride Tablets—See PF Vol. 24, No. 2, page Triamterene and Hydrochlorothiazide Tablets—See PF Vol. 27,
5929. No. 3, page 2584.
Ringer's Injection—See PF Vol. 27, No. 4, page 2777. Trichlorfon—See PF Vol. 26, No. 6, page 1576.
Pharmacopeial Forum
Tripelennamine Hydrochloride Injection—See PF Vol. 27, No. 1, (191) Identification Tests—General—See PF Vol. 27, No. 6, page
page 1824. 3349.
Trolamine Salicylate—See PF Vol. 27, No. 4, page 2780. (281) Residue on Ignition—See PF Vol. 27, No. 2, page 2269.
Crystallized Trypsin for Inhalation Solution—See PF Vol. 27, No. OTHER TESTS AND ASSAYS
l,page 1824.
Tylosin—See PF Vol. 27, No. 4, page 2780. (381) Elastomeric Closures for Injections—See PF Vol. 26, No. 4,
Urofollitropin—See PF Vol. 27, No. 2, page 2207. page 1108.
Urofollitropin for Injection—See PF Vol. 27, No. 5, page 3045. (561) Articles of Botanical Origin—See PF Vol. 27, No. 5, page
Valrubicin—See PF Vol. 26, No. 5, page 1346. 3072.
Valrubicin Intravesical Solution—See PF Vol. 26, No. 1, page 211. (581) Vitamin D Assay—See PF Vol. 26, No. 4, page 1111.
Valsartan Capsules—See PF Vol. 27, No. 5, page 3050. Physical Tests and Determinations
Valsartan and Hydrochlorothiazide Tablets—See PF Vol. 27, No.
4, page 2780. (621J Chromatography—See PF Vol. 27, No. 6, page 3352.
Vancomycin—See PF Vol. 27, No. 4, page 2783. (625) Clarity and Degree of Opalescence of Liquids—See PF Vol.
Vancomycin Hydrochloride—See PF Vol. 27, No. 4, page 2784. 26, No. 6, page 1616.
Vancomycin Injection—See PF Vol. 27, No. 4, page 2784. (627) Degree of Color of Liquids—See PF Vol. 26, No. 6, page
Vancomycin for Injection—See PF Vol. 27, No. 4, page 2785. 1617.
Vancomycin Hydrochloride for Injection—See PF Vol. 27, No. 4, 643 Total Organic Carbon—See PF Vol. 27, No. 6, page 3356.
page 2786. 645 Water Conductivity—See PF Vol. 27, No. 5, page 3076.
Sterile Vancomycin Hydrochloride—See PF Vol. 27, No. 4, page 661 Containers—See PF Vol. 27, No. 4, page 2817.
2786. 671 Containers—Permeation—See PF Vol. 27, No. 6, page
Vecuronium Bromide—See PF Vol. 27, No. 5, page 3053. 3357.
Verteporfin—See PF Vol. 27, No. 3, page 2585. 724 Drug Release—See PF Vol. 27, No. 6, page 3358.
Verteporfin for Injection—See PF Vol. 27, No. 3, page 2587. 776 Optical Microscopy—See PF Vol. 26, No. 1, page 229.
Vinorelbine Tartrate—See PF Vol. 27, No. 5, page 3054. 781 Optical Rotation—See PF Vol. 27, No. 4, page 2819.
Sterile Water for Injection—See PF Vol. 27, No. 4, page 2787. ' 795) Pharmacy Compounding—See PF Vol. 27, No. 5, page
Purified Water—See PF Vol. 27, No. 5, page 3057. 3078.
Xylazine—See PF Vol. 27, No. 5, page 3057. (905) Uniformity of Dosage Units—See PF Vol. 27, No. 3, page
Yohimbine Hydrochloride—See PF Vol. 27, No. 2, page 2218. 2595.
Yohimbine Injection—See PF Vol. 27, No. 2, page 2219. General Information
Zidovudine Capsules—See PF Vol. 27, No. 5, page 3058.
Zileuton—See PF Vol. 27, No. 6, page 3335. (1010) Analytical Data—Interpretation and Treatment—See PF
Vol. 27, No. 5, page 3086.
EXCIPIENTS (1035) Biological Indicators for Sterilization—See PF Vol. 27, No.
USP and NF Excipients, Listed by Category—See PF Vol. 26, No. 4, page 2820.
2, page 447. (1046) Gene and Cell Therapy Products—See PF Vol. 27, No. 1,
page 1835.
(1047) Biotechnology-Derived Articles—Tests—See PF Vol. 27,
GENERAL CHAPTERS No. 2, page 2277.
(1116) Microbiological Evaluation of Clean Rooms and Other
General Tests and Assays Controlled Environments—See PF Vol. 25, No. 3, page 8264.
General Requirements for Tests and Assays (1118) Monitoring Devices—Time, Temperature, and Humidity—
See PF Vol. 26, No. 2, page 481.
1} Injections—See PF Vol. 27, No. 5, page 3068. (1119) Near-Infrared Spectrophotometry—See PF Vol. 27, No. 5,
11) USP Reference Standards—See PF Vol. 22, No. 6, page 3212; page 3101.
PF Vol. 23, No. 4, page 4500; PF Vol. 24, No. 2, page 5965; (1141) Packaging, Storage, and Distribution of Pharmacopeial Ar-
PF Vol. 24, No. 5, page 6925; PF Vol. 25, No. 2, page 7876; ticles—See PF Vol. 26, No. 2, page 493.
PF Vol. 25, No. 3, page 8222; PF Vol. 25, No. 4, page 8561; (1146) Packaging Practice—Repackaging a Single Solid Oral
PF Vol. 25, No. 5, page 8893; PF Vol. 25, No. 6, page 9222; Drug Product into a Unit-Dose Container—See PF Vol. 27,
PF Vol. 26, No. 1, page 218; PF Vol. 26, No. 2, page 471; PF No. 4, page 2827.
Vol. 26, No. 3, page 793; PF Vol. 26, No. 4, page 1101; PF (1151) Pharmaceutical Dosage Forms—See PF Vol. 26, No. 2,
Vol. 26, No. 5, page 1369; PF Vol. 26, No. 6, page 1606; PF page 499.
Vol. 27, No. 1, page 1832; PF Vol. 27, No. 2, page 2268; PF (1186) Shipping and Storage of Labile Preparations—See PF Vol.
Vol. 27, No. 3, page 2594; PF Vol. 27, No. 4, page 2806; PF 25, No. 6, page 9248.
Vol. 27, No. 5, page 3071; and PF Vol. 27, No. 6, page 3348. (1191) Stability Considerations in Dispensing Practice—See PF
(13) Concordance of Foreign Pharmacopeial Tests and Assays— Vol. 26, No. 5, page 1378.
See PF Vol. 24, No. 1, page 5612. (1206) Sterile Drug Products for Home Use—See PF Vol. 26, No.
Apparatus for Tests and Assays 3, page 812.
(1207) Sterile Product Packaging—Integrity Evaluation—See PF
(41) Weights and Balances—See PF Vol. 26, No. 6, page 1607. Vol. 27, No. 5, page 3111.
Microbiological Tests
(55) Biological Indicators—Resistance Performance Tests— See REAGENTS, INDICATORS, AND SOLUTIONS
PF Vol. 27, No. 4, page 2807.
^ Microbial Limit Tests—See PF Vol. 27, No. 2, page 2269. Reagent Specifications
62) Microbiological Procedures for Absence of Objectionable Agarose—See PF Vol. 27, No. 6, page3363.
Microorganisms—See PF Vol. 27, No. 2, page 2269. Ammonia Water, Stronger—See PF Vol. 27, No. 6, page 3363.
(71) Sterility Tests—See PF Vol. 26, No. 4, page 1102. Ammonium Pyrrolidinedithiocarbamate—See PF Vol. 27, No. 5,
page 3115.
Chemical Tests and Assays Ammonium Formate—See PF Vol. 25, No. 4, page 8586.
Aniline Sulfate—See PF Vol. 27, No. 2, page 2277.
LIMIT TESTS
© 2002 The United States Pharmacopeial Convention, Inc.. All Rights Reserved.
Pharmacopeial Forum
Antifoam Reagent—See PF Vol. 26, No. 6, page 1621. Methyl Benzenesulfonate—See PF Vol. 24, No. 4, page 6591.
L-Aspartic Acid—See PF Vol. 27, No. 6, page 3363. 3-Methyl-2-benzothiazolinone Hydrazone Hydrochloride— See
Azure A—See PF Vol. 27, No. 5, page 3115. PF Vol. 25, No. 3, page 8280.
Biuret—See PF Vol. 26, No. 2, page 503. Methyl Green—See PF Vol. 27, No. 2, page 2279.
Branched Polymeric Sucrose—See PF Vol. 27, No. 6, page 3363. 1-Methylpiperazine—See PF Vol. 27, No. 1, page 1903.
Butyrolactone—See PF Vol. 22, No. 6, page 3248. N-Methylpyrrolidine—See PF Vol. 27, No. 5, page 3116.
Canada Balsam—See PF Vol. 27, No. 2, page 2278. Monooleoylglycerol—See PF Vol. 26, No. 6, page 1622.
Carmine—See PF Vol. 27, No. 2, page 2278. Morin—See PF Vol. 25, No. 3, page 8280.
w-Chlorobenzoic Acid—See PF Vol. 26, No. 4, page 1132. 1-Naphthylamine—See PF Vol. 27, No. 5, page 3116.
1-Chloronaphthalene—See PF Vol. 27, No. 6, page 3364. Nickel Chloride Hexahydrate—See PF Vol. 26, No. 5, page 1382.
Compactin—See PF Vol. 27, No. 3, page 2595. Nickel(II) Sulfate Heptahydrate—See PF Vol. 27, No. 5, page
0.5 M Copper Sulfate Solution—See PF Vol. 26, No. 5, page 1382. 3116.
Cupric Nitrate—See PF Vol. 27, No. 6, page 3364. Nicotinamide Adenine Dinucleotide—See PF Vol. 27, No. 3, page
Cyclohexylmethanol—See PF Vol. 25, No. 1, page 7582. 2596.
Deoxyadenosine Triphosphate—See PF Vol. 27, No. 6, page 3364. /^-'Nicotinamide Adenine Dinucleotide—See PF Vol. 27, No. 3,
Deoxycytidine Triphosphate—See PF Vol. 27, No. 6, page 3364. page 2596.
Deoxyguanosine Triphosphate—See PF Vol. 27, No. 6, page 3364. /z-Nonylamine—See PF Vol. 27, No. 6, page 3368.
Deoxyribonucleic Acid Polymerase—See PF Vol. 27, No. 6, page Nonylphenol Polyoxyethylene Ether—See PF Vol. 27, No. 6, page
3365. 3368.
Deoxythymidine Triphosphate—See PF Vol. 27, No. 6, page 3365. Oligo-deoxythymidine—See PF Vol. 27, No. 6, page 3368.
Dextran, High Molecular Weight—See PF Vol. 27, No. 5, page Pentadecanoic Acid Methyl Ester—See PF Vol. 26, No. 6, page
3115. 1622.
Dibutylammonium Phosphate—See PF Vol. 26, No. 4, page 1132. 2-Pentanone—See PF Vol. 26, No. 4, page 1132.
Dicyclohexyl—See PF Vol. 25, No. 1, page 7582. o-Phenanthroline Monohydrochloride Monohydrate—See PF Vol.
Dicyclohexyl Phthalate—See PF Vol. 26, No. 2, page 504. 27, No. 1, page 1904.
Diethylpyrocarbonate—See PF Vol. 27, No. 6, page 3365. Phenol Red, Sodium—See PF Vol. 27, No. 6, page 3368.
2,7-Dihydroxynapthalene—See PF Vol. 21, No. 3, page 823. Phenoxyacetic Acid—See PF Vol. 27, No. 1, page 1904.
N,N-Dimethyldodecylamine-N-oxide—See PF Vol. 27, No. 4, 3-Phenoxybenzoic Acid—See PF Vol. 27, No. 3, page 2596.
page 2837. Phenylacetic Acid—See PF Vol. 27, No. 1, page 1904.
2,5-Dimethylphenol—See PF Vol. 27, No. 6, page 3364. Polyoxyethylene (20) Sorbitan Monolaurate—See PF Vol. 27, No.
3,5-Dimethylphenol—See PF Vol. 27, No. 3, page 2596. 6, page 3368.
1,4-Dimethylpiperazine—See PF Vol. 27, No. 1, page 1903. Polysaccharide Molecular Weight Standards—See PFVol. 27, No.
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl Tetrazolium Bro- 5, page 3116.
mide—See PF Vol. 27, No. 6, page 3365. Propionaldehyde—See PF Vol. 24, No. 6, page 7328.
Dirnethyltin Dibromide—See PF Vol. 25, No. 3, page 8280. Protein Standard Solution (8 g/dL)—See PF Vol. 26, No. 6, page
Dioleoylglycerol—See PF Vol. 26, No. 6, page 1622. 1622.
Racemic Epinephrine—See PF Vol. 23, No. 4, page 4529. (-)-Pseudoephedrine—See PF Vol. 23, No. 5, page 4872.
a-Ergocryptine—See PF Vol. 27, No. 4, page 2837. Putrescine Dihydrochloride—See PF Vol. 27, No. 6, page 3369.
Escin—See PF Vol. 27, No. 4, page 2837. Reverse Transcriptase—See PF Vol. 27, No. 6, page 3369.
17a-Estradiol—See PF Vol. 27, No. 2, page 2278. Ribonuclease Inhibitor—See PF Vol. 27, No. 6, page 3369.
Ether, Peroxide-Free—See PF Vol. 27, No. 6, page 3365. Silver Chloride, Granular Reagent—See PF Vol. 26, No. 5, page
Ethidium Bromide—See PF Vol. 27, No. 6, page 3366. 1383.
4'-Ethoxyacetophenone—See PF Vol. 26, No. 5, page 1382. /?-Sitosterol—See PF Vol. 26, No. 3, page 835.
Ethylbenzene—See PF Vol. 25, No. 1, page 7582. Soda Lime—See PF Vol. 27, No. 4, page 2838.
Fast Green FCF—See PF Vol. 27, No. 2, page 2278. Sodium Iodate—See PF Vol. 27, No. 6, page 3369.
9-Fluorenylmethyl Chloroformate—See PF Vol. 25, No. 5, page Tetrahydrofuran, Peroxide-Free—See PF Vol. 27, No. 6, page
8916. 3369.
Formamide, Anhydrous—See PF Vol. 27, No. 5, page 3115. l,l,4,4-Tetraphenyl-l,3-butadiene—See PF Vol. 26, No. 6, page
L-Glutamic Acid—See PF Vol. 27, No. 6, page 3366. 1623.
L-Glutamine—See PF Vol. 27, No. 6, page 3366. Thionine Acetate—See PF Vol. 27, No. 2, page 2279.
Guanidine Isothiocyanate—See PF Vol. 27, No. 6, page 3366. Thymidine—See PF Vol. 27, No. 6, page 3369.
Heptafluorobutyric Acid—See PF Vol. 26, No. 4, page 1132. Toluidine Blue—See PF Vol. 27, No. 2, page 2280.
L-Histidine Hydrochloride Monohydrate—See PF Vol. 27, No. 6, Toluidine Blue O—See PF Vol. 27, No. 2, page 2280.
page 3366. o:,o;,Q:-Trifluoro-p-cresol—See PF Vol. 27, No. 3, page 2596.
Hydrazine Sulfate—See PF Vol. 27, No. 4, page 2837. Trimethyltin Bromide—See PF Vol. 25, No. 3, page 8281.
Hydroxy Naphthol Blue—See PF Vol. 27, No. 6, page 3366. Trioleoylglycerol—See PF Vol. 26, No. 6, page 1623.
Hypoxanthine—See PF Vol. 27, No. 6, page 3367. Tris(hydroxymethyl)aminomethane Acetate—See PF Vol. 27, No.
Indole—See PF Vol. 25, No. 4, page 8586. 5, page 3117.
Indole-3-carboxylic Acid—See PF Vol. 25, No. 4, page 8586. Tris(hydroxymethyl)aminomethane Hydrochloride—See PF Vol.
Iodoethane—See PF Vol. 24, No. 6, page 7327. 27, No. 6, page 3370.
Isoferulic Acid—See PF Vol. 27, No. 4, page 2837. N-Tris(hydroxymethyl)methylglycine—See PF Vol. 27, No. 5,
Isopropyl Acetate—See PF Vol. 26, No. 4, page 1132. page 3117.
2-Isopropylphenol—See PF Vol. 27, No. 4, page 2838. L-Tyrosine Disodium—See PF Vol. 27, No. 6, page 3370.
Isorhamnetin—See PF Vol. 27, No. 2, page 2279. Uridine—See PF Vol. 27, No. 3, page 2597.
Kaempferol—See PF Vol. 27, No. 2, page 2279. Vinyl Acetate—See PF Vol. 21, No. 2, page 466.
Linoleic Acid—See PF Vol. 27, No. 6, page 3367. 2-Vinylpyridine—See PF Vol. 26, No. 2, page 504.
a-Lipoic Acid—See PF Vol. 27, No. 6, page 3367. l-Vinyl-2-pyrrolidone—See PF Vol. 22, No. 6, page 3249.
Manganese Dioxide—See PF Vol. 27, No. 6, page 3367. Zinc Sulfate Heptahydrate—See PF Vol. 26, No. 2, page 504.
Manganese Dioxide, Activated—See PF Vol. 27, No. 6, page
Indicator and Test Papers
3367.
Mercurous Nitrate—See PF Vol. 27, No. 6, page 3368.
Pharmacopeial Forum
Hydroxy Naphthol Blue Indicator—See PF Vol. 27, No. 6, page Caprylocaproyl Macrogolglycerides—See PF Vol. 26, No. 2, page
3370. 448.
Hydroxy Naphthol Blue Trituration—See PF Vol. 27, No. 6, page Caraway—See PF Vol. 27, No. 4, page 2790.
3370. Caraway Oil—See PF Vol. 27, No. 4, page 2791.
Thiazole Yellow Paper—See PF Vol. 27, No. 5, page 3117. Carbomer 941—See PF Vol. 27, No. 6, page 3338.
Test Solutions Carbomer Copolymer— See PF Vol. 27, No. 2, page 2219.
Carbomer Interpolymer—See PF Vol. 27, No. 2, page 2222.
Buffer Solutions—See PF Vol. 27, No. 6, page 3371. Carboxymethylcellulose Sodium 12—See PF Vol. 26, No. 6, page
Cupric Citrate TS—See PF Vol. 27, No. 5, page 3117. 1577.
Ferroin TS—See PF Vol. 27 No. 1, page 1905. Cardamom Oil—See PF Vol. 27, No. 4, page 2791.
Iodine, Diluted TS—See PF Vol. 27, No. 6, page 3372. Cardamom Seed—See PF Vol. 27, No. 4, page 2792.
Mercuric-Potassium Iodide TS, Alkaline—See PF Vol. 27, No. 6, Compound Cardamom Tincture—See PF Vol. 27, No. 4, page
page 3372. 2793.
Nickel Standard Solution TS—See PF Vol. 27, No. 5, page 3117. Cellulose Acetate Butyrate—See PF Vol. 25, No. 2, page 7861.
Perchloric Acid TS—See PF Vol. 27 No. 1, page 1905. Cetostearyl Alcohol—See PF Vol. 26, No. 6, page 1350.
Potassium Iodide and Starch TS—See PF Vol. 27, No. 6, page Cetyl Palmitate— See PF Vol. 27, No. 1, page 1825.
3373. Chamomile—See PF Vol. 27, No. 5, page 3059.
Potassium Thiocyanate TS—See PF Vol. 27, No. 5, page 3118. Cherry Juice—See PF Vol. 27, No. 4, page 2793.
Volumetric Solutions Cherry Syrup—See PF Vol. 27, No. 4, page 2795.
Chocolate—See PF Vol. 27, No. 4, page 2795.
Edetate Disodium, Twentieth-Molar (0.05 M)—See PF Vol. 27, Chocolate Syrup—See PF Vol. 27, No. 4, page 2796.
No. 6, page 3373. Chondroitin Sulfate Sodium—See PF Vol. 27, No. 5, page 3059.
Reagent Footnotes Chondroitin Sulfate Tablets—See PF Vol. 27, No. 5, page 3063.
Clove Oil—See PF Vol. 27, No. 4, page 2796.
Footnote 43—See PF Vol. 27, No. 6, page 1133. Copovidone—See PF Vol. 24, No. 5, page 6891.
Footnote 85—See PF Vol. 26, No. 4, page 1133. Purified Cotton Filler—See PF Vol. 26, No. 1, page 213.
Footnote 87—See PF Vol. 26, No. 5, page 1383. Crospovidone—See PF Vol. 27, No. 5, page 3065.
Footnote 88—See PF Vol. 26, No. 6, page 1623. Dimethicone—See PF Vol. 27, No. 6, page 3338.
Footnote 89—See PF Vol. 26, No. 6, page 1623. Echinacea angustifolia—See PF Vol. 26, No. 6, page 1578.
Footnote 92—See PF Vol. 27, No. 3, page 2597. Powdered Echinacea angustifolia—See PF Vol. 26, No. 6, page
Footnote 93—See PF Vol. 27, No. 3, page 2597. 1583.
Footnote 94—See PF Vol. 27, No. 3, page 2597. Powdered Echinacea angustifolia Extract—See PF Vol. 26, No. 6,
Footnote 95—See PF Vol. 27, No. 3, page 2597. page 1583.
Footnote 96—See PF Vol. 27, No. 5, page 3118. Echinacea pallida—See PF Vol. 26, No. 6, page 1585.
Footnote 97—See PF Vol. 27, No. 5, page 3118. Powdered Echinacea pallida—See PF Vol. 26, No. 6, page 1588.
Footnote 98—See PF Vol. 27, No. 5, page 3118. Powdered Echinacea pallida Extract—See PF Vol. 26, No. 6, page
Footnote 99—See PF Vol. 27, No. 6, page 3374. 1588.
Footnote 100—See PF Vol. 27, No. 6, page 3374. Echinacea purpurea Root—See PF Vol. 26, No. 6, page 1590.
Footnote 101—See PF Vol. 27, No. 6, page 3374. Powdered Echinacea purpurea—See PF Vol. 26, No. 6, page 1593.
Footnote 102—See PF Vol. 27, No. 6, page 3374. Powdered Echinacea purpurea Extract—See PF Vol. 26, No. 6,
REFERENCE TABLES page 1594.
Eleuthero—See PF Vol. 26, No. 6, page 1596.
Container Specifications for Capsules and Tablets—See PF Vol. Powdered Eleuthero—See PF Vol. 26, No. 6, page 1598.
27, No. 6, page 3374. Powdered Eleuthero Extract—See PF Vol. 26, No. 6, page 1599.
Description and Relative Solubility of USP and NF Articles—See Ethyl Acetate—See PF Vol. 27, No. 4, page 2797.
PF Vol. 23, No. 4, page 4533; PF Vol. 23, No. 5, page 4874; Ethylcellulose—See PF Vol. 25, No. 2, page 7866.
PF Vol. 23, No. 6, page 5310; PF Vol. 24, No. 5, page 7017; Fennel Oil—See PF Vol. 27, No. 4, page 2797.
PF Vol. 25, No. 2, page 7930; PF Vol. 25, No. 3, page 8282; Garlic Delayed-Release Tablets—See PF Vol. 27, No. 2, page
PF Vol. 25, No. 4, page 8589; PF Vol. 25, No. 5, page 8917; 2224.
PF Vol. 25, No. 6, page 9254; PF Vol. 26, No. 1, page 251; PF
Vol. 26, No. 2, page 504; PF Vol. 26, No. 2, page 505; PF Vol. Ginger Capsules—See PF Vol. 27, No. 2, page 2227.
26, No. 3, page 837; PF Vol. 26, No. 4, page 1135; PF Vol. 26, Ginkgo—See PF Vol. 27, No. 2, page 2229.
No. 5, page 1385; PF Vol. 26, No. 6, page 1623; PF Vol. 27, Powdered Ginkgo Extract—See PF Vol. 27, No. 2, page 2233.
No. 1, page 1907; PF Vol. 27, No. 2, page 2281; PF Vol. 27, Ginkgo Capsules—See PF Vol. 27, No. 2, page 2238.
No. 3, page 2601; PF Vol. 27, No. 4, page 2839; PF Vol. 27, Ginkgo Tablets—See PF Vol. 27, No. 2, page 2240.
No. 5, page 3120; PF Vol. 27, No. 6, page 3374. American Ginseng—See PF Vol. 27, No. 2, page 2243.
Powdered American Ginseng—See PF Vol. 27, No. 2, page 2247.
NF MONOGRAPHS Powdered American Ginseng Extract—See PF Vol. 27, No. 2, page
Acacia Syrup—See PF Vol. 27, No. 4, page 2787. 2247.
Diluted Acetic Acid—See PF Vol. 27, No. 4, page 2788. Asian Ginseng Capsules—See PF Vol. 26, No. 3, page 775.
Acetyltributyl Citrate—See PF Vol. 27, No. 5, page 3058. Asian Ginseng Tablets—See PF Vol. 27, No. 2, page 2254.
Acetyltriethyl Citrate—See PF Vol. 27, No. 5, page 3058. Goldenseal—See PF Vol. 27, No. 2, page 2255.
Myristyl Alcohol—See PF Vol. 27, No. 3, page 2589. Powdered Goldenseal—See PF Vol. 27, No. 2, page 2257.
Anise Oil—See PF Vol. 27, No. 4, page 2789. Powdered Goldenseal Extract—See PF Vol. 27, No. 2, page 2258.
Benzalkonium Chloride—See PF Vol. 27, No. 4, page 2789. Hawthorn Leaf with Flower—See PF Vol. 26, No. 5, page 1357.
Benzalkonium Chloride Solution—See PF Vol. 27, No. 5, page Powdered Hawthorn Leaf with Flower—See PF Vol. 26, No. 5,
page 1362.
3059. Hydroxypropyl Beta Cyclodextrin—See PF Vol. 24, No. 6, page
Benzyl Alcohol—See PF Vol. 27, No. 4, page 2790.
Butylated Hydroxyanisole—See PF Vol. 27, No. 3, page 2590. 7284.
Calcium Silicate—See PF Vol. 27, No. 6, page 3337. Isopropyl Myristate—See PF Vol. 26, No. 5, page 1362.
Calcium Sulfate—See PF Vol. 27, No. 6, page 3337. Kava—See PF Vol. 26, No. 3, page 779.
Powdered Kava—See PF Vol. 26, No. 3, page 782.
Pharmacopeia! Forum
Powdered Kava Extract—See PF Vol. 26, No. 3, page 783. Ubidecarenone Capsules—See PF Vol. 27, No. 2, page 2265.
Semisolid Kava Extract—See PF Vol. 26, No. 3, page 784. Ubidecarenone Tablets—See PF Vol. 27, No. 2, page 2267.
Kava Capsules—See PF Vol. 26, No. 3, page 785. Valerian Capsules—See PF Vol. 27, No. 1, page 1825.
Kava Tablets—See PF Vol. 26, No. 3, page 787. Vanilla—See PF Vol. 27, No. 4, page 2804.
Lauroyl Macrogolglycerides—See PF Vol. 26, No. 2, page 456. Vanilla Tincture—See PF Vol. 27, No. 4, page 2805.
Lemon Oil—See PF Vol. 27, No. 4, page 2798. Xanthan Gum Solution—SeePF Vol. 27, No. 6, page 3347.
Licorice—See PF Vol. 26, No. 5, page 1363. NUTRITIONAL SUPPLEMENTS
Licorice Fluidextract—See PF Vol. 27, No. 4, page 2799.
Linoleoyl Macrogolglycerides—See PF Vol. 26, No. 2, page 457. USP MONOGRAPHS
a-Lipoic Acid—See PF Vol. 27, No. 6, page 3338.
Magnesium Aluminometasilicate—See PF Vol. 27, No. 3, page Calcium and Vitamin D with Minerals Tablets—See PF Vol. 27,
2590. No. 2, page 2283.
Magnesium Aluminosilicate—See PF Vol. 27, No. 3, page 2593. Minerals Capsules—See PF Vol. 27, No. 1, page 1908.
Maltitol Solution—See PF Vol. 27, No. 6, page 3340. Minerals Tablets—See PF Vol. 27, No. 1, page 1916.
Methacrylic Acid Copolymer— See PF Vol. 27, No. 4, page 2800. Oil-Soluble Vitamins Capsules—See PF Vol. 27, No. 1, page 1919.
Powdered Milk Thistle Extract—See PF Vol. 27, No. 2, page 2259. Oil-Soluble Vitamins Tablets—See PF Vol. 27, No. 1, page 1925.
Milk Thistle Capsules—See PF Vol. 27, No. 2, page 2261. Oil- and Water-Soluble Vitamins Capsules—See PF Vol. 27, No. 1,
Milk Thistle Tablets—See PF Vol. 27, No. 2, page 2263. page 1927.
Mono- and Di-glycerides—See PF Vol. 27, No. 5, page 3065. Oil- and Water-Soluble Vitamins Oral Solution—See PF Vol. 27,
Oleic Acid—See PF Vol. 26, No. 5, page 1366. No. 1, page 1935.
Oleoyl Macrogolglycerides—See PF Vol. 26, No. 2, page 459. Oil- and Water-Soluble Vitamins Tablets—See PF Vol. 27, No. 1,
Orange Oil—See PF Vol. 27, No. 4, page 2800. page 1937.
Orange Syrup—See PF Vol. 27, No. 4, page 2801. Oil- and Water-Soluble Vitamins with Minerals Capsules— See PF
Sweet Orange Peel Tincture—See PF Vol. 27, No. 4, page 2802. Vol. 27, No. 1, page 1942.
Poloxamer—See PF Vol. 27, No. 4, page 2802. Oil- and Water-Soluble Vitamins with Minerals Oral Solution—
Polyethylene Glycol—See PF Vol. 27, No. 5, page 3067. See PF Vol. 27, No. 1, page 1955.
Purified Rayon Filler—See PF Vol. 26, No. 1, page 216. Oil- and Water-Soluble Vitamins with Minerals Tablets—See PF
St. John's Wort—See PF Vol. 26, No. 2, page 460. Vol. 27, No. l,page 1962.
Powdered St. John's Wort—See PF Vol. 25, No. 2, page 7876. Water-Soluble Vitamins Capsules—See PF Vol. 27, No. 1, page
Powdered St. John's Wort Extract—See PF Vol. 26, No. 2, page 1989.
463. Water-Soluble Vitamins Tablets—See PF Vol. 27, No. 1, page
Sodium Starch Glycolate—See PF Vol. 22, No. 6, page 3202. 1995.
Sorbitol—See PF Vol. 27, No. 6, page 3342. Water-Soluble Vitamins with Minerals Capsules—See PF Vol. 27,
Noncrystallizing Sorbitol Solution—See PF Vol. 27, No. 6, page No. 1, page 2003.
3344. Water-Soluble Vitamins with Minerals Oral Solution—See PF Vol.
Stearoyl Macrogolglycerides—See PF Vol. 26, No. 2, page 467. 27, No. 1, page 2012.
Sucrose—See PF Vol. 22, No. 6, page 3206. Water-Soluble Vitamins with Minerals Tablets—See PF Vol. 27,
Sunflower Oil—See PF Vol. 27, No. 4, page 2803. No. 1, page 2013.
Suspension Structured Vehicle—See PF Vol. 27, No. 6, page 3346. GENERAL CHAPTERS
Sugar-Free Suspension Structured Vehicle—See PF Vol. 27, No. 6,
page 3346. (2040) Disintegration and Dissolution of Nutritional Supple-
Tributyl Citrate—See PF Vol. 27, No. 5, page 3067. ments—See PF Vol. 26, No. 3, page 838.
Triethyl Citrate—See PF Vol. 27, No. 5, page 3068.
Ubidecarenone—See PF Vol. 26, No. 6, page 1601.
Pharmacopeia! Forum
Proposed Revisions and New Text Previously Presented in PF but Now Canceled
(Canceled proposals may be republished at any time in a future number of Pharmacopeial Forum)
[PF28(1)-PF28(6)]
PF Page Numbers of Canceled Proposals
Title and Proposal Vol. No. Page(s)
USP Monographs
7-Aminodesacetoxycephalosporanic Acid (new) 26 1534
6-Aminopenicillanic Acid (new) 27 1745
Delavirdine Mesylate (new) 24 7143
Delavirdine Mesylate Tablets (new) 24 7145
Diethylcarbamazine Citrate—Limit of 1-methylpiperazine and 27 1775
/, 4-dimethylpiperazine
Diethylcarbamazine Citrate Tablets—Limit of 1-methylpiperazine 27 1777
and 1,4-dimethylpiperazine
Estradiol—Assay 25 9140
Glipizide—Ordinary impurities 27 1786
Heparin Sodium—Identification 25 9153
Hydroxizine Hydrochloride Tablets—Dissolution 27 2553
(subsection Medium, Apparatus)
Rimantidine Hydrochloride (new) 24 5927
Rimantidine Hydrochloride Tablets (new) 24 5929
Ritonavir (new) 24 7176
Ritonavir Capsules (new) 24 7178
Trichlorfon—Labeling 26 1576
USP and NF Excipients, Listed by Category 26 447
USP General Test Chapters
(11) USP Reference Standards 27 1832
USP 6-Aminopenicillanic Acid RS
(1151) Pharmaceutical Dosage Forms—Bioavailability 24 5828
1,4-Dimethylpiperazine (new) 27 1403

1-Methylpiperazine (new) 27 1903
1-MethylpyrroHdone (new) 24 7199
Phenoxyacetic Acid (new) 27 1904
Phenylacetic Acid (new) 27 1904
(-)Pseudoephedrine (new) 23 4872
Reference Tables
Description and Relative Solubility—-6-Aminopenicillanic Acid 27 1907
NF Monographs
Purified Cotton Filler (new) 26 213
Purified Rayon Filler (new) 26 216
HARMON
This section contains monographs or chapters undergoing harmonization by the Pharmacopoeial Discussion Group (PDG).
The PDG consists of the United States Pharmacopeia, the European Pharmacopoeia, and the Japanese Pharmacopoeia. The
process of harmonization is composed of several steps (Stages).
Stage 1: Identification The PDG identifies items to be harmonized and designates a coordinating pharmacopeia for each
item. The PDG distributes the work by consensus among the three participating pharmacopeias. Harmonization may be
carried out retrospectively for existing monographs or chapters, or prospectively for new monographs or chapters.
Stage 2: Investigation The investigation process conducted by the coordinating pharmacopeia results in the preparation of
a Stage 3 draft monograph or chapter accompanied by a report giving the rationale for the proposal and including validation
data where appropriate. This report is based on input that comes from users, authorities, producers, associations, literature,
experts, and staff.
Stage 3: Proposal The three pharmacopeias publish the Stage 3 draft in the next available issue of their Forums. In PF, this
stage usually appears as PROPOSAL STAGE 3 under Previews in the Harmonization section. Each pharmacopeia analyzes
the comments it receives and submits the consolidated comments to the coordinating pharmacopeia, which then reviews
those comments and prepares a harmonized Stage 4 draft.
Stage 4: Official Inquiry The Stage 4 draft is published in the Forum of each pharmacopeia. In PF, this stage appears as
OFFICIAL INQUIRY STAGE 4 under In-Process Revision in the Harmonization section. Each pharmacopeia analyzes the
comments it receives and submits the consolidated comments to the coordinating pharmacopeia, which then reviews those
comments, prepares a harmonized Stage 5A draft, and sends it to the other two participating pharmacopeias.
Stage 5: Consensus
A. Provisional
The Stage 5A draft is reviewed and commented on by the other two pharmacopeias. When consensus is reached, a
CONSENSUS STAGE 5B document is prepared by the coordinating pharmacopeia.
B. Final
The Stage 5B draft (consensus document) is sent by the coordinating pharmacopeia to the other two participating
pharmacopeias for final approval.
Stage 6: Adoption Each pharmacopeia incorporates the harmonized Stage 5B draft according to its own procedure.
Adopted items are published by the three pharmacopeias in their Supplements or, where applicable, in a new edition of
their Pharmacopeias.
Stage 7: Date of Implementation The pharmacopeias inform each other of the date of implementation in the particular
region.
Pharmacopeial Forum
128 HARMONIZATION Vol. 28(1) [Jan.-Feb. 2002]
HARMONIZATION 127
Pharmacopeial Forum
Vol. 28(1) [Jan.-Feb. 2002] HARMONIZATION 129
to the procedure described below. This test is usually used

GENERAL CHAPTERS for determining the content of inorganic impurities in an or-
ganic substance. AUSP26
General Tests and Assays ^Procedure AUSP26
—Accurately "weigh 1 to 2 g of the substance, or the amount spe-
cified in the individual monograph, in a suitable crucible that pre-
viously has been ignited
A
at about 600 + 50° for 30 mmutes,Aas.P2({
cooled
Chemical Tests and Assays A
in a desiccator (silica gel or other suitable desiccant),AC/s7,2(;
and weighed.
A
Moisten the sample with a small amount (usually 1 mL) of
sulfuric acid.AttS.P2(j
Heat, gently at first,
A
at a temperature as low as practicable AasP2( j
until the substance is thoroughly charred. Cool, then, unless other-
BRIEFING wise directed in the individual monograph, moisten the residue
with 1 mL of sulfuric acid, heat gently until white fumes no longer
(281) Residue on Ignition, USP 25 page 1927 and page 2325 are evolved, and ignite at 800 J_ 25°,
of PF 27(2) [Mar.-Apr. 2001]. The Japanese Pharmacopoeia is the A
600 ± 50°,AUSP26
coordinating pharmacopeia for the international harmonization of
compendial standards for this general test chapter. The CONSEN- unless another temperature is specified in the individual mono-
SUS STAGE 5B harmonization draft for this general chapter was graph, until the carbon is consumed.
published in Harmonization in the previously mentioned PF. A
Ensure that flames are not produced at any time during the
Comments received in response to that draft indicated that it
may be difficult or impossible to adhere to the proposed general procedure..^*
chapter requirement to "ensure that flames are not produced at Cool in a desiccator
any time during the procedure" when performing the initial diges- A
tion and charring steps for some low melting materials. The new (silica gel or other suitable desiccant),A[/iSP2(j
sentence being proposed for addition at the opening of this general weigh, and calculate the percentage of residue. If the amount of the
chapter is intended to address this issue by allowing different resi- residue so obtained exceeds the limit specified in the individual
due on ignition test procedures where necessary in specific mono- monograph, again moisten the residue with 1 mL of sulfuric acid,
graphs. heat and ignite as before, and again calculate the percentage of re-
sidue. Unless otherwise specified, continue the
A
(PA6: W.L. Paul) RTS—32552-1 repeat the sulfuric acid moistening andAUSP26
ignition
A
as beforeAl/5P2(5
until constant weight is attained or until the percentage of residue
Change to read: complies with the limit in the individual monograph. Conduct the
ignition in a well-ventilated hood, protected from air currents, and
at as low a temperature as is possible to effect the complete com-
bustion of the carbon. A muffle furnace may be used, if desired,
(281) RESIDUE ON IGNITION and its use is recommended for the final ignition at 800 ± 25°.
A
600 + 50° USP26
Calibration ofthe muffle furnace may be carried out using an ap-
propriate digital temperature meter and a working thermocouple
A
Unless otherwise specified in the individual monograph, probe calibrated against a standard thermocouple traceable to the
National Institute of Standards and Technology. Verify the accu-
determine the amount of residue on ignition by the proce- racy of the measuring and controlling circuitry of the muffle fur-
nace by checking the positions in the furnace at the control set
dure in this general chapter. The residue on ignition / sul- point temperature of intended use. Select positions that reflect
the eventual method of use with respect to location ofthe specimen
fated ash test is a method to measure the amount of under test. The tolerance is + 25° at each position measured.
Sulphated Ash tests found in the British, a«4-European,
residual substance not volatilized from a sample when the A
and JapaneseAas.P2(S
sample is ignited in the presence of sulfuric acid according Pharmacopoeias are considered equivalent to this test, except
where noted.
PHARMACOPEIAL PREVIEWS
This section contains potential revisions not yet targeted for official adoption. These may include drafts for new monographs
or chapters; drafts for standards that would require new or unusual technology; drafts for which more data are required; or
changes that would affect numerous monographs, thus having a broad impact on individual products. Readers should review
the drafts in this section and provide comments to the appropriate staff liaison whose name is cited in the Briefing (use the
Staff Directory to find the contact information).
Briefings Each Preview is preceded by a Briefing in the following format:
BRIEFING
the revision. Other relevant information. (For example, if a chromatographic method is being used, column
specifications and retention times for compounds of interest.) Finally, the Committee designation (see How
To Use PF), the name of the scientific staff liaison who handled this item, and USP tracking correspondence
number, as shown in the example below:
Symbols No symbols are used in this section, as Previews are not yet targeted for official adoption.
Pharmacopeial Forum
132 PHARMACOPEIAL PREVIEWS Vol. 28(1) [Jan.-Feb. 2002]

Bismuth Subsalicylate Tablets [new] 133
Nystatin 134
Nystatin Cream 134
Nystatin Lozenges 135
Nystatin Ointment 135
Nystatin Topical Powder 136
Nystatin Oral Suspension 136
Nystatin Tablets 137
Nystatin and Triamcinolone Acetonide Cream 137
Nystatin and Triamcinolone Acetonide Ointment 138
MONOGRAPHS (NF) 139
Chaste Tree [new] 139
Powdered Chaste Tree [new] 142
(1072) Disinfectants and Antiseptics [new] 143
(1198) Standardized Imprint Codes for Solid Oral Dosage Forms [new] 152
(1223) Validation of Alternative Microbiological Methods [new] 154
© 2002. The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
Vol. 28(1) [Jan.-Feb. 2002] PHARMACOPEIAL PREVIEWS 133
MONOGRAPHS (USP) per mL.

Assay preparation—Transfer an accurately weighed
portion of finely powdered Tablets, equivalent to about 90
mg of bismuth subsalicylate, to a 200-mL volumetric flask,
BRIEFING add about 150 mL of 1 N nitric acid, and sonicate for 2

minutes. Dilute with 1 N nitric acid to volume and
Bismuth Subsalicylate Tablets. Because there is no existing
USP monograph for this dosage form, a new monograph, based on transfer 20.0 mL to a 100-mL volumetric flask, and dilute
NDA-approved methods of analysis, is being previewed. The ana-
lytical method is based upon UV/VIS spectrophotometric measure- with 1 N nitric acid to volume. Centrifuge a portion at
ments at a wavelength of 463 nm.
4500 rpm for at least 10 minutes.
(PA2: J. Kelly) RTS—32974-1
Procedure—Transfer 10.0 mL, accurately measured, of
the Assay preparation and the Standard preparation to
Add the following: separate 50.0-mL volumetric flasks. Add 10.0 mL of 10%
Bismuth Subsalicylate Tablets ascorbic acid solution and 25.0 mL of 20% potassium
iodide solution into each volumetric flask, and dilute with
1 N nitric acid to volume. Concomitantly determine the
» Bismuth Subsalicylate Tablets contain not less
absorbance of the solutions at the wavelength of
maximum absorbance at about 463-nm with a suitable
of the labeled amount of bismuth subsalicylate
spectrophotometer using the combined reagent solutions
(C7H5Bi04). as the blank. Calculate the quantity, in mg, of C 7 H 5 Bi0 4
Packaging and storage—Preserve in tight containers. in the portion of Tablets taken by the formula:
Labeling—Label chewable Tablets to indicate that they are (362.11 / 208.98X0(4,/4)

to be chewed before swallowing.
in which 362.11 and 208.98 are the molecular weights of
Identification—
bismuth subsalicylate and bismuth, respectively; C is the
A: It meets the requirements of the tests for Bismuth
concentration, in (ig per mL, of bismuth in the Standard pre-
(191). are
paration; and./4M and 4 the absorbances of the solutions
B: After acidifying with nitric acid it meets the
from the Assay preparation and the Standard preparation,
requirements of the test for Salicylate (191) with ferric
respectively.
chloride TS.
Container Specifications for Capsules and Tablets
Assay—
Add the following:
Standard preparation—Transfer about 500 mg of T
Bismuth Subsalicylate Tablets
bismuth, accurately weighed, to a 200-mL volumetric
flask, dissolve in 12-mL of nitric acid, and dilute with
0.01 N nitric acid to volume. Transfer 10.0 mL into a
500-mL volumetric flask, and dilute with 1 N nitric acid
to volume to obtain a concentration of 50 ug of Bismuth
Pharmacopeial Forum
134 PHARMACOPEIA!. PREVIEWS Vol. 28(1) [Jan.-Feb. 2002]
contains 5-um packing LI. The flow rate is about 1 mL

BRIEFING
per minute. Chromatograph the Standard preparation, and
Nystatin, USP 25 page 1255; Nystatin Cream, USP 25 page
1255; Nystatin Lozenges, USP 25 page 1255; Nystatin Oint- record the peak responses as directed for Procedure: the
ment, USP 25 page 1255; Nystatin Topical Powder, USP 25 page
1256; Nystatin Oral Suspension, USP 25 page 1256; Nystatin relative standard deviation for replicate injections is not
Tablets, USP 25 page 1256; Nystatin and Triamcinolone Aceto-
nide Cream, USP 25 page 1259; Nystatin and Triamcinolone more than 2.0%.
Acetonide Ointment, USP 25 page 1259.
A new liquid chromatographic Assay is proposed as a replace- Procedure—Separately inject equal volumes (about 20
ment for the microbial Assay in these monographs. The proposed
liquid chromatographic method is based on analyses performed uL) of the Standard preparation and the Assay prepara-
with the 5-jxm Symmetry C18 brand of LI column. Quantitation
is based on the sum of the peak areas of the two major isomers tion into the chromatograph, record the chromatograms,
of nystatin, typical retention times for which were about 11.7
and 17.5 minutes. The method is based on the published procedure and measure the areas for the major peak and for the
of Phyllis Wilson and Ann Stewart in JAOAC /of.,2001, 84(4),
1050-1055. The hew liquid chromatographic Assay is also pro- minor peak at a relative retention time of about 1.5.
posed for Nystatin Lotion, Nystatin for Oral Suspension, Nystatin
Vaginal Suppositories, and Nystatin Vaginal Tablets. Calculate the potency, in USP Nystatin Units, in each mg
of the Nystatin taken by the formula:
in which Wv and Ws are the weights, in mg, of Nystatin and

Change to read:
Assay—Prooood with Nyatatin aa dirootod under Antibiotics—Mt- USP Nystatin RS taken to prepare the Assay preparation
cmbial -Assays (&4-)T
and the Standard preparation, respectively; P is the desig-
Mobile phase—Prepare a mixture of methanol, water, and
nated potency, in USP Nystatin Units per mg, of USP Nys-
dimethylformamide (550:300:150), and allow to equilibrate
tatin RS; and rând rs are the sums of the areas of the major
for an hour. Make adjustments if necessary (see System
and minor nystatin peaks obtained from the Assay prepara-
tion and the Standard preparation, respectively. [NOTE—At
the end of the day, wash the column with a mixture of water
Nystatin RS, accurately weighed, to a low-actinic 50-mL
and methanol (1:1) for an hour, followed by a methanol
volumetric flask, add about 48 mL of Mobile phase, and
wash, at a flow rate of about 1 mL per minute.]
sonicate for 2 minutes. Dilute with Mobile phase to
volume, and mix.[NOTE—Use this solution within 24
hours, if stored in the refrigerator.]
Assay preparation—Transfer about 5 mg of Nystatin,
accurately weighed, to a low-actinic 50-mL volumetric
flask, add 48 mL of Mobile phase, and sonicate for 2
BRIEFING
minutes. Dilute with Mobile phase to volume, and mix.
[NOTE—Use this solution within 24 hours, if stored in the Nystatin Cream, USP 25 page 1255—See briefing under
Nystatin. [NOTE—The Assay under Nystatin Lotion cross-refer-
refrigerator.] ences the Assay in this monograph.]
Chromatographic system (see Chromatography (PA7: W.Wright) RTS—35276-1

Pharmacopeial Forum

Assay—Proooed as dirootod for Nyotatin under Antibiotics—Mt- Assay—Prooood ao dirootod for Nyotatin underlintibiotics—M-
crobied Assays< (%±), blending a suitable aoouratoly weighed por cmbial Assays (84), blending not loss than 5 Lozongo3 for 18 to
tion of Cream in a high speed blonder for 3 to 5 minutes with a 20 minutoa in a high opood blonder jar containing 100.0 mL of
suffioiont aoouratoly measured volumo of dirnothylformamido to water. Add 400.0 mL of dimethylformamido, and blond for an ad
givo a oonoontration of about dQO USP Nyotatin Unto por mL. Di ditional 10 minutoo. Dilute an aoouratoly moaaured volumo of this
lute this stook solution quantitatively with Buffer1 No. 6 to obtain a solution quantitatively with a mixture of dimothylformamido and
Test Dilution having a concentration assumed to bo oqual to the water (4:1) to obtain a stock solution containing about 400 USP
median dooo lovol of the Standard. Nystatin Units por mL. Dilute an aoourately moaaurod volumo of
Mobile phase, Standard preparation, and Chroma- this stook solution quantitatively with Buffer No. 5to obtain a Test
Dilution having a nystatin oonoontration assumed to bo equal to tho
tographic system—Proceed as directed in the Assay under median do30 lovol of the Standard. [NOTE—Tho Test Dilution of
tho specimen and tho toot dilutions of tho Standard contain tho oamo
Nystatin. amount of dimothylformamido (about 1%).]
Assay preparation—Transfer an accurately weighed Mobile phase, Standard preparation, and Chromato-
quantity of Cream, equivalent to about 25,000 USP graphic system—Proceed as directed in the ^.waypreviewed
Nystatin Units, to a low-actinic 50-mL volumetric flask. under Nystatin.
Add 10 mL of dimethylformamide, and 30 mL of warm Assay preparation—Blend 1 or more Lozenges, equiva-
methanol. Sonicate for 10 minutes, shake for 15 minutes, lent to about 400,000 USP Nystatin Units, for about 20 min-
add sufficient water to bring the volume to about 48 mL, utes in a high-speed blender jar containing 50.0 mL of
and shake. Allow to cool to room temperature, dilute with water. Add 200.0 mL of a mixture of methanol and di-
water to volume, and mix. Pass this solution through a filter methylformamide (300:80), and blend an additional 10 min-
having a porosity of 0.45 um. utes. Transfer 7.0 mL of the clear solution to a 25-mL
Procedure—Proceed as directed in the Assay under volumetric flask, dilute with Mobile phase to volume, and mix
Nystatin. Calculate the potency, in USP Nystatin Units, in Procedure—Proceed as directed in the Assay under Nys-
each g of Cream taken by the formula: tatin. Calculate the potency, in USP Nystatin Units, in each
Lozenge taken by the formula:
(\25llN)(WsP){rulrs),
in which Wv is the weight, in g, of Cream taken to prepare
the Assay preparation; and the other terms are as defined in which iV is the number of Lozenges taken; and the other
therein. terms are as defined therein.
BRIEFING BRIEFING
Nystatin Lozenges, USP 25 page 1255—See briefing under Nystatin Ointment, USP 25 page 1255—See briefing under
Nystatin. Nystatin.
(PA7: W.Wright) RTS—35276-2 (PA7: W.Wright) RTS—35276-3
Pharmacopeial Forum

Assay—Prooood with Ointmont as dirootod in tho Assay undor Assay—Prooood with Topioal Powdor as dirootod in tho Assay un
Nystatin Cream. dor Nyotatin Croam.
Mobile phase, Standard preparation, and Chromato- Mobile phase, Standard preparation, and Chroma-
graphic system—Proceed as directed in the Assay under tographic system—Proceed as directed in the Assay under
Nystatin. Nystatin.
Assay preparation—Transfer an accurately weighed Assay preparation—Transfer an accurately weighed
quantity of Ointment, equivalent to about 25,000 USP quantity of well-mixed Powder, equivalent to about
Nystatin Units, to a low-actinic 50-mL volumetric flask. 13,000 USP Nystatin Units, to a low-actinic 25-mL
Add 10.0 mL of dimethylformamide, and mix on a vortex volumetric flask. Add 20 mL of Mobile phase, sonicate
mixer for about 3 minutes until the Ointment is dispersed. for about 5 minutes, and shake for about 10 minutes.
Decant the clear solution, transfer 2.0 mL of this solution Dilute with Mobile phase to volume, and mix. Centrifuge
to a 10-mL volumetric flask, dilute with a mixture of for about 10 minutes, and pass this solution through a
methanol and water (70:35) to volume, and mix. Pass this syringe fitted with a filter having a porosity of 0.45|xm.
solution through a syringe fitted with a filter have a Procedure—Proceed as directed in the Assay under
porosity of 0.45 urn. Nystatin. Calculate the potency, in USP Nystatin Units, in
Procedure—Proceed as directed in the Assay under each g of Topical Powder taken by the formula:
Nystatin. Calculate the potency, in USP Nystatin Units, in
each g of Nystatin Ointment taken by the formula:
in which Wv is the weight, in g, of Topical Powder taken to
{WsPIWv){ryl rs),
prepare the Assay preparation; and the other terms are as
in which Wv is the weight, in g, of Ointment taken to prepare defined therein.
the Assay preparation; and the other terms are as defined
therein.
BRIEFING
Nystatin Oral Suspension, USP 25 page 1256—See briefing

under Nystatin. [NOTE—The Assay under Nystatin for Oral Sus-
BRIEFING pension cross-references the Assay in this monograph.]
Nystatin Topical Powder, USP 25 page 1256—See briefing (PA7: W.Wright) RTS—35276-5
under Nystatin.
(PA7: W. Wright) RTS—35276-4
Change to read:
Assay—Prooood as directed for Nystatin under Antibiotics—M-
cmbial Assays (%±), blonding a suitable accurately moasurod vol
umo of Oral Suspension, froshly mixod and froo from air bubbles,
for 3 to 5 minutes in a high spood blondor with a sufficient aoou
Pharmacopeial Forum
ratoly measured volumo of dimothylformamido to obtain a oolution oonoontration. Diluto an aoouratoly measured portion of thio 3olu
of oonvoniont oonoontration. Diluto an aoouratoly measured portion tion quantitatively with dimothylformamido to obtain a stook solu
of this solution quantitatively with dimothylformamido to obtain a tion containing about 400 USP Nystatin Units per mL. Dilute this
stock solution containing about 400 USP Nystatin Units per mL. stock solution quantitatively with-Buffcr No. 6 to obtain a Test Di
Diluto this 3took solution quantitatively with Buffer No. 6 to obtain lution having a oonoontration assumed to bo equal to tho median
a Tc3t Dilution having a oonoontration assumed to bo equal to the doso lovol of the Standard.
median done lovol of tho Standard. Mobile phase, Standard preparation, and Chromato-
Mobile phase, Standard preparation, and Chromato-
graphic system—Proceed as directed in the Assayundev
graphic system—Proceed as directed in the Assay under
Nystatin.
Nystatin.
Assay preparation— Transfer 1 or more Tablets,
Assay preparation—Transfer an accurately weighed
equivalent to about 500,000 USP Nystatin Units, to a low-
quantity of Oral Suspension, freshly mixed and free from
actinic 250-mL volumetric flask, add 200 mL of a mixture
air bubbles, equivalent to about 100,000 USP Nystatin
of methanol, dimethylformamide, and water (75:20:5), and
Units, to a low-actinic 200-mL volumetric flask. Add
sonicate for about 20 minutes until the Tablets disintegrate.
sufficient Mobile phase to bring the volume to about 190
Shake for about 15 minutes, dilute with a mixture of
mL, sonicate for about 5 minutes, and shake for about 10
methanol, dimethylformamide, and water (75:20:5) to
minutes. Dilute with Mobile phase to volume, and mix
volume, and mix for about 2 minutes. Allow to stand for
about 5 minutes. Transfer 7.0 mL of the clear solution to
a 25-mL volumetric flask, dilute with Mobile phase to
each mL of Oral Suspension taken by the formula:
volume, and mix. Pass, this solution through a filter having
A{WsPIV){rvlrs), a porosity of 0.45 urn.
in which Fis the volume, in mL, of Oral Suspension taken Procedure—Proceed as directed in the Assay under
to prepare the Assay preparation; and the other terms are as Nystatin. Calculate the potency, in USP Nystatin Units, in
defined therein. each Tablet taken by the formula:
(125 nN){WsP)(ru/rs),
in which N is the number of Tablets taken; and the other

terms are as defined therein.
BRIEFING
Nystatin Tablets, USP 25 page 1256—See briefing under

Nystatin. [NOTE—The Assays under Nystatin Vaginal Supposi-
tories and Nystatin Vaginal Tablets cross-reference the Assay under
Nystatin Tablets.]
BRIEFING
Nystatin and Triamcinolone Acetonide Cream, USP 25
page 1259—See briefing under Nystatin.

Change to read:
Assay—Prooood ao dirootod for Nyotatin undor Antibiotics—Mt-
cmbial Assays (M), blending not loss than 5 Tablets for 3 to 5 min
utos in a high-speed blonder with a suffioiont aoouratoly measured
volume of dimothylformamido to obtain a solution of oonvoniont
Pharmacopeial Forum
Change to read:
Assay for nystatin—Proceed ao dirootcd for nystatin under And BRIEFING
bio tics—Micvobial Assays (84-);blending a suitable, accurately
weighed portion of Cream in a high speed blonder for 3 to 5 min Nystatin and Triamcinolone Acetonide Ointment, USP 25
utoa with a auffioiont, accurately measured volume of dimothylfor
mamido to give a convenient concentration. Dilute an accurately page 1259—See briefing under Nystatin.
measured volumo of tho solution so obtained quantitatively with
dimothylformamido to obtain a otook solution containing about (PA7: W.Wright) RTS—35276-8
400 USP Nystatin Unito per mL. Dilute an accurately moaaurod
volume of this stock solution quantitatively with Buffet' No. 6 to
obtain a Test Dilution having a concentration of nyotatin assumed
to bo equal to the median doso level of the Standard.
Mobile phase, Standard preparation, and Chromato- Change to read:
graphic system—Proceed as directed in the Assay under Assay for nystatin—Proceed as-directed for nystatin under And
biotics—Micmbial Assays (£4-); blending a suitable, accurately
Nystatin. weighed portion of Ointment in a high spood blonder for 3 to 5
minutoo with a sufficient, accurately moasurod volume of di
Assay preparation—Transfer an accurately weighed mothylformamido to givo a convenient concentration. Dilute an ao
ourately measured volumo of tho solution oo obtainod
quantity of Cream, equivalent to about 25,000 USP quantitatively with dimothylformamido to obtain a stock oolution
containing about 400 USP Nystatin Units per mL. Dilute an aocu
Nystatin Units, to a low-actinic 50-mL volumetric flask. ratoly measured volumo of thia otook oolution quantitatively with
Euffcp-No. 6 to obtain a Test Dilution having a concentration of
Add 10 mL of dimethylformamide, and 30 mL of warm nystatin assumed to bo equal to tho median doso lovol of tho Stan
methanol. Sonicate for 10 minutes, shake for 15 minutes, Mobile phase, Standard preparation, and Chromato-
add sufficient water to bring the volume to about 48 mL, graphic system—Proceed as directed in the Assay under
and shake. Allow to cool to room temperature, dilute with Nystatin.
water to volume, and mix. Pass this solution through a filter Assay preparation—Transfer an accurately weighed
having a porosity of 0.45 um. quantity of Ointment, equivalent to about 25,000 USP
Procedure—Proceed as directed in the Assay under Nystatin Units, to a 50-mL centrifuge tube. Add 10.0 mL
Nystatin. Calculate the potency, in USP Nystatin Units, in of dimethylformamide, and mix on a vortex mixer for
each g of Cream taken by the formula: about 3 minutes until the Ointment is dispersed. Decant
the clear solution, transfer 2.0 mL of this solution to a 10-
mL volumetric flask, dilute with a mixture of methanol and
in which Wv is the weight, in g, of Cream taken to prepare water (70:35) to volume, and mix. Pass this solution through
the Assay preparation; and the other terms are as defined a syringe fitted with a filter having a porosity of 0.45 Jim.
therein. Procedure—Proceed as directed in the Assay under
each g of Ointment taken by the formula:
in which Wv is the weight, in g, of Ointment taken to prepare

the Assay preparation; and the other terms are as defined
therein.
Pharmacopeia! Forum
MONOGRAPHS (NF) USP Reference standards (II)—USPAgnuside RS. USP

Casticin RS. USP Powdered Chaste Tree Extract RS.
Macroscopic—Mature chaste tree fruits are spherical to

ovoid, 2 to 4 mm in diameter, very hard, usually with a
short pedicil. The fruit is reddish brown to black, slightly
BRIEFING rough, and covered with glandular hairs. There are four
Chaste Tree; Powdered Chaste Tree. Because there are no grooves perpendicular to one another, and a slight
existing monographs for these articles, new monographs are being
previewed. The method in the test for Content ofcasticin is based depression on the apex, more evident on large fruits. The
on the method published in "Quantitative High Performance Li-
quid Chromatography Analysis of Casticin in the Fruits of Fitex internal appearance of the fruit is yellowish. The internal
agnus-castus", E. Hoberg, B. Meier, and O. Sticher, Pharmaceu-
tical Bio. 2001, 39 (1), 57-61. The liquid chromatographic proce- structure of the fruit includes four compartments, each
dures in the test for Content ofcasticin are based on analyses
performed with the Hypersil ODS brand of LI column. The typical containing an oblong seed with a high fat content. A
retention time for casticin is about 6 minutes. The method in the
test for Content of agnuside is based on the method published in group of up to six spongy, light tan, immature fruits also
"An Analytical High Performance Liquid Chromatography Meth-
od for the Determination of Agnuside and/?-Hydroxybenzoic Acid accompanies mature fruits. The fruit is often covered by a
Contents in Agni-casti Fructus", E. Hoberg, B. Meier, and O. Sti-
cher, Phytochem. Anal. 2000, 11, 327-329. The liquid chromato- tubular, greenish gray, fine tomentous calyx, which is
graphic procedures in the test for Content of agnuside are based on
analyses performed with the Hypersil ODS brand of LI column. persistent and has five teeth.
The typical retention time for agnuside is between 7.8 and 8.1 min-
utes. Microscopic—The exocarp is brown and narrow,
consisting of parenchymatous cells with thin walls and
partially lignified cells with many pitted thickenings on
the inside. In surface view, the exocarp shows an
Add the following:
epidermis of polygonal cells with irregular thickenings
Chaste Tree and glandular hairs, each with a short single-celled stalk
and a four-celled head containing essential oil. The outer
» Chaste tree consists of the dried ripe fruits of mesocarp consists of several layers of brown, isodiametric
parenchyma cells. The inner mesocarp consists of finely
Vitex agnus-castus L. (Fam. Verbenaceae). It con-
pitted sclerenchymatous cells, some with moderately
tains not less than 0.05 percent of agnuside and
thickened walls, others consisting of isodiametric stone
not less than 0.08 percent of casticin, calculated
cells with small lumen. The endocarp consists of a layer
on the dried basis.
of small brown sclereid cells. The seeds are small, having
Packaging and storage—Store in a well-closed, light- large cotyledons surrounded by thin-walled large
resistant container, protected from moisture. parenchymatous cells that have ribbed thickenings. The
Labeling—The label states the Latin binomial and, nutritive tissue and the cells of the germ contain aleuron
following the official name, the part of the plant contained grains and oil globules. Starch is absent. The outer
in the article. epidermis of calyx is composed of polygonal cells,

covered by abundant unicellular or multicellular curved
Pharmacopeial Forum
trichomes. The inner epidermis of calyx is glabrous and RF value to a similar zone in the chromatogram of the
composed of rectangular, elongated cells with slightly Standard solution; and one yellowish green zone (above a
wavy walls. blue zone) that is near the solvent front and that corresponds
Identification— in color and RF value to a similar zone in the chromatogram
A: Thin Layer Chromatographic Identification Test of the Standard solution. Other colored zones of varying
(201) intensities may be observed in the chromatogram of the
Test Solution—Transfer about 1 g of the powdered plant Test solution.
material to a screw-capped centrifuge tube. Add 10 mL of B: The chromatogram of the Test solution in the test for
methanol, and heat in a water bath at 60° for 10 to 15 Content of casticin shows a peak at the retention time
minutes, cool, and filter. Apply 60 uL to the plate in corresponding to the casticin peak in the chromatogram of
bands that are 2 cm in length. the Standard solution.
Standard solution—Transfer about 100 mg of USP Microbial limits (2021)—It meets the requirements of the
Powdered Chaste Tree Extract RS to a screw-capped tests for absence of Salmonella species and Escherichia
centrifuge tube. Add 1 mL of methanol, and heat in a coli. The total aerobic microbial count does not exceed
water bath at 60° for 10 minutes. Centrifuge, and use the 106 per g, the total combined molds and yeast count does
clear supernatant. Apply 20 to 30 uL to the plate. not exceed 104 per g, and the enterobacterial count does
Developing solvent system—Use the upper phase of a not exceed 103.
mixture of ethyl acetate, methanol, and water (77:15:8). Loss on drying (731)—not more than 10.0%.
Spray Reagent—Prepare a solution of p-dimethyl- Foreign organic matter (561): not more than 3.0%.
aminobenzaldehyde in 1 N hydrochloric acid containing
Total ash (561): not more than 8.0%.
10 mg per mL.
Acid-insoluble ash (561): not more than 2.0%
Procedure—Develop the chromatogram to a length of
not less than 18 cm, and dry the plate in a current of air.
Heavy metals, Method III (231): not more than 20 ug per
Spray the plate with Spray Reagent, and heat for 10
g-
minutes at 120°. The chromatogram obtained from the
Test solution shows the following: a blue zone (at an RF Content of casticin—
value of about 0.21) that turns pink in time due to the Solution A—Use filtered and degassed methanol.
presence of aucubin and that corresponds in color and RF Solution B—Use a filtered and degassed solution of 5.88
value to a similar zone in the chromatogram of the g of phosphoric acid in 1000 mL of water.
Standard solution; a blue zone (at an RF value of about Mobile phase—Use variable mixtures of Solution A and
0.44) that turns pink in time as a result of the presence of Solution B as directed for Chromatographic system. Make
agnuside and that corresponds in color and RF value to a adjustments if necessary (see System Suitability under
similar zone in the chromatogram of the Standard Chromatography (621)).
solution; one yellow zone at an RF value that is between Standard solution—Dissolve an accurately weighed
that of agnuside and aucubin and corresponds in color and quantity of USP Casticin RS in methanol, with sonication.
Dilute quantitatively, and stepwise if necessary, with
Pharmacopeial Forum
methanol to obtain a solution having a known concentration chromatograph, record the chromatograms, and measure
of about 0.05 mg per mL. Filter through a cellulose the areas of the analyte peaks. Identify the retention time
membrane having a 0.45-um or finer porosity. of the peak corresponding to casticin in the Test solution
Test solution—Weigh accurately approximately 1000 mg by comparison with the chromatogram of the Standard
of ground plant material, and place in a suitable container solution. Calculate the percentage of casticin in the
with stopper. Extract twice with 40 mL of methanol, using portion of Chaste Tree taken by the formula:
a hand homogenizer at 19000 rpm for 2 minutes. Filter each
supernatant, and transfer to a 250-mL round-bottom flask.
in which C is the concentration, in mg per mL, of USP Cas-
Rinse the residue with methanol, and filter the resulting
ticin RS in the Standard solution; Wis the weight, in mg, of
solution into the flask. Evaporate the combined extract to
the Chaste Tree taken to prepare the Test solution; and rv
dryness. Dissolve the residue in methanol, quantitatively
and rs are the peak responses of casticin obtained from the
transfer to a 20-mL volumetric flask, and dilute with
methanol to volume. Filter through a cellular membrane
Content of agnuside—
having a 0.45-um or finer porosity.
Chromatographic system (see Chromatography Solvent: a mixture of water and methanol (95:5).
(621))—The liquid chromatograph is equipped with a Solution A—Use filtered and degassed acetonitrile.
348-nm detector and a 3.1-mm x 12.5-cm column that Solution B—Use a filtered and degassed solution of 5.88
contains 5-um packing LI. The column temperature is g of phosphoric acid in 1000 mL of water.
maintained at 25°. The flow rate is about 1.0 mL per Standard solution—Dissolve an accurately weighed
minute. The chromatograph is programmed as follows. quantity of USP Agnuside RS in Solvent, with sonication.
Chromatograph the Standard solution, and record the peak Dilute quantitatively, and stepwise if necessary, with
responses as directed for Procedure: the tailing factor for methanol to obtain a solution having a known
casticin is not more than 2.0; and the relative standard concentration of about 0.125 mg per mL. Filter through a
deviation for replicate injections is not more than 2.0%. cellulose membrane having a 0.45-um or finer porosity.
Test solution—Weigh accurately approximately 1000 mg
of ground plant material, and place in a suitable container
with a stopper. Extract twice with 40 mL of methanol,
0 50 50 equilibration using a hand homogenizer at 19000 rpm for 2 minutes.
0-13 50-+65 50-»35 linear gradi- Centrifuge, and transfer each supernatant to a 250-mL
ent round-bottom flask. Rinse the residue with methanol, and
13-18 65-+100 35^0 linear gradi- filter the resulting solution into the flask. Evaporate the
ent combined extract to dryness, and dissolve the residue in 2
18-23 100->50 0-»50 linear gradi- mL of Solvent. Quantitatively transfer the solution to a
ent solid-phase extraction cartridge packed with neutral
Procedure—Separately inject equal volumes (about 10 uL) aluminum oxide previously conditioned with 5 mL of
of the Standard solution and the Test solution into the Solvent. Connect the cartridge to a vacuum pressure not
Pharmacopeia! Forum
exceeding 300 mbar, and collect the eluate. Rinse the round- comparison with the chromatogram obtained from the
bottom flask with 2 mL of Solvent, and pass this solution Standard solution. Calculate the percentage of agnuside in
through the cartridge, apply the vacuum, and collect the the portion of Chaste Tree taken by the formula:
eluate. Rinse the cartridge with 4 mL of Solvent, and
l000(C/W)(ru/rs),
collect the eluate. Combine the eluates from the cartridge,
in which C is the concentration, in mg per mL, of USP Ag-
transfer to a 10-mL volumetric flask, and dilute with
nuside RS in the Standard solution; Wis the weight, in mg,
Solvent to volume.
of the Chaste Tree taken to prepare the Test solution; and rv
and rs are the peak responses of agnuside obtained from the
258-nm detector and a 3.1-mm x 12.5-cm column that
contains 5-jim packing LI. The column temperature is
maintained at 25°. The flow rate is about 1.3 mL per
minute. The chromatograph is programmed as follows.
Chromatograph the Standard solution, and record the peak
responses as directed for Procedure: the tailing factor for
BRIEFING
agnuside is not more than 2.0; and the relative standard
Powdered Chaste Tree— See briefing under Chaste Tree.
deviation for replicate injections is not more than 2.0%.
Add the following:
0 7 93 Equilibration
0-0.6
A f. C
7->10 93^90 Linear gradient Powdered Chaste Tree
U.O—J
10 90 Isocratic
5-7
7 1%
10-»14 90->86 Linear gradient » Powdered chaste tree is chaste tree reduced to
1—1J
14->15 86<-85 Linear gradient a powder or very fine powder. It contains not less
13-13.1
15^100 85-»0 Linear gradient than 0.05 percent of agnuside and not less than
13.1-18
100 0 Isocratic
18-18.1 0.08 percent of casticin, calculated on the dried
100->7 0^93 Linear gradient
18.1-23 basis.
7 93 Isocratic
Procedure—Separately inject equal volumes (about 10 Packaging and storage—Preserve in well-closed
uL) of the Standard solution and the Test solution into the containers.
chromatograph, record the chromatograms, and measure the Labeling—The label states the Latin binomial and,
areas of the analyte peaks. Identify the retention time of the following the official name, the part of the plant from
peak corresponding to agnuside in the the Test solution by which the article was derived.
USP Reference standards (11)—USP Agnuside RS. USP
Casticin RS. USP Powdered Chaste Tree Extract RS.
Pharmacopeial Forum
Botanic characteristics—Powdered Chaste Tree is dark Comments should be sent to USP Headquarters for considera-
tion by the Expert Committee on Analytical Microbiology no later
brown, with a musty, slightly aromatic odor, and a taste than June 1,2002.
resembling that of sage. The following characteristics are (AMB: D. Porter) RTS—35157-1
present: fragments of the calyx with covering and
glandular trichomes on the outer side and rectangular,
Add the following:
elongated cells with slightly wavy walls on the inner side;
fragments of exocarp with trichomes and cells with large
(1072) DISINFECTANTS AND
pits in the outer wall; thin-walled parenchymatous cells
ANTISEPTICS
and globules of fixed oil; stone-pitted cells from the
mesocarp; ovoid, lignified cells with bands of reticulate INTRODUCTION
thickening from the testa; and endosperm and cotyledons A sound cleaning and sanitization program is needed to
with fixed oil. prevent the microbial contamination of Pharmacopeial arti-
Other requirements—It meets the requirements of the tests cles in controlled environments used for manufacture. Drug
products may be contaminated via their pharmaceutical in-
for Identification, Microbial limits, Loss on drying, Total
gredients, process water, packaging components, manufac-
ash, Acid-insoluble ash, Pesticide residues, Heavy metals,
turing environment, processing equipment, and
Content ofcasticin, and Content of agnuside under Chaste
manufacturing operators. Current Good Manufacturing
Tree.
Practices (cGMPs) emphasize the size, design, construction,
and location of buildings and construction materials and the
GENERAL CHAPTERS appropriate material flow to facilitate cleaning, mainte-

nance, and proper operations for the manufacture of drug
products. When disinfectants are used in a manufacturing
General Information environment, care must be taken to prevent the drug product
from becoming contaminated with chemical disinfectants as
a result of the inherent toxicity of the disinfectants. The re-
quirements for aseptic processing include readily cleanable
BRIEFING
floors, walls, and ceilings having smooth and nonporous
(1072) Disinfectants and Antiseptics. This new general infor- surfaces; particulate, temperature, and humidity controls;
mation chapter provides guidance pertaining to disinfectants and
antiseptics. Sections for definitions, the role of disinfectants in and cleaning and disinfecting procedures to produce and
aseptic processing, types of disinfectants, disinfectant practices
in the pharmaceutical industry, disinfectant effectiveness valida- maintain aseptic conditions. The cleaning and sanitization
tion, environmental monitoring, and operator training are pre-
sented. program must achieve specified cleanliness standards, con-
trol microbial contamination of products, and be designed to
prevent the chemical contamination of pharmaceutical in-
gredients, product-contact equipment, packaging materials,
and ultimately the drug products. These principles also ap-
ply to nonsterile dosage forms where the microbial contam-
Pharmacopeia! Forum
ination is controlled by the selection of appropriate pharma- Chemical disinfectant—A chemical agent used on in-
ceutical ingredients, utilities, manufacturing environments, animate surfaces and objects to destroy infectious fungi,
sound equipment cleaning procedures, products especially viruses, and bacteria, but not necessarily their spores. Spor-
formulated to control water activity, inclusion of suitable icidal and antiviral agents are considered special classes of
preservatives, and product packaging design. disinfectants.
In addition to disinfectants, antiseptics are used to de- Cleaning agent—An agent for the removal of product
contaminate human skin and exposed tissue. Chemical ster- residues that may inactivate sanitizing agents or harbor mi-
ilants may be used to decontaminate surfaces in croorganisms from facility and equipment surfaces.
manufacturing and sterility testing areas. Furthermore, ster- Decontamination—The removal of microorganisms
ilants may be used for the sterilization of Pharmacopeial ar- by disinfection or sterilization.
ticles, and UV irradiation may be used as a surface sanitizer. Disinfectant—A chemical or physical agent that de-
This general information chapter will discuss the selec- stroys harmful microorganisms when applied to a surface.
tion of suitable chemical disinfectants and antiseptics; the Sanitizing agent—An agent for reducing the number
demonstration of their bactericidal, fungicidal, and sporici- of all forms of microbial life including fungi, viruses, and
dal efficacy; the application of disinfectants in the pharma- all forms of bacteria and their spores.
ceutical manufacturing area; and regulation and safety Sporicidal agent—An agent that destroys bacterial and
considerations. Additional information not covered in the fungal spores when used in sufficient concentration for a
chapter may be obtained from standard texts on disinfec- specified contact time. It is expected to kill all other vegeta-
1
tants and antiseptics. tive microorganisms.
Sterilant—An agent that destroys all forms of microbi-
DEFINITIONS
al life including fungi, viruses, and all forms of bacteria and
Antiseptic—An agent that inhibits or destroys microor-
their spores. Sterilants are liquid or vapor-phase agents.
ganisms on living tissue including skin, oral cavities, and
The order of resistance of clinically significant micro-
open wounds.
organisms to chemical disinfectants from most to least resis-
tant is listed in Table 1.
1
Ascenzi, J.M., Ed. Handbook of Disinfectants and Antiseptics, 5th ed.;
Marcel Dekker: New York, 1995.; Block, S.S., Ed. Disinfection, Steriliza-
tion, and Preservation, 5"1 ed.; Lippincott Williams & Wilkins Publishers:
Philadelphia, 2000.; Russell, A.D.; Hugo, W.B.; Ayliffe, G.A.J., Eds. Prin-
ciples and Practices of Disinfection, Preservation and Sterilization, 3rd ed.;
Blackwell Science Inc.: London, 1999.
Pharmacopeia! Forum
Table 1. The Resistance of Some Clinically Important Table 2. General Classification of Antiseptics,
Microorganisms to Chemical Disinfectants (Listed in Disinfectants, and Sporicidal Agents
Order of Decreasing Resistance) Example
Chemical Type Classification
Type of Examples Aldehydes Sporicidal agent 2% Glutaldehyde
Microorganisms Alcohols General purpose 70% Isopropyl
Bacterial spores Bacillus subtilis and Clostridium disinfectant, alcohol, 70%
sporogenes antiseptic, ethyl alcohol
Mycobacteria Mycobacteria tuberculosis antiviral agent
Non-lipid coated Poliovirus and rhinovirus Chlorine and Sporicidal agent 0.5% Sodium
viruses sodium hypochlorite
Fungi Trichophyton, Cryptococcus, and hypochlorite
Candida spp. Phenolics General purpose 500 jig per g
Vegetative bacteria Pseudomonas aeruginosa, disinfectant Chlorocresol,
Staphylococcus aureus, and 500 jig per g
Salmonella spp. chloroxylenol
Lipid-coated viruses Herpes simplex virus, hepatitis B Ozone Sporicidal agent 8% Gas by weight
virus, and human immunodefi- Hydrogen Vapor phase 4 ug per g H2O2
ciencv virus peroxide sterilant, liquid vapor, 10-25%
CLASSIFICATION OF DISINFECTANTS sporicidal agent, solution, 3%
Chemical disinfectants are classified by their chemical antiseptic solution
type. This includes aldehydes, alcohols, halogens, perox- Substituted Antiseptic agent 0.5% Chlorhexi-
ides, quaternary ammonium compounds, and phenolic com- diguanides dine gluconate
pounds (see Table 2). Peracetic acid Liquid sterilant, 0.2% Peracetic
vapor phase acid, 1 ug per g
sterilant peracetic acid
Ethylene oxide Vapor-phase 600 ugpergETO
sterilant
Quaternary General purpose 200 ug per g
ammonium disinfectant, Benzalkonium
compounds antiseptic chloride
/3-propiolactone Sporicidal agent 100ugperg/?-pro-

piolactone
Pharmacopeial Forum
The effectiveness of a disinfectant depends on its intrin- EPA registers chemical disinfectants marketed in the United
sic biocidal activity, the concentration of the disinfectant, States, and requires manufacturers to supply product infor-
the contact time, the nature of the surface disinfected, the mation on the use dilution, type of microorganisms killed,
hardness of water used to dilute the disinfectant, the amount and the necessary contact time (see Table 3). Certain liquid
of organic materials present on the surface, the type, and the chemical sterilizers intended for use on critical or semi-cri-
number of microorganisms present. Under the Federal In- tical devices are defined and regulated by FDA.
secticide, Fungicide, and Rodenticide Act (FIFRA), the
Table 3. Biocidal Activity, Organic Inactivation, Residual Activity, and Applications of Some Common Disinfectants
Chemical Bactericidal Fungicidal Sporicidal Inactivated by Residual Application

Class Organics Activity
Alcohols yes yes no no no antiseptic, removing disinfectant

residues
Aldehydes yes yes yes no yes disinfecting instruments
Chlorines yes yes yes yes no disinfecting surfaces
(hypochlor-
ite)
Hydrogen yes yes yes yes no antiseptic, vapor-phase sterilant
peroxide
Phenolics yes yes no weakly yes disinfecting surfaces
Peracetic acid yes yes yes no yes vapor-phase sterilant
Quaternary yes weak no yes yes antiseptic, disinfecting surfaces
ammonium
compounds
Substituted yes yes no no yes antiseptic; disinfecting
diguanides instruments
(chlorhexi-
dine)
Iodophors yes yes no no yes antiseptic
(providone
-iodine)
Ethylene yes yes yes no no vapor phase sterilant
dioxide
Pharmacopeial Forum
SELECTION OF AN ANTISEPTIC FOR HAND THEORETICAL DISCUSSION OF

AND SURGICAL SITE DISINFECTION DISINFECTANT ACTIVITY
Hands and surgical sites are disinfected in a hospital Plots of the log of the number of microorganisms per
setting to reduce the resident flora and to remove transient mL surviving in a disinfectant solution indicate that first-or-
flora (e.g., Streptococcus pyogenes) and methicillin-resis- der kinetics can be applied as a reasonable approximation to
tant S. aureus and P. aeruginosa that have been implicated the reduction in microbial count with respect to time. In
in hospital-associated infection . Use of antiseptics to disin- practice, the plots show a more sigmoid curve with a slower
fect hands has been shown to be more effective than soap initial reduction in numbers followed by an increasing rate
and water in reducing the counts of bacteria on the skin; re- with respect to time.
peated antiseptic use further reduces these counts. The rate constant, K, for the disinfection process can be
Common antiseptics include 4% chlorhexidine, 10% calculated by the formula:
providine-iodine, 3% hexachlorophane, 70% isopropyl al- (1/OOogiVAO,
cohol, and 0.5% chlorhexidine in 95% ethanol. in which t is the time, in minutes, for the microbial count to
be reduced from NQ to N; No is the initial number of organ-
SELECTION OF A DISINFECTANT FOR USE
IN A PHARMACEUTICAL MANUFACTURING isms, in cfu per mL; and N is the final number, in cfu per
ENVIRONMENT
mL, of organisms.
When selecting a disinfectant for use in a pharmaceuti-
As with a first-order chemical reaction, the same con-
cal manufacturing area, the following points must be con-
centration of disinfectant reduces the number of organisms
sidered: the number and types of microorganisms to be
more rapidly at elevated temperatures. This can be ex-
controlled; the spectrum of activity of commercially avail-
pressed as a temperature, T, coefficient per 10° rise in tem-
able disinfectants; the claims as a sterilant; the disinfectant
perature, Ql0, calculated by the formula:
or sanitizer supported by the EPA registrations; the concen-
tration, application method, and contact time of the disinfec- Time to decontamination at T° I
tant; the nature of the surface material being disinfected and

its compatibility with the disinfectant; the amount of organic Time to decontamination at (T +10)°,
compounds on the surface that may inactivate a disinfectant; in which 7: is T-10.
the possible need to maintain a residual bactericidal activity Further evidence that a first-order reaction is an inade-
of the disinfectant on the surface; the corrosiveness of the quate description of disinfection is that the Ql0 values for
disinfectant to equipment with repeated application; the chemical and enzyme reactions are 2 to 3, while the com-
safety considerations for operators applying the disinfec- mon disinfectants phenol and ethanol have a Ql0 of 4 and
tant; the compatibility of the disinfectant with cleaning 45, respectively.
agents and other disinfectants; the planned disinfectant rota- Critical to the successful employment of disinfectants is
tion; and the steps that need to be taken to avoid the contam- an understanding of the effect of disinfectant concentration
2
ination of pharmaceutical products by disinfectant. on microbial reduction. A plot of the log of the time to re-
duce the microbial population in a standard inoculum to
Denny, V.F.; Marsik, F.J. Current Practices in the Use of Disinfectants
within the Pharmaceutical Industry. PDA J. of Pharmaceutical Sci. and zero against the log of the disinfectant concentration is a
Tech., 1997,57, (6), 227-228.
Pharmacopeial Forum
straight line with the slope of the line termed the concentra- Another important consideration may be the pH of the
tion exponent, n. The relationship can be expressed as fol- disinfectant. Many disinfectants are more active in the io-
lows: nized form, while others are more active in the nonionized
form. The degree of ionization will depend on the pKa of the
n = (log of the kill time at concentration C2) - (log of the kill
agent and the pH of the disinfection environment. For exam-
time at concentration Cj)/(log Cx - log C2),
ple, phenol, with a pKa of 10, will be more effective at a pH
in which Cx and C2 are the higher and lower disinfectant below 7 where it is nonionized, while acetic acid will be
concentrations, respectively. more effective at a pH below 4 where it is ionized.
The wide differences in concentration exponents, n,
have practical consequences in picking the use dilution of MECHANISM OF DISINFECTANT ACTIVITY
different disinfectants and in using dilution to neutralize a Table 5 lists the sites and modes of action of some re-
disinfectant in disinfectant-effectiveness testing and routine presentative disinfectants.
microbial monitoring of the manufacturing environment.

For example, mercuric chloride has a concentration expo-
Table 5. Mechanism of Disinfectant Activity Against
nent of 1, so a threefold dilution will reduce the disinfectant
Microbial Cells
activity by 31 (or by one-third), while phenol with a concen-
tration exponent of 6 will have a 3 6 (or a 729-fold) reduction Target Disinfectant
in disinfectant activity. Disinfectants with a larger concen-
Cell wall Formaldehyde, hypochlorite,
tration exponent or dilution coefficient rapidly lose activity
and mercuricals
when diluted. The concentration exponents for some disin-
Cytoplasmic membrane, Anilides and
fectants are listed in Table 4.
action on membrane hexachlorophane
Table 4. Concentration Exponents of Common Anti- potential
septics, Disinfectants, and Sterilants Membrane enzymes, action Hexachlorophane

on electron-transport
Disinfectant Concentration Exponents
Hydrogen peroxide 0.5 Action on ATP Chlorhexidine and ethylene

Mercuric chloride 1 oxide
Chlorhexidine 2 Action on enzymes with Ethylene oxide,
Formaldehyde 1 -SH groups glutaraldehyde, hydrogen
Ethanol 9 peroxide, hypochlorite,
Phenol 6 iodine, and mercuricals
Quaternary ammonium 0.8 to 2.5 Action on general Alcohols, chlorhexidine, and
compounds membrane permeability quaternary ammonium
Aliphatic alcohols 6.0 to 12.7 compounds
Phenolic compounds 4 to 9.9
Pharmacopeial Forum
sition of their product, include toxicology data to document

Table 5. Mechanism of Disinfectant Activity Against their product is safe if used as directed on the label, include
Microbial Cells {Continued) efficacy data to document their claims of effectiveness
Target Disinfectant against specific organisms and to support the directions

for use provided in the labeling, and provide labeling that
Action on general Alcohols, chlorhexidine, and
reflects the required elements for safe and effective use.
membrane permeability quaternary ammonium
While these directions provide valuable information, they
compounds
may not be helpful in terms of the products' use as disinfec-
Cell contents, general Chlorhexidine, aldehydes,
tants in a manufacturing environment.
coagulation hexachlorophane, and
In the United States, the official disinfectant testing
quaternary ammonium
methods are published by AOAC International3 and include
compounds
the Phenol-Coefficient Test, Use-Dilution Method Test, and
Ribosomes Hydrogen peroxide and
Sporicidal Carrier Test. A scientific study submitted for EPA
mercuricals
review in support of disinfectant registration must be con-
Nucleic acids Hypochlorites
ducted at a laboratory facility that follows the Good Labora-
Thiol groups Ethylene oxide,
tory Practices (GLP) regulations (21 CFR 58). To
glutaraldehyde, hydrogen
demonstrate the efficacy of a disinfectant within a pharma-
peroxide, hypochlorite,
ceutical manufacturing environment, it may be deemed nec-
mercuricals
essary to conduct the following tests: use-dilution tests
(screening disinfectants for their efficacy at various concen-
MICROBIAL RESISTANCE TO
DISINFECTANTS trations and contact times against a wide range of standard
The development of microbial resistance to antibiotics test organisms and environmental isolates); surface chal-
is a well-described phenomenon. The development of mi- lenge tests (using standard test microorganisms and micro-
crobial resistance to disinfectants is less likely, as disinfec- organisms that are typical environmental isolates, applying
tants are more powerful biocidal agents than antibiotics and disinfectants to surfaces at the selected use concentration
are applied in high concentrations against low populations with a specified contact time, and determining the log reduc-
of microorganisms, so the selective pressure for the devel- tion of the challenge microorganisms); and a statistical com-
opment of resistance is less profound. parison of the frequency of isolation and numbers of
microorganisms isolated prior to and after the implementa-
DISINFECTANT CHALLENGE TESTING tion of a new disinfectant. For the surface challenge tests,
Under FIFRA, the EPA requires companies that register the test organisms are enumerated using swabs, surface
public health antimicrobial pesticide products including dis- rinse, or contact plate methods. Neutralizers that inactivate
infectants, sanitization agents, sporicidal agents, and steri-
lants to ensure the safety and effectiveness of their
products before they are sold or distributed. Companies re-
3
Cuniff, P. A., Ed. Official Methods of Analysis of AOAC International,
gistering these products must address the chemical compo- 15th ed.,; Association of Official Analytical Chemists: Arlington, VA, 1990
Pharmacopeial Forum
the disinfectants must be included in either the diluent or application). The efficacy of the neutralizes and their ability
microbiological media used for microbial enumeration or to recover inoculated microorganisms from the material
both (see Table 6). must be demonstrated during the use-dilution or surface
challenge studies. Points to remember are that disinfectants
Table 6. Neutralizing Agents for Common Disinfectants are less effective against the higher numbers of microorgan-
isms used in laboratory challenge tests than the numbers that
Disinfectant Neutralizing Agent
are found in clean rooms (see Microbiological Evaluation of
Alcohols Dilution or tween 80 Clean Rooms and Other Controlled Environments (1116));
Glutaraldehyde Glycine and sodium bisulfite that inocula from the log growth phase that are typically em-
Sodium Sodium thiosulfate ployed in laboratory tests are more resistant than those from
hypochlorite a static or dying culture or stressed organisms in the envir-
Chlorhexide Tween 80 and lecithin onment; and that microorganisms may be physically re-
Mercuric chloride Thioglycollic acid moved during actual disinfectant application in the
and other mercu- manufacturing area.
ricals Typical challenge organisms that may be employed are
Quaternary Tween 80 and lecithin listed in Table 7.
ammonium
compounds
Table 7. Typical Challenge Organisms
Phenolic Dilution or tween 80 and lecithin
compounds AOAC Challenge Organisms Typical Environmental
Universal neutralizer broths may be formulated to con- Isolates
tain a range of neutralizing agents. For example, Day/Eng- Bactericide: Escherichia Bactericide: Micrococcus
ley (D/E) broth contains 0.5% polysorbate 80, 0.7% coli,ATCC 11229; luteus, S. epidermdis,
lecithin, 0.1% sodium thioglycollate, 0.6% sodium thiosul- S. aureus, ATCC 6538; Coynebacterium jeikeium,
fate, 0.25% sodium bisulfite, 0.5% tryptone, 0.25% yeast P. aeruginosa, ATCC P. vesiclaris
extract, and 1.0% dextrose; letheen broth contains 0.5% 15442
polysorbate 80, 0.07% lecithin, 1.0% peptamin, 0.5% beef Fungicide: C. albicans, Fungicide: P. chrysogenum,
extract, and 0.5% sodium chloride; and Tryptone-Azolectin- ATCC 10231 or 2091; A. niger
Tween (TAT) broth base + tween 20 contains 4.0% (v/v) Penicillium chrysogenum,
polysorbate 20, 0.5% lecithin, and 2.0% tryptone. ATCC 11709; Aspergillus
In practice, sufficient organisms need to be inoculated niger, ATCC 16404
on a 2-inch x 2-inch square of the surface being decontami- Sporicide: B. subtilis, ATCC Sporicide: B. sphaericus, B.
nated to demonstrate at least a 2 ( for bacterial spores) to 3 19659 thureneensis
(for vegetative bacteria) log reduction during a predeter-
mined contact time (i.e., 10 minutes over and above the re-
covery observed with a control upon disinfectant
Pharmacopeial Forum
Because a wide range of different materials of con- address the assignment of responsibility, establishment of
struction are used in clean rooms and other controlled areas, schedules, details of cleaning operations, protection of clean
each material needs to be evaluated separately to validate equipment prior to use, inspection for cleanliness immedi-
the efficacy of a given disinfectant. Table 8 contains a list ately prior to use, and maintenance of cleaning and sanitiza-
of common materials used in clean room construction. tion records.
Involved staff require training in microbiology, indus-
Table 8. Typical Surfaces to be Decontaminated by Dis- try practices for cleaning and sanitization, safe handling of
infectants in a Pharmaceutical Manufacturing Area concentrated disinfectants, the preparation and disposal of
disinfectants, and the appropriate application methods. It
Material Application
must be emphasized that the preparation of the correct dilu-
Stainless steel 305L and Work surfaces, filling tions is critical since many disinfectant failures are attribu-
316L grades equipment, tanks, etc. table to use of excessively diluted disinfectant solutions.
Glass Windows and vessels Typically, disinfectants used in aseptic filling areas are di-
Plastic, vinyl Curtains luted with Water for Injection and are prepared aseptically.
Plastic, polycarbonate Insulation coating Since it is theoretically possible for the selective pressure of
Lexan (plexiglass) Shields the continuous use of a single disinfectant to result in the
Epoxyl coated gypsum Walls and ceilings presence of disinfectant-resistant microorganisms in a man-
Fiber glass reinforced Wall paneling ufacturing area, regulatory agencies advocate the rotation of
plastic disinfectants. Common practices include the daily use of a
Tyvek Equipment wraps phenolic compound and weekly use of a sporicidal agent or
Terrazzo tiles Floors the rotation of daily use of phenolic and quaternary ammo-
DISINFECTANTS IN A CLEANING AND nium compounds and weekly use of a sporicidal agent.
SANITIZATION PROGRAM
Other options may also be supported. Disinfectants applied
The selection of suitable disinfectants and the verifica-
on potential product contact surfaces are typically removed
tion of their effectiveness in surface challenge testing is cri-
with 70% alcohol wipes. The use of a sporicidal agent is fre-
tical in the development of a cleaning and sanitization
quently limited to weekly application, since they are com-
program.
monly oxidizing agents and may corrode stainless steel
Issues associated with the successful implementation of
equipment and degrade other materials used in facility con-
such a program are the development of written procedures,
struction. Facilities must be periodically cleaned to remove
staff training, selection of the disinfectant rotation, institu-
any disinfectant residues.
tion of application methods and contact times, environmen-
The greatest safety concerns are in the handling of con-
tal monitoring to demonstrate efficacy, and personnel safety.
centrated disinfectants and the mixing of incompatible dis-
The cGMP 21 CFR 211.67, Equipment Cleaning and
infectants. For example, concentrated sodium hypochlorite
Maintenance, details the requirements for written proce-
solutions (at a concentration of more than 5%) are strong
dures for cleaning, maintenance, and sanitization of pharma-
oxidants and will decompose on heating, on contact with
ceutical manufacturing equipment. These procedures must
Pharmacopeial Forum
acids, and under influence of light and will produce toxic Meeting, the Safe Medication Use Expert Committee and the Phar-
maceutical Dosage Forms Expert Committee have approved the
and corrosive gases including chlorine. In contrast, dilute publication of the current proposal in PF for public review and
comment. These expert committees acknowledge that circum-
solutions (at a concentration of less than 0.5%) are not con- stances may have changed and technological advances may have
occurred in this area since 1993 and, therefore, welcome reader
sidered hazardous. Under no circumstances should disinfec- comments regarding this proposal or alternatives to it. Comments
should be submitted to Dr. W. Larry Paul at USP headquarters by
tants of different concentrations be mixed. Material Safety April 15,2002.
Data Sheets for all the disinfectants used in a manufacturing (SMU: E. Cowley, W. L. Paul; PDF: G. Huang) RTS—
35056-1
area must be available to personnel handling these agents.
Appropriate safety equipment such as face shields, safety
glasses, gloves, and uniforms must be issued to personnel
handling the disinfectant preparation, and personnel must
(1198) STANDARDIZED IMPRINT
CODES FOR SOLID ORAL
be trained in the proper use of this equipment. Safety
DOSAGE FORMS
showers and eye wash stations must be situated in the work
area where disinfectant solutions are prepared. BACKGROUND
Concern has increased in recent years regarding the is-
sue of patient confusion and concern resulting from the in-
ability of patients and health care professionals to identify
BRIEFING
solid oral dosage forms quickly and easily. The problem is
(1198) Standardized Imprint Codes for Solid Oral Dosage
Forms. One of the resolutions adopted by the USP Convention most evident in those instances where product selection may
at the April 2000 USP Quinquennial Meeting provided that
"USP should explore the advisability and feasibility of developing cause different generically equivalent products of the same
and promoting standardized imprint coding for all solid oral dosage
forms, after a date to be determined by the USP Board of Trustees drug to be dispensed to the same patient at different times.
in cooperation with appropriate partners, to aid practitioners' and
consumers' ability to readily identify and safely use medications." The problem becomes compounded when additional gener-
This is not a new topic for USP. A Stimuli article on this topic
was published on pages 1002-1003 ofPF16(5)[Sept.-Oct. 1990]. ically equivalent products are dispensed, since the generic
Also, an October 1990 proposal was published in USP DI Update
that suggested the assignment of an alphanumeric code to each equivalents may not bear any physical similarity to each
drug or unique combination of drugs. Subsequent proposals were
published in USP DI Update in October 1991 and May 1993. A other. For patients receiving multiple prescriptions that are
flexible drug imprinting system was established by FDA in their
September 13, 1993 Final Rule. (See 21 CFR §206.10.) This rule candidates for generic equivalent selection, the need to iden-
provided that "Unless exempted under §206.7, no drug product in
solid oral dosage form may be introduced or delivered for introduc- tify the dosage forms and differentiate among them is even
tion into interstate commerce unless it is clearly marked or im-
printed with a code imprint that, in conjunction with the more acute.
product's size, shape, and color, permits the unique identification
of the drug product and the manufacturer or distributor of the pro- In addition to this concern about patient confusion,
duct. Identification of the drug product requires identification of its
active ingredients and its dosage strength. For purposes of this sec- health care providers are often put in the situation of having
tion, code imprint means any single letter or number or any com-
bination of letters and numbers, including, e.g., words, company to identify medicines that patients are taking. Drug products
name, and National Drug Code, or a mark, symbol, logo, or mono-
gram, or a combination of letters, numbers, and marks or symbols, frequently must be identified in conjunction with a regular
assigned by a drug firm to a specific drug product."
Errors have been reported through the USP-ISMP Medication office or pharmacy visit, during a home care visit, or during
Errors Reporting Program in which patients have mistakenly
mixed medications in one prescription vial and were unable to ea- an emergency, such as where an overdose is suspected. In
sily separate the medications to their proper vials due to inadequate
markings on the medications. response to 21 CFR §206.10, most solid oral dosage forms
With the adoption of the "standardized imprint code" resolution
by the USP Convention in 2000 and the adoption of a similar re- are currently identified by some combination of manufac-
solution by the American Medical Association at its 2000 Annual
Pharmacopeial Forum
turer-specific color, shape, and markings. However, the in- to avoid potential confusion with the numerals 1, 0,
dividual practitioner, in many cases, does not have the re- and 2. In some circumstances the numbers 6 and 9
sources available to make the identification. may also not be used.). Lettering that facilitates optical
The guidelines presented in this general information character recognition, such as the OCR-A font, for im-
chapter provide a standardized visual identification system prints is recommended, and if possible, all or some of
for solid oral dosage forms intended for human and veteri- the dropped letters may be reinstituted in the future to
nary use. This system is intended to be non-manufacturer- increase the number of potential combinations, if the
specific in that each given strength of drug or unique com- potential for confusion can be eliminated.A vast major-
bination of strengths of drugs will be assigned a specific ity of products available as solid oral dosage forms are
nonproprietary code that will be utilized by every manufac- large enough to allow imprinting, inscription, emboss-
turer of this dosage form. To enhance international accep- ing, or printing of a 4-character code on one side of the
tance and application, these guidelines incorporate the product. Other products that are too small to handle a 4-
system of codes for antibiotics developed by the Interna- character code will be assigned 2-character or 3-charac-
tional Chemotherapeutic Society in collaboration with the ter codes. Some products that are very small, such as
WHO Regional Office for the Western Pacific (WPRO). Nitroglycerin Tablets, will necessarily be exempt since
imprints will not be feasible.Assignment will be ran-
GENERAL GUIDANCE dom after selected pre-assignments have been made
1. Each strength of a drug or unique combination of to account for certain alphanumeric codes that are cur-
strengths of drugs will be assigned by USP an alphanu- rently used by manufacturers or distributors and for the
meric code of 4 characters (2-character or 3-character 2-character and 3-character codes currently being used
codes may be utilized in certain instances). Thus, for for antibiotics by the International Chemotherapeutic
example, 10-mg propranolol hydrochloride tablets Society. Other than as stated above, commonly used ab-
would be assigned one code, while the 20-mg or any breviations and acronyms will not be used to make pre-
other strength of the single entity would be assigned a assignments.The randomly generated assignment lists
different code (however, the first 3 characters of the will be screened and altered before fmalization so as
code for all propranolol products would remain con- to avoid potentially confusing or inappropriate charac-
stant, with the fourth character changing to signify ter (letter or number) strings (e.g., "25MG").
the different strengths). Propranolol hydrochloride 2. Identifiers will be assigned to all prescription and non-
and hydrochlorothiazide combination products would prescription drugs (whether compendial or noncompen-
be assigned entirely different codes. Each manufacturer dial), available as solid oral dosage forms for human
or distributor of the same-strength generic substance or and veterinary use. Assignments will also be made
combination would use the same code.Approximately for vitamins, minerals, and nutritional supplements.
1,000,000 possible unique combinations of the code 3. The strength of the product will be included as part of
would be available for assignment (10 numbers and the code. The name of the manufacturer or distributor
22 letters of the alphabet; I, O, Q, and Z are not used will not be part of the code. The manufacturer or distri-
Pharmacopeial Forum
butor name or logo can be imprinted elsewhere on the to microbiological test methods. General microbiological methods
covered include qualitative, quantitative, and microbial identifica-
tablet or capsule. tion methods.
Comments should be sent to USP Headquarters for considera-
4. The use of the USP identifiers is voluntary. A list of as- tion by the Expert Committee on Analytical Microbiology no later
than June 1,2002.
signments will be published in Pharmacopeial Forum
(AMB: D. Porter) RTS—35158-1
and on the USP web site, and manufacturers, distribu-
tors, and purchasers may make use of the identifiers as
they choose. Similarly, if the United States Food and
Drug Administration determines a standardized im-
(1223) VALIDATION OF
ALTERNATIVE
printing requirement to be necessary or, if other na-
MICROBIOLOGICAL METHODS
tional or international bodies, e.g., national drug
regulatory bodies, pharmacopeias, or the World Health INTRODUCTION
Organization wish to endorse a system of standard Microbiological testing laboratories sometimes use test
codes, then the USP identifiers could be used for that methods other than those described in the general chapters
purpose. for microbial recovery and identification for a variety of rea-
5. Because the program is voluntary, and as certain exist- sons such as economics, higher throughput, and conveni-
ing codes will undoubtedly continue to be used by cer- ence. Validation of these substitute methods is required.
tain manufacturers or distributors, each USP-assigned The Tests and Assays section in the General Notices and Re-
alphanumeric identifier will include a unique symbol quirements provides some guidance on the validation of al-
(such as an underscore or an asterisk) to differentiate ternate methods, citing that the method under consideration
it from other identifiers. If the USP identifiers become must provide an advantage in accuracy, sensitivity, preci-
the standard and if the program is mandated, this unique sion, selectivity, or adaptability to automation or computer-
symbol will be dropped. ized data reduction or other special circumstances. The
6. As new products are developed, new identifier assign- section also notes that in the event of a dispute, only the re-
ments will be made, published for review in accordance sult obtained by the compendial test is conclusive.
with normal procedures, and maintained by USP. Proposed alternative tests must be adequately vali-
dated. General information chapter Validation of Compen-
dial Methods (1225) provides guidance on the validation
of chemical assays proposed for adoption as compendial as-
BRIEFING
says. It is the purpose of this general information chapter to
(1223) Validation of Alternative Microbiological Methods.
The purpose of this new general information chapter is to provide provide guidance on the demonstration of the suitability of
guidance for validating methods for use as alternatives to the offi-
cial compendial microbiological methods. The official compendial alternative microbiological methods to be used as part of, or
microbiological methods assume the use of traditional microbiolo-
gical methods (i.e., planting, broth growth, biochemical reactions). in lieu of, compendial assays.
Although Procedures in the section Tests and Assays in the Gen-
eral Notices and Requirements provides for the use of alternate
methods, no guidance is provided on how to demonstrate that
the new method is at least suitable for its intended use as is the
traditional (validated) method. This chapter is similar in many re-
spects to general information chapter Validation of Compendial
Methods (1225) but provides an emphasis particularly relevant
Pharmacopeial Forum
TYPES OF MICROBIOLOGICAL TESTS is taken as evidence of the presence of viable microorgan-

It is critical to the validation effort to identify the por- isms in the test sample. Other examples of this type of test-
tion of the test addressed by alternate technology. For exam- ing are those tests designed to evaluate the presence or
ple, there are a variety of technologies available to detect the absence of a particular type of microorganism in a sample
presence of viable cells. These techniques may have appli- (e.g., coliforms in potable water, Listeria monocytogenes
cation in a variety of tests (e.g., bioburden, sterility test) but in food, etc.).
may not, in fact, entirely replace the critical aspects of the
Quantitative Tests for Enumeration of Microorganisms—
test. For example, a sterility test by membrane filtration may
The standard plate count method is the archetype of this
be performed according to the compendial procedure up to
class of tests used to estimate the number of viable micro-
the point of combining the processed filter with the recovery
organisms present in a sample. The Most Probable Number
media, after which the presence of viable cells might then be
(MPN) method is another of these tests. MPN was devel-
demonstrated by use of some of the available technologies
oped as a means to estimate the number of viable microor-
(see Table 1). Validation of this application would, there-
ganisms present in a sample not amenable to direct plating.
fore, require validation of the recovery system employed
rather than the entire test.
Identification Tests—The classical methods of identifica-
tion used in compendial tests are biochemical and morpho-
Table 1. Examples of Technologies to Demonstrate the
logical characterization of an unknown microorganism.
Presence of Viable Organisms
Recently developed methods have streamlined and auto-
Technology Application mated aspects of this identification test, especially in the
growth in liquid culture qualitative determination areas of data handling, analysis, and storage. Several new
impedance qualitative determination approaches that have been integrated into these methods in-
ATP bioluminescence qualitative determination clude biochemical reactions, carbon substrate utilization,
flow cytometry qualitative determination characterization of fatty acid composition, and restriction
head space gas measurement qualitative determination endonuclease banding patterns of 16S rDNA.
plate counts quantitative determination
General Concerns—Validation of a microbiological meth-
epifluorescent vital dye quantitative determination
od is the process by which it is experimentally established
There are three major types of determinations specific
that the performance characteristics of the method meet the
to microbiological tests, including tests to determine if mi-
requirements for the intended application. As microbiologi-
croorganisms are present in a sample, tests to quantify the
cal tests have three basic applications, three separate sets of
number of microorganisms (or to enumerate a specific sub-
validation criteria are required. These concerns are de-
population of the sample), and tests designed to identify mi-
scribed below, and summarized in Table 2.
croorganisms.
Qualitative Tests for the Presence or Absence of Mi-

croorganisms—The sterility test is the most common ex-
ample of this test; the turbidity of a liquid growth medium
Pharmacopeial Forum
Table 2. Validation Parameters by Type of microbiological method is expressed as the relative rates of
Microbiological Test false positive and false negative results between the new
Identification method and the compendial method using a standardized,
Parameter Qualitative Quantitative
Tests low-level inoculum.
Tests Tests
yes yes Determination—The rate of occurrence of false nega-

accuracy yes
precision no yes no tive results in the presence of the sample for the two meth-
specificity yes yes yes ods is estimated using low levels of standard challenge
detection yes yes no organisms. This design is similar to the standard bacterios-
limit tasis/fungistasis test; however, the level of microorganisms
quantification no yes no inoculated must be very low (not more than 5 cfu per unit).
limit This low level of inoculum will ensure a frequency of failure
linearity no yes no rates sufficiently high enough to provide a means to com-
range no yes no pare the two methods. The alternate method must provide
robustness yes yes yes at least as high a recovery as the compendial method.
rueeedness ves yes ves

Specificity—
VALIDATION OF QUALITATIVE TESTS FOR
RECOVERY OF MICROORGANISMS IN A Definition—The specificity of an alternate qualitative
SAMPLE
microbiological method is its ability to detect a range of mi-
Accuracy— croorganisms that may be present in the test article.
Definition—The accuracy of a qualitative microbiologi- Determination—This concern is adequately addressed

cal method is described as the closeness of the test results by growth promotion of the media for qualitative methods
obtained by the test method to the value obtained by the that rely upon growth to demonstrate microbial presence or
compendial method. absence of microorganisms. However, for those methods
that do not require growth as an indicator of microbial pre-
Determination—An example of accuracy is shown in
sence, the specificity of the assay for microbes assures that
the case of a sterility test comparing the rate products pro-
extraneous matter in the test system does not interfere with
duce positive and negative results using the alternative
the test.
method versus the compendial method.
Detection Limit—
Precision—
Definition—The detection limit is the lowest number of
Definition—The precision of a qualitative microbiolo-
microorganisms in a sample that can be detected under the
gical method is the degree of agreement between the alter-
stated experimental conditions. A microbiological detection
nate method and the compendial method when the
limit test determines the presence or absence of microorgan-
procedures are performed repeatedly on different lots of
isms. Due to the nature of microbiology, the detection limit
the same product. The precision of an alternative qualitative
Pharmacopeial Forum
refers to the number of organisms present in the original be paid to the inherent instability of microbiological suspen-
sample before any dilution or incubation steps; it does not sions, and experimental protocols must be randomized to
refer to the number of organisms present at the point of as- eliminate bias. As there are no agreed upon standards for
say. current methods, acceptance criteria are problematic. It is
essential, however, that an estimate of the ruggedness of
Determination—The two methods (alternative and com-
the alternate procedure be developed.
pendial) are assessed by inoculation with a low number of
standard challenge microorganisms (not more than 5 cfu per Robustness—
unit) followed by a measurement of recovery. The level of
Definition—The robustness of a qualitative microbiolo-
inoculation must be adjusted until at least 50% of the sam-
gical method is a measure of its capacity to remain unaf-
ples show growth in the compendial test. It is necessary to
fected by small but deliberate variations in method
repeat this determination several times, as the detection limit
parameters and provides an indication of the method's relia-
of an assay is determined from a number of replicates (not
bility during normal usage.
less than 5). The ability of the two methods to detect the pre-
sence of single organisms can be demonstrated using the Determination—Robustness is a validation parameter
chi-square test. best suited to determination by the supplier of the test meth-
od. As there are not agreed upon standards for current meth-
Quantification Limit, Linearity, and Range—Not ap-
ods, acceptance criteria are problematic and must be tailored
plicable to qualitative assays.
to the specific technique. It is essential, however, that an es-
Ruggedness— timate of the robustness of the alternate procedure be devel-

oped.
Definition—The ruggedness of a qualitative microbio-
logical method is the degree of precision of test results ob- VALIDATION OF QUANTITATIVE
ESTIMATION OF VIABLE
tained by analysis of the same samples under a variety of MICROORGANISMS IN A SAMPLE
normal test conditions, such as different analysts, instru-
ments, lots of reagents, laboratories, etc. Ruggedness can Accuracy—
be defined as the intrinsic resistance to the influences ex-
Definition—The accuracy of a quantitative microbiolo-
erted by operational and environmental variables on the re-
gical method is the closeness of the test results obtained
sults of the microbiological method. Ruggedness is a
by the alternate method to the value obtained by the com-
validation parameter best suited to determination by the sup-
pendial method. Accuracy must be demonstrated across
plier of the test method who has easy access to multiple in-
the practical range of the test. Accuracy is usually expressed
struments and batches of components.
as the percentage of recovery of microorganisms by the as-
Determination—One method to demonstrate rugged- say method.
ness is to prepare a suspension of microorganisms and test
at least several replicates against each assay variable in or-
der to compare values among laboratories. Attention must
Pharmacopeial Forum
Determination—Accuracy is demonstrated by prepar- is not larger than the compendial method. Results ± 0 . 5 log
ing a suspension of microorganisms at the upper end of are considered precise in microbiological testing.
the range of the test, serially diluted down to the lower
Specificity—
end of the range of the test. For example, if the alternative
method is meant to replace the traditional plate count meth- Definition—The specificity of a quantitative microbiolo-
od for viable counts, then a reasonable range might be from gical method is its ability to detect a range of microorgan-
6
10° to 10 cfu per mL. If it is, instead, a replacement for the isms that demonstrate the method is fit for its intended
MPN method, a much more narrow range may be used. At purpose.
least five suspensions across the range of the test must be
analyzed for each challenge organism. The alternate method Determination—Specificity is demonstrated using the
must provide an estimate of viable microorganisms not less compendial organisms.
than 70% of the estimate provided by the compendial meth-

Detection Limit—Not applicable to quantitative assays.
od.
Quantification Limit—
Precision—
Definition—The quantification limit is a parameter of
Definition—The precision of a quantitative microbiolo- quantitative assays for low levels of microorganisms in sam-
gical method is the degree of agreement among individual ple matrices. It is the lowest number of microorganisms that
test results when the procedure is applied repeatedly to mul- can be determined with acceptable precision and accuracy
tiple samplings of suspensions of laboratory microorgan- under the stated experimental conditions.
isms across the range of the test. The precision of a
microbiological method is usually expressed as the standard Determination—As it is not possible to obtain a reliable
deviation or relative standard deviation (coefficient of varia- sample containing a known number of microorganisms, it is
tion). essential that the quantification limit of an assay is deter-

mined from a number of replicates (n > 5) at each of at least
Determination—Precision is demonstrated by preparing five different points across the range of the assay. The quan-
a suspension of microorganisms at the upper end of the tification limit is not greater than the compendial method.
range of the test and serially diluted down to the lower
end of the range of the test. At least 5 suspensions across Linearity—
the range of the test must be analyzed. For each suspension

Definition—The linearity of a quantitative microbiolo-
at least 10 replicates must be assayed in order to be able to
gical test is its ability to produce results that are proportional
calculate statistically significant estimates of the standard
to the concentration of microorganisms present in the sam-
deviation or relative standard deviation (coefficient of varia-
ple within a given range.
tion). Generally, a coefficient of variation in the 10 % to
15% range is acceptable. Irrespective of the specific results, Determination—The linearity must be determined over
the alternate method must have a coefficient of variation that the range of the test. A method to determine this is to select
at least five concentrations of each standard challenge mi-
Pharmacopeial Forum
croorganism and conduct at least five replicate readings of environmental variables of the microbiological method on
each concentration. The appropriate measure of linearity is test results.
the F-test, demonstrating that deviations from linearity do
Determination—Ruggedness is a validation parameter
not exceed the variability of the data. This is done by deter-
best suited to determination by the supplier of the test meth-
mining the ratios of deviations from the linearity mean
od with easy access to multiple instruments and batches of
square to the within-groups mean square. The F ratio for
components.
the alternate method does not exceed that of the compendial
test. The ratio of deviations from the linearity mean square Robustness—
to the within-groups mean square will equal 1 if the data are
Definition—The robustness of a microbiological method
described by a straight line. This ratio will be greater than 1
is a measure of its capacity to remain unaffected by small
if they are not a straight line, as the deviations from linearity
but deliberate variations in method parameters and provides
will exceed the variability of the data. Probability of the data
an indication of its reliability during normal usage.
variations are then derived from a table of critical F values.
A graphic depiction of deviations from linearity can also be Determination—Robustness is a validation parameter
plotted as residuals from the regression against the estimate. best suited to determination by the supplier of the test meth-
An unequal distribution of the residual values around zero od.
would indicate non-linearity.
VALIDATION OF ALTERNATIVE MICROBIAL
Range—
IDENTIFICATION METHODS
There is a large body of evidence that different meth-
Definition—The range of a quantitative microbiological ods vary considerably in their ability to identify microorgan-
method is the interval between the upper and lower levels of isms in compendial articles. It must be accepted that a
microorganisms that have been determined with precision, method of identification needs to be internally consistent
accuracy, and linearity using the method as written. but may differ from others in identification of unknown iso-
lates. In other words, identification of an isolate based on
Determination—The range of the method is demon-
biochemical activity may lead to one conclusion, identifica-
strated by verifying that the method provides acceptable
tion by fatty acid analysis to another, identification by DNA
precision, accuracy, and linearity when applied to samples
analysis may lead to a third, and other methods may lead to
throughout the range.
alternate conclusions. Microbiological identifications by a
Ruggedness— particular system flow directly from previous experience
with that system, and therefore may well differ from identi-
Definition—The ruggedness of a quantitative microbio-
fications by another system. It is critical, however, that each
logical method is the degree of precision of test results ob-
system provide a consistent identification of isolates from
tained by analysis of the same samples under a variety of
compendial articles, but it is not required that each agree
normal test conditions, such as different analysts, instru-
with all other methods.
ments, lots of reagents, etc. Ruggedness is normally ex-
pressed as the lack of influence of operational and
© 2002 The United States Pharmacopeial Convention, inc. All Rights Reserved.
Pharmacopeial Forum
Accuracy— Ruggedness—
Definition—Not applicable beyond standard organisms. Definition—Ruggedness is normally expressed as the

The accuracy of a microbiological identification method is lack of influence of operational and environmental variables
the closeness of the test results obtained by the test method of the microbiological identification method on test results.
to the value obtained by the compendial method.
Determination—Ruggedness is a validation parameter
Determination—Accuracy is demonstrated with a ser- best suited to determination by the supplier of the test meth-
ies of well-defined stock culture organisms. od with easy access to multiple instruments and batches of
components.
Precision—
Robustness—
Definition—The precision of a microbiological identifi-
cation method is the degree of agreement among individual Definition—The robustness of a microbiological meth-
test results when the procedure is applied repeatedly to mul- od is a measure of its capacity to remain unaffected by small
tiple samplings of suspensions of laboratory microorgan- but deliberate variations in method parameters; robustness
isms across the range of the test. provides an indication of its reliability during normal usage.
Specificity, Detection Limit, Quantification Limit, Lin- Determination—Robustness is a validation parameter

earity, and Range—Not applicable to microbiological best suited to determination by the supplier of the test meth-
identification methods. od but in any event does not exceed that of the compendial
method.
STIMULI TO THE
REVISION PROCESS
This section may contain the following:
• reports or statements of authoritative committees
• original research reports
• evaluations of new and existing pharmacopeial methods
• commentaries
• articles relevant to compendial issues
These items are publised to stimulate discussion and continual review of pharmacopeial standards. Generally, if an Expert
Committee publishes an article on which they are specifically seeking comment, this will be clearly stated in the article.
Readers may submit comments on issues raised in this section, but comment is not as critical as that for In-Process Revision
and Pharmacopeial Previews sections. Readers interested in submitting should see Instructions to Authors.
STIMULI TO THE REVISION PROCESS
Stimuli articles do not necessarily reflect the policies Pharmacopeial Forum
162 of the USPC or the USP Council of Experts Vol. 28(1) [Jan.-Feb. 2002]

Method Considerations for Caco-2 Permeability Assessment in the Biopharmaceutics
Classification System, Sanna Tolle-Sander and James E. Polli 164
FIP Recommendations for Biopharmaceutical Characterization of Herbal Medicinal Products,
Friedrich Lang, Konstantin Keller, Michael Ihrig, Joy Oudtshoorn-Eckard, Helga Moller, Srini Srinivasan,
and Yu He-ci, Hankintatukku 173
Pharmacopeial Forum Stimuli articles do not necessarily reflect the policies
V o l . 28(1) [Jan.-Feb. 2 0 0 2 ] of the USPC or the USP Council of Experts 163
Instructions to Authors
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Method Considerations for Caco-2 Permeability Assessment in the Biopharmaceutics

Classification System
Sanna Tolle-Sander and James E. Polli1, Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy
ABSTRACT TWO suggestions regarding methodology for permeability classification are described. The first suggestion
concerns comparing a test drug's permeability, PdrUg, to that of metoprolol, Pmetop, by considering the ratio Pdrug I Pmetop and the
ratio's lower 90% confidence limit. High permeability is concluded if the lower 90% confidence limit ofPdrug IPmetop is at least
0.90. The second suggestion concerns the utilization of permeability data from metoprolol and mannitol, Pman, to assess the
ongoing system suitability of Caco-2 monolayers used for permeability classification. A minimum ratio of Pmetop / Pman allows
for confidence in permeability classification. A lower 90% confidence limit for Pmetop I Pman of 5 ensures that the measured
permeability, Pdrug, is not upward-biased due to poor Caco-2 monolayer integrity.
INTRODUCTION phylline has high permeability). This emphasizes the need

to appreciate the differing approaches to even calculate per-
In the context of the Biopharmaceutics Classification
meability from the same flux data.
System (BCS), the aim of permeability determination is to
Secondly, a method to compare Pdrug to Pmetop that parallels
classify the permeability of a test drug as either high or low.
the approach to assess bioequivalence of plasma profiles is
One technique to measure permeability employs Caco-2
suggested. This method is based upon the construction of
monolayers, which have been utilized for over ten years
as a drug discovery tool (/). In contrast to drug discovery, the lower 90% confidence limit for the ratio ofPdrug I PmetOp.
the main purpose of BCS classification is not to rank-order a CALCULATION OF PERMEABILITY FROM CACO-2 FLUX
series of compounds; rather, it is to classify a drug as having DATA
high or low permeability.
Four methods to calculate permeability are compared in
Given the purpose in performing Caco-2 studies for BCS Table 1 and discussed below. These approaches emanate
permeability classification, methods that are refined differ- from two considerations: 1) the application of the transport
ently from those in drug discovery are needed. The objec- approach versus the slope approach in calculating perme-
tives in this article are two-fold: 1) to suggest methodology ability from flux data; and 2) whether the donor concentra-
to statistically compare a test drug's permeability, Pdrug, to tion is considered fixed at the initial donor concentration for
that of metoprolol, Pmetop, where metoprolol is a high-perme- all times or adjusted for drug loss from donor with time.
ability reference compound; and 2) to suggest methodology
to assess ongoing system suitability of Caco-2monolayers. Transport Approach Versus Slope Approach
The suggestions herein are illustrated by way of example,
using theophylline as a test drug. All four approaches to calculate permeability are appar-
ently the same in that each is based on the same mass trans-
METHODOLOGY TO COMPARE DRUG PERMEABILITY TO fer equation:
METOPROLOL
The BCS Guidance indicates metoprolol may serve as a dM R _

high-permeability reference compound (2). In order to clas- (1)
dt
sify the drug of interest (i.e., the test drug) as highly perme-
able, Pdrug needs to be about as high as Pmetop. Such an
assessment requires both calculation of permeability from
Caco-2 flux data and a method by which to compare Pdrug in which dMR is the amount of drug, in /imoles, accumu-
to the Pmetop. lated in the receiver compartment during the time interval
Firstly, four different methods to calculate permeability dt;dt is the length of the time interval in seconds; P is the
are examined in this article, each using the same theophyl- apparent drug permeability coefficient in cm/sec; A is the
line flux data. As the results below show, all .four methods area, in cm2, of the monolayer; and CD is the drug concen-
do not yield the same absolute permeability values, although tration, in mM, in the donor compartment. In a typical per-
each method provides the same final assessment (i.e., theo- meability study, drug transport from a donor compartment
into a receiver compartment is observed, usually over sev-
1
Correspondence should be addressed to James E. Polli, University of eral time intervals (e.g., 0-10 minutes, 10-20 minutes, 20-
Maryland School of Pharmacy, 20 North Pine Street, Baltimore, MD 30 minutes, etc.). CD declines with time due to transport.
21201; Telephone: (410) 706-8292; E-mail: jpolli@rx.umaryland.edu.
Vol. 28(1) [Jan.-Feb. 2002] of the USPC or the USP Council of Experts 165
From Equation 1, permeability, P, for each time interval Method Comparison

can be calculated by the formula:
s s There are four ways to calculate permeability: using
p__dM R /dt either the transport approach or the slope approach and
(2) using either donor adjustment or fixed donor concentration.
ACn
The methods discussed in Table 1, Methods A, B, C, and D,
use different combinations of each of the four approaches.
Method A applies Equation 2 for each time interval and
in which dMssR is the mass transported across the mono- measures the change of drug in the receiver compartment.
layer at steady-state in //moles; and the other terms are as The remaining CD from one time interval becomes the sub-
defined above. P from each time interval is calculated and sequent time intervals starting CD (i.e., performs donor ad-
used to determine the reported P. The approach using Equa- justment). Loss from the donor is estimated from the
tion 2 is termed here the transport approach. cumulative amount appearing in the receiver.
Alternately, the reported P can be calculated by consider- Method B is the same as Method A, except the initial CD is
ing the cumulative mass transported versus the time profile used for all time intervals (i.e., fixed donor concentration is
from Equation 1 by the formula: applied). The decrease in CD with time is assumed to be neg-
ligible in Method B.
Methods C and D employ the slope approach to calculate
p = (3) P. As with Method A, Method C adjusts CD each time inter-
val. Method D assumes CD to be constant for all time inter-
vals.
For each method, flux data is considered only if a steady
in which slope is the linear slope (i.e., steady-state portion) state is attained, mass balance is between 85% and 105%,
of the cumulative mass transported versus time profile, in \i and the comparison of metoprolol and mannitol indicate
mole /sec; and the other terms are as defined above. The ap- system suitability, as discussed below.
proach using Equation 3 is termed here as the slope ap-
proach. Influence of Different Calculation Methods
The slope approach and the transport approach use iden-
tical data in different ways. Typically, data are obtained To illustrate the influence of calculation Methods A, B, C,
from each monolayer via sampling over several time inter- and D on the resulting P value, each method was applied to
vals, resulting in the need to pool data and calculate a single a theophylline data set (Table 2). Metoprolol was used as a
permeability value for each monolayer. The approaches dif- high-permeability standard; mannitol was employed as a
fer in the manner that data is pooled to calculate an indivi- low-permeability standard. All tests were run at a pH of
dual P value from each monolayer. In the slope approach 6.8. Initial CDs of mannitol, metoprolol, and theophylline
(i.e., Equation 3), flux data from the time intervals for each were 0.004 mM, 0.44 mM, and 0.1 mM, respectively.
monolayer is immediately pooled because the slope utilizes As shown in Table 2, Methods A and C yielded similar P
cumulative mass transported versus time data across all time values, as did Methods B and D. Table 2 also shows that
intervals. In the transport approach, data is only pooled in theophylline Pdrug is dependent upon donor adjustment.
the final calculation, after P for each time interval is calcu- The Pdmg was about 45 x 10"6 cm/sec with donor adjustment;
lated from Equation 2, and is then averaged to yield an in- however, the Pdrug was only about 36 x 10'6 cm/sec without
dividual P for each monolayer. The individual P values are donor adjustment. Hence, donor adjustment resulted in
combined into an average drug P, which is reported as a higher P value, compared to when CD was considered fixed
mean P with standard error of the mean (SEM). at the initial theophylline concentration of 0.1 mM. This dif-
ference in Pdrug was statistically significant (ANOVA, Tu-
key's p < 0.001). This effect was attributed to
Adjusted Versus Fixed CD theophyllines high permeability, where CD dropped from
0.1 mM to approximately 0.07 mM within one hour; hence,
A second factor takes into consideration whether the do- CD was not constant during the flux experiment. Co became
nor concentration is assumed fixed at the initial CD at all progressively smaller, resulting in a higher P value than if
times or adjusted for drug loss from the donor with time. CD was always taken to be 0.1 mM.
For high-permeability drugs, CD can easily decrease by For metoprolol and mannitol, Methods A,B,C, and D re-
30% or more during the flux study. The CD to calculate a sulted in similar P values (ANOVA p > 0.3 for each), as
P value for each time interval may be adjusted for the mass shown in Table 2. A donor adjustment effect was qualita-
lost to the receiver during the previous time interval. The tively observed for metoprolol, although it was not statisti-
process of correcting CD for drug loss into the receiver is cally significant. Due to metoprolol's smaller (and slightly
termed here donor adjustment. If the donor concentration more variable) P value relative to theophylline's P, adjusting
is assumed fixed (i.e., no donor adjustment is applied), the CD or using the initial CD throughout had no statistically sig-
process is termed here as fixed donor concentration. nificant effect; the decrease in the metoprolol CD over time
Stimuli articles do not necessarily reflect the policies Pharmacopeia! Forum
was not as large as the drop observed for the more perme- from the same flux data. Additionally, a method to compare
able theophylline. A donor adjustment effect was not appar- Pdrug to Pmetop is suggested, which is based upon the construc-
ent for mannitol (ANOVA p= 0.36) because its permeability tion of the lower 90% confidence limit for the ratio Pdrug I
is low, and the mannitol CD remained essentially unchanged. •* metop-
Hence, for a highly permeable compound such as theo- It should be noted, although all the studies above were
phylline, where CD significantly declines with time (e.g., performed at a pH of 6.8, Pmetop is pH-dependent (Fig. 1).
30% in 1 hour), Methods A and C provide higher P values It is unclear what pH or pHs are necessary. However, given
than Methods B and D. It is well-known that inter-laboratory metoprolol's high permeability at higher pHs, the use of a
differences in permeability values occur. Perhaps the perme- pH of 6.8 is perhaps a conservative method to classify a
ability calculation method alone can explain part of this compound's permeability as either high or low versus meto-
variability. Nevertheless, as shown below, the effect of per- prolol.
forming or not performing donor adjustment is eliminated
when the ratio of theophylline versus metoprolol is consid- METHODOLOGY TO ASSESS ONGOING SYSTEM
ered. Therefore, the permeability calculation method may be SUITABILITY OF CACO-2 MONOLAYERS
of interest in comparing permeability values across different
laboratories and perhaps is an issue to which to be sensitive, Prior to classifying drug permeability as high or low, a
albeit not necessarily an important issue for the BCS. laboratory must demonstrate system suitability for the meth-
od. For Caco-2 studies, the permeability of 20 compounds
METHOD TO COMPARE PDRUG TO THE PMETOP must be measured, and a plot of the human fraction ab-
Metoprolol has been suggested as a high-permeability sorbed versus the Caco-2 permeability must be made (2).
standard (2, 3). However, it may not be clear how to com- In order to ensure ongoing system suitability when per-
pare the Pdrug to Pmetop. Need theophylline permeability ex- forming subsequent drug classification, a low permeability
ceed metoprolol permeability? If so, by how much? What marker such as mannitol is needed. Mannitol is hydrophilic
statistics are needed? A method to compare Pdrug to Pmetop and permeates the monolayer through the paracellular
is suggested here. This method parallels the approach to as- "aqueous pore" pathway (e.g., tight junctions, along with
sess bioequivalence of plasma profiles and is based upon the permeation through any monolayer defects). Mannitol's per-
construction of the lower 90% confidence interval for the meability is low, unless the monolayer is damaged, because
ratio of Pdrug I Pmetop- It is suggested that the lower 90% con-tight junctions of a confluent cell monolayer offer only little
fidence limit ofPdrug I Pmetop need be greater than or equal to area for transport (4). In essence, mannitol is an indicator of
0.90 in order for the test drug to be deemed highly perme- monolayer integrity.
able. This criterion provides confidence that the test drug is A compound with high passive permeability, such as me-
at least nearly as permeable as metoprolol. toprolol, mostly uses the transcellular pathway, along with a
Table 3 presents the ratio of Pdrug I Pmetop at a pH of 6.8. minor contribution of the paracellular pathway to overall
Theophylline and metoprolol were present in the same do- metoprolol permeability. A drug with a larger molecular size
nor solution. Methods A, B, C, and D yielded the same BCS than mannitol would generally be expected to possess a
result of high Pdrug, since the lower confidence limit in all paracellular permeability less than mannitol's P value. Pman,
cases was larger than 0.90. Moreover, the mean Pdrug I Pmetop then, is a conservative (i.e., rather high) estimate of meto-
ratios from all four methods were the same, even though do- prolol's paracellular permeability, given metoprolol's
nor adjustment yielded higher absolute P values {Methods A slightly larger molecular size (<5). Therefore, mannitol's per-
and C) than when no donor adjustment was performed meation can be considered to represent the paracellular
{Methods B and D), as shown in Table 3. transport contribution in the permeability determination of
It should be noted that both Table 3 and this report only metoprolol across competent Caco-2 monolayers (Fig. 2).
discuss the passive apical-to-basolateral permeability of The following method is presented to utilize the ratio of
theophylline and do not present other important considera- metoprolol and mannitol permeabilities as an ongoing sys-
tions in permeability classification (e.g., determination of tem suitability test. Given that the fraction doses of meto-
the test drug's susceptibility to efflux). prolol and mannitol absorbed are 95% and 16%,
respectively (5), the Pme(op / Pman ratio for the Caco-2 mono-
SUMMARY OF METHODOLOGY layer needs to be some minimum value well above 1, in or-
A methodology to compare a Pdrug to Pmetop is suggested to der to discriminate between highly permeable and lowly
classify permeability as high or low, where metoprolol is a permeable drugs. The lower 90% confidence limit of
high-permeability reference marker. Four different methods Pmetop I Pman should be > 5, in order for permeability results
to calculate permeability were examined, each using the to be considered, as demonstrated below. A sufficient differ-
same flux theophylline data set. All four methods did not ence between metoprolol and mannitol permeabilities
always provide the same absolute P values, although all four would indicate that the paracellular pathway contributes
methods did provide similar Pdrug I Pmetop results and final as- only a fraction to the permeability of a high passive perme-
sessment results (i.e., theophylline is highly permeable). ability compound.
Nevertheless, this first point emphasizes the need to appreci-
ate the differing approaches to even calculate permeability
The influence of increasing paracellular permeability on creases (i.e., as the monolayer becomes progressively more
the apparent or overall permeability of compounds with "leaky"). As in Fig. 3, the four plotted data points in each
high, medium, and low transcellular permeability (P,rans) series in Fig. 4 correspond to a 0%, 5%, 10%, and 20% in-
was simulated. The permeability of mannitol was used as crease in P (left to right), due to increased Pman above 2 x
the paracellular permeability of the simulated compounds. 10"6 cm/sec. Again, in each series the left-most data point
P was calculated by the formula: utilized a Pman value of 2 x 10 6 cm/sec (i.e., 0% increase
in/ 3 ).
1 1 1 Fig. 4 demonstrates that, for drugs with at least moderate
(4) P, a PdmS I Pman ratio of > 5 or more ensures that an increase
p aq cell aq P +P
man trans in P due to monolayer "leakiness" is less than 10%. A Pdrug I
Pman of five or more ensures that P is not over-estimated due
to poor monolayer integrity. In Fig. 4, a 10% increase in P
in which Paq and Pceu are the permeability coefficients, in requires a ratio ofPdrug I Pman about four or lower. Because a
cm/sec, of the aqueous boundary layer and cell monolayer, minimum Pdrug I Pman ratio of five results in a less than 10%
respectively. Paq was fixed for all cases at 1 x 10-4 cm/sec. error in P, this minimum value ensures sensitivity of the
Pceii is the sum of combined paracellular (Pman) and transcel- monolayer to discriminate between high and low permeabil-
lular (Ptrans) transport, assuming passive transport only. ity compounds. To establish ongoing system suitability, a
In the simulation investigation of the influence of Pman on minimum Pmewp I Pman of 5 is reasonable because it implies
P values, Ptrans was varied from 1 x 10"6 cm/sec to 70 x 10'6 that not more than one-fifth of metoproloFs flux across the
cm/sec, representing low to high transcellular permeability. monolayer is attributable to aqueous pores and monolayer
Pman was varied between 1 x 10"6 cm/sec and 31 x 10"6 cm/ defects.
sec. As a point of reference, Pman typically is less than 4 x This analysis suggests that the Pmetop I Pman ratio can serve
10"6 cm/sec in a 4-day Caco-2 system (5). Pman = 2 x 10"6 as an assessment of ongoing functionality of Caco-2 mono-
cm/sec indicates that a monolayer is well-formed. Pmart is layers to classify passive permeability. As discussed above,
used as the paracellular permeability contribution of the (si- P of the test drug is compared against Pmetop to classify the
mulated) test drug. test drug as a high or low permeability compound. With a P
In Fig. 3, P values increased with increasing Pman for all of about 30 x 10"6 cm/sec, metoprolol is represented in Fig.
drugs, most dramatically for drugs with low Ptrans. For exam- 4 by the closed diamonds (P,ram. = 40 x 10"6 cm/sec). A 10%
ple, the P value of a low permeability drug (P,rans = 1 x 10'6 increase in Pmetop in Fig. 4 required Pmetop I Pman= 3.96, which
cm/sec) increased 20% when Pman was marginally increased is well below a value of 5.
from 2.0 x 10"6 cm/sec to 2.62 x 10-6 cm/sec. Meanwhile, P In Table 4, the Pmetop I Pman ratio and its lower 90% con-
of a high permeability drug (Ptrans - 70 x 10-6 cm/sec) in- fidence limit is shown for the theophylline data set. Perme-
creased 20% only after Pman was increased 15-fold (from ability values were calculated using Method A. The lower
2.0 x 10-6 cm/sec to 30.9 x 10'6 cm/sec). The four plotted 90% confidence limit for Pmetop I Pman was well above 5.
data points in each series in Fig. 3 correspond to a 0%, 5%, Hence, given the results in Table 3 for theophylline, along
10%, and 20% increase in P (left to right), due to increased with the PmetOp I Pman ratio in Table 4 indicating the ongoing
Pman above 2 x 10"6 cm/sec. In each series, the left-most data suitability of the Caco-2 monolayers, it is concluded that
point utilized a Pman value of 2.0 x 10"6 cm/sec. theophylline is a high permeability drug.
Fig. 3 emphasizes that the paracellular pathway, as quan-
titatively represented by Pman, is one of two parallel routes SUMMARY
for a drug to permeate in a passive fashion across Caco-2
In the BCS, the aim of permeability determination is to
monolayers. Ptrans is the other route. Either mechanism can
classify the permeability of a test drug as either high or
dominate total permeability. In Fig. 3, when Pman > Ptrans, P is
low. Two suggestions regarding methodology of Caco-2
particularly sensitive to changes in Pman. Conversely, when
permeability classification have been put forward and exem-
Pman < Ptrans, P is relatively insensitive to changes in Pman,
plified by a theophylline permeability data set. The first sug-
such that apparently large Pman values do not compromise
gestion details a method to compare a test drug's
an interpretation that a highly permeable drug is indeed
permeability to metoprolol's permeability to assess whether
highly permeable. Of course, in order for the monolayer
the drug is highly or lowly permeable by considering the
to be discriminating, a practical difference between the per-
Pdrug I Pmetop ratio. This method parallels the approach to as-
meability of mannitol and a reference high permeability
sess bioequivalence of plasma profiles and is based upon the
drug is needed.
construction of the lower 90% confidence limit for the ratio
Fig. 4 addresses the issue of assessing system suitability of theophylline permeability versus metoprolol permeabil-
of Caco-2 monolayer to differentiate between high and low ity, Pdmg I Pmetop- High permeability is concluded if the lower
permeability drugs. Using data from the same simulation 90% confidence limit of Pdrug I Pmetop is at least 0.90. It was
study above, Fig. 4 depicts the dependence of P values on also noted that several methods to calculate P exist and can
the Pdrug I Pman ratio. Fig. 4 essentially parallels Fig. 3, in that provide different absolute permeability values, albeit not an
the drug P value increases when Pman is increased. The Pdrug I
Pman ratio in Fig. 4 decreases from left-to-right as Pman in-
issue for the BCS. Table 4 lists theophylline's Pdrug I Pmetop REFERENCES
ratio and lower 90% confidence limit, which indicates theo- 1. Hidalgo 1.1 Cultured intestinal epithelial cell models. Pharm.
phylline to be highly permeable. Biotechnol. 1996, 5:, 35-50.
The second suggestion concerns the utilization of meto- 2. CDER, Guidance for Industry: Waiver of In Vivo Bioavail-
ability and Bioequivalence Studies for Immediate Release Solid
prolol and mannitol permeability data to assess ongoing sys- Oral Dosage Forms Containing Certain Active Moieties/Active In-
tem suitability of Caco-2 monolayers, by considering a gredients Based on a Biopharmaceutics Classification System.
minimum acceptable ratio of Pmetop I Pman that would allow Food and Drug Administration: Rockville, MD, 2000.
for confidence in permeability classification. A lower 90% 3. (1089) In Vitro Absorption-Indicating Cell Culture System.
confidence limit for Pmetop I PmM of >5 will ensure that the Pharmacopeial Previews, PF 25(5), 1999, 8733-8737.
measured P is not upward-biased by poor Caco-2 mono- 4. Soergel K.H. Showdown at the tight junction. Gastroenterol-
layer integrity. In Table 4, the lower 90% confidence limit ogy. 1993, 705(4): 1247-50.
for Pmetop I Pman was well above 5, indicating ongoing system 5. Lentz K.A; Hayashi J.; Lucisano L.J.; Polli I E . Development
of a more rapid, reduced serum culture system for Caco-2 mono-
suitability, such that the high permeability classification of layers and application to the biopharmaceutics classification sys-
theophylline is considered valid. tem. Int. J. of Pharm. 2000, 200(1), 41-51.
6. Adson A.; Raub T.J.; Burton P.S.; Barsuhn C.L.; Hilgers
ACKNOWLEDGEMENTS A.R.; Audus K.L.; Ho N.F. Quantitative approaches to delineate
paracellular diffusion in cultured epithelial cell monolayers. J.
The authors wish to thank Dr. Ajaz S. Hussain for his Pharm. Sci. 1994, 53(11), 1529-36.
helpful comments about the manuscript. We also thank
Dr. Kimberley Lentz and Dr. Bhagwant Rege for making
the data sets available to us.
Table 1. Methods to Calculate Permeability from Flux Data

Method Equation Donor Concentration Adjustment
A transport approach (Equation 2) yes
B transport approach (Equation 2) no
C slope approach (Equation 3) yes
D slope approach (Equation 3) no
Table 2. Influence of Calculation Method on Apparent Permeability2

p P
•*• drug
•* metop 'man
Method
6
x 10 (cm/sec) x 106 (cm/sec) x 106 (cm/sec)
A 44.6 (± 0.6)3 32.8 (± 3.0) 1.96 (± 0.05)
B 36.7 (± 0.1) 28.5 (± 2.3) 1.96 (±0.05)
C 45.0 (± 0.4)3 32.8 (± 2.6) 1.87 (±0.06)
D 36.1 (± 0.3) 27.5 (± 1.6) 1.86 (±0.05)
mean permeability (± SEM)

Donor adjustment resulted in significantly higher permeability.
Table 3. Influence of Calculation Method on Permeability Ratios and Their Lower 90% Confidence Limits:
Theophylline Data
Lower 90% Confidence Limit of
Method^ M e a n Pdrug I Pmet0 p IP
£
* drug ' metop
A 1.38 (±0.21) 1.15
B 1.32 (±0.08) 1.11
C 1.39 (±0.11) 1.19
D 1.30 (±0.101 1.17
No significant differences between PdntJPmelop across Methods A, B, C, and D (ANOVA p > 0.16).
Table 4. Assessment of Theophylline Permeability Classification and Ongoing System Suitability

Lower 90% Confidence
Attribute Metric Metric Mean Value Limit of Metric
theophylline classification p IP 1.38 (± 0.12) 1.15
•* drug < * metop
ongoing system suitability
P IP
16.7 (± 1.1) 14.5
* metop 1 *• man
Absolute permeability values calculated via Method A.
6 7 8
PH
Fig. 1. Dependence of metoprolol permeability on pH. Consistent with metoprolol's weakly basic chemistry, metoprolol permeability
decreases as metoprolol is ionized at a lower pH.
bulk solution (well mixed)
aqueous
diffusion lavcr
tell monoLiver
SfiftKN
Fig. 2. Schematic of drug transport across Caco-2 monolayer. From a bulk solution, the drug must permeate across the aqueous boundary
layer (characterized by Paq) and the cell monolayer. Passive permeability across the cell monolayer is the sum of transcellular permeability
(P,ram) ^^ paracellular permeability (/%„). In the analysis of the minimum required Pmelop I Pman ratio, Ppara for metoprolol is assumed to be
equal to Pman.
60 -i
J2
at)
irme
40 -
3fl -
Ê 20 -
&. 10 -
5 10 15 20 25 30 35
Mannitol Permeability (cm/sec >: 1Cf)
Fig. 3. Dependence of apparent drug permeability on mannitol permeability. The legend denotes drug transcellular permeability (cm/sec x
106). Monolayers with higher mannitol permeability yield higher apparent drug permeability. Mannitol is used here as an indicator of
monolayer "leakiness" (i.e., paracellular permeability and monolayer defects). However, the sensitivity of a drug's permeability to mannitol
permeability depends upon the transcellular permeability of the drug, where drugs with high transcellular permeability (e.g. 70 x 10'6 cm/
sec) are less sensitive to monolayer defects. Labels in 0%, 5%, 10%, and 20% from left to right denote the % increase in P caused by
increased /"„,, as compared to the P value where Pman of 2.0 x 106 cm/sec was used.
25
Ratio of Apparent Permeability vs
Mannitol Permeability
Fig. 4. Dependence of apparent drug permeability on the ratio of apparent drug permeability versus mannitol permeability. Legend denotes
drug transcellular permeability (cm/sec x 106). This analysis suggests that the ratio of metoprolol permeability versus mannitol perme-
ability Pmelop I Pman can serve as a metric for monolayer suitability, with a minimum Pmetop I Pmm ratio of five required for acceptable suitability.
Pmetop I Pman ratios below five (to the right of dashed vertical line) may result in increased drug permeability, due to compromised monolayer
integrity. Labels in 0, 5, 10 and 20 % from left to right denote the % increase in P caused by increased Pman, as compared to the P value
where Pmm of 2.0 x 106 cm/sec was used.
Pharmacopeia! Forum Stimuli articles do not necessarily reflect the policies
FIP1 Recommendations for Biopharmaceutical Characterization of Herbal Medicinal Products

Members of the Herbal Medicinal Products Working Group, International Pharmaceutical Federation: Dr. Friedrich Lang,2 Chair, Firma
Dr. W. Schwabe, Karlsruhe, Germany; Prof. Dr. Konstantin Keller, Bundesinstitutfur Arzneimittel und Medizinprodukte, Bonn, Germany;
Dr. Michael Ihrig, Zentrallaboratorium Deutscher Apotheker, Eschbom, Germany; Ms. Joy Oudtshoorn-Eckard, J. a. B. Pharmaceutical
Consultants, Johannesburg, South Africa; Prof. Dr. Helga Moller, Zentrallaboratorium Deutscher Apotheker, Eschborn, Germany;
Dr. Srini Srinivasan, United States Pharmacopeia; Dr. Yu He-ci, Hankintarukku OY, Finland
ABSTRACT In this article, a working group of the International Pharmaceutical Federation (FIP) reports on their draft of
recommendations for the biopharmaceutical characterization of herbal medicinal products. On the basis of their composition
and efficacy, plant extracts are classified as Type A (containing constituents solely responsible for therapeutic activity), Type
Bl (containing chemically defined constituents possessing active markers, and Type B2 (containing no constituents docu-
mented as being determinant or relevant for efficacy or as having pharmacological or clinical relevance). At present, different
brands of herbal medicinal products are often uncritically substituted one for the other. Using the proposed classification
system, recommendations are presented for deciding what biopharmaceutical studies are needed to evaluate products that
may be substituted for an approved medicinal product.
It is recommended that products containing extracts of Type A or Bl, but not B2, should comply with the Note for
Guidance on the Investigation of Bioavailability and Bioequivalence (2). A waiver of the bioequivalence requirement can be
justified by considerations of certain characteristics of both the active pharmaceutical ingredient and the actual medicinal
product.
INTRODUCTION The existing tight network of rules concerning dissolution

testing (1) and investigation of bioavailability and bioequi-
[Note—This article was first published in Pharmazeu- valence (2) has not yet been completely transferred to
tische Industrie (Pharmaceutical Industry), Pharm. Ind., HMPs. The first steps in that direction are the USP drafts
2001, 63 (10).] of monographs on dietary supplement products that include
In 1999, the International Pharmaceutical Federation dissolution testing and a European Agency for the Evalua-
(FIP) Special Interest Group (SIG) Quality of Pharmaceuti- tion of Medicinal Products (EMEA) proposal on Guidance
cals established a working group to provide recommenda- on Specifications for HMPs (3). In most cases, there is no
tions for biopharmaceutical characterization of herbal doubt that a complete and rapid dissolution of the whole
medicinal products (HMPs). In light of the current European plant extract is a prerequisite for clinical efficacy of HMPs.
and American regulatory guidelines on quality for HMPs, it Yet some lipid and essential oil herbal drug formulations
was felt that there is a need for clarification of biopharma- will not completely dissolve.
ceutical characteristics, taking into account the classification
The present paper proposes strategic and practical gui-
of HMPs.
dance in deciding what biopharmaceutical studies are nec-
In contrast to chemically defined drug products, the bio- essary for HMPs and how these studies should be
pharmaceutical quality and behavior of herbal medicinal conducted. Because different brands of HMPs are often un-
products (HMPs) are often not well documented. In most critically substituted one for the other by physicians, phar-
cases, in vitro/in vivo biopharmaceutical characterization macists and patients, special attention will also be given to
is complicatedby the complex composition of herbal drug scientific aspects of substitution of herbal medicinal pro-
preparations, extensive metabolism of constituents, and ducts from the same plant and also to the question of
the resulting analytical difficulties. Moreover, the active whether clinical or bioequivalence studies may be replaced
pharmaceutical ingredient (API) of HMPs is generally de- by in vitro investigations.
fined to be the whole herbal preparation, i.e., the extract
in its entirety. Only in selected cases have individual or
groups of constituents been identified as being responsible
for the therapeutic activity (see Table 1 below).
1
International Pharmaceutical Federation
2
Correspondence should be addressed to Dr. Friedrich Lang, Mailbox
410925, D-76209 Karlsruhe, Germany. Please submit comments on this
draft within 2 months after publication.
CHEMICAL COMPOSITION AND CLASSIFICATION OF ACTIVE sification seems to be useful in determining the scientific le-
PHARMACEUTICAL INGREDIENTS IN HMP AS A vel and future efforts for biopharmaceutical characterization
PREREQUISITE FOR BIOPHARMACEUTICAL of HMPs. Table 1 lists some examples from the European
CHARACTERIZATION and German Pharmacopoeias {4).
For herbal drug preparations in which the entire extract is
Table 1. Extract Monographs of the European and the
regarded as the active pharmaceutical ingredient (API), the
German Pharmacopoeias
following extract types can be identified on the basis of
pharmaceutical-analytical, pharmacological-toxicological, European Pharmacopoeia German Pharmacopoeia
and clinical findings:
Aloe dry extract, Valerian root dry extract (B2)
Type A Extracts containing constituents {single standardized (A)
or groups) that are solely responsible Buckthorn bark dry Ipecacuanha dry extract,
for the known and acknowledged/well extract, standardized standardized (A)
documented therapeutic activity: (A)
Adjustment (standardization) to a de- Senna leaf dry Rhubarb dry extract,
fined content is acceptable (e.g., standar- extract, standardized standardized (A)
dized Senna leaf dry extract) using inert (A)
excipients or preparations with a higher Belladonnae leaf dry Horse Chestnut seed dry
or lower content. extract, standardized extract, standardized (A)
(A)
Type Bl Extracts containing chemically defined St. Johns Wort dry Ginkgo dry extract,
constituents {single or groups) posses- extract (Bl)* standardized (Bl)
sing relevant pharmacological proper- Milk thistle fruit dry
ties {active markers): extract, standardized (A)*
These substances are likely to contri-
bute to the clinical efficacy; however, draft in Pharmeuropa
evidence that they are solely responsible
for the clinical efficacy is not yet avail-
able (e.g., extracts of Ginkgo and of St. SPECIAL ASPECTS OF HERBAL MEDICINAL PRODUCTS:
John's Wort). The characterization of INVESTIGATIONS OF BIOAVAILABILITY OR
these extracts should take into consid- BlOEQUIVALENCE
eration, as far as possible and where re-
levant, the particular state of knowledge In many cases, HMPs are based on traditionally known
concerning the documented efficacy, herbal materials and preparations (extracts). Their use is of-
quality, and safety of an extract. Standar- ten well established but not based on systematic preclinical
dization by blending different lots of an and clinical studies. Traditional HMPs may show great dif-
herbal drug before extraction, or by mix- ferences in the type of extracts used (even from the same
ing different lots of herbal drug prepara- plant), the dosage forms, and strengths. The role of bioavail-
tions is appropriate and acceptable. ability and bioeqivalence (BA/BE), in the case of substitu-
Adjustment using excipients is not action of one product by another, has not yet been classified.
ceptable. In relatively few cases have HMPs been developed using
documented pharmacological, toxicological, and clinical
Type B2 Extracts containing no constituents experiments either from known traditional herbs (e.g. Silibi-
documented as either being determinant num marianum. in Europe), or from herbs and indications
or relevant for efficacy, or having phar- not included in the acknowledged traditional use (e.g., Gink-
macological or clinical relevance: go biloba). These HMPs often contain concentrated or pur-
In these cases, chemically defined ified extracts in order to improve the dosage or to reduce
constituents (markers) without known side effects. For new HMPs or those that are developed
therapeutic activity, may be used for by advanced technology, a question arises regarding the re-
control purposes (e.g., Valerian or sting- quirements for a product intended to be substituted for the
ing nettle root extract). These markers specific approved herbal medicinal product.
may be used to monitor good manufac- The EMEA Note for Guidance on the Investigation of
turing practice or as an indication of the Bioavailability and Bioequivalence (in principle for chemi-
assay/content of the drug product. cally defined active substances) contains definitions that
may also be applicable to HMPs (2).
This classification system implies that an extract may pro-
gress from Type B2 to Bl, and even to Type A as additional
knowledge about the extract is acquired. The proposed clas-
PHARMACEUTICAL EQUIVALENCE THERAPEUTIC EQUIVALENTS

Herbal medicinal products are pharmaceutically equiva- A medicinal product is therapeutically equivalent to an-
lent if they contain the same quantity of the same active sub- other product if it contains the. same API and clinically
stance that complies with the same specifications in the shows the same efficacy and safety as that of another pro-
same dosage form. Pharmaceutical equivalence does not ne- duct for which the efficacy and safety has been demon-
cessarily imply bioequivalence because differences in the strated. For chemically defined substances, demonstration
excipients and/or the manufacturing process may lead to of comparative bioavailability or bioequivalence is gener-
faster or slower dissolution and/or absorption. ally the most appropriate method for substantiating the ther-
A strict interpretation of the above for HMPs would im- apeutic equivalence of medicinal products that are
ply that extracts from the same plant are not pharmaceutical pharmaceutical equivalents or alternatives, provided those
equivalents if manufactured by different methods and with substances contain only excipients that are generally recog-
different extraction solvents. Different formulations, using nized as not having an influence on safety and efficacy.
the same extracts (e.g. coated tablets or soft gelatine cap- Therapeutic equivalence of HMPs may in many instances
sules, even immediate-release products) may also not auto- be demonstrated by either the biopharmaceutical classifica-
matically be regarded as pharmaceutical equivalents. tion system (BCS) or clinical studies rather than by bioequi-
Therefore, the significance of the same specification is of valence studies. Under certain circumstances, BCS data on
great importance (3). the API (plant extracts or constituents relevant for efficacy)
may qualify for a bioavailability/bioequivalence study
waiver. In many cases, however, clinical studies are required
Essentially Similar Product to demonstrate therapeutical equivalence.
A proprietary medicinal product is essentially similar to
another product if it has the same qualitative and quantita- IN VITRO DISSOLUTION TESTING OF HERBAL MEDICINAL
tive composition in terms of active substance/s (principles), PRODUCTS
the same pharmaceutical form, and, where necessary, bioe- In vitro dissolution testing is performed to determine the
quivalence with the reference product has been demon- rate and quantity of drug substances dissolved in a specific
strated by appropriate bioavailability studies. By extra- time. It is an important tool for characterization of the bio-
polation, for immediate-release products, the concept of es- pharmaceutical quality of a dosage form during develop-
sentially similar also applies to different oral forms (e.g. ta- ment and for controlling the quality of marketed products.
blets and capsules) with the same active substance/s (see the Comprehensive Guidelines for Dissolution Testing of Solid
Rules Governing Medicinal Products in the European Com- Oral Products have been established by FIP (7).
munity, Notice to Applicants, Vol 2A). The EMEA proposal (3) includes the dissolution test,
An essentially similar product is one that is intended to be which can, however, be omitted for rapid-release herbal
substituted for an innovator product. An innovator product medicinal products without constituents having known ther-
is a medicinal product authorized and marketed on the basis apeutic activity. The EMEA Note for Guidance does not ex-
of a full dossier, including chemical, biological, pharmaceu- plicitly cover herbal medicinal products containing extracts
tical, pharmacological-toxicological and clinical data. In the with constituents of known therapeutic activity (Type A) or
case of HMPs and plant extracts, essential similarity is de- pharmacologically relevant constituents (Type Bl). There-
termined by the manufacturing process (product by pro- fore, the FIP Working Group recommends defining the con-
cess). Essential similarity may be assumed if the stituent which may be tested for in vitro dissolution.
production methods and the specification are the same or es-
sentially the same. ACCEPTANCE CRITERIA
To ensure pharmaceutical equivalence (essentially similar In accordance with the EMEA proposal (5), disintegra-
composition), the specified herbal material, the drug pre- tion instead of dissolution testing may be sufficient for ra-
paration with the drug:extract ratio (DER), and the principal pidly dissolving products containing herbal drug
extraction method (mainly the primary extraction solvent) preparations that are highly soluble throughout the physio-
must be used. The more the constituents are qualitatively logical pH range. Acceptance criteria with a single point
and quantitatively congruent, the more such extracts are measurement are appropriate for immediate-release drug
equivalent. Essentially similar extracts must correspond products. Multiple point acceptance criteria are necessary
with respect to all of their constituents. Their fingerprints for modified-releasedosage forms.
should match qualitatively and quantitatively. Extensive si- Procedures and acceptance criteria should be set on the
milarity is most important especially if efficacy and safety basis of bioavailability/bioequivalence (BA/BE) studies
have been demonstrated for an individual plant extract in and in vivo dissolution data calculated from plasma concen-
its specific composition. trations measured in clinical studies. For HMPs, however,
relevant data are not available in the published literature.
For setting specifications, the physico-chemical properties,
e.g., the solubility and permeability of the API summarized lubility, high permeability; Class II, low solubility, high per-
in the Biopharmaceutical Classification System (BCS), are meability; Class III, high solubility, low permeability; and
useful. Class IV, low solubility, low permeability. In this context,
The following three categories of immediate-release high solubility and high permeability are defined as follows:
HMPs containing different types of API (extracts) have to High solubility implies that the highest dosage strength is
be considered in dissolution testing. more than 90% soluble in 250 mL of buffer. High perme-
ability implies that more than 80% of the dose is absorbed
Type A Dosage forms with extracts containing after oral administration. According to the BCS, a waiver of
constituents with known and acknowl- BA/BE studies is granted for Class I drugs. As an extension
edged therapeutic activity, solely re- of this, a waiver was also proposed for Class III drugs (7).
sponsible for the clinical efficacy: Some BCS principles were recently integrated into the
The API is adjusted (standardized) to Note for Guidance on the Investigation of Bioavailability
a defined content of the active com- and Bioequivalence for immediate-release forms (2). In or-
pound. The dissolution test is feasible. der to qualify for waiver of in vivo bioequivalence studies,
The quality of the individual product according to the Note for Guidance, the following character-
must be documented. istics should be considered:
Type Bl Extracts containing chemically defined
Characteristics related to the active pharmaceutical in-
constituents (single or groups) posses-
gredient.
sing relevant pharmacological proper-
• risk of therapeutic failure or adverse reactions
ties (active markers). It is likely that
• risk of bioinequivalence
these substances contribute to the clini-
• solubility (highest dosage strength in 250 mL of each of
cal efficacy:
three pharmacopoeial buffers preferably at pH 1.0, 4.6,
The dissolution test is feasible for ac- and 6.8)
tive markers. The choice of active mar-
• pharmacokinetic properties
kers for dissolution testing has to be
justified with respect to the particular
state of knowledge concerning efficacy, Characteristics related to the medicinal product.
quality, and safety of an extract. • rapid dissolution (85% dissolved within 15 minutes)
• excipients
• manufacture
Type B2 Dosage forms with extracts where no
constituents at all are acknowledged as
being determinant or relevant for effi- The Note for Guidance indicates that investigation of the
cacy, or as having pharmacological or solubility and the rapid dissolution of the API is of greater
clinical relevance. importance than investigation of the permeability of the ac-
tive pharmaceutical ingredient. Although it seems reason-
able to assume that bioavailability of an active ingredient
THE RELEVANCE OF THE BIOPHARMACEUTICAL depends on both solubility and permeability, only solubi-
CLASSIFICATION SYSTEM (BCS) FOR HMPS lity/dissolution may be pharmaceutically controlled and in-
fluenced by the pharmaceutical formulation. Therefore, for
The Biopharmaceutical Classification System (BCS),
which was originally developed for chemically defined syn- immediate-release herbal medicinal products, the solubility
thetic drug substances, may be helpful for HMPs as well (5). of the total extract and known pharmacological active con-
The BCS takes into account the physicochemical character- stituents are crucial parameters for a waiver of bioequiva-
istics of a compound, in particular their solubility in aqueous lence or clinical studies.
buffer systems of physiological pH, and their permeability
through gastrointestinal membranes (6). According to this
BCS, APIs are classified into four groups: Class I, high so-
EXAMPLES OF A 3-CLASS MODEL IN BIOPHARMACEUTICAL CHARACTERIZATION
DECISION TREES
Decision Tree 1 for Immediate-Release HMPs Containing Type A Extracts
BA/BE-study analytically possible?
BA/BE or clinical studies clinical studies necessary; BA/BE study necessary;

not necessary specification of in vitro dissolution specification
of in vitro dissolution
* characteristics as described above: no risk of therapeutic failure or adverse reactions, no risk of

bioinequivalence (2).
Stimuli articles do not necessarily reflect the policies Pharmacopeia] Forum
Decision Tree 2 for Immediate-Release HMPs Containing Type Bl Extracts:
characteristics* fulfilled?
reference and test product

essentially similar?**
yes
BA/BE or clinical clinical studies necessary; BA/BE study;

studies not necessary specification of in vitro dissolution specification of in vitro dissolution
•characteristics as described above; no risk of therapeutic failure or adverse reactions, no risk of

bioinequivalence (2).
** essentially similar as described above and according to reference (2).
Decision Tree 3 for Immediate-Release HMPs Containing Type B2 Extracts
Reference and test BCS-solubility of

formulation essentially extracts equivalent?
BA/BE or clinical studies not clinical study

necessary necessary
* essentially similar as described above and according to reference (2).
EXAMPLES AND COMMENTS formed with the specific dosage form. The specification
for the silymarin dissolution rate must be indicated for the
Decision Tree 1 purpose of registration and routine control of the marketed
product.
Formulations Containing Dry Extracts ofMilk Thistle (Car- Decision Tree 2

duus marianus)
Formulations Containing Dry Extracts of St. John's Wort
The reference product is a hard gelatine capsule contain-
(Hypericum perforatum)
ing 173-186.7 mg of dry extract from milk thistle fruits, cor-
responding to 140 mg of silymarin (calculated as silibinin).
The primary extraction solvent is ethyl acetate (> 97 %). The reference product is a coated tablet containing 300
The DER is 36-44:1. The test product to be substituted mg of dry extract from St John's Wort. The extraction sol-
for the reference product is a coated tablet containing vent is 80% methanol (v/v). The DER is 4-7:1. The test pro-
170-200 mg of dry extract from milk thistle fruits corre- duct is a hard gelatine capsule containing 425 mg of dry
sponding to 140 mg of silymarin (calculated as silibinin). extract from St John's Wort. The extraction solvent is
The primary extraction solvent is acetone. The DER is methanol 60% (w/w). The DER is 3.5-6:1.
35-45:1. Characteristics—The characteristics according to refer-
Characteristics—The characteristics of active substances ence (2) are not fulfilled. The total solubility of St. John's
and medicinal products as described in reference (2) are not Wort extract is less than 90% (see experimental data below).
fulfilled. The solubility of milk thistle extracts under physio- The known active markers, hyperforin and hypericines, are
logical conditions is low. A risk of bioinequivalence may be not soluble under BCS test conditions. The reference and
expected as a result of differences in solubility of the ex- test products have different specifications and are neither
tracts and differences in the dissolution profiles of the phar- pharmaceutically equivalent nor essentially similar.
maceutical formulations. The test product is neither Decision—Bioanalytical examinations are feasible and
pharmaceutically equivalent to the reference product nor es- are described for hyperforin and hypericin (9, 10). BA/BE
sentially similar. studies with respect to those markers are therefore possible.
Alternatively, clinical studies of the test product may be
Decision—BA/BE studies are feasible for silymarin (8).
Bioavailability or bioequivalence must be demonstrated by
relevant studies or alternatively by clinical studies per-
conducted. The specification for dissolution of active mar- A sample of 200 mg of the dry extract of milk thistle, cor-
kers should be indicated for registration and for routine con- responding to the specification of the test product (as de-
trol of the marketed product. scribed above in Formulations Containing Dry Extracts of
Milk Thistle under Examples and Comments) was dissolved
Decision Tree 3 in Buffers I—III. The solubility data obtained are listed in Ta-
ble 2 below. [Note—The solubility data of silibinin were ta-
Formulations Containing Dry Extracts of Valerian Roots ken from the literature (11).}
(Valerianae officinal)
Table 2. Solubility of Dry Extracts of Milk Thistle
The reference product is a sugar-coated tablet containing in Buffers I-III
125 mg of Valerian root extract. The extraction solvent is Buffer I Buffer II Buffer III
70% ethanol (v/v). The DER is 4-6.7:1. The test product
is a film-coated tablet containing 500 mg of Valerian root Milk thistle 18% 18% 25%
extract. The extraction solvent is 70% ethanol (v/v). The extract
DER is 4-7:1. batch 1
Characteristics—The test product is not essentially sim- Milk thistle 24% 27% 30%
ilar to the reference product, especially concerning strength extract
or potency. The extracts that are present in both dosage batch 2
forms may be assumed to be practically identical with re- Silibinin at 8 mg/250 ml
gard to their specifications. The solubility of the two dosage pH7.4
forms in the BCS buffers may also be assumed identical. It
is shown that even at the high dose of 500 mg, Valerian ex-
tracts are soluble in all BCS buffers. Decision Tree 2
Decision—Bioavailability or clinical studies may be
waived under these circumstances. Formulations containing dry extracts of St. John's Wort
(Hypericum perforatum)
EXPERIMENTAL DATA AND GUIDE FOR PRACTICAL
ASPECTS OF SOLUBILITY TESTS A sample of 425 mg of dry extract of St John's Wort cor-
responding to the specification of the reference product (as
GENERAL CONDITIONS FOR THE DETERMINATION OF THE
described above in Formulations Containing Dry Extracts
SOLUBILITY OF EXTRACTS AND ACTIVE MARKERS IN BCS
BUFFERS
of St. John s Wort under Examples and Comments) was dis-
solved in Buffers I-III. The solubility data obtained are
The solubility of extracts and active markers in BCS buf- listed in Table 3 below.
fers is examined,and it is determined if the quantity of ex-
tract contained in the highest strength of the product Table 3. Solubility of Extracts with methanol
dissolves in 250 mL each of Buffers I—III at 37° (Buffer I, in Buffers I-III
pH 1.0; Buffer II, pH 4.6; and Buffer III, pH 6.8).
After stirring for 60 minutes, the residues are filtered, Buffer I Buffer II Buffer III
dried at 10° for 2 hours, and weighed. As plant extracts
Extracts Batch 1 75% 94% 93%
may often contain rather insoluble "matrix" components
such as tannins, proteins, and other polymeric compounds with Batch 2 71% 84% 91%
assumed not to be linked to efficacy, extracts with a solubi- methanol Batch 3 80% 93% 95%
lity greater than 90% are classified as very soluble. Extracts 80%
with solubility less than 90% are classified as problematical. Hyperforin <250 ng/ 2.5 mg/ 7.5 mg/
Active markers are also classified as problematical if their (from 250 ml 250 ml 250 ml
solubility from extracts is less than 90%. extract)*
Hypericines <250 fig/ 8 mg/250 10 mg/250
(from 250 ml ml ml
EXAMPLES extract")
Decision Tree 1 * Assuming that 425 mg of St. John's Wort extract contain 0.85 mg of hy-
pericines (0.2 %) and 8.5 mg of hyperforine (2 %), the requirements for
BCS-solubility are not fulfilled.
Formulations Containing Dry Extracts of Milk Thistle (Car-
duus marianus)
Decision Tree 3 lity behavior of the dosage form, bioavailability, bioequiva-

lence or clinical studies may be waived. The Note for
Guidance, however, may be applied in the case of extreme
A formulation containing dry extracts of Valerian roots (Va- differences in solubility of the extracts.
lerianae officinalis)
REFERENCES
A sample of 500 mg of Valerian root dry extract, corre-
sponding to the specification of the reference product (as de-
scribed above in Formulations Containing Dry Extracts of 1. International Pharmaceutical Federation (FIP). FIP-
Valerian Roots under EXAMPLES AND COMMENTS) was Guidelines for Dissolution Testing of Solid Oral Pro-
dissolved in Buffers I—III. The solubility data are listed in ducts. Pharm. Ind. 1997, 59, 760.
Table 4 below. 2. Note for Guidance on the Investigation of Bioavailabil-
ity and Bioequivalence. CMPW/EWP/QWP/1401/98.
Table 4. Solubility of Dry Extracts of Valerian Root in 3. Note for Guidance on Specifications: test procedures
Buffers I-III and acceptance criteria for herbal drugs, herbal drug
preparations and herbal medicinal products. CPMP/
Valerian Root QWP/2820/00.
Extract Buffer I Buffer II Buffer III 4. Lang, F.; Stumpf, H. Considerations on future pharma-
Batch 1 97% 98% 99% copoeial monographs for plant extracts. Pharmeuropa,
Batch 2 93% 90% 99% 1999, 11, 268-275.
Batch 3 96% 92% 95% 5. Blume H.H.; Schug B.S. Biopharmaceutical character-
isation of herbal medicinal products: are in vivo studies
necessary? Europ. J. Drug Metabol. Pharmacokinet.,
SUMMARY 25, 41-48.
6. Amidon, G.L.; Lennernas, H.; Shah, V.P.; Crison, J.R.
Plant extracts can be classified on the basis of their com- A theoretical basis for a biopharmaceutic drug classifi-
position and efficacy into 3 categories (A, Bl, and B2). Her- cation: the correlation of in vitro drug product dissolu-
bal medicinal products containing extracts of categories A tion and in vivo bioavailability. Pharm. Res.,1995, 12,
or B1 should comply with the Note for Guidance on the In- 413^20.
vestigation of Bioavailability and Bioequivalence (2). 7. Blume, H.H.; Schug, B. Class III drugs-better candi-
In order to justify waiver of the bioequivalence require- dates for BA/BE waiver? Eur. J. Pharm. ScL, 1999,
ment, the following characteristics should be considered. 117-121.
8. Schulz, H.U.; Schiirer, M.; Krumbiegel, G.; Wachter,
Characteristics related to the active pharmaceutical in- W.; Weyhenmeyer, R.; Seidel, G. Untersuchungen
gredient zum Freisetzungsverhalten und zur Biodquivalenz von
• risk of therapeutic failure or adverse reactions Silymarin-Prdparaten. Arzneim.-Forsch. /Drug Res.,
• risk of bioinequivalence 1995, 45, 61-64.
• solubility (highest dosage strength in 250 ml of each of 9. Kerb, R.; Brockmoller, J.; Staffeldt, B.; Ploch, M.;
three pharmacopoeial buffers preferably at pH 1.0,4.6, Roots, I. Single-dose and steady-state pharmacoki-
6.8) netics of hypericin and pseudohypericin. Antimicrob.
• pharmacokinetic properties Agents Chemother, 1996, 40, 2087-2093.
10. Biber, A.; Fischer, H.; Romer, A.; Chatterjee, S.S. Oral
Characteristics related to the medicinal product bioavailability of hyperforin from Hypericum extracts
• rapid dissolution (85% dissolved within 15 minutes) in rats and human volunteers. Pharmacopsychiat.,
• excipients 1998, 57 (Suppl.), 36-43.
• manufacture 11. Ihrig, M.; Dedina, E.; Moller, H. Empfehlung einer ein-
Herbal medicinal products containing extracts of Type B2 heitlichen Spezifikation fur Silymarin-Fertigarzneimit-
need not comply with the above Note for Guidance. In the tel. Pharm. Ztg., 2000, 35, 2861-2870.
case of high solubility of API extracts or equivalent solubi-
NOMENCLATURE
This section includes supplements to the latest edition of the USP Dictionary of USAN and International Drug Names that
incorporate new United States Adopted Names (USAN) and revisions to existing Dictionary names. Also listed are Proposed
and Recommended International Nonproprietary Names (INN) when they have been announced by the World Health Orga-
nization.
Possible names suggested for use as USAN and INN are listed for public review and comment along with information on how
nonproprietary names are devised. In addition, readers may find articles relevant to current compendial nomenclature issues
that also occasionally report on related matters pertaining to USAN and INN.
Pharmacopeial Forum
184 NOMENCLATURE Vol. 28(1) [Jan.-Feb. 2002]
USP Dictionary of USAN and International Drug Names

2001 USP DICTIONARY SUPPLEMENT 4
IMPORTANT—Save this Supplement. This and all supplements appearing in PF are needed to keep the 2001 edition of
the USP Dictionary (USPD) up to date. The cumulative contents of the supplements to the current (2001) edition will be
included in the next complete edition of the Dictionary.
New United States Adopted Names (USAN)

The following are newly established United States Adopted Names (USAN). These names will not be listed cumulatively; see preceding
and succeeding numbers of P F for other new USAN to supplement the Dictionary main volume.
Amdoxovir [200J] (am dox' oh veer). CgH12N6O3. 252.23. (1) glucopyranosyl-(l-»4)-0-2-0-sulfo-a-L-idopyranuronosyl-

1,3-Dioxolane-2-methanol, 4-(2,6-diamino-9/f-purin-9-yl)-, (l-»4)-2-deoxy-6-0-sulfo-2-(sulfoamino)-a-D-glucopyrano-
(2R,4R)-; (2) (2i?,4i?)-4-(2,6-Diamino-9//-purin-9-yl)-l,3-di- side, decasodium salt. CAS-114870-03-0. Antithrombotic (in-
oxolane-2-methanol. CAS-145514-04-1. Antiviral used in direct and selective synthetic factor Xa inhibitor). (Diosynth
the treatment of HIV-1 and hepatitis B infections {reverse B.V., Netherlands); (Sanofi Chimie, France) <0>£K 90107A;
transcriptase inhibitor). (Triangle) <?(-)-DAPD; DAPD ORG 31540
Amotosalen Hydrochloride [2001] (a moe toe' sa len). Glufanide Disodium [2001] (gloo' fa nide). C 1 gH 17 N 3 Na 2 0 5 .
C17H19NOi.HCl. 337.80. (1) 7//-Furo[3,2-g][l]benzopyran- 377.30. (1) L-Tryptophan, L-a-glutamyl-, disodium salt; (2)
7-one, 3-[(2-aminoethoxy)methyl]-2,5,9-trimethyl-, hydro- L-a-Glutamyl-L-tryptophan, disodium salt. CAS-237068-57-
chloride; (2) 3-[(2-Aminoethoxy)methyl]-2,5,9-trimethyl- 4. Treatment ofKaposi's sarcoma and solid tumor cancers
7//-furo[3,2-g-][l]benzopyran-7-one hydrochloride. CAS- (angiogenesis inhibitor); immunomodulator. (Cytran)
161262-45-9. Photochemical treatment (light-activated psor- [Note—Marketed in theformer USSR as Thymogen.] <?IM862
alen derivative intended for use in the inactivation of viruses,
bacteria, and leukocytes in platelet concentrates and fresh
frozen plasma in blood bank settings). (Cerus) <?S-59 Lutropin Alfa [2001] (loo' troe pin alfa). C 4 3 7 H 6g2 N 122 O li4 S 13
(a-subunit). 10,205.69 (a-subunit); Q 7 7H 9Z9 N 165 D, 61 S 14 (/?
-subunit). 13,202.49 (/?-subunit). (1) Luteinizing hormone
Cilengitide [2001] (sye len' gi tide). C 27 H 40 N 8 O 7 . 588.66. Cy- (human a-subunit reduced complex human /?-subunit re-
clo(L-arginylglycyl-L-a-asparryl-D-phenylalanyl-iV-methyl-L- duced), glycoform a. [a-subunit]: Chorionic gonadotropin
valyl). CAS-188968-51-6. INN. Angiogenesis inhibitor. (human a-subunit protein moiety reduced); [/?-subunit]: Lu-
(Merck, Germany) teinizing hormone (human /?-subunit protein moiety re-
duced); (2) Luteinizing hormone (human a-subunit
reduced), complex with luteinizing hormone (human ^-subu-
Cipralisant Maleate [2001] (ci pral' is ant). C 14 H 20 N 2 .C 4 H 4 O 4 . nit reduced), glycoform a. CAS-152923-57-4; CAS-56832-
332. (1) 1/7-Imidazole, 4-[(li?,2i?)-2-(5,5-dimethyl-l-hexy- 30-5 [a-subunit]; CAS-53664-53-2 [/?-subunifj. INN; BAN.
nyl)cyclopropyl]-, (22)-2-butenedioate (1:1); (2) 4-[(\R,2R)- Treatment of chronic anovulation due to hypogonadotropic
2-(5,5-Dimethyl-l-hexynyl)cyclopropyl]imidazole maleate hypogonadism. Luveris (Serono) <?ATC G03 GA Gonadotro-
(1:1). CAS-223420-20-0. Treatment of attention deficit hyper- pins
active disorders (ADHD), age related memory dysfunction,
and other cognitive disorders (histamine H3 antagonist). Per-
ceptin (Gliatech) -0-GT-2357 Tadalafll [2001] (tab. da' la fil). C 2 ,H 19 N 3 O 4 . 389.41. (1) Pyrazi-
no[r,2':l,6]pyrido[3,4-6]indole-l,4-dione, 6-(l,3-benzo-
dioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R-
Ecalcidene [2001] (ee kal' si deen). C 29 H 45 NO 3 . 455.00. Piperi- 12ai?)-; (2) (6i?,12ai?)-2,3,6,7,12,12a-Hexahydro-2-methyl-
dine, 1 -[(1 a,3f3,5Z,7E,20S)-1,3-dihydroxy-24-oxo-9,10-se- 6-[3,4-(methylenedioxy)phenyl] pyrazino[l',2':l,6]pyri-
cochola-5,7,10(19)-trien-24-yl]-. CAS-150337-94-3. do[3,4-6]indole-l,4-dione; (3) (6i?-rra«5)-6-(l,3-Benzodiox-
Treatment of psoriasis. (Farmatis S.R.L., Italy) [Note—Spon- ol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazi-
sor is Johnson & Johnson Consumer Products Worldwide.] no[l ',2': 1,6]pyrido[3,4-6]indole-l ,4-dione. CAS-171596-29-
5. Treatment of male erectile and female sexual dysfunction.
Fondaparinux Sodium [2001] (fon da par' in ux). (Lilly) WC351
C31H43N3Na10O49S8. 1728.05. [Fondaparin Sodium is INN.]
(1) a-D-Glucopyranoside, methyl O-2-deoxy-6-0-sulfo-2- Vardenafil Dihydrochloride [200/] (var den' a fil).
(sulfoamino)-a-D-glucopyranosyl-(l-*4)-(9-/3-D-glucopyra- C23H32N6O4S.2HC1. 561.47. Piperazine, l-[[3-(l,4-dihydro-
nuronosyl-(l-»4)-0-2-deoxy-3,6-di-0-sulfo-2-(sulfoamino)- 5-metnyl-4-oxo-7-propylimidazo[5, l-_/][l ,2,4]triazin-2-yl)-4-
a-D-glucopyranosyl-(l-»4)-0-2-0-sulfo-a-L-idopyranuro- ethoxyphenyl]sulfonyl]-4-ethyl-, dihydrochloride. CAS-
nosyl-(l-+4)-2-deoxy-2-(suIfoamino)-, 6-(hydrogen sulfate), 224789-15-5. Treatment of erectile dysfunction (PDE 5 inhib-
decasodium salt; (2) Methly 0-2-deoxy-6-<9-sulfo-2-(sulfoa- itor). (Bayer)
mino)-a:-D-glucopyranosyl-( 1 ->4)-0-/3-D-glucopyranurono-
syl-(l->4)-0-2-deoxy-3,6-di-0-sulfo-2-(sulfoamino)-a-D-
Pharmacopeial Forum
Vol. 28(1) [Jan.-Feb. 2002] NOMENCLATURE 185
Revisions of United States Adopted Names (USAN)

The following are revisions of existing United States Adopted Names (USAN) and other names.
Ensulizole [1999] (en sul' i zole). USP. C, 3 H 10 N,O 3 S. 274.30. (1) Change to read:
l//-Benzimidazole-5-sulfonic acid-2-phenyl-; (2) 2-Phenyl- Methyl Benzylidene Camphor (previously used name) — See En-
benzimidazole-5-sulfonic acid. CAS-27503-81-7. [Namepre- zacamene.
viously used: Phenylbenzimidazole Sulfonic Acid.] [Note—
The International Cosmetic Ingredient (INCI) name for ensu-
lizole is phenylbenzimidazole sulfonic acid.] Motexafin Gadolinium
Change the pronunciation to read:
(moe texs' a fin)
Change to read: Change the name of the manufacturer to read:
Hydroxypropyl Methylcellulose (previously used name) See (Pharmacyclics, Inc.)
Hypromellose.
Motexafin Lutetium
Hypromellose. USP. [Hydroxypropylmethylcellulose is JAN.] (1) Change the name of the manufacturer to read:
Cellulose, 2-hydroxypropyl methyl ether; (2) Cellulose hy- (Pharmacyclics, Inc.)
droxypropyl methyl ether. CAS-9004-65-3. INN; BAN. Gen-
Teal (Ciba Vision, US Ophthalmics); Goniosol (Ciba Vision,
US Ophthalmics); Isopto Tears (Alcon); Methocel E, F, J, K Change to read:
(Dow Chemical); Tearisol (Ciba Vision, US Ophthalmics); Octyl Methoxycinnamate (previously used name) — See Octinox-
Ultra Tears (Alcon); component of Biontears (Alcon); compo- ate.
nent of Estivin II (Alcon); component of Isopto Frin (Alcon);
component of Tears Naturale (Alcon); component of Tears Change to read:
Naturale II (Alcon); component of Tears Naturale Free (Al- Octyl Salicylate (previously used name) — See Octisalate.
con) [Name previously used: Hydroxypropyl Methylcellu-
lose.]
Change to read:
USP DI Category: Pharmaceutic aid (suspending agent); phar- Phenylbenzimidazole Sulfonic Acid (previously used name) —
maceutic aid (tablet excipient); pharmaceutic aid (viscosity-in- See Ensulizole.
creasing agent).
Tebipenem
Change to read: Change the chemical name to read:
Isoamyl Methoxycinnamate (previously used name) — See Ami- (4/?,5/?,65)-3-[[l-(4,5-dihydro-2-thiazolyl)-3-azetidinyl]thio]-6-
loxate. [(1R)-1 -hydroxyethyl]-4-methyl-7-oxo-1 -azabicyclo[3.2.0]hept-2-
ene-2-carboxylic acid (2,2-dimethyl-l-oxopropoxy) methyl ester.
Change to read:
Menthyl Anthranilate (previously used name) — See Meradimate.
Pharmacopeia! Forum
Proposed and Recommended International Nonproprietary Names
International Nonproprietary Names (INN) are devised Recommended INN Recommended INN
by the World Health Organization (WHO). Adekalant Lerdelimumab
Under its charter, the WHO is empowered simply to re- Alemtuzumab Levmetamfetamine
commend specific actions or procedures to its Member Aliskiren Lixivaptan
States. This limitation is incorporated into the WHO pro- Amiloxate Melevodopa
gram concerned with the selection of international non- Bevacizumab Meradimate
proprietary names for pharmaceutical substances, in that
Biotin Norelgestromin
the WHO first publishes the selected names as proposals
("Proposed International Nonproprietary Names"). A peri- Bivatuzumab Octinoxate
od of four months from the date of publication in WHO Capravirine Octisalate
Drug Information is allowed for entering comments on, or Capromorelin Opaviraline
objections to, any proposal on the part of Member States or Cridanimod Opebacan
other interested parties. In general, an objection reflects a Doripenem Oritavancin
belief that the proposal concerned is confusingly close to
Ecraprost Ozogamicin
(i.e., conflicts with) a name already in use, perhaps in only
a restricted area in which the party has a proprietary interest Elarofiban Paliperidone
in the form of trademark rights. In the event that no objec- Ensulizole Pitavastatin
tion is received, the WHO proceeds with listing and publish- Enzacamene Rimonabant
ing the names so devised as recommendations ("Recom- Eptaplatin Rostaporfin
mended International Nonproprietary Names"), which
Ezetimibe Rosuvastatin
many Member States then recognize as the sole or preferred
Fondaparinux Sodium Rotigotine
nonproprietary name for use within their respective terri-
tories. Fosamprenavir Ruplizumab
Fosfluconazole Sitaxentan
Recommended International Nonproprietary Names Fasveset Sulfamazone
The following 52 nonproprietary names have been se- Gadofosveset Talaporfin
lected by the World Health Organization (WHO) as Recom- Gemtuzumab Ticalopride
mended International Nonproprietary Names. This list, with
Idraparinux Sodium Tolvaptan
chemical names or descriptions and the molecular formulae,
Isatoribine Vilazodone
appears in WHO Drug Information, Vol 15, No. 1, 2001.
Labradimil
Ladirubicin
Pharrnacopeial Forum
Suggested United States Adopted Names
The United States Adopted Names (USAN) program is both trademarks and nonproprietary names. An effort is
the specifically organized effort in the United States directed made to discourage the occasional, undesirable practice of
to producing simple and useful nonproprietary names for incorporating in trademarks the syllables used in an estab-
drugs while the drugs are still in the investigational stages. lished nonproprietary name, or syllables recommended for
The American Medical Association (AMA), the American USAN. Such trademarks may act as a bar to the subsequent
Pharmaceutical Association (APhA), and the United States adoption of appropriate nonproprietary names for closely re-
Pharmacopeial Convention (USPC) jointly sponsor the lated drugs.
USAN program with representation from the FDA.
The suggested nonproprietary names for the drugs de-
Each U.S. Adopted Name is chosen with the expectation scribed in the following list are under consideration by the
that it will be suitable for prescribing and dispensing pur- USAN Council. The name(s) being considered for each
poses and for designation as the title of the monograph, drug substance, and the applicable category, are separated
should the article be recognized in the official United States by double spacing from the name(s) and category for the
Pharmacopeia or National Formulary. A measure of the next listed drug substance. Where two or more names are
prestige and recognition of the value of the USAN program being considered for the same drug substance, the names
can be found in the following regulations published by the are single-spaced, and the applicable category term is writ-
Commissioner of Food and Drugs and the Secretary of ten only once to the right of the single-spaced group of
Health and Human Services in the Federal Register of Feb- names.
ruary 1988.
Any comments or protests should be addressed to Sandra
All who are concerned with the prescription, dispensing, Van Laan, Technical Associate, USAN Council, American
use, sale or manufacture of drugs may, in the absence of the Medical Association, 515 North State Street, Chicago, Illi-
designation of an official name by the FDA, rely on the cur- nois 60610.
rent compendial name or the U.S. Adopted Name (USAN) Suggested USAN Category
listed in this volume as being the established name in accor-
Abatapcim Alfa
dance with the Federal Food, Drug, and Cosmetic Act. Signatapcim
Abatapcimus Alfa Immunosuppression
A formal procedure1 is followed by the USAN Council in Signatapcim Alfa
selecting an established name for a drug. The USAN Coun- Signatapcimus Alfa
cil Secretary is also an ex officio member of the Interna-
Acamprosate Calcium Treatment of alcohol
tional Nonproprietary Names (INN) Committee. USAN dependency
Guiding Principles are concordant with World Health Orga-
nization (WHO) principles, and all USANs for substances Acrobermin (adenovirus vector)
Acrobermin VEGF121
also named by the INN Committee are systematically pro- (adenovirus vector)
cessed through the INN Committee. This ensures that, with Acrobermin VEGF121 ADV
very rare exceptions, USANs are identical to INNs and Balibermin
Biobermin
available for world-wide use. Bosabermin (adenovirus
Treatment of coronary artery
vector) disease (CAD) class II-IV
A suggestion for a USAN originates usually from a firm Bosabermin VEGF121
angina and peripheral artery
or an individual who has developed a substance of potential (adenovirus vector) disease
therapeutic utility to the point where there is a distinct pos- Bosabermin VEGF121 ADV
Vasobermin
sibility of its being marketed in the United States of Amer- Visobermin
ica. Occasionally, the initiative is taken by the USAN Vorobermin (adenovirus vector)
Council in the form of a request to parties interested in a Vorobermin VEGF121
(adrenovirus vector)
substance for which a nonproprietary name appears to be Vorobermin VEGF121 ADV
lacking.
Adepovan Antiatherosclerotic
Submissions to the USAN Council are expected to con- Luvaspion
form to the established Guiding Principles2 and to be rea-
sonably free from conflict with other names, including
1
USP Dictionary of USAN and International Drug Names, Preface.
2
Ibid., Appendix VII.
Pharmacopeial Forum
Suggested USAN Category Suggested USAN Category

Adiresil Artagoxoforb
Amitusupene (adenovirus Bariloxoforb
vector) Barilubant
Amitusupene p53 (adenovirus Eitagoxoforb
vector) Etagoloxan Antineoplastic
Amitusupene p53 ADV Antineoplastic Etagolubant
Apopitel Etalubloxan
Paritusupene (adenovirus Igolubant
vector) Tagolubant
Paritusupene p53 (adenovirus
vector) Asedapine Maleate
Paritusupene p53 ADV Aseridone Maleate Antischizophrenic
Cloxepidone Maleate
Afolipasim
Afosilipam Atamapimod
Amidofosnate Belmapimod
Amifolipam Cimapilene
Amilipasim Antiathewgenic Cimapimod Treatment of rheumatoid
Fosbenamide Domapimod arthritis, Crohn s disease,
Fosbepamide Doramapimod psoriasis
Foslipamide Mapizole
Ibrilipam Mapkinazole
Piramapimod
Allerbtinib Dihydrochloride
Calertinib Dihydrochloride Atracitabine Antiviral; used to treat
Canertinib Dihydrochloride Baltacitabine HIV/AIDS; nucleoside
Denertinib Dihydrochloride Treatment of epithelial tumors Carvacitabine reverse transcriptase
Panerbtinib Dihydrochloride inhibitor (NRTJ)
Panertinib Dihydrochloride
Quaderbtinib Dihydrochloride Benzulind
Berolind A pro-apoptotic cGMP
Alvimopan Fluridilind phosphodiesterase type 1 and
Benzimopan Flutolind 2 inhibitor used in the
Benzipramide Narcotic antagonist Gemolind
Penimopan treatment of breast cancer
Ractalind
Phenyleridine Xactalind
Amiganan Beprosomib
Camiganan Beprotesomib Antineoplastic
Camitide Brotezomib
Cipoganan Antimicrobial
Ciproganan Biciclounone
Periganan Boloprostone
Tamiganan Lubiprostone Treatment of constipation
Zamitide Nobiprostone
Ubiciclonone
Anpocartilin Alfa Treatment of rheumatoid
Anpomuctolin arthritis Caprobate Sodium
Isbocartilin Alfa Caprozate Sodium Oral absorption promoter
Docapricate Sodium
Apaselag Drocapozate Sodium
Apselagon Alfa
Domaselag Cetiramycin
Epselagon Alfa Treat acute myocardial Dactromycin
Ipselagon Alfa infarction and prevention Declomycin
Nimapsel of deep vein thrombosis Rodelcomycin Antibacterial
Paltaselag Vectomycin
Sipapsel Vectromycin
Torapsel Velectomycin
Arednermin Immunostimulant Coslizumab
Imlizumab
Immunelizumab Immunosuppressant
Suplimzumab
Suplizumab
Pharmacopeial Forum

Dinuquapir Tetrasodium
Dinuquasol Tetrasodium Firosentan Treatment of prostate cancer;
Diuridine Tetrasodium Mucosal hydration Mendoentan endothelin ETA receptor
Tetraphosphate Pirosentan antagonist
Fodiuridine Tetraphosphate Porosentan
Edotreotide Antineoplastic Hemoglobin Crosraffimer

Hemoglobin Raffimer Blood substitute
Efaproxiral Enhancement of radiation Hemogloraffimer
therapy
Lufanibzumab
Purified Estrogens Luficizumab
Sulfated Estrogens Hormone replacement therapy Miranibzumab Treatment of age-related
Mircizumab macular degeneration
E2F Oligodecoy Hexasodium Retanibzumab
Salt Prevention of graft failure Retcizumab
Exogestin Hormonal contraception; Pravalamer Sodium

Letogestin hormone replacement Provalemer Sodium
therapy Sodium Polystyrene Sulfonate Antidiarrheal
Tesogestin
Tosagestin Trovelamer Sodium
Febuxostat Management of hyperuricemia Talaprofin Sodium For use in photodynamic

in patients with gout therapy
Pharmacopeial Forum
Suggested International Nonproprietary Names
International Nonproprietary Names (INN) are devised drug substance, the names are single-spaced, and the applic-
by the World Health Organization (WHO). INNs for sub- able category term is written only once to the right of the
stances originating within the United States are applied for single-spaced group of names.
through the USAN Council. INN and USAN Guiding Prin-
Any comments or protests should be addressed to Sandra
ciples are concordant, which assures that, with very few ex-
Van Laan, Technical Associate, USAN Council, American
ceptions, INNs and USANs are identical.
Medical Association, 515 North State Street, Chicago, Illi-
Under its charter, the WHO is empowered simply to re- nois 60610.
commend specific actions or procedures to its Member Category
Suggested INN
States. This limitation is incorporated into the WHO pro-
Alvimopan Narcotic antagonist
gram concerned with the selection of international non-
proprietary names for pharmaceutical substances, in that Betosiban Treatment of imminent preterm
the WHO first publishes the selected names as proposals Durosiban birth
Otrasiban
("Proposed International Nonproprietary Names"). A peri-
od of four months from the date of publication in WHO Canertinib Treatment of epithelial tumors
Drug Information is allowed for entering comments on, or
Captide Treatment of myocardial
objections to, any proposal on the part of Member States or Endotide infarction
other interested parties. In general, an objection reflects a Microtide
belief that the proposal concerned is confusingly close to
Carospirone Antipsychotic
(i.e., conflicts with) a name already in use, perhaps in only Duperaxine
a restricted area in which the party has a proprietary interest Herispirone
in the form of trademark rights. In the event that no objec-
Cetiramycin Antibacterial
tion is received, the WHO proceeds with listing and publish-
ing the names so devised as recommendations ("Re- Edocarban Antineoplastic
commended International Nonproprietary Names"), which Edocarbax
Incarbax
many Member States then recognize as the sole or preferred
nonproprietary name for use within their respective terri- Hemoglobin Raffimer Blood substitute
tories.
Ibrilipam Antiatherogenic
The names for the drugs that are categorized in the fol-
lowing list are under consideration for the selection of Lubiprostone Treatment of constipation
new Proposed International Nonproprietary Names. The
name(s) being considered for each drug substance, and the Monavaptan Treatment of heart failure
Mozavaptan
applicable category, are separated by double spacing from Privaptan
the name(s) and category for the next listed drug substance.
Where two or more names are being considered for the same Siplizumab Immunosuppressant
INDEX
This is a cumulative directory for the content of all issues of PF beginning with PF 28(1).
Pharmacopeial Forum
192 INDEX Vol. 28(1) [Jan.-Feb. 2002]
[Note—This index covers Vol. 28 No. 1, pp. 1-193] Powdered Nettle (NF) 108
Powdered Nettle Extract (NF) 109
GENERAL NOTICES AND REQUIREMENTS (USP) Nifedipine Capsules (USP) 78
"Official" and "Official Articles"—USP 32 Norgestimate and Ethinyl Estradiol Tablets (USP) 79
Oxycodone and Acetaminophen Capsules (USP) 27
GENERAL NOTICES AND REQUIREMENTS (NF) Nystatin (USP) 134
"Official" and "Official Articles"—NF 88 Nystatin Cream (USP) 134
Nystatin Lozenges (USP) 135
MONOGRAPHS Nystatin Ointment (USP) 135
Acebutolol Hydrochloride Capsules (USP) 33 Nystatin Topical Powder (USP) 136
Alendronate Sodium Tablets (USP) 33 Nystatin Oral Suspension (USP) 136
Amoxicillin Capsules (USP) 36 Nystatin Tablets (USP) 137
Amoxicillin Tablets (USP) 36 Nystatin and Triamcinolone Acetonide Cream (USP) 137
Amoxicillin and Clavulanate Potassium for Oral Suspension Nystatin and Triamcinolone Acetonide Ointment (USP) 138
(USP) 36 Oxycodone Hydrochloride (USP) 84
Amoxicillin and Clavulanate Potassium Tablets (USP) 37 Pentazocine and Naloxone Hydrochlorides Tablets (USP) 84
Atenolol Tablets (USP) 38 Praziquantel (USP) 84
Barium Sulfate (USP) 38 Pseudoephedrine Hydrochloride Extended-Release Tablets (USP) 85
Barium Sulfate Suspension (USP) 38 Streptomycin Injection (USP) 86
Barium Sulfate for Suspension (USP) 39 Streptomycin for Injection (USP) 86
Benazepril Hydrochloride Tablets (USP) 39 Streptomycin Sulfate (USP) 87
Benzethonium Chloride Concentrate (USP) 41 Thyroid Tablets (USP) 88
Benzylpenicilloyl Polylysine Concentrate (USP) 42
Bismuth Subsalicylate Tablets (NF) 133 GENERAL CHAPTERS
Bismuth Subsalicylate Magma (USP) 43 Disinfectants and Antiseptics (1072) (USP) 143
Cefpodoxime Proxetil (USP) 44 Reference Standards (11) (USP) Ill
Cefpodoxime Proxetil for Oral Suspension (USP) 48 Residue on Ignition (281) (USP) 112, 129
Cefpodoxime Proxetil Tablets (USP) 49 Stability Considerations in Dispensing Practice (1191) (USP) . . . 112
Chaste Tree (NF) 139 Standardized Imprint Codes for Solid Oral Dosage Forms (1198)
Powdered Chaste Tree (NF) 142 (USP) 143
Chlorothiazide Sodium for Injection (USP) 51 Validation of Alternative Microbiological Methods (1223) (USP) 143
Cholestyramine for Oral Suspension (USP) 51
Cimetidine Tablets (USP) 52 REAGENTS, INDICATORS, AND SOLUTIONS
Clomipramine Hydrochloride Capsules (USP) 52 Reagent Specifications
Clonazepam Tablets (USP) 54 FD&C Blue No. 1 (USP) 115
Clorazepate Dipotassium Tablets (USP) 54 Water, HPLC Grade (USP) 115
Clorsulon (USP) 55
Digoxin Tablets (USP) 55 REFERENCE TABLES
Dinoprostone (USP) 56 Containers Specifications for Capsules and Tablets 115
Ergoloid Mesylates Tablets (USP) 59 Description and Relative Solubility 116
Fluoxymesterone (USP) 59
Furosemide Oral Solution (USP) 59 GENERAL SUBJECTS
Garlic Delayed-Release Tablets (NF) 89 Biopharmaceutics
Glucosamine Hydrochloride (NF) 92 Biopharmaceutics Classification System: See Method
Glucosamine Potassium Sulfate Chloride (NF) 94 Consideration for Caco-2 Permeability Assessment in the
Glucosamine Sodium Sulfate (NF) 95 Biopharmaceutics Classification System, Sanna Tolle-Sander
Glucosamine Tablets (NF) 97 and James E. Polli 164
Glucosamine and Chondroitin Sulfate Tablets (NF) 98 FIP Recommendations for Biopharmaceutical
Glutaral Concentrate (USP) 60 Characterization of Herbal Medicinal Products by Friedrich
Glyburide Tablets (USP) 60 Lang, Konstantin Keller, Michael Ihrig, Joy Oudtshoom-
Hydrochlorothiazide (USP) 60 Eckard, Helga Moller, Srini Srinivasan, Yu He-ci 173
Hydrocodone Bitartrate (USP) 63 Canceled Revision Proposals 126
Hydrogen Peroxide Concentrate (USP) 65 First Interim Revision Announcement 25
Hydroxyzine Hydrochloride Tablets (USP) 27
Insulin Human (USP 26) 65 Harmonization
Insulin Lispro (USP) 66 Residue on Ignition (281) 129
Insulin Lispro Injection (USP) 69 He-ci, Yu: See Lang, Friedrich 173
Iohexol (USP) 70 Ihrig, Michael: See Lang, Friedrich 173
Isosorbide Concentrate (USP) 71 Interim Revision Announcement
Kava (NF) 100 First Interim Revision 25
Powdered Kava (NF) 104 International Pharmaceutical Federation: See FIP
Lactulose Concentrate (USP) 71 Recommendations for Biopharmaceutical Characterization of
Letrozole Tablets (USP) 71 Herbal Medicinal Products 173
Levocarnitine (USP) 71 Keller, Konstantin: See Lang, Friedrich 173
Lincomycin Hydrochloride Soluble Powder (USP) 73 Lang, Friedrich, Keller, Konstantin, Ihrig, Michael, Oudtshoom-
Mannitol Injection (USP) 73 Eckard, Joyh, Moller, Helga, Srinivasan, Srini, He-ci, Yu: FIP
Methadone Hydrochloride Oral Solution (USP) 74 Recommendations for Biopharmaceutical Characterization of
Methyltestosterone (USP) 74 Herbal Medicinal Products 173
Misoprostol Dispersion (USP) 76 Method Consideration for Caco-2 Permeability Assessment in the
Myrrh (USP) 78 Biopharmaceutics Classification System by Sanna Tolle-
Nettles (NF) 105 Sander and James E. Polli 164
Pharmacopeial Forum
Vol. 28(1) [Jan.-Feb. 2002] INDEX 193
Moller, Helga: See Lang, Friedrich 164 Srinivasan, Srini: See Lang, Friedrich 173
Policies and Announcements Tolle-Sander, Sanna and Polli, James E.: see Method Consideration
How to Comment 20 for Caco-2 Permeability Assessment in the Biopharmaceutics
Update on the Annual Edition of USP-NF 19 Classification System 164
Polli, James E.: See Tolle-Sander, Sanna 164
REFERENCE STANDARDS
CATALOG
Changes in Reference Standards prices and numbers
U.S. Pharmacopeia
The Standard of QualitfM
Dear USP Reference Standards Customer:
The USP family joins me in wishing you a happy and prosperous New Year. We renew our commit-
ment to offering you superior Reference Standards, with the best service.
As we continuously work to enhance the quality of our Reference Standards and customer service,
some important changes have become necessary and will soon start to affect you. Here's an overview
of four key changes—please note that they take effect on different dates.
Annual price increase

Effective January 1, 2002, prices of USP Reference Standards increase by 4%. This price increase
rate is tied to the Consumer Price Index (CPI) for medical commodities—prescription and OTC
drugs and medical supplies. For the one-year period ending September 2001, the average CPI for
medical commodities was 4.3%.
The current prices are reflected in this catalog. Please note that a few Reference Standards may
be subject to different pricing adjustments (and not a 4% increase) based on market value, cost of
materials, and/or extraordinary expenses.
New system of lot numbers

New Reference Standards lots are identified by unique expanded lot numbers that provide important
information. These numbers allow each Reference Standard to be easily traced to specific lots.
The new lot numbers will have three parts as this example indicates:
Gl A 001
Calendar year
Current lot (A=2OO1, B=2002, etc.) Sequential
configuration number
New Reference Standards vials already are carrying the new lot numbers. You'll see the expanded
numbers in the catalog starting with the March/April 2002 issue.
Further changes, as listed below, will take effect as USP establishes its comprehensive new ERP business
system designed to enhance customer service. We expect to convert to this system in early 2002. Please call
USP Customer Service at 1-800-227-8772 or 301-881-0666 for updates on when the conversion is expected
to take place.
Quantity discounts by item

Quantity discounts will soon be applied on the number of units per item, and not on the total number
of units of all items ordered. The discount rates will continue to be 5% for 5-24 units and 10% for
25+ units.
The current discount structure will be available at least until the end of January 2002. You might
want to take advantage of it by consolidating your orders, especially if you typically order different
types of Reference Standards and less than 5-24 units of each. Plan ahead, consolidate your future
12601 Twinbrook Parkway requirements, and send in a single order by the end of January 2002. You can still get 5-10% off
Rockville, MD 20852 your total order.
Continued on reverse.
301-881-0666
www.usp.org
Catalog numbers expanded by one digit
A leading digit " 1 " will be added to all existing catalog numbers of Reference Standards. For
example, the catalog number 03150-3 will become 103150-3. The old catalog number will be
maintained as the root.
Until current Reference Standards lots are depleted, vials will continue to show the old catalog
number. The new catalog numbers will appear on all catalogs, invoices and shipping documents.
You might want to start preparing to incorporate the new catalog numbers in your Reference
Standards ordering documents.
Please call USP Customer Service at 1-800-227-8772 or 301-881-0666 if you have any questions
about the changes and their impact. You can depend on USP to continue to provide quality products
and service.
Sincerely,
Alan Nichols
Director, Reference Standards Marketing
Official USP Reference Standards Catalog Jan.-Feb. 2002
INTRODUCTION
parentheses following each name (all are in single containers
Catalog on the Internet unless otherwise specified).
For the convenience of our online customers, access to this Column 3 (Current Lot) identifies the current lot designation
catalog is available on the Internet at www.usp.org/refstd/. This of each official item being distributed as of the date of this list.
online version is updated frequently to include changes in Where the Current Lot is blank the item is not in distribution.
official lot status, description, and other pertinent information.
Column 4 (Change Code) lists codes that identify USP
Importance of Reference Standards Reference Standards that have had a change in lot status,
Official USP and NF Reference Standards are made available as description, or other pertinent information since the printing of
required for use in assays and tests appearing in USP-NF. They the September 26,2001, official Catalog. Interpretations of
help ensure that quality requirements established by the these codes are:
USP-NF are met, and that the official methods of analysis are Change Interpretation
performed. They are subject to rigorous testing, evaluation, and Code
quality control, and are approved for use by the USP Reference 1 New Standard Available for Distribution
Standards Committee. 2 New Lot in Distribution
3 Change in Package Size or Description
How to Order 4 Correction of Typographical Error
On pages 26-27, you'll find information on how to order by phone, mail,
5 New Catalog Number—Use for All Orders
internet, or fax, both domestically and internationally, and other
6 Previous Lot No Longer Official; Only Current
pertinent information. Order forms are located in the back of this
Lot to be Used
catalog. Please note that USP Reference Standards are not
7 Valid Use Date of Previous Lot Extended
returnable for exchange or refund.
8 Change in Catalog Number and Name
9 DISCONTINUED
Product Listings
10 Special Pricing in Effect
On pages 5-22, you'll find a full list of USP and NF Reference
11 Valid Use Date Added For Previous Lot; Next
Standards, with information updated as of November 21,2001.
Lot in Preparation.
Additional, authenticated substances, not currently required as
Official USP or NF Reference Standards, are also provided Column 5 (Previous Lot/Valid Use Date) identifies any lot no
under the supervision of the USP Reference Standards longer being distributed, but which is still considered an official
Committee. They fall into three groups: (1) former USP and NF USP Reference Standard through the last day of the indicated
Reference Standards, not required in the current USP or NF, but month and year. (For example, an indicated entry of "F-l
for which sufficient demand remains; (2) FCC Reference (06/00)" means that the previous lot F-l is no longer being
Standards, specified in the current edition of the Food Chemicals distributed, but is considered official through June 30,2000.) If
Codex; and (3) Authentic Substances (AS), which are highly the word "NONE" appears in this column, it indicates that
purified samples of chemicals, including substances of abuse, because of a change in monograph requirements, or stability
that are collaboratively tested and made available as a service limitations, etc., any previous lot is no longer considered official
primarily to analytical, clinical, pharmaceutical, and research and should not be used.
laboratories.
USP'Reference Standards
How to Read Product Listings USP Reference Standards are established and released under the
Column 1 (Catalog Number) designates the catalog number authority of the USPC Board of Trustees upon recommendation
that has been assigned to each Reference Standard and Authentic of the USP Reference Standards Committee, which passes on the
Substance. Please include the catalog number on your orders. selection and suitability of each lot. The critical characteristics of
each lot of specimen selected for the standard are usually
Column 2 (Description) gives a description of each article as
determined independently in three or more laboratories. The
designated in the compendium and/or on the label and the Drug
USP Reference Standards Laboratory (see Preface to USP 24-
Enforcement Administration Control Schedule, if applicable.
NF19) and the FDA laboratories participate in testing almost all
The quantity of material provided per container is given in
new Standards and replacements for existing Standards. In
Your official site for drug standards information. www.usp.org

Jan.-Feb. 2002 Official USP Reference Standards Catalog
INTRODUCTION
addition, laboratories throughout the nation, both academic and differences in the actual units of potency and in some cases to
industrial, participate in the testing. Reference Standards are share in the preparation of a reference standard. Since some USP
specifically required in many Pharmacopeial assays and tests Reference Standards are standardized in terms of the
and are provided solely for such use; suitability for other corresponding International Standards, the relevant USP Units
nonofficial application(s) rests with the purchaser. Originally and the International Units of potency are generally identical.
introduced for the biological assays of USP X, reference
standards are now required for numerous other procedures as Current Lots
well. This reflects the extensive use of modern chromatographic It is the responsibility of each analyst to ascertain that his
and spectrophotometric methods, which require measurements particular supply of USP Reference Standard is current.
relative to a reference standard to attain accurate and
To ensure ready access to the latest information, the USPC
reproducible results.
publishes the Official Catalog of Reference Standards and
USP Reference Standards are substances selected for their high Authentic Substances, and the lot designations, bimonthly in
purity, critical characteristics, and suitability for the intended Pharmacopeial Forum. This system offers more positive control
purpose. Heterogeneous substances, of natural origin, also are and flexibility in responding to revisions in Reference Standard
designated "Reference Standards" where needed. Usually these usage than would expiration dates. The Catalog in the most
are the counterparts of international standards. recent Pharmacopeial Forum identifies items that are official in
the USP Reference Standards collection at the time of
Other Reference Substances publication.
As a service, the USPC tests and distributes additional
Two columns appear in the Catalog to identify the current
authenticated substances not currently required as USP or NF
official lots. One column identifies the official lot currently
Reference Standards. These also are provided under the
being shipped by USPC. If the field is blank then the current lot
supervision of the USP Reference Standards Committee. These
is not in distribution. In some cases, the previous lot may still be
additional substances fall into three groups:
considered official. If so, it is identified in the second column.
(1) former USP and NF Reference Standards, not required in the Ordinarily the previous lot is carried in official status for about
current USP or NF but for which sufficient demand remains; one year after the current lot has depleted unless, because of a
(2) FCC Reference Standards, specified in the current edition of change in monograph requirements or stability limitation, the
the Food Chemical Codex; previous lot is found to be no longer suitable. Indication is given
(3) Authentic Substances (AS), which are highly purified for the month and year through which previous lots may be used.
samples of chemicals, including substances of abuse, that are
collaboratively tested and made available as a service primarily Proper Use of USP Reference Standards
to analytical, clinical, pharmaceutical, and research laboratories. Unless a USP Reference Standard label states a specific potency
or content, the USP Reference Standard is taken as being
The distribution of controlled substances is subject to the 100.0% pure for the USP purposes for which it is provided. The
regulations and licensing provisions of the Drug Enforcement suitability of a USP Reference Standard for noncompendial
Administration of the Department of Justice. application is left up to the user.
A program to provide international biological standards and
chemical reference substances is maintained by the World To serve its intended purpose, each USP Reference Standard
Health Organization, an agency of the United Nations. The must be properly stored, handled, and used. Generally, USP
WHO program is concerned with reference materials for Reference Standards should be stored in their original stoppered
antibiotics, biologicals, and chemotherapeutic agents. As a rule, containers away from heat and protected from light. Avoid
an International Standard for a material of natural origin is humid storage areas in particular. Where special storage
discontinued once the substance responsible for its characteristic conditions are necessary, directions are given on the label.
activity has been isolated, identified, and prepared in such forms
Neither Reference Standards nor Authentic Substances are
that it can be completely characterized by chemical and physical
intended for use as drugs, dietary supplements, or as medical
means. The USP Reference Standards Committee collaborates
devices.
closely with the WHO in order to minimize unavoidable
Online ordering. www.usp.org

INTRODUCTION
Many USP tests and assays are based on comparison of a test procedures and refers to General Test Chapter (11) USP
specimen with a USP Reference Standard. In such cases, Reference Standards for additional information and instructions.
measurements are made on preparations of both the test Instructions for the proper use and storage of each required USP
specimen and the USP Reference Standard. Where it is directed Reference Standard are given in General Chapter (l 1) of USP
that a Standard solution or a Standard preparation be prepared 24-NF 19. These instructions are to be the same as those
for a quantitative determination by stepwise dilution or appearing on the corresponding USP Reference Standard label.
otherwise, it is intended that the Reference Standard substance Where, in an isolated instance, the specific label instruction
shall be accurately weighed (see General Chapters Weights and differs from the text in the published list, the instruction on the
Balances (41) and Volumetric Apparatus (31) in USP 24-NF19). label of the item from the current lot takes precedence. A
Due account should also be taken of the relatively large errors situation may be infrequently encountered where it is necessary,
associated with weighing small masses (see also Dilution under on scientific grounds, to effect immediately a change in the
General Notices). instructions. This change can be made easily on the label of the
Reference Standard, whereas the formal process for revising the
Assay and test results are determined on the basis of
compendial text requires more time. Thus, it is especially
comparisons of the specimen under test with a USP Reference
important to refer to the current Supplement to USP-NF for
Standard that has been freed from, or corrected for, volatile
official revisions to the following list.
residues or water content as instructed on the label. Where
special drying requirements for Reference Standards are found
in specific sections of USP or NF monographs, those supersede USP Reference Standard Specified in USP and NF
the usual instructions (see Procedures under Tests and Assays in Monographs and General Chapters
the General Notices). Where a USP Reference Standard is NOTE—Consult the latest Supplement or Interim Revision
required to be dried before using, transfer an amount, sufficient Announcement Pertaining to USP and to NF for revisions,
after drying, to a clean and dry vessel. Do not use the original additions, or deletions. Revisions, additions, and deletions of
container as the drying vessel, and do not dry a specimen individual USP Reference Standards are listed cumulatively in
repeatedly at temperatures above 25 degrees. Where the each Supplement to USP-NF under (l l) USP Reference
titrimetric determination of water is required at the time a Standards.
Reference Standard is to be used, proceed as directed for Method
I under General Chapter Water Determination (921).
Instrumental or microanalytical methods are accpetable for this

purpose. When using typical amounts, about 50 mg, of the
Reference Standard, titrate with a fourfold dilution of the
Reagent.
The USP Reference Standard(s) section of an individual USP or
NF monograph or general chapter names the USP Reference
Standard(s) (l l) required for assay and test

Development Process for USP Reference Standards
New monograph New application for an Inventory depletion

existing reference standard
Bulk material is obtained
Material is tested and characterized through

collaborative testing involving a minimum of
3 labs-industry, FDA, and USP
Data from the collaborative study are reviewed

by USP staff scientists
Compilation of collaborative study is sent to the USP

Reference Standards Committee for evaluation
f
USP Reference Standards Committee accepts,
recommends further testing, or rejects the material
f
Once approved, the material is subdivided
and labeled
Material passes through a series of quality control

checks before release into USP inventory for distribution

USP and FCC Reference Standards and Authentic Substances

Previous Previous
Cat. Curr. Change Lot/Valid Cat. Curr. Change Lot/Valid
No. Description Lot Code* Use Date Price No. Description Lot Code* Use Date Price
00060-1 AcebutololHCI(125mg) F-1 $144.00 01850-5 Amantadine HCI (200 mg) H $144.00
00100-3 Acenocoumarol (200 mg) F $144.00 01920-2 Amcinonide (200 mg) F-1 $144.00
00150-2 Acepromazine Maleate F-1 (05/02) $144.00 01950-8 Amikacin (200 mg) I $144.00
(250 mg) 01970-1 Amiloride HCI (500 mg) H $144.00
XREF 5-Acetamido-3-amino- 01975-6 Aminobenzoate Potassium F-1 $144.00
2,4,6-triiodo-benzoic Acid (200 mg)
(50 mg) (Limit test) 01976-7 Aminobenzoate Sodium F $144.00
(Please order Cat. No. (200 mg)
18402-7) 01980-3 Aminobenzoic Acid (200 H $144.00
00300-9 Acetaminophen (400 mg) J-1 J (05/02) $114.00 mg) (This is the para form)
00400-1 Acetanilide Melting Point L $69.00 02000-8 Aminobutanol (500 mg) G-1 $360.00
Standard (500 mg) (Limit test)
(Approximately 114 02100-0 Aminocaproic Acid (200 F-4 $144.00
degree(s)) mg)
00500-4 Acetazolamide (2 g) J $144.00 02170-3 A/-(Aminocarbonyl)-A/-[([5- F-1 $450.00
00600-7 Acetohexamide (250 mg) H $144.00 nitro-2-furanyl]-methylene)-
00650-6 Acetohydroxamic Acid F $144.00 amino]-glycine (25 mg)
(200 mg) (Limit test)
00700-0 Acetophenazine Maleate F-1 $144.00 XREF 3-Amino-4-carboxamid-
(200 mg) opyrazole Hemisulfate (50
00800-2 a-d-2-Acetoxy-4-dimethyl- G-3 $450.00 mg) (Limit test) (Please
amino-1,2-diphenyl-3- order Cat. No. 01302-4)
methylbutane (125 mg) 02250-2 4-Amino-6-chloro-1,3- G-4 $450.00
(Limit test) benzenedisulfonamide
00850-1 Acetylcholine Chloride G $144.00 (100 mg) (Limit test)
(200 mg) 02280-8 2-Amino-5-chloroben- H-1 $450.00
00900-5 Acetylcysteine (200 mg) H $144.00 zophenone (25 mg) (Limit
00990-1 Acetyltributyl Citrate (500 F $144.00 test)
mg) 02340-3 3-Amino-6-chloro-1- I $450.00
00992-3 Acetyltriethyl Citrate (500 F-1 F (05/02) $144.00 methyl-4-phenylcarbostyril
mg) (25 mg) (Limit test)
01206-5 Acyclovir (300 mg) I $182.00 XREF 2-Amino-2'-chloro-5-
01210-1 Adenine (200 mg) G-1 $144.00 nitrobenzophenone (25
01212-3 Adenosine F $144.00 mg) (Limit test) (Please
01214-5 Agigenin (25 mg) F $144.00 order Cat. No. 14033-8)
01250-9 L-Alanine (200 mg) F-2 $144.00 XREF 4-Amino-6-chloro-A/3-
01255-3 Albendazole (200 mg) G $144.00 methyl-m-benzenedi-
01260-0 Albuterol (200 mg) I $144.00 sulfonamide(IOOmg)
01263-3 Albuterol Sulfate (200 mg) J $144.00 (Limit test) (Please order
01275-7 Alclometasone H $144.00 Cat. No. 42401-8)
Dipropionate (300 mg) XREF 2-Amino-4-chlorophenol
01295-0 Alliin (25 mg) F $1410.00 (50 mg) (Limit test)
01300-2 Allopurinol (250 mg) 1-1 I (07/02) $144.00 (Please order Cat. No.
01302-4 Allopurinol Related G F-3 (05/02) $450.00 13052-7, Chlorzoxazone
Compound A (50 mg) Related Compound A) •
(Limit test) (Formerly Cat. XREF 3-Amino-4-(2-chloro- 1
No. 02200-3,3-Amino-4- phenyl)-6-nitrocarbostyril
1
1
carboxamidopyrazole
Hemisulfate) (Please order Cat. No. 1
01305-7 S-Allyl-L-Cysteine (25 mg) F $450.00 14032-7) 1
01400-5
(Limit test)
F
XREF 2-Amino-2',5-dichloroben- 1
1
Alphaprodine HCI Cll (250 $166.00 zophenone (25 mg) (Limit
mg) test) (Please order Cat. 1
01500-8
01600-0
Alprazolam CIV (200 mg)
Alprostadil (25 mg)
H
H
$166.00
$1410.00 02520-5
No. 37033-8)
Aminoglutethimide (200 F
1
1
$144.00 1
01710-5 Altretamine (500 mg) F $144.00 mg)
01750-2 Dried Aluminum Hydroxide F-1 $144.00 02530-7 m-Aminoglutethimide (100 G $450.00 1
1
Gel (200 mg) nig) (Limit test)
XREF indicates Cross Reference

Note: Where the Current Lot is blank the item is not in distribution *See page 3 for Change Code Interpretation

Previous Previous
02535-1 Aminohippuric Acid (200 F-1 $144.00 03436-3 Amrinone Related F-1 $144.00
mg) Compound C (50 mg)
02580-6 2-[3-Amino-5-(n-meth- F $450.00 03600-8 Anileridine HCI Cll (250 F $166.00
ylacetamido)-2,4,6- mg)
triiodobenzamido]-2- 03650-7 3-Anilino-2-(3,4,5- G-1 $450.00
deoxy-d-glucose (25 mg) trimethoxybenzyl)
(Limit test) acrylonitrile (25 mg) (Limit
02600-4 m-Aminophenol (300 mg) F $450.00 test)
(Limit test) 03800-3 Antazoline Phosphate (200 H G-1 (04/02) $144.00
XREF 3-Amino-4-phenoxy-5- mg)
sulfamoylbenzoic Acid (25 03900-6 Anthralin (200 mg) H $144.00
mg) (Limit test) (Please 04000-5 Antipyrine (200 mg) G 6 $144.00
order Cat. No. 07832-5) 04070-8 Apigenin-7-glucoside (30 F $450.00
XREF a-Aminopropiophenone mg) (Limit test)
HCI (50 mg) (Limit test) 04100-8 Apomorphine HCI (250 G $150.00
(Please order Cat. No. mg)
09680-4) 04160-9 Apraclonidine HCI (100 G $443.00
02640-1 Aminosalicylic Acid (125 F-1 $114.00 mg)
mg) 04200-0 Aprobarbital CHI (200 mg) F-1 $166.00
02660-5 3-Amino-2,4,6- G $450.00 (AS)
triiodobenzoic Acid (50 04250-0 L-Arginine (200 mg) G-1 $144.00
mg) (Limit test) 04260-1 Arginine HCI (125 mg) F-1 $114.00
02700-7 5-Amino-2,4,6-triiodo-/V- F-1 $450.00 04270-3 Arsanilic Acid (25 mg) F $144.00
methylisophthalamic Acid 04300-3 Ascorbic Acid (1 g) P $144.00
(50 mg) (Limit test) (Vitamin C)
02900-2 Amitriptyline HCI (200 mg) I $144.00 04370-6 Aspartame (200 mg) H $144.00
02990-9 Ammonio Methacrylate F-1 $144.00 04372-8 Aspartame Related H $450.00
CopolymerTypeA(100 Compound A (75 mg)
mg) (Limit test) (Formerly Cat.
02991-0 Ammonio Methacrylate F-1 $144.00 No. 06300-0,5-Benzyl-3,6-
Copolymer Type B (100 dioxo-2-piperazineacetic
mg) Acid)
03000-1 AmobarbitalCII(200mg) F-2 $166.00 04400-6 Aspirin (500 mg) H 2 G-1 (11/02) $144.00
03100-4 Amodiaquine HCI (500 mg) G-1 $144.00 04430-1 Astemizole (200 mg) F $144.00
03140-1 Amoxapine (200 mg) G F-1 (04/02) $144.00 04440-3 Atenolol (200 mg) H $144.00
03150-3 Amoxicillin (200 mg) I $144.00 04500-9 Atropine Sulfate (500 mg) L-2 L-1 (06/02) $144.00
03200-7 Amphotericin B (125 mg) J-1 (07/02) $114.00 04533-7 Avobenzone (500 mg) F $144.00
03300-0 Ampicillin (Anhydrous) J-1 6 $144.00 04550-8 Aurothioglucose (100 mg) G 6 $144.00
(200 mg) (For Potency 04560-0 AzaerythromycinA(100 G F-1 (02/02) $144.00
Determinations) mg)
03320-3 Ampicillin Sodium (125 G-1 $114.00 04575-6 Azaperone (200 mg) F $144.00
mg) (For Identification 04580-3 Azatadine Maleate (200 F-1 $144.00
Use Only. For Potency mg)
Use Cat. No. 03300-0) 04600-1 Azathioprine (200 mg) H $144.00
H 03340-7 Ampicillin (Trihydrate) (200 G $144.00 04605-6 Azithromycin (100 mg) G $144.00
mg) (For Identification 04610-3 Azlocillin Sodium (200 mg) F $144.00
Use Only. For Potency 04614-7 Azoaminoglutethimide F $450.00
Use Cat. No. 03300-0) (100 mg) (Limit test)
H 03400-2 Amprolium (200 mg) F-1 F (04/02) $144.00 04620-5 Aztreonam (200 mg) F-1 $144.00
* f l 03430-8 Amrinone (500 mg) G $144.00 04630-7 Aztreonam E-isomer (50 F $144.00
$ • 03432-0 Amrinone Related F $144.00 mg)
Compound A (100 mg) 04640-9 Open Ring Aztreonam (50 F $144.00
1 9 03434-1 Amrinone Related F-1 $450.00 mg)
Compound B (100 mg) 04730-0 Bacampicillin HCI (200 mg) 11 F (11/02) $144.00
(Limit test) 04750-3 Bacitracin (1 g) G $144.00
(Susceptibility disk
• standard)



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04800-7 Bacitracin Zinc (200 mg) 11 M-1 (11/02) $144.00 07150-8 Biotin (200 mg) H $144.00
04820-0 Baclofen (500 mg) I $144.00 07200-1 Biperiden (200 mg) F-1 $144.00
04822-2 Baclofen Related H $360.00 07300-4 Biperiden HCI (200 mg) F-3 $144.00
Compound A (50 mg) XREF 2-(4-Biphenylyl)propionic
(Limit test) (Formerly Cat. Acid (100 mg) (Limit test)
No. 11670-8,4-(4- (Please order Cat. No.
Chlorophenyl)-2- 28576-0)
pyrrolidinone) 07400-7 Bisacodyl(125mg) I $114.00
04850-6 Beclomethasone K $144.00 07470-0 2,5-Bis-(D-arabino-1,2,3,4- F $450.00
Dipropionate (200 mg) tetrahydoxybutyl)pyrazine
04900-0 Bendroflumethiazide (200 G-1 $144.00 (25 mg) (Limit test)
mg) XREF A/,/V-Bis-(1,3-dihydroxy-2-
05000-9 Benoxinate HCI (200 mg) F-2 $114.00 propyl)-5-amino-2,4,6-
05100-1 Benzalkonium Chloride (5 J $144.00 triiodoisophthalamide (50
mLofapprox. 10% mg) (Limit test) (Please
aqueous solution) order Cat. No. 34472-4)
05400-0 Benzocaine (500 mg) I $144.00 XREF 4,4'-Bis[4-(p-chlorophenyl)- I (07/02)
05500-2 Benzoic Acid (300 mg) F-5 $144.00 4-hydroxypiperidino]-
05600-5 Benzonatate (1 g) H $144.00 butyrophenone (25 mg)
05650-4 1,4-Benzoquinone (200 G 6 $144.00 (Limit test) (Please order
mg) (System Suitability Cat. No 30301-3)
Use Only) 07520-3 Bis (2-ethylhexyl)maleate F-2 $450.00
05900-3 Benzphetamine HCI CHI F-1 $166.00 (250 mg) (Limit test)
(200 mg) (AS) 07550-9 p-Bis (di-n-propyl)carba- F $450.00
06000-2 Benzthiazide (200 mg) F $144.00 mylbenzenesulfonamide
06100-5 Benztropine Mesylate (200 H $144.00 (50 mg) (Limit test)
mg) 07553-1 Bismuth Citrate (100 mg) F $144.00
06200-8 Benzyl Benzoate (5 g) I $144.00 07555-3 Bismuth Subsalicylate (100 F $144.00
XREF 5-Benzyl-3,6-dioxo-2- mg)
piperazineacetic Acid (250 07600-2 4,4'-Bis[1,2,3,6-tetrahydro- G $450.00
mg) (Limit test) (Please 4-(2-oxo-1 -benzimidazol-
order Cat. No. 04372-8) inyl)-1-pyridyl]butyro-
06400-3 1-Benzyl-3-methyl-5- F-1 $450.00 phenone (25 mg) (Limit
aminopyrazole HCI (25 test)
mg) (Limit test) 07630-8 Bleomycin Sulfate (15 mg) I $284.00
06500-6 Bephenium F $144.00 07635-2 Bretylium Tosylate (200 F-1 $144.00
Hydroxynaphthoate (500 mg)
mg) 07650-1 Bromocriptine Mesylate I $144.00
06570-9 Betaine Hydrochloride F-1 2 F (11/02) $144.00 (150 mg)
(200 mg) 07700-5 Bromodiphenhydramine F-1 $144.00
06600-9 Betamethasone (200 mg) K $144.00 HCI (200 mg)
06700-1 Betamethasone Acetate I $144.00 07770-8 8-Bromotheophylline (400 G F (07/02) $144.00
(500 mg) mg)
06730-7 Betamethasone Benzoate F-1 $144.00 07800-8 Brompheniramine Maleate I $114.00 •
(200 mg) (125 mg)
06770-4 Betamethasone J $114.00 07830-3 Bumetanide (250 mg) G $144.00 1
Dipropionate (125 mg) 07832-5 Bumetanide Related F-2 $450.00 1
06800-4 Betamethasone Sodium 1-1 $144.00 Compound A (25 mg)
Phosphate (500 mg) (Limit test) (Formerly Cat. 1
06900-7 Betamethasone Valerate
(200 mg)
J $144.00 No. 02610-6,3-Amino-4-
phenoxy-5-
1
1
06990-3
07000-6
Betaxolol HCI (200 mg)
Betazole HCI (200 mg)
G
H
$144.00
$144.00 07850-7
sulfamoylbenzoic Acid)
Bupivacaine HCI (1 g) G-2 2 G-1 (08/02)
11
$144.00 1
07100-9 Bethanechol Chloride (200 G $144.00 07870-0 Buprenorphine HCI CV (50 F-1 $166.00 1
mg) mg)
07130-4 Bile Salts (10 g) (Formerly H-1 $114.00
07871-1 Buprenorphine Related F 1
$144.00 1
Cat. No. 61500-5, Sodium Compound A (50 mg)
Taurocholate) 07880-2 Buspirone HCI (200 mg) G $144.00 1


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Cat Curr. Change Lot/Valid Cat Curr. Change Lot/Valid
07900-0 Butabarbital Clll (200 mg) G $166.00 09320-5 Carbarsone (200 mg) F $144.00
08000-0 Butacaine Sulfate (600 F $144.00 09350-0 Carbenicillin Indanyl G $144.00
mg) Sodium (300 mg)
08100-2 Butalbital CHI (200 mg) G-2 2 G (05/02) $166.00 09400-4 Carbenicillin Monosodium G-2 $144.00
08150-1 Butamben (200 mg) F $144.00 Monohydrate (200 mg)
08230-0 Butoconazole Nitrate (200 F $144.00 09550-6 Carbidopa (400 mg) I $144.00
mg) 09600-0 Carbinoxamine Maleate 11 G-1 (11/02) $144.00
08250-4 Butorphanol Tartrate CIV J $166.00 (200 mg)
(500 mg) 09640-7 Carboplatin(IOOmg) G $147.00
08280-0 Monotertiary-butyl-p- F $144.00 09650-9 Carboprost Tromethamine F-1 $450.00
benzoquinone(100mg) (25 mg)
(FCC) 09660-0 Carisoprodol (1 g) G F-2 (05/02) $144.00
08290-1 Butyl 3-(butylamino)-4- F-1 $450.00 09675-7 Carteolol HCI (200 mg) F-1 $144.00
phenoxy-5-sulfamoyl- 09680-4 Cathinone HCI Cl (50 mg) I $450.00
benzoate (25 mg) (Limit (Limit test) (Formerly Cat.
test) No. 02620-8, a-Aminopro-
08300-8 2-fert-Butyl-4-hydroxy- K $144.00 piophenone HCI)
anisole (200 mg) 09690-6 Cefaclor (400 mg) H $144.00
08310-0 3-tert-Butyl-4- J 6 $144.00 09691-7 Cefaclor, Delta-3 Isomer G $144.00
hydroxyanisole (200 mg) (30 mg)
08400-0 Butylparaben (200 mg) H-1 6 $144.00 09710-4 Cefadroxil(125mg) I $114.00
08500-3 Caffeine (200 mg) J I (06/02) $144.00 09730-8 Cefamandole Lithium (200 H $144.00
08600-6 Caffeine Melting Point I $85.00 mg)
Standard (1 g) 09740-0 Cefamandole Nafate (200 H $144.00
(Approximately 236 mg)
degree(s)) 09750-1 Cefamandole Sodium (250 F $144.00
08610-8 Calcifediol (75 mg) G $144.00 mg) (For Identification
08635-6 Calcium Ascorbate (200 F-1 $144.00 Use Only)
mg) (For Identification 09760-3 Cefazolin (400 mg) K $144.00
Use Only) 09765-8 Cefixime (500 mg) F $144.00
XREF Calcium Formyltetra- 09777-1 Cefmenoxime HCI (350 F $144.00
hydrofolate (50 mg) (AS) mg)
(For Qualitiative Use 09778-2 Cefmetazole (200 mg) F-1 F (04/02) $144.00
Only) (Please Order Cat. 09775-0 Cefonicid Sodium (1 g) G $144.00
No. 28602-7) 09770-5 Cefoperazone Dihydrate H $144.00
08680-0 Calcium Gluceptate (200 F-1 $144.00 (200 mg)
mg) 09780-7 Ceforanide (200 mg) F-1 $144.00
08690-2 Calcium Lactobionate (200 F-1 6 $144.00 09790-9 Cefotaxime Sodium (250 I $114.00
mg) mg)
08700-9 Calcium Pantothenate N-1 $144.00 09797-5 Cefotetan (500 mg) G $144.00
(200 mg) (Vitamin Bs) 09800-5 Cefotiam HCI (325 mg) F $144.00
08720-2 Calcium Saccharate (200 F $144.00 09804-9 Cefprozil E-lsomer (50 mg) F-1 $144.00
•g j 08800-1
mg)
Candicidin (200 mg) F $144.00
09805-0 Cefprozil z-lsomer (200
mg)
F $144.00
i« 08900-4 Cannabidiol Cl (25 mg) F-2 $166.00 09810-7 Cefoxitin (500 mg) I $144.00
(AS) (For Qualitiative Use 09812-9 Ceftazidime, Delta-3- G $144.00
Only) Isomer (25 mg)
£ f l 09000-3 Cannabinol CI (25 mg) F-2 (05/02) $166.00 09813-0 Ceftazidime Pentahydrate H $144.00
(AS) (300 mg)
» 09100-6 Capreomycin Sulfate (200 G $144.00 09817-3 Ceftizoxime (200 mg) H $144.00
mg) 09818-4 Ceftriaxone Sodium (350 F $144.00
I I 09110-8 Capsaicin(100mg) G-1 G (03/02) $144.00 mg)
3 09120-0 Captopril (200 mg) H $144.00 09819-5 Ceftriaxone Sodium E- H $144.00
Captopril Disulfide (100 G $450.00 Isomer (25 mg) (For
mg) (Limit test) System Suitability Use
^ 09200-9 Carbachol (200 mg) G $144.00 Only)
09300-1 Carbamazepine (100 mg) J $144.00



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Cat Curr. Change Lot/Valid Cat. Curr. Change Lot/Valid
09820-9 Cefuroxime Sodium (200 H $144.00 XREF 6-Chloro-4-(o-chloro-

mg) phenyl)-2-quinazo!ine-
09822-0 Cefuroxime Axetil (500 G F-1 (05/02) $144.00 carboxylic Acid (25 mg)
mg) (Limit test) (Please order
09823-1 Cefuroxime Axetil Delta-3- G $144.00 Cat. No. 37035-0)
Isomers (35 mg) XREF 6-Chloro-4-(o-chloro-
09830-0 Cellulose Acetate (125 mg) F-1 $114.00 phenyl)-2-quinazoline
09835-5 Cellulose Acetate F-1 $114.00 Methanol (25 mg) (Limit
Phthalate (125 mg) test) (Please order Cat.
09870-8 Cephaeline HBr (200 mg) G-1 $450.00 No. 37036-0)
(Limit test) XREF 7-Chloro-1,3-dihydro-5-
09900-8 Cephalexin (250 mg) I-2 $144.00 phenyl-2H-1,4-benzo-
10200-0 Cephalothin Sodium (200 I $144.00 diazepin-2-one (50 mg)
mg) (Limit test) (Please order
10240-8 Cephapirin Benzathine F $144.00 Cat. No. 46840-0)
(100 mg) XREF 7-Chloro-1,3-dihydro-5-
10250-0 Cephapirin Sodium (200 I (07/02) $144.00 phenyl-2H-1,4-benzo-
mg) diazepin-2-one 4-Oxide
10280-5 Cephradine (200 mg) J $144.00 (25 mg) (Limit test)
10300-3 Cetyl Alcohol (100 mg) I $144.00 (Please order Cat. No.
10400-6 Cetylpyridinium Chloride I $144.00 11002-0)
(500 mg) XREF 2-Chloro-4-N-furfuryl-
10600-1 Chlorambucil (125 mg) G $114.00 amino-5-sulfamolybenzoic
10700-4 Chloramphenicol (200 mg) N $144.00 acid (50 mg) (Limit test)-
10730-0 Chloramphenicol Palmitate G-1 $144.00 (Please order Cat. No.
(200 mg) 28702-0)
10740-1 Chloramphenicol Palmitate F-1 $450.00 XREF 2-Chloro-3,5-dimethyl- 6
Nonpolymorph A (200 mg) phenol (50 mg) (Limit
(Limit test) test) (Please order Cat.
10750-3 Chloramphenicol Palmitate G $450.00 No. 12272-2)
Polymorph A (200 mg) XREF (o-Chlorophenyl)diphenyl-
(Limit test) methanol (25 mg) (Limit
10900-0 Chlordiazepoxide CIV (200 H-1 $166.00 test) (Please order Cat.
mg) No. 14102-4)
11000-9 Chlordiazepoxide HCI CIV G-4 $166.00 XREF 4-(4-Chlorophenyl)-2-
(200 mg) pyrrolidinone (75 mg)
11002-0 Chlordiazepoxide Related G $450.00 (Limit test) (Please order
Compound A (25 mg) Cat. No. 04822-2)
(Limit test) (Formerly Cat. 11555-6 beta-Chlorogenin (20 mg) F $144.00
No. 11500-2,7-Chloro-1,3- (For Identification Use
dihydro-5-phenyl-2H-1,4- Only)
benzodiazepin-2-one 4- 11700-8 Chloroprocaine HCI (200 F-3 $144.00
Oxide) mg)
XREF p-Chlorobenzhydryl- G-1 (01/02) 11800-0 Chloroquine Phosphate I $144.00 •
piperazine (25 mg) (Please (500 mg)
order Cat. No. 33305-8) XREF 4-Chloro-5-sulfamoyl- 1
11250-3 Chlorobutanol (200 mg) G 6 $144.00 anthranilic Acid (100 mg) 1
(For Identification Use (Limit test) (Please order 1
Only) Cat. No. 28703-0) 1
XREF 6-Chloro-4-(o-chloro- 11930-9 4'-Chloro-3'-sulfamoyl-2- F-3 $450.00 1
1
phenyl)-2-quinazoline- benzophenone Carboxylic
carboxaldehyde (25 mg) Acid (100 mg) (Limit test) 1
(Limit test) (Please order 12100-5 Chlorothiazide (200 mg) G $144.00 1
1
Cat. No. 37034-9) 12200-8 Chlorotrianisene (1 g) F $144.00 1
12270-0 Chloroxylenol(125mg) F-1 $114.00 1


Previous Previous
12272-2 Chloroxylenol Related F-1 $450.00 13440-4 Clavam-2-carboxylate F $450.00

Compound A (50 mg) Potassium (1 Pellet) (Limit
(Limit test) (Formerly Cat. test)
No. 11550) 13442-6 Clavulanate Lithium (200 I 2 H (09/02) $144.00
12300-0 Chlorpheniramine Maleate L-1 $114.00 mg)
(125 mg) 13450-6 Clemastine Fumarate (250 I $144.00
12310-2 Chlorpheniramine Maleate F $144.00 mg)
Extended-Release Tablets 13500-0 Clidinium Bromide (2 g) G $144.00
(Drug Release Calibrator, 13502-1 Clindinium Bromide I $450.00
Single-Unit) (60 Tablets) Related Compound A (250
12400-3 Chlorphenoxamine HCI F-1 $144.00 mg) (Limit test) (Formerly
(200 mg) Cat. N. 32720-4 3-
12500-6 Chlorpromazine HCI (200 J $144.00 Hydroxy-1 -methylquinucl-
mg) indinium Bromide (250 mg)
12600-9 Chlorpropamide (200 mg) H $144.00 (Limit test)
12700-1 Chlorprothixene (200 mg) F-1 $144.00 13600-2 Clindamycin HCI (200 mg) G-3 $396.00
12900-7 Chiortetracyciine HCI (200 J-1 . J (02/02) $144.00 13700-5 Clindamycin Palmitate HCI F-2 $396.00
mg) (200 mg)
13000-6 Chlorthalidone (125 mg) H-1 $114.00 13800-8 Clindamycin Phosphate H-2 $198.00
13050-5 Chlorzoxazone (500 mg) I $144.00 (125 mg)
13052-7 Chlorzoxazone Related G-1 $450.00 13820-1 Clioquinol (500 mg) L-1 $144.00
Compound A (25 mg) 13840-5 Clobetasol Propionate F-1 6 $144.00
(Limit test) (Formerly Cat. (200 mg)
No. 02240-6,2-Amino-4- 13842-7 Clobetasol Propionate F $144.00
chlorophenol) Related Compound A (50
13100-9 Cholecalciferol (30 L $147.00 mg)
mg/ampul; 5 ampuls) 13850-7 Clocortolone Pivalate (200 G $144.00
(Vitamin Da) mg)
13180-3 Delta 4,6-cholestadienol F $144.00 13890-4 Clofazimine (200 mg) F $144.00
(30 mg) 13900-0 Clofibrate (1 g) I $144.00
13200-1 Cholesteryl Caprylate (200 F $144.00 14000-0 Clomiphene Citrate (500 H $144.00
mg) mg)
13300-4 Cholestyramine Resin (500 I $114.00 14010-1 Clomiphene Related F $144.00
mg) Compound A (100 mg)
13350-3 Cholic Acid (2 g) (AS) F-2 $144.00 14030-5 Clonazepam CIV (200 mg) G $166.00
13363-8 Chromium Picolinate (100 F 4 $144.00 14032-7 Clonazepam Related G-1 $450.00
mg) (For Identification Compound A (25 mg)
Test Only) (Limit test) (Formerly Cat.
13400-7 Chymotrypsin (300 mg) I $144.00 No. 02460-0,3-Amino-4-
13403-0 Ciclopirox Olamine (125 G $114.00 (2-chlorophenyl)-6-
mg) nitrocarbostyril)
13405-1 Cilastatin Ammonium Salt F-1 $144.00 14033-8 Clonazepam Related H $450.00
(100 mg) Compound B (25 mg)
| 9 13406-2 Cimetidine (200 mg) I $144.00 (Limit test) (Formerly Cat.
U 13407-3 Cimetidine HCI (200 mg) F $144.00 No. 02380-0,2-Amino-2'-
M 13410-9 Cinoxacin (200 mg) F $144.00 chloro-5-nitrobenzo-
9 13431-3 Ciprofloxacin (125 mg) G-1 $114.00 phenone)
1
H 3432-4 Ciprofloxacin Ethylene- I $144.00 14040-7 Clonidine HCI (200 mg) G $144.00
diamine Analog (25 mg) 14050-9 Clorazepate Dipotassium F-1 $166.00
p« 13433-5 Ciprofloxacin HCI (400 mg) H $144.00 CIV (125 mg)
<M 13435-7 Cisplatin (100 mg) H $144.00 14070-2 Clorsulon (200 mg) F $144.00
|fl 13436-8 Citric Acid (200 mg) F (07/02) $144.00 14100-2 Clotrimazole (200 mg) J $114.00
5M 13437-9 Clarithromycin (75 mg) F-3 6 $144.00 14102-4 Clotrimazole Related I 6 $450.00
|fl 13438-0 Clarithromycin Related G $144.00 Compound A (25 mg)
••I Compound A (50 mg) (Limit test) (Formerly Cat.
No. 11650-4)
•
10
Online ordering, www.usp.org


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14190-9 Cloxacillin Benzathine (200 F-1 F (03/02) $144.00 15865-0 Cyclosporine Resolution F $381.00
mg) (For Identification Mixture (25 mg) (Replaces
Use Only) Cat. No. 15870-8
14200-5 Cloxacillin Sodium (200 K $144.00 Cyclosporine U (25 mg))
mg) XREF Cyclosporine U (25 mg)
14300-8 Cocaine HCI Cll (250 mg) H-2 $166.00 (Please order Cat. No.
14380-2 Codeine W-Oxide Cl (50 11 F-1 (11/02) $166.00 15865-0)
mg) 15900-8 Cyclothiazide (200 mg) F-1 $144.00
14400-0 Codeine Phosphate Cll I $166.00 16100-0 Cyproheptadine HCI (500 11 F-4 (11/02) $144.00
(100 mg) mg)
14500-3 Codeine Sulfate Cll (250 H-2 H-1 (01/02) $166.00 16150-9 L-Cysteine HCI (200 mg) H $144.00
mg) 16200-2 Cytarabine (250 mg) G-2 $144.00
14600-6 Colchicine (300 mg) J I (05/02) $144.00 16230-8 Dacarbazine(125mg) H $114.00
14650-5 Colestipol HCI (200 mg) F-1 $144.00 16232-0 Dacarbazine Related G $450.00
14700-9 Colistimethate Sodium H $144.00 Compound A (50 mg)
14800-1 Colistin Sulfate (200 mg) G-1 $144.00 16233-0 Dacarbazine Related F-1 6 $450.00
14900-4 Corticotropin (5.6 M $114.00 Compound B (100 mg)
Units/vial; 5 viais) (Limit test)
15000-3 Cortisone Acetate (150 I $144.00 16240-0 Dactinomycin (50 mg) I $395.00
mg) 16250-1 Danazol (200 mg) H $144.00
15035-3 Creatinine (100 mg) (For F $144.00 16400-8 Dapsone (125 mg) G-3 $114.00
Identification Use Only) 16470-0 Daunorubicin HCI (100 K $443.00
15050-2 Cromolyn Sodium (500 J $144.00 mg)
mg) 16500-0 Decamethonium Bromide F $144.00
15070-6 Crospovidone (200 mg) G $144.00 (250 mg)
15100-6 Crotamiton (200 mg) H-1 $144.00 16600-3 Deferoxamine Mesylate I $144.00
15200-9 Cyanocobalamin (1.5 g of N $144.00 (500 mg)
mixture with mannitol; 10.7 16630-9 Dehydroacetic Acid (200 F $144.00
fig/mg of mixture) (Vitamin mg)
B«) 16640-0 Dehydrocarteolol HCI (100 F $450.00
15250-8 Cyclacillin (200 mg) G $144.00 mg) (Limit test)
15300-1 Cyclizine (1 g) F $144.00 16650-2 Dehydrocholic Acid (200 F $144.00
15400-4 Cyclizine HCI (200 mg) G $144.00 mg)
15450-3 Cyclobenzaprine HCI (200 F-3 $144.00 16900-1 Demecarium Bromide (250 F $144.00
mg) mg)
15455-8 Alpha Cyclodextrin (50 mg) F-1 $144.00 17000-0 Demeclocycline HCI (200 H $144.00
15456-9 Beta Cyclodextrin (250 F-1 $144.00 mg)
mg) 17100-3 Denatonium Benzoate 11 H (09/02) $144.00
15470-7 Cyclomethicone 4 (200 F-2 2 F-1 (06/02) $144.00 (200 mg)
mg) 17170-6 Desacetyl Diltiazem HCI I $450.00
15480-9 Cyclomethicone 5 (125 F-2 $114.00 (50 mg) (Limit test)
mg) 17200-6 Desipramine HCI (125 mg) H-1 $114.00
15490-0 Cyclomethicone 6 (200 F-1 $144.00 17300-9 Deslanoside (100 mg) H-1 $144.00 •
mg) 17350-8 Desoximetasone (200 mg) G $144.00 1
15600-0 Cyclopentolate HCI (300 H $144.00 17400-1 Desoxycorticosterone I $144.00 1
mg) Acetate (200 mg)
15700-2 Cyclophosphamide (500 J $114.00 17500-4 Desoxycorticosterone G 1
$114.00 1
mg) Pivalate(125mg)
15750-1 2-Cyclopropylmethyl- F $450.00 17600-7 Dexamethasone (125 mg) J $114.00 1
I
amino-5- chlorobenzo- 17650-6 Dexamethasone Acetate G $144.00 1
phenone (50 mg) (Limit (200 mg)
test) 17700-0 Dexamethasone J $144.00 1
I
15800-5 Cycloserine (200 mg) G $144.00 Phosphate (200 mg)
15850-4 Cyclosporine (50 mg) H-1 2 H (11/02) $443.00 17800-2 Dexbrompheniramine I $144.00 1
I
Maleate (200 mg)
17900-5 Dexchlorpheniramine G $144.00 1 |
Maleate (500 mg)
11


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17950-4 Dexpanthenol (500 mg) H (02/02) $148.00 20080-4 Dihydrocodeine Bitartrate H $166.00
18000-4 Dextroamphetamine G $174.00 Cll (200 mg)
Sulfate Cll (500 mg) 20100-2 17 a -Dihydroequitin (50 H $144.00
18050-3 Dextromethorphan (2 g) H $450.00 mg)
18100-7 Dextromethorphan HBr I $144.00 20200-5 Dihydroergotamine I $144.00
(500 mg) Mesylate (250 mg)
18130-2 Dextrose (1 g) J-1 2 J (11/02) $114.00 20300-8 Dihydrostreptomycin J $144.00
18150-6 Diacetylated Mono- G $144.00 Sulfate (200 mg)
glycerides (200 mg) 20400-0 Dihydrotachysterol (30 I $144.00
18200-0 Diacetylfluorescein (200 H 2 G (01/02) $144.00 mg/ampul; 4 ampuls)
mg) 20410-2 Dihydroxyacetone (250 F $144.00
18300-2 Diacetylmorphine HCI J $166.00 mg)
(Heroin HCI) Cl (25 mg) 20500-3 Diltiazem HCI (200 mg) I $144.00
(AS) 20600-6 Dimenhydrinate (100 mg) I $144.00
18400-5 Diatrizoic Acid (100 mg) G $144.00 20800-1 Dimethisoquin HCI (2 g) G $144.00
18402-7 Diatrizoic Acid Related I $450.00 XREF a-d-4-Dimethylamino-1,2- G-4 (04/02)
Compound A (50 mg) diphenyl-3-methyl-2-
(Limit test) (Formerly Cat. butanolHCI(125mg)
No. 00200-6,5-Acetamido- (Limit test) (Please Order
3-amino-2,4,6-triiodo- Cat. No. 57520)
benzoic Acid) 21010-5 A/-(3-Dimethylamino- F $144.00
18500-8 DiazepamCIV(100mg) I 6 $166.00 propyl)-2-aza-8,8-diethyl-8-
18502-0 Diazepam Related I 2 H-1 (11/02) $450.00 germaspiro [4:5]decane-
Compound A (25 mg) 1,3-dione
(Limit test) (Formerly Cat. 21100-6 Dimethyl Sulfoxide (3 g) F-3 F-2 (05/02) $144.00
No. 42420-0,2-Methyl- 21300-1 Dinoprost Tromethamine F $1410.00
amino-5-chlorobenzo- (50 mg)
phenone) 21400-4 Dioxybenzone(150mg) F $144.00
18600-0 Diazoxide (200 mg) G $144.00 21600-0 Diphemanil Methylsulfate H $144.00
18700-3 Dibucaine HCI (200 mg) 1 2 H-2 (11/02) $144.00 (500 mg)
18800-6 Dichlorphenamide (200 G-1 $144.00 21790-9 Diphenhydramine Citrate G $114.00
mg) (125 mg)
18880-0 Diclofenac Sodium (200 G-1 $144.00 21800-5 Diphenhydramine HCI (200 1 $144.00
mg)
18881-1 Diclofenac Related G (05/02) $453.00 21900-8 Diphenoxylate HCI Cll 1 H (03/02) $166.00
Compound A (100 mg) (200 mg)
(Limit test) 22030-2 Dipivefrin HCI (200 mg) 1 $144.00
18900-9 Dicloxacillin Sodium (500 H $144.00 22050-6 Dipyridamole (200 mg) H $144.00
mg) 22070-0 Dirithromycin (200 mg) F $144.00
19000-8 Dicumarol (200 mg) G $144.00 22100-0 Disodium Guanylate (300 F-1 $144.00
19100-0 DicyclomineHCI(125mg) H $114.00 mg) (FCC)
19200-3 Dienestrol(125mg) I $114.00 22200-2 Disodium Inosinate (500 F $144.00
• 19300-6 Diethylcarbamazine Citrate G-1 $144.00 mg) (FCC)
(200 mg) 22250-1 Disopyramide Phosphate H-1 H (03/02) $144.00
|J 19350-5 Diethyl Phthalate (200 mg) G $144.00 (200 mg)
« 19400-9 Diethylpropion HCI CIV H $166.00 22300-5 2,4-Disulfamyl-5-trifluoro- G $450.00
(200 mg) methylaniline (125 mg)
H 19500-1 Diethylstilbestrol (200 mg) K-4 $144.00 (Limit test)
IB 19700-7 Diethyltoluamide (3 g) H $114.00 22400-8 Disulfiram (200 mg) F-3 F-2 (07/02) $144.00
±m 19730-2 Diflorasone Diacetate (200 G $144.00 22450-7 Dobutamine HCI (600 mg) H-1 $144.00
mg) 22470-0 Docusate Calcium (500 11 G-1 (07/02) $144.00
| I 19750-6 Diflunisal (200 mg) G $144.00 mg)
g» 19800-0 Digitalis (3 g) F $144.00 22480-2 Docusate Sodium (500 J 1-1 (05/02) $144.00
3 19900-2 Digitoxin (200 mg) M $144.00 mg)
9 20000-0 Digoxin (250 mg) N-1 $144.00 22490-4 Docusate Potassium (100 F-1 $144.00
• 20060-0 Dihydrocapsaicin (50 mg) F-1 $144.00 mg)
22520-4 Dopamine HCI (200 mg) G F-5 (05/02) $144.00
12



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22500-0 Doxapram HCI (200 mg) F-3 $144.00 24300-2 Erythromycin Estolate (200 G $144.00
22550-0 Doxepin HCI (500 mg) I $144.00 mg) (For Identification
Use Only. For Potency
22600-3 Doxycycline Hyclate (200 I $144.00 Use No. 24200-0)
mg) 24500-8 Erythromycin H $144.00
22700-6 Doxylamine Succinate H $144.00 Ethylsuccinate (200 mg)
(300 mg) (For Identification Use
22900-1 Droperidol (250 mg) H-1 $144.00 Only. For Potency Use
23000-0 Dyclonine HCI (200 mg) G $144.00 No. 24200-0)
23100-3 Dydrogesterone (200 mg) H $144.00 24600-0 Erythromycin Gluceptate G $144.00
23150-2 Dyphylline (200 mg) G-2 2 G-1 (11/02) $144.00 (200 mg) (For
23180-8 Econazole Nitrate (200 G $144.00 Identification Use Only.
mg) For Potency Use No.
23200-6 Edetate Calcium Disodium G-3 $144.00 24200-0)
(200 mg) 24700-3 Erythromycin Lactobionate H-1 H (01/02) $144.00
23300-9 Edetate Disodium (200 H G-2 (04/02) $144.00 (200 mg) (For
mg) Identification Use Only.
23350-8 Edetic Acid (200 mg) F-1 $144.00 For Potency Use No.
23400-1 Edrophonium Chloride H $144.00 24200-0)
(200 mg) 24800-6 Erythromycin Stearate G-1 $144.00
23500-4 Emetine HCI (300 mg) G $144.00 (200 mg) (For
23527-4 Enalaprilat (300 mg) I $114.00 Identification Use Only.
23530-0 Enalapril Maleate (200 mg) J $144.00 For Potency Use No.
23550-3 Endotoxin (10,000 USP G-1 $144.00 24200-0)
Endotoxin Units) 24900-9 Erythrosine Sodium (100 F $144.00
23580-9 Enflurane (1 mL) G-1 $144.00 mg)
23600-7 Ephedrine Sulfate (200 11 H-1 (11/02) $144.00 25000-8 Estradiol (500 mg) K $144.00
mg) 25100-0 Estradiol Benzoate (250 G-1 $144.00
23650-6 4-Epianhydrotetracycline 1-1 $450.00 mg)(AS)
HCI (50 mg) (Limit test) 25200-3 Estradiol Cypionate (200 G-1 $144.00
23680-1 Epilactose (200 mg) (Limit G $450.00 mg)
test) 25400-9 Estradiol Valerate (100 K (05/02) $144.00
23700-0 Epinephrine Bitartrate (200 O $144.00 mg)
mg) 25450-8 Estriol (100mg) J $144.00
23750-9 Epitetracycline HCI (200 F $450.00 25500-1 Estrone (200 mg) K $144.00
mg) (Limit test) 25550-0 Estropipate (350 mg) I 6 $144.00
23800-2 Equilin (25 mg) I $144.00 25600-4 Ethacrynic Acid (200 mg) F $144.00
23900-5 Ergocalciferol (150 mg; 30 O $156.00 25700-7 Ethambutol HCI (200 mg) 11 G (08/02) $144.00
mg/ampul; 5 ampuls) 26000-1 Ethinyl Estradiol (150 mg) P $144.00
(Vitamin D2) 26100-4 Ethionamide (200 mg) G $144.00
23950-4 Ergoloid Mesylates (300 I $144.00 26280-1 Ethopabate (125 mg) F $144.00
mg) 26282-3 Ethopabate Related F $144.00
24000-4 Ergonovine Maleate (100 N M-1 (07/02) $144.00 Compound A (25 mg)
mg) 26300-0 Ethopropazine HCI (300 G $144.00 •
24100-7 Ergosterol (50 mg) (For H $144.00 mg)
Identification Use Only) 26400-2 Ethosuximide (125 mg) H 6 $114.00 11
24150-6 Ergotamine Tartrate (150 H $144.00 26450-1 Ethotoin (200 mg) F $144.00 1
mg) 26500-5 Ethoxzolamide (200 mg) F $144.00 1
24155-0 Ergotaminine(IOOmg) F-1 $144.00 26550-4 Ethylcellulose (1 g) H-1 $144.00 1
24200-0 Erythromycin (250 mg) M $144.00 26600-8 Ethyl Maltol (1 g) (FCC) H $144.00 1
24201-0 ErythromycinB(150mg) G $144.00 26650-7 Ethylnorepinephrine HCI F $144.00 1
24202-1 Erythromycin C (50 mg) F-2 F-1 (02/02) $144.00 (200 mg)
24203-2 Erythromycin Related F-1 $144.00 26700-0 Ethylparaben (200 mg) H $144.00 1 1
Compound N (50 mg) 26750-0 Ethyl Vanillin (200 mg) F-1 $144.00 1
(Resolution Solution Use 26800-3 Ethynodiol Diacetate (200 H-1 $144.00 1
Only) mg)
26850-2 Etidronate Disodium (200 F-2 $144.00 1 1
mg)
13

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26860-4 Etidronic Acid G $144.00 27740-1 Fluoride Dentifrice: Sodium G-1 $450.00
Monohydrate (1 g) Monofluorophosphate
26870-6 Etodolac (400 mg) G 6 $144.00 (1000 ppm)/Silica (5.25
oz.)
26872-8 Etodolac Related F-1 F(05/02) $144.00 27742-3 Fluoride Dentifrice: Sodium F-1 $450.00
Compound A (25 mg) Monofluorophosphate
26880-8 Etoposide (300 mg) G $114.00 (1500 ppm)/Silica (5.25
26882-0 Etoposide Related F-1 $144.00 oz.)
Compound A (25 mg) 27745-6 Fluoride Dentifrice: 11 G (11/02) $450.00
26900-6 Evans Blue (200 mg) G $144.00 Stannous Fluoride—Silica
26920-0 Famotidine(125mg) H-1 2 H (11/02) $114.00 (4oz.)
26938-9 Felodipine (200 mg) F $144.00 27800-7 Fluorometholone (200 mg) 11 H-1 (11/02) $144.00
26950-5 Fenoprofen Calcium (500 G-1 $144.00 27810-9 Fluorometholone Acetate F $144.00
mg) (200 mg)
26955-0 Fenoprofen Sodium (500 G F-1 (05/02) $144.00 27830-2 Fluoroquinolonic Acid (50 G $450.00
mg) mg) (Limit test)
27000-5 Fentanyl Citrate Cll (100 J (05/02) $166.00 27900-0 Fluorouracil (250 mg) H-1 H (01/02) $144.00
mg) 27980-4 Fluoxetine HCI (200 mg) F-1 $144.00
27040-2 Finasteride (200 mg) F $144.00 27981-5 Fluoxetine Related G 4 $450.00
27080-0 Flecainide Acetate (200 F $144.00 Compound A (15 mg) (For
mg) System Suitability Use
27082-1 Flecainide Related F $450.00 Only)
Compound A (75 mg) 27982-6 Fluoxetine Related F-2 2 F-1 (09/02) $144.00
(Limit test) Compound B (5 mL of a
27100-8 Floxuridine (250 mg) F-2 $144.00 0.01 N HCI solution,
27200-0 Flucytosine (200 mg) F $144.00 approx. 2 mg/mL) (For
27300-3 Fludrocortisone Acetate H $144.00 System Suitability Use
(250 mg) Only)
27400-6 Flumethasone Pivalate I H (01/02) $144.00 28000-9 Fluoxymesterone CHI (200 G-2 $166.00
(200 mg) mg)
27450-5 Flunisolide (200 mg) I $144.00 28080-3 Fluphenazine Decanoate G 6 $147.00
27460-7 Flunixin Meglumine (300 F-1 $144.00 Dihydrochloride (500 mg)
mg) 28100-1 Fluphenazine Enanthate H $114.00
27500-9 Fluocinolone Acetonide J $144.00 Dihydrochloride (125 mg)
(100 mg) 28200-4 Fluphenazine HCI (125 H $114.00
27600-1 Fluocinonide(100mg) I $144.00 mg)
27700-4 Fluorescein (200 mg) F-1 $144.00 28400-0 Flurandrenolide (100 mg) H $144.00
27720-8 Fluoride Dentifrice: Sodium F $450.00 28500-2 Flurazepam HCI CIV (200 I $166.00
Fluoride—Calcium mg)
Pyrophosphate (high beta- 28530-8 Flurazepam Related H-1 $450.00
phase) (180 g) Compound C (50 mg)
27725-2 Fluoride Dentifrice: Sodium I $423.00 (Limit test)
Fluoride/Silica (4.5 oz) 28560-3 Flurazepam Related H $450.00
JM 27727-4 Fluoride Dentifrice; Sodium F $450.00 Compound F (50 mg)
Fluoride/Sodium Bicarb- (Limit test)
onate Powder (4 oz.) 28575-0 Flurbiprofen (200 mg) G $144.00
S 27730-0 Fluoride Dentifrice: Sodium G $450.00 28576-0 Flurbiprofen Related H $450.00
Monofluorophosphate— Compound A (100 mg)
Calcium Carbonate (4.6 (Limit test) (Formerly Cat.
oz.) No. 07350-3,2-(4-
m 27735-4 Fluoride Dentifrice: Sodium G $450.00 Biphenylyl)propionic Acid)
Monofluorophosphate/Di- 28580-7 Flurbiprofen Sodium (200 F $144.00
calcium Phosphate (4.6 mg) (For Identification
oz.) Use Only)
28585-1 Flutamide (200 mg) G $144.00
H 28586-2 o-Flutamide (50 mg) F-1 $144.00
•1 (System Suitability Use)
14


Official USP Reference Standards Catalog Jan .-Feb. 2002

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Cat. Cure Change Lot/Valid Cat. Curr. Change Lot/Valid
28600-5 Folic Acid (500 mg) P $144.00 29550-5 Glyburide (200 mg) G 2 F-2 (11/02) $144.00
(Vitamin M or Vitamin Be) 29560-7 Glycerin (2 mL) G $144.00
28602-7 Folic Acid Related H-1 $144.00 29570-9 Glyceryl Behenate (200 F-2 $144.00
Compound A (50 mg) mg)
(Fomerly Cat. No. 08650- 29580-0 Glycine (200 mg) F-3 $144.00
5, Calcium Formyltetra- 29600-9 Glycopyrrolate (200 mg) G $144.00
hydrofolate) 29700-1 Human Chorionic H $144.00
Gonadotropin (1 vial, 5,760
28620-9 4-Formylbenzenesulfon- F $450.00 USP Units per package)
amide (50 mg) (Limit test) 29800-4 Gramicidin (200 mg) H-1 (07/02) $144.00
28630-0 10-Formylfolic Acid (25 F-1 $144.00 29900-7 Griseofulvin (200 mg) 11 H-1 (09/02) $144.00
mg) 29920-0 Griseofulvin Permeability H $144.00
28650-4 Fructose (125 mg) I-2 2 1-1(11/02) $114.00 Diameter (2 g)
28670-8 Fumaric Acid (200 mg) G (04/02) $144.00 30000-4 Guaiacol (1 g) K $144.00
28680-0 Furazolidone (200 mg) G-2 6 $144.00 30100-7 Guaifenesin (200 mg) 11 H (09/02) $144.00
28700-8 Furosemide (125 mg) J $114.00 30140-4 Guanabenz Acetate (200 G $144.00
28702-0 Furosemide Related J 2 I (08/02) $450.00 mg)
Compound A (50 mg) 30160-8 Guanadrel Sulfate (200 F-1 $144.00
(Limit test) (Formerly Cat. mg)
No. 11510-4,2-Chloro-4- 30180-1 Guanethidine Monosulfate F $144.00
A/-furfurylamino-5-sulfa- (200 mg)
molybenzoic Acid) 30200-0 Guanethidine Sulfate (500 G-1 $144.00
28703-0 Furosemide Related H $450.00 mg)
Compound B (100 mg) 30210-1 GuanfacineHCI(125mg) F-1 $114.00
(Limit test) (Formerly Cat. 30230-5 Halazepam CIV (200 mg) F $166.00
No. 11900-3,4-Chloro-5- 30250-9 Halcinonide (300 mg) F $144.00
sulfamoylanthranilic Acid) 30300-2 Haloperidol (200 mg) I H-1 (05/02) $144.00
28730-3 Gabapentin (250 mg) F $144.00 30301-3 Haloperidol Related J 2 $450.00
28732-5 Gabapentin Related F $450.00 Compound A (25 mg)
Compound A (100 mg) (Limit test) (Formerly Cat.
(Limit test) No. 07500 4,4-Bis[4-p-
28750-7 Gadodiamide (500 mg) F $144.00 chlorophenyl)-4-hydroxy-
28752-1 Gadodiamide Related F $450.00 piperidinoj-butyrophenone
Compound B (50 mg) 30330-8 Haloprogin (200 mg) F $144.00
28760-9 Gadopentetate F 1 $144.00 30350-1 Halothane (1 mL) F-1 $144.00
Monomeglumine (500 mg) 30400-5 Heparin Sodium (10x1 K-4 $144.00
28770-0 Galactose (200 mg) (Limit F-4 $450.00 mL)
test) 30500-8 Hexachlorophene (500 I $144.00
28800-0 Gallamine Triethiodide F $144.00 mg)
(200 mg) 30700-3 Hexobarbital Clll (500 mg) F $166.00
28850-0 Gemfibrozil (200 mg) H $144.00 30800-6 Hexylcaine HCI (1 g) F-1 $144.00
28900-3 Gentamicin Sulfate (200 K $144.00 30820-0 Hexylene Glycol (125 mg) G F-2 (04/02) $144.00
mg) 30830-7 Hexylresorcinol (200 mg) F $144.00
29000-2 Gentian Violet (650 mg) F $144.00 30850-5 L-Histidine (200 mg) F-2 $144.00 •
29100-5 Gibberellic Acid (200 mg) G $144.00 30900-9 Histamine Dihydrochloride L $144.00 1
(FCC) (250 mg)
29150-4 Powdered Ginger (500 mg) F $144.00 31000-8 Homatropine HBr (200 mg) 11 H (08/02) $144.00 I 1
29200-8 Gitoxin (50 mg) (Limit G $450.00 31100-0 Homatropine 6 $144.00 1
test) Methylbromide (250 mg)
29250-7 Glipizide (125 mg) G $114.00 31200-3 Hyaluronidase (500 mg) H $144.00 I 1
29260-9 Glipizide Related G-1 $450.00 31300-6 Hydralazine HCI (200 mg) 11 J-1 (09/02) $144.00 I
Compound A (25 mg) 31400-9 Hydrochlorothiazide (200 I H (05/02) $144.00 1
(Limit test) mg)
29400-3 Glucagon (25 mg, 0.95 H $144.00 31500-1 Hydrocodone Bitartrate Cll 1-1 2 I (07/02) $166.00 1|
U/mg) (250 mg)
29484-8 L-gamma-Glutamyl-S-allyl- F $624.00 31600-4 Hydrocortisone (200 mg) M $144.00 I 1
L-cysteine (25 mg) 31700-7 Hydrocortisone Acetate K $144.00 |
29500-6 Glutethimide Cll (500 mg) F $166.00 (200 mg)
15
Your official site for drug standards information, www.usp.org

Previous Previous
Cat. Curr. Change Lot/Valid Cat Curr. Change Lot/Valid
31730-2 Hydrocortisone Butyrate H $144.00 33650-0 Imidazole (200 mg) (Limit G $450.00
(200 mg) test)
31800-0 Hydrocortisone Cypionate F $144.00 33680-6 Imidurea (200 mg) H $144.00
(200 mg) 33700-4 Iminodibenzyl (25 mg) H $450.00
31900-2 Hydrocortisone H G-3 (03/02) $144.00 (Limit test)
Hemisuccinate (200 mg) 33780-9 Imipenem Monohydrate G $144.00
32000-1 Hydrocortisone Phosphate F-1 $144.00 (100 mg)
Triethylamine (200 mg) 33800-7 Imipramine HCI (200 mg) I 6 $144.00
32100-4 Hydrocortisone Valerate F-1 F (07/02) $144.00 33880-1 Indapamide (250 mg) H 2 G (07/02) $144.00
(200 mg) 33900-0 Indigotindisulfonate H $144.00
32200-7 Hydroflumethiazide (200 F-2 $144.00 Sodium (200 mg)
mg) 34000-9 Indocyanine Green (200 6 $144.00
32300-0 Hydromorphone HCI Cll I $166.00 mg)
(50 mg) 34100-1 Indomethacin (200 mg) I $144.00
32400-2 Hydroquinone (500 mg) G-1 6 $144.00 34200-4 Insulin (100 mg) H $144.00
32500-5 Hydroxyamphetamine HBr G $144.00 34210-6 Insulin Human (100 mg) 11 H (11/02) $144.00
(200 mg) 34220-8 Insulin (Beef) (100 mg) F $144.00
32700-0 Hydroxychloroquine I $144.00 34230-0 Insulin (Pork) (100 mg) F $144.00
Sulfate (200 mg) 34250-3 locetamic Acid (200 mg) F $144.00
32720-4 3-Hydroxy-1-methylqui- H (04/02) $450.00 34300-7 lodipamide (200 mg) G $144.00
nuclidinium Bromide (250 34430-5 o-lodohippuric Acid (100 F $144.00
mg) (Limit test) [Name mg)
Change Cat. No. 13502-1] 34450-9 fodoquinol (100 mg) G (07/02) $144.00
32900-6 Hydroxyprogesterone H $144.00 34460-0 lohexol(100mg) F-1 $114.00
Caproate (200 mg) 34462-2 lohexol Related F-1 6 $450.00
32950-5 9-Hydroxypropantheline F-1 $450.00 Compound A (100 mg)
Bromide (50 mg) (Limit (Limit test)
test) 34464-4 lohexol Related F $450.00
32980-0 Hydroxypropyl Cellulose F-1 $144.00 Compound B (50 mg)
33000-5 Hydroxypropyl G-1 G (02/02) $144.00 34466-6 lohexol Related F $144.00
Methylcellulose (250 mg) Compound C (100 mg)
XREF Hydroxypropyl 34470-2 lopamidol (200 mg) G $144.00
Methylcellulose Phthalate 34472-4 lopamidol Related G $450.00
(100 mg) (Please order Compound A (50 mg)
Cat. No. 33530-4, (Limit test) (Formerly Cat.
Hypromellose Phthalate) No. 07480-1, A/,/V-Bis-
33200-0 Hydroxyurea (200 mg) H $144.00 (1,3-dihydroxy-2-propyl)-5-
33300-3 Hydroxyzine HCI (500 mg) H $144.00 amino-2,4,6-triiodoiso-
33305-8 Hydroxyzine Related H 4 $144.00 phthalamide)
Compound A (25 mg) 34473-5 lopamidol Related F $450.00
(Formerly Cat. No. 11230; Compound B (100 mg)
p-Chlorobenzhydryl- (Limit test)
•1
| « 33400-6
piperazine)
Hydroxyzine Pamoate (500 G-1 $144.00
34480-4
34482-6
lopromide (400 mg)
lopromide Related
F
F
$144.00
$450.00
9 33500-9 Hyoscyamine Sulfate (125 11 G-1 (08/02) $114.00 (Limit test)
mg) 34483-7 lopromide Related F $450.00
H 33520-2 Hypereside(50 mg) F 1 $790.00 Compound B (50 mg)
£• 33530-4 Hypromellose Phthalate F-1 $144.00 (Limit test)
(100 mg) (Formerly Cat. 34500-2 lothalamic Acid (200 mg) G $144.00
No. 33010-7) 34510-4 loversol (200 mg) F $144.00
m
»• 33550-8 Ibuprofen (750 mg) J I (06/02) $144.00 34511-5 loversol Related F $450.00
| l 33570-1 Idarubicin HCI (50 mg) G $443.00 Compound A (50 mg)
JJS 33600-1 Idoxuridine (250 mg) H $144.00 (Limit test)
™ 33620-5 Ifosfamide (500 mg) G $144.00
16


Official USP Reference Standards Catalog Jan-Feb. 2002

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34512-6 loversol Related F $450.00 35930-2 Levamisole HCI (125 mg) F-1 $114.00
Compound B (50 mg) 35950-6 Levmetamfetamine Cll (75 F $166.00
(Limit test) mg)
34520-6 loxilan (400 mg) F 1 $144.00 35980-1 Levobunolol HCI (200 mg) G $144.00
34522-8 loxilan Related Compound F $450.00 35990-3 Levocarnitine (400 mg) F-2 $144.00
A (100 mg) (Limit test) 35992-5 Levocarnitine Related F-1 $144.00
34600-5 Ipodate Calcium (200 mg) F $144.00 Compound A (100 mg)
34700-8 Ipodate Sodium (200 mg) F-1 $144.00 36100-9 Levodopa (200 mg) I $144.00
34800-0 Isocarboxazid (200 mg) F-1 $144.00 36200-1 Levo-a-acetylmethadol F-1 $166.00
34850-0 Isoetharine HCI (250 mg) F-2 $144.00 HCI Cll (25 mg) (AS)
34900-3 Isoflurane (1 mL) H $144.00 36250-0 Levonordefrin (200 mg) F-1 $144.00
34950-2 L-lsoleucine (200 mg) 11 F-1 (09/02) $144.00 36300-4 Levopropoxyphene G $144.00
34960-4 Isomalathion (50 mg) F $450.00 Napsylate (200 mg)
(Limit test) 36400-7 Levorphanol Tartrate Cll H $166.00
34965-9 Isometheptene Mucate F $144.00 (500 mg)
(200 mg) 36500-0 Levothyroxine (500 mg) K $144.00
34970-6 Isoniazid (200 mg) H $144.00 36600-2 Lidocaine (250 mg) L $144.00
35000-2 Isopropamide Iodide (200 F-2 $144.00 36700-5 Lincomycin HCI (200 mg) H-1 $144.00
mg) 36750-4 Lindane (200 mg) F-2 $144.00
35040-0 Isopropyl Myristate (500 I $144.00 36800-8 Liothyronine (250 mg) L $144.00
mg) 36860-9 Lisinopril (300 mg) I 6 $144.00
35060-3 Isopropyl Palmitate (500 I $144.00 36900-0 Lithium Carbonate (300 F-2 $144.00
mg)
35100-5 Isoproterenol HCI (125 mg) K $114.00 37000-0 Loperamide HCI (200 mg) G-1 $144.00
35200-8 Isosorbide (75% solution, 1 I $144.00 37020-3 Loracarbef (200 mg) F $144.00
g) 37022-5 Loracarbef L-lsomer (25 F $144.00
35300-0 Diluted Isosorbide Dinitrate 1-1 $144.00 mg)
(500 mg of 25% mixture 37030-5 Lorazepam CIV (200 mg) G-2 $166.00
with mannitol) 37032-7 Lorazepam Related G $450.00
35350-0 Isotretinoin (200 mg) I $144.00 Compound A (25 mg)
35400-3 Isoxsuprine HCI (200 mg) F-3 $144.00 (Limit test) (Formerly Cat.
35420-7 Isradipine (200 mg) F $144.00 No. 11300-7,7-Chloro-5-
35421-8 Isradipine Related F $144.00 (ochlorophenyl)-i ,3-
Compound A (25 mg) dihydro-3-acetoxy-2H-1,4-
35500-6 Kanamycin Sulfate (200 J $144.00 benzodiazepin-2-one)
mg) 37033-8 Lorazepam Related F-2 $450.00
35600-9 Ketamine HCI Clll (250 G-2 $166.00 Compound B (25 mg)
mg) (Limit test) (Formerly Cat.
35650-8 Ketoconazole (200 mg) G-3 $144.00 No. 02490-5,2-Amino-2' ,5-
35663-2 Ketoprofen (200 mg) G $144.00 dichlorobenzophenone)
35664-3 Ketoprofen Related G $450.00 37034-9 Lorazepam Related G F-3 (01/02) $450.00
Compound A (25 mg) Compound C (25 mg)
(Limit test) (Limit test) (Formerly Cat.
35666-5 Ketorolac Tromethamine G $144.00
(200 mg)
No. 11310-9,6-Chloro-4-
(ochlorophenyl)-2-quinaz-
•
35665-4 Labetalol HCI (200 mg) G F-2 (01/02) $144.00 olinecarboxaldehyde) 1
1
35667-6 Anhydrous Lactose (100 G $144.00 37035-0 Lorazepam Related F-2 $450.00 1
mg) Compound D (25 mg)
35670-1 Lactose Monohydrate (500 G-1 2 G (08/02) $144.00 (Limit test) (Formerly Cat. 1
1
mg) No. 11320-0,6-Chloro-4-
35680-3 Lactulose (1 g) H $144.00 (ochlorophenyl)-2- 1
35688-0 Lanolin (20 g) F $144.00 quinazolinecarboxylic Acid) 1
35690-5 Lanolin Alcohols (5 g) F $144.00 37036-0 Lorazepam Related G F-3 (07/02) $450.00 1 1
35700-1 L-Leucine (200 mg) G-1 $144.00 Compound E (25 mg)
35800-4 Leucovorin Calcium (500 J-1 4 J (05/02) $148.00 (Limit test) (Formerly Cat. 1
mg) No. 11330-2,6-Chloro-4- 1
35900-7 Levallorphan Tartrate (200 G $144.00 (t>chlorophenyl)-2- 1
mg) quinazoline Methanol) 1
17


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37060-0 Lovastatin (125 mg) H $114.00 XREF Melting Point Standard -

37070-2 Loxapine Succinate (125 F-2 $114.00 Phenacetin (500 mg;
mg) approximately 135
37100-2 Lysergic Acid Diethylamide I $166.00 degree(s)) (Please order
Tartrate(LSD)CI(10mg) Cat. No. 51400-8)
(AS) (For Qualitiative Use XREF Melting Point Standard -
Only) Sulfanilamide (1 g;
37150-1 L-Lysine Acetate (200 mg) F $144.00 approximately 165
37200-5 L-Lysine HCI (200 mg) H $144.00 degree(s)) (Please order
37300-8 Mafenide Acetate (200 mg) F $144.00 Cat. No. 63300-7)
37400-0 Magaldrate (200 mg) F-1 $144.00 XREF Melting Point Standard -
37430-6 Magnesium Salicylate (200 F-1 $144.00 Sulfapyridine (2 g;
mg) approximately 191
37440-8 Malathion (500 mg) 6 $144.00 degree(s)) (Please order
37450-0 Maleic Acid (300 mg) G $450.00 Cat. No. 63500-2)
(Limit test) XREF Melting Point Standard -
37460-1 Malic Acid (Racemic) (200 F-1 $144.00 Vanillin (1 g; approximately
mg) (For Identification 82 degree(s)) (Please
Use Only) order Cat. No. 71100-9)
37490-7 Maltitol (200 mg) G $144.00 38100-6 Menadione (200 mg) H-3 $144.00
37500-3 Maltol (4 g) (FCC) G $144.00 (Vitamin K3)
37505-8 Mandelic Acid (500 mg) F $144.00 38170-9 Menthol (250 mg) H $144.00
37510-5 Mannitol (200 mg) H $144.00 38200-9 Mepenzolate Bromide (200 F $144.00
37520-7 Maprotiline HCI (200 mg) H 2 G (07/02) $144.00 mg)
37530-9 Mazindol CIV (350 mg) G $166.00 38300-1 Meperidine HCI Cll (200 I $166.00
37550-2 Mebendazole (200 mg) G $144.00 mg)
37570-6 Mebrofenin (100 mg) (For F $144.00 38400-4 Mephentermine Sulfate F-1 $144.00
Identification Use Only) (250 mg)
37600-6 Mecamylamine HCI (200 F-2 $144.00 38500-7 Mephenytoin (250 mg) G $144.00
mg) 38600-0 Mephobarbital CIV (250 G $166.00
37650-5 MechlorethamineHCI(100 F-1 $144.00 mg)
mg) 38700-2 Mepivacaine HC! (200 mg) H $144.00
37700-9 Meclizine HCI (500 mg) 1-1 $144.00 38800-5 Meprednisone (200 mg) G $144.00
37750-8 Meclocycline G $144.00 38900-8 Meprobamate CIV (200 G-1 G (03/02) $166.00
Sulfosalicylate (300 mg) mg)
37780-3 Meclofenamate Sodium H $144.00 39000-7 Meprylcaine HCI (200 mg) F $144.00
(500 mg) 39100-0 3-Mercapto-2-methyl- G $450.00
37800-1 Medroxyprogesterone H-1 $144.00 propanoic Acid 1,2-
Acetate (200 mg) Diphenylethylamine Salt
37900-4 Medrysone (500 mg) F $144.00 (75 mg) (Limit test)
37960-5 Mefenamic Acid (200 mg) F-2 $144.00 39200-2 Mercaptopurine (500 mg) I (07/02) $144.00
37910-6 Megestrol Acetate (500 I $144.00 39270-5 Mesalamine (200 mg) G $144.00
•
|fl 37930-0
mg)
Melphalan HCI (200 mg) G $144.00
39300-5 Mesoridazine Besylate
(250 mg)
1-1 $144.00
H XREF Melting Point Standard - 39400-8 Mestranol (200 mg) J $144.00

Acetanilide (500 mg; 39550-0 Metaproterenol Sulfate F-3 $144.00
approximately 114 (200 mg)
degree(s)) (Please order 39600-3 Metaraminol Bitartrate F-3 $144.00
Cat. No. 00400-1) (200 mg)
U XREF Melting Point Standard - 39640-0 Methacrylic Acid F-2 $144.00
Caffeine (1 g; Copolymer A (200 mg)
approximately 236 39650-2 Methacrylic Acid F-2 $144.00
m degree(s)) (Please order
Cat. No. 08600-6) 39660-4
Copolymer B (200 mg)
Methacrylic Acid G $114.00
m Copolymer C (100 mg)
39700-6 Methacycline HCI (200 mg) H $144.00
•
18



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39800-9 Methadone HCI Cll (200 H-1 $166.00 42700-5 Methyldopate HCI (200 G-2 $144.00
mg)
39900-1 Methamphetamine HCI Cll I $166.00 42800-8 Methylene Blue (250 mg) G $144.00
(125 mg) 42900-0 Methylenedioxy-3,4- F-1 $166.00
40100-1 Methantheline Bromide F-1 $144.00 amphetamine HCI (MDA)
(200 mg) Cl (25 mg) (AS)
40200-4 Methapyrilene Fumarate F-1 $144.00 43000-0 Methylergonovine Maleate J ! (05/02) $144.00
(200 mg) (50 mg)
40400-0 Methaqualone Cl (500 mg) F-1 $166.00 43030-5 Methyl Laurate (500 mg) F $144.00
40500-2 Metharbital Cill (200 mg) F-2 $166.00 43032-7 Methyl Linoleate (5 x 50 F $144.00
40600-5 Methazolamide (500 mg) G-1 $144.00 mg)
40700-8 Methdilazine (200 mg) F-1 $144.00 43034-9 Methyl Linolenate (5 x 50 F $144.00
40800-0 Methdilazine HCI (200 mg) G $144.00 mg)
40900-3 Methenamine (500 mg) G $144.00 43050-9 3-OMethylmethyldopa (50 G-1 $450.00
40950-2 Methenamine Hippurate F $144.00 mg) (Limit test)
(200 mg) 43100-2 Methyl 5-methyl-3-isox- F-1 $450.00
40960-4 Methenamine Mandelate F-2 $144.00 azolecarboxylate (25 mg)
41000-2 Methicillin Sodium (500 I $144.00 43150-1 Methyl Myristate (300 mg) F $144.00
mg) 43155-6 Methyl Oleate (500 mg) F $144.00
41100-5 Methimazole (200 mg) G $144.00 43160-3 Methyl Palmitate (300 mg) F $144.00
41150-4 L-Methionine (200 mg) G $144.00 43162-5 Methyl Palmitoleate (300 F $144.00
41200-8 Methocarbamol (200 mg) H-1 $144.00 mg)
41300-0 Methohexital CIV (500 mg) F-2 $166.00 43200-5 Methylparaben (125 mg) J $114.00
41400-3 Methotrexate (500 mg) I $144.00 43300-8 Methylphenidate HCI Cll I $133.00
41500-6 Methotrimeprazine (125 F-2 $114.00 (125 mg)
mg) 43400-0 Methylphenidate HCI H-1 $450.00
41600-9 Methoxamine HCI (200 F $144.00 Erythro Isomer (Cll) (50
41700-1 Methoxsalen (500 mg) H $144.00 43402-2 Methylphenidate Related G $450.00
41800-4 Methoxyflurane (1 mL) G $144.00 Compound A (50 mg)
41900-7 Methoxyphenamine HCI F $144.00 (Limit test) (Formerly Cat.
(250 mg) No. 53350-1, a-Phenyl-2-
42000-6 3-Methoxytyrosine (50 mg) H $450.00 piperidineacetic Acid HCI)
(Limit test) 43500-3 Methylprednisolone (200 H $144.00
42100-9 Methscopolamine Bromide G $144.00 mg)
(200 mg) 43600-6 Methylprednisolone G-2 $144.00
42200-1 Methsuximide (500 mg) F-2 $144.00 Acetate (200 mg)
42400-7 Methyclothiazide (200 mg) G $144.00 43700-9 Methylprednisolone H $144.00
42401-8 Methyclothiazide Related G $450.00 Hemisuccinate (200 mg)
Compound A (100 mg) 43750-8 Methyl Stearate (300 mg) F $144.00
(Limit test) (Formerly Cat. 43800-1 Methyltestosterone Clll J 6 $166.00
No. 02420-2) (200 mg)
XREF 2-Methylamino-5-chloro- 44000-3 Methysergide Maleate H $144.00 •
benzophenone (25 mg) (200 mg)
(Limit test) (Please order 44080-8 Metoclopramide G 1
$144.00 1
Cat. No. 18502-0) Hydrochloride (500 mg)
42423-3 Methyl Caprate (300 mg) F $144.00 44100-6 Metocurine Iodide (300 G $144.00 1
1
42424-4 Methyl Caproate (300 mg) F $144.00 mg)
42425-5 Methyl Caprylate (300 mg) F $144.00 44120-0 Metolazone (200 mg) F-1 $144.00 1 1
42430-2 3-O-Methylcarbidopa (50 G $450.00 44128-7 Metoprolol Fumarate (200 F $144.00 1
mg) (Limit test) mg)
42450-6 Methylcellulose (1 g) (AS) F-2 $144.00 44130-1 Metoprolol Tartrate (200 H 1
$144.00 1
42500-0 4-Methyl-2,5-dimethoxy- F $166.00 mg)
amphetamine HCI (STP) 44150-5 Metrizamide (500 mg) F $144.00 1
1
Cl (25 mg) (AS) 44200-9 Metronidazole(100mg) I $144.00 1
42600-2 Methyldopa (500 mg) I $144.00 44300-1 Metyrapone (200 mg) H $144.00 1
19

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44320-5 Metyrosine (200 mg) F $144.00 45730-1 Naproxen (200 mg) I $144.00
44325-0 Mexiletine HCI (200 mg) F-1 $144.00 45740-3 Naproxen Sodium (200 I $144.00
44330-7 Mezlocillin Sodium (350 G $144.00 mg)
mg) 45750-5 Natamycin (200 mg) I $144.00
44340-9 Miconazole (200 mg) G-1 G (07/02) $144.00 45800-9 Neomycin Sulfate (125 L-2 6 $114.00
44350-0 Miconazole Nitrate (200 I $144.00 mg)
mg) 45900-1 Neostigmine Bromide (200 G $144.00
44400-4 Minocycline HCI (200 mg) H-2 07/02) $144.00 mg)
44420-8 Minoxidil (125 mg) H $114.00 46000-0 Neostigmine Methylsulfate I $144.00
44470-7 Mitomycin (50 mg) K $443.00 (200 mg)
44500-7 Mitotane (500 mg) F $144.00 46050-0 Netilmicin Sulfate (500 mg) H G (05/02) $144.00
44520-0 Mitoxantrone HCI (400 mg) H $461.00 46100-3 Niacin (200 mg) H-1 $144.00
44522-2 Mitoxantrone Related F-1 $144.00 46200-6 Niacinamide (500 mg) M-1 $144.00
Compound A HCI (30 mg) (Vitamin B3)
44545-9 Moiindone HCI (500 mg) F $144.00 46330-4 Nicotine Bitartrate G $144.00
44547-0 Mometasone Furoate (200 F-1 $144.00 Dihydrate (500 mg)
mg) 46350-8 Nifedipine (125 mg) 1-1 $114.00
44550-6 Monobenzone (200 mg) F $144.00 46360-0 Nifedipine Nitrophenyl- K $450.00
44580-1 Mono- and Di-acetylated F $144.00 pyridine Analog (25 mg)
Monoglycerides (200 mg) (Limit test)
44600-0 Monoglycerides (125 mg) H $114.00 46370-1 Nifedipine Nitrosophenyl- K J (07/02) $450.00
44680-4 Monostearyl Maleate (100 G $450.00 pyridine Analog (25 mg)
mg) (Limit test) (Limit test)
44695-0 Moricizine HCI (100 mg) F $144.00 46400-1 Nitrofurantoin (500 mg) 11 1-1(11/02) $144.00
44700-2 Morphine Monohydrate Cll G $166.00 46500-4 Nitrofurazone (200 mg) H-1 6 $144.00
(50 mg) (AS) 46550-3 Nitrofurfural Diacetate (100 F-1 $450.00
44800-5 Morphine Sulfate K $266.00 mg) (Limit test)
(Pentahydrate) Cll (500 46600-7 5-Nitro-2-furfuraldazine G $450.00
mg) (500 mg) (Limit test)
44850-4 Moxalactam Disodium F-1 $144.00 46650-6 Diluted Nitroglycerin (5 G $144.00
(500 mg) amps, each has approx.
44890-1 Mupirocin (50 mg) (For F-1 F (03/02) $144.00 200 mg of a 0.948%
Identification Use Only— solution in propylene
For Assay Use Cat. glycol)
#44892-3) 46660-8 3-Nitro-4-phenoxy-5- F-1 $450.00
44892-3 Mupirocin Lithium (100 G $144.00 sulfamoylbenzoic Acid (25
44900-8 Myristyl Alcohol (1 g) G F (02/02) $144.00 46780-4 Nizatidine (200 mg) G $144.00
44970-0 Nadolol (200 mg) F-3 F-2 (04/02) $144.00 46795-0 Nonoxynol 9 (0.5 mL) H-1 H (03/02) $144.00
45000-7 Nafcillin Sodium (200 mg) H $144.00 46800-2 Nonoxynol10(200mg) F $144.00
45040-4 Naftifine HCI (200 mg) F $144.00 46840-0 Nordazepam CIV (50 mg) H $450.00
45100-0 Nalidixic Acid (200 mg) G $144.00 (Limit test) (Formerly Cat.
• 45200-2 Nalorphine HCI CHI (250 $166.00 No. 11400-0,7-Chloro-1,3-
mg) dihydro-5-phenyl-2H-1,4-
|fl 45300-5 Naloxone(125mg) K-1 $114.00 benzodiazepin-2-one)
ffl 45350-4 Naltrexone (200 mg) G $144.00 46850-1 Norepinephrine Bitartrate H $114.00
S 45352-6 Naltrexone Related F $166.00 (125 mg)07.00)
Compound A Cll (30 mg) 46900-5 Norethindrone (200 mg) J-1 2 J (07/02) $144.00
(System Suitability Use 47000-4 Norethindrone Acetate I $144.00
Only) (100 mg)
21 45400-8 Nandrolone Clll (50 mg) F-3 $450.00 47100-7 Norethynodrel (200 mg) G $144.00
(Limit test) 47150-6 Norfloxacin (200 mg) H $144.00
! • 45500-0 Nandrolone Decanoate I $166.00 47200-0 Norgestrel (125 mg) I $114.00
Clll (250 mg) 47300-2 Noroxymorphone HCI Cll H $450.00
H 45600-3 Nandrolone Phenprop- H $166.00 (50 mg) (Limit test)
ionate Clll (250 mg) 47400-5 Nortriptyline HCI (200 mg) I $144.00
45700-6 Naphazoline HCI (200 mg) K $144.00 47450-4 Noscapine (500 mg) G $144.00
20



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47500-8 Novobiocin (200 mg) G-2 $144.00 49800-3 Paramethasone Acetate G $144.00
47600-0 Nylidrin HCI (200 mg) F-2 $144.00 (200 mg)
47700-3 Nystatin (200 mg) N $144.00 49870-6 Parbendazole (200 mg) F $144.00
47750-2 Octoxynol 9 (200 mg) G $144.00 49900-6 Pargyline HCI (200 mg) F-1 $144.00
47780-8 Octyldodecanol (200 mg) G $144.00 50000-3 Paromomycin Sulfate (125 G $144.00
47810-8 Ofloxacin (200 mg) F-2 2 F-1 (08/02) $144.00 mg)
47850-5 Omeprazole (200 mg) H 4 G-1 (04/02) $144.00 50040-0 Parthenolide (25 mg) F $144.00
47900-9 Orphenadrine Citrate (200 G 2 F-4 (05/02) $144.00 50050-2 Particle Count Set (2 I 4 H (09/02) $450.00
mg) blanks and 2 suspensions)
48100-0 Oxacillin Sodium (200 mg) J I (03/02) $144.00 50080-8 Penbutolol Sulfate (200 F $144.00
48150-0 Oxamniquine (200 mg) F $144.00 mg)
48170-3 Oxamniquine Related F $450.00 50100-6 Penicillamine (200 mg) H $144.00
Compound A (25 mg) 50110-8 Penicillamine Disulfide H $450.00
(Limit test) (100 mg) (Limit test)
48180-5 Oxamniquine Related F $450.00 50200-9 Penicillin G Benzathine J $144.00
Compound B (25 mg) (200 mg) (For
(Limit test) Identification Use Only—
48200-3 Oxandrolone CHI (50 mg) F-4 $166.00 For Potency Use Cat. No.
48300-6 Oxazepam CIV (200 mg) G-1 $166.00 50250-8)
48350-5 Oxprenolol HCI (200 mg) H $144.00 50250-8 Penicillin G Potassium I $144.00
48400-9 Oxtriphylline (500 mg) G $144.00 (200 mg)
48500-1 Oxybenzone(150mg) G $144.00 50255-2 Penicillin G Procaine (200 F-1 $144.00
48510-3 Oxybutynin Chloride (200 11 G (11/02) $144.00 mg) (For Identification
mg) Use Only—For Potency
48511-4 Oxybutynin Related G $450.00 Use Cat. No. 50250-8)
Compound A (100 mg) 50270-1 Penicillin G Sodium (200 L-3 6 $144.00
(Limit test) (Formerly Cat. mg) (For Identification
No. 53180-1) Use Only—For Potency
48519-1 Oxycodone Cll (200 mg) H $166.00 Use Cat. No. 50250-8)
48600-4 Oxymetazoline HCI (200 I $144.00 50448-9 Penicillin V (200 mg) (For F $144.00
mg) Identification Use Only—
48700-7 Oxymetholone CHI (200 G $166.00 For Potency Use Cat. No.
mg) 50450-3)
48800-0 Oxymorphone Cll (500 G $166.00 50450-3 Penicillin V Potassium G-1 $144.00
mg) (200 mg)
48900-2 Oxyphenbutazone (1 g) H $144.00 50500-7 Pentazocine CIV (500 mg) H $166.00
49010-3 Oxyquinoline Sulfate (200 F-1 F (07/02) $144.00 50550-6 Pentetic Acid (100 mg) F-1 6 $144.00
mg) 50700-2 Pentobarbital Cll (200 mg) 11 H-1 (08/02) $166.00
49100-4 Oxytetracycline (200 mg) 1-1 $144.00 51000-7 Pepsin (5 g) F-2 $144.00
49130-0 Oxytocin (5 vials, 46 USP F $144.00 51080-1 Perflubron (0.5 mL) F $144.00
units per vial) 51100-0 Perphenazine (200 mg) I $144.00
49150-3 Padimate O (300 mg) G $144.00 51120-3 Perphenazine Sulfoxide G-1 2 G (07/02) $450.00
49200-7 Palmitic Acid (500 mg) I $144.00 (100 mg) (Limit test)
49300-0 Pamoic Acid (250 mg) G-3 $144.00 51200-2 Phenacemide (250 mg) F $144.00 |
XREF Pancreatin (2 g) (Please 51300-5 Phenacetin (500 mg) H-1 $144.00 1
order Cat. No. 49405-7 51400-8 Phenacetin Melting Point H-2 $85.00 1
and/or Cat. No. 49407-9) Standard (500 mg)
49405-7 Pancreatin Amylase and I $144.00 (Approximately 135 1
Protease (2 g) degree(s)) 1
49407-9 Pancreatin Lipase (2 g) I $144.00 51500-0 Phenazopyridine HCI (200 G-4 $144.00 1
1
49450-1 Racemic Panthenol (200 G $144.00 mg)
mg) 51600-3 Phencyclidine HCI Cll (25 G $166.00 1 1
49480-7 Pantolactone (500 mg) F $450.00 mg) (AS)
(Limit test)
6
51650-2 Phendimetrazine Tartrate G $166.00 1 1
49500-5 Papain (1 g) H $144.00 CHI (350 mg)
49600-8 Papaverine HCI (200 mg) H $144.00 51700-6 Phenelzine Sulfate (200 G 2 F-1 (04/02) $144.00 1 1
49700-0 Paramethadione (500 mg) G $144.00 mg)
1
21


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51730-1 D-Phenethicillin Potassium F $450.00 53800-6 Phytonadione (500 mg) M-1 6 $144.00
(200 mg) (Limit test) (Vitamin Ki)
51760-7 L-Phenethicillin Potassium F $144.00 53850-5 Pilocarpine (300 mg) F $144.00
(200 mg) 53890-2 Pilocarpine HCI (200 mg) H $144.00
52000-0 Phenformin HCI (200 mg) G $144.00 53900-9 Pilocarpine Nitrate (200 I $144.00
52200-6 Phenindione (250 mg) F $144.00 mg)
52230-1 Pheniramine Maleate (100 F $144.00 53950-8 Pimozide (200 mg) G $144.00
mg) 53970-1 Pindolol (200 mg) H-1 $144.00
52300-9 Phenmetrazine HCI Cll F-2 $166.00 54100-0 Piperacetazine (250 mg) F $144.00
(200 mg) 54150-0 Piperacillin (500 mg) H $144.00
52400-1 Phenobarbital CIV (200 J $166.00 54170-3 Piperazine Adipate (200 F $144.00
mg)
52490-8 Phenolphthalein (250 mg) F-3 $144.00 54180-5
Piperazine Citrate (200
F $144.00
52500-4 Phenolsulfonphthalein F-2 $144.00 mg)
(100 mg) 54190-7 Piperazine Dihydrochloride F $144.00
52600-7 Phenoxybenzamine HCI G $144.00 (200 mg)
(250 mg) 54200-3 Piperazine Phosphate (200 F $144.00
52700-0 Phenprocoumon (200 mg) F-1 $144.00 mg)
52800-2 Phensuximide (500 mg) G $144.00 54300-6 Piperidolate HCI (200 mg) F $144.00
52850-1 Phentermine HCI CIV (200 G $166.00 54450-8 Piroxicam (200 mg) H $144.00
mg) XREF Plastic, Negative Control
52900-5 Phentolamine HCI (300 F $144.00 (Please order Cat. No.
mg) (To be discontinued 54670-7)
on depletion of this lot) 54520-5 Plicamycin (50 mg) H 2 $443.00
53000-4 Phentolamine Mesylate I $144.00 54540-9 Polacrilex Resin (100 mg) F $144.00
(200 mg) 54550-0 Polacrilin Potassium (200 F-2 $144.00
53050-3 L-Phenylalanine (200 mg) H G (02/02) $144.00 mg)
53080-9 Phenylbenzimidazole F $144.00 54630-0 Polydimethylsiloxane (500 G-5 $144.00
Sulfonic Acid (200 mg) mg)
53100-7 Phenylbutazone (250 mg) 1-1 $144.00 54670-7 Polyethylene, High Density G $144.00
XREF Phenylcyclohexylglycolic (3 strips) (Formerly Cat.
Acid (100 mg) (Limit test) No. 54500-1, Plastic,
(Please order Cat. No. Negative Control)
48511-4, Oxybutynin 54680-9 Polyethylene, Low Density G $144.00
Related Compound A) (3 strips)
53300-2 PhenylephrineHCI(125 K $114.00 54685-3 Polyethylene Oxide (100 F-1 $144.00
mg) mg) (For Identification
53330-8 5-Phenylhydantoin (100 F $450.00 Use Only)
mg) (Limit test) 54690-0 Polyethylene Tereph- F $144.00
XREF oc-Phenyl-2- thalate (PET) (3 Strips)
piperidineacetic Acid HCI 54692-2 Polyethylene Tereph- F $144.00
(50 mg) (Limit test) thalate G (PETG) (3 Strips)
• (Please order Cat. No.
43402-2)
54700-7 Polymyxin B Sulfate (200
mg)
K $144.00
| f l 53385-1 Phenyipropanediol (100 F $450.00 54740-4 Polyoxyl 50 Stearate (200 F $144.00

mg) (Limit test) mg)
| f l 53390-9 Phenylpropanolamine F $144.00 54790-3 Polyoxyl 40 Stearate (200 F-2 $144.00
Bitartrate (100 mg) mg)
H
=• 53400-5 Phenylpropanolamine HCI J I (02/02) $144.00 54800-0 Polythiazide (200 mg) F-1 $144.00
(250 mg) 55000-1 Potassium Gluconate (200 G $144 .00
9 53500-8 Phenytoin (200 mg) 1-1 $144.00 mg)
r f l 53550-7 Phenytoin Sodium (200 H $144.00 55100-4 Potassium Guaiacol- 1-1 $144.00
mg) sulfonate (500 mg)
1 53570-0 Phosphated Riboflavin (50 G $114.00 55115-0 Potassium Sucrose G-1 $144.00
mg) Octasulfate (300 mg)
Bi 53700-3 Physostigmine Salicylate H-1 $144.00
(200 mg)
22



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55130-0 Potassium Trichloro- G-1 $450.00 57030-4 Propafenone HCI (200 mg) G $144.00
ammineplatinate (20 mg) 57050-8 Propantheline Bromide 11 H (11/02) $144.00
(Limit test) (200 mg)
55150-3 Povidone(100mg) F-1 6 $144.00 57100-1 Proparacaine HCI (200 G $144.00
55300-0 Pralidoxime Chloride (200 G-2 $144.00 mg)
mg) 57300-7 Propoxycaine HCI (200 F $144.00
55400-2 Pramoxine HCI (500 mg) 11 H (11/02) $144.00 mg)
55450-1 Prazepam CIV (500 mg) 11 F-1 (11/02) $166.00 57400-0 Propoxyphene HCI Cll K $166.00
55460-3 Praziquantel (200 mg) G 2 F-3 (07/02) $144.00 0g)
55465-8 Praziquantel Related F-1 $450.00 57500-2 Propoxyphene Napsylate H $166.00
Compound A (50 mg) Cll(1g)
(Limit test) 57520-6 Propoxyphene Related G-5 $450.00
55466-9 Praziquantel Related F-2 $450.00 Compound A (50 mg)
Compound B (50 mg) (Limit test) (Formerly
(Limit test) Cat. No. 21000)
55467-0 Praziquantel Related F-2 $450.00 57600-5 Propranolol HCI (200 mg) H-1 6 $144.00
Compound C (50 mg) 57650-4 Propylene Carbonate (200 F $144.00
(Limit test) mg)
55470-5 Prazosin HCI (500 mg) G-1 $144.00 57670-8 Propylene Glycol (1 mL) H $144.00
55500-5 Prednisolone (200 mg) M L-1 (04/02) $144.00 (For Identification Use
55600-8 Prednisolone Acetate (200 J 1-1 (02/02) $144.00 Only)
mg) 57672-0 Propylene Glycol Diacetate F $144.00
55650-7 Prednisolone H-1 $114.00 (250 mg)
Hemisuccinate (125 mg) 57680-0 Propyl Gallate (200 mg) G $144.00
55800-3 Prednisolone Tebutate F $144.00 57700-8 Propylparaben (200 mg) I $144.00
(200 mg) 57800-0 Propylthiouracil (200 mg) G $144.00
55900-6 Prednisone (250 mg) L K-1 (01/02) $144.00 57850-0 Prostaglandin A1 (25 mg) G $489.00
55950-5 Prednisone Tablets N 2 M (09/02) $166.00 (Limit test)
(Dissolution Calibrator, 58000-2 Protriptyline HCI (200 mg) F-1 $144.00
Disintegrating) (30 tablets) 58100-5 Pseudoephedrine HCI (125 J 2 I (05/02) $114.00
56100-8 Priiocaine HCI (200 mg) F-2 $144.00 mg)
56150-7 Primaquine Phosphate F-1 $144.00 58150-4 Pseudoephedrine Sulfate G F-2 (05/02) $144.00
(200 mg) (200 mg)
56200-0 Primidone (200 mg) G $144.00 58400-3 Pyrantel Pamoate (1 g) I $144.00
56300-3 Probenecid (200 mg) H-1 $144.00 58500-6 Pyrazinamide (200 mg) G $144.00
56330-9 Probucol (200 mg) G F-1 (01/02) $144.00 58600-9 Pyridostigmine Bromide H $144.00
56332-0 Probucol Related F-1 $450.00 (200 mg)
Compound A (25 mg) 58700-1 Pyridoxine HCI (200 mg) P $144.00
(Limit test) (Vitamin Be)
56333-1 Probucol Related F-1 $450.00 58800-4 Pyrilamine Maleate (200 H $144.00
Compound B (25 mg) mg)
(Limit test) 58900-7 Pyrimethamine (200 mg) G (07/02) $144.00
56334-2 Probucol Related F-2 $450.00 59200-1 Pyrvinium Pamoate (500 G $144.00
Compound C (25 mg)
(Limit test) 59220-5
mg)
Quazepam CIV (200 mg) F $166.00 1 •
56350-2 Procainamide HCI (200 H $144.00 59222-7 Quazepam Related F $450.001
56400-6
56500-9
Procaine HCI (200 mg) H
F
$144.00 (Limit test) 1
1
Procarbazine HCI (200 $144.00 59300-4 Quinacrine HCI (200 mg) F-1 $144.00 1
mg) 59400-7 Quinethazone (1.5 g) G $144.00 1
56600-1 Prochlorperazine Maleate H-1 $144.00 59450-6 Quinic Acid (200 mg) F $144.00 1
(200 mg) 59500-0 Quinidine Gluconate (200 H $144.00 1
56700-4 Procyclidine HCI (200 mg) G $144.00 mg)
56800-7 Progesterone (200 mg) H-5 2 H-4 (07/02) $114.00 59550-9 Quinidine Sulfate (500 mg) H-1 $144.00 1 1
56850-6 L-Proline (200 mg) F-2 F-1 (01/02) $144.00 59700-5 Quinine Sulfate (200 mg) H $144.00 1
56900-0 Promazine HCI (200 mg) G $144.00 59750-4 Quininone (50 mg) (Limit G-1 $450.00 1
57000-9 Promethazine HCI (500 K $144.00 test)
mg) 1
23


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59800-8 3-Quinuclidinyl Benzilate H 6 $476.00 XREF Sodium Taurocholate (20

(25 mg) (Limit test) g) (Please order Cat. No.
59840-5 Ranitidine HCi (200 mg) G $144.00 07130-4)
59850-7 Ranitidine Related H $144.00 61600-8 1,4-Sorbitan (200 mg) H $144.00
Compound A (50 mg) 61700-0 Sorbitol (125 mg) H $114.00
59860-9 Ranitidine Related G F-4 (04/02) $450.00 61800-3 Spectinomycin HCI (200 F-2 $144.00
Compound B (50 mg) mg)
(Limit test) 61900-6 Spironolactone (125 mg) J-1 $114.00
59870-0 Ranitidine Related I $144.00 61950-5 Squalane (500 mg) G-1 $144.00
Compound C (50 mg) 62000-5 Stanozolol Clll (200 mg) F-3 $166.00
59900-0 RauwolfiaSerpentina(15 G $144.00 62100-8 Stearic Acid (500 mg) J 6 $144.00
9) 62200-0 Stearyl Alcohol (125 mg) H-1 $114.00
60100-0 Reserpine (200 mg) N $144.00 62300-3 Streptomycin Sulfate (200 I $144.00
60200-3 Resorcinol (200 mg) H-1 $144.00 mg)
60270-6 Ribavirin (200 mg) H $267.00 62350-2 Succinylcholine Chloride H $144.00
60300-6 Riboflavin (500 mg) M-1 $144.00 (500 mg)
(Vitamin B2) 62360-4 Succinylmonocholine G $450.00
60380-0 Rifabutin (50 mg) 11 F (11/02) $144.00 Chloride (150 mg) (Limit
60400-9 Rifampin (300 mg) J $144.00 test)
60420-2 Rifampin Quinone (50 mg) H 6 $144.00 62362-6 Sucralose (400 mg) F $144.00
60470-1 Ritodrine HCI (200 mg) G-1 $144.00 62363-7 Sucrose (100 mg) G-1 $144.00
60620-8 Roxarsone (200 mg) F $144.00 62364-8 Sufentanil Citrate Cll (25 G F-1 (04/02) $166.00
60650-3 Rutin(100mg) F $144.00 mg)
60700-7 Saccharin (200 mg) G-3 6 $144.00 62367-0 Sulbactam (250 mg) G $144.00
60800-0 Salicylamide (200 mg) F-3 $144.00 62368-1 Sulconazole Nitrate (200 F-1 F (05/02)) $144.00
60900-2 Salicylic Acid (125 mg) J-1 2 J (10/02) $114.00 mg)
60950-1 Salicylic Acid Tablets O N (02/02) $144.00 62370-6 Sulfabenzamide (200 mg) G $144.00
(Dissolution Calibrator, 62380-8 Sulfacetamide (300 mg) G-1 $144.00
Non-disintegrating) (33 62400-6 Sulfacetamide Sodium I $144.00
tablets) (500 mg)
60980-7 Salsalate (125 mg) G $114.00 62450-5 Sulfachlorpyridazine (200 F $144.00
61000-1 Scopolamine HBr (250 mg) 1-1 $144.00 mg)
61100-4 Secobarbital Cll (200 mg) H $166.00 62500-9 Sulfadiazine (200 mg) I $144.00
61190-0 Selegiline HCI (200 mg) G $144.00 62600-1 Sulfadimethoxine (200 mg) F-3 $144.00
61200-7 Sennosides (250 mg) H $144.00 62650-0 Sulfadoxine (200 mg) F-1 (07/02) $144.00
61250-6 L-Serine (200 mg) G $144.00 62800-7 Sulfamerazine (1 g) H $144.00
61260-8 Silver Sulfadiazine (200 I $144.00 62900-0 Sulfamethazine (1 g) G-3 $144.00
mg) 63000-9 Sulfamethizole (200 mg) F-2 $144.00
61263-0 Silybin (50 mg) F $144.00 63100-1 Sulfamethoxazole (200 1-1 I (04/02) $144.00
61264-1 Silydianin (20 mg) F $144.00 mg)
61265-2 Simethicone (50 g) G $144.00 63150-0 Sulfamethoxazole Afo- H 6 $450.00
61270-0 Simvastatin (200 mg) H G (02/02) $144.00 glucoside (25 mg) (Limit
• 61280-1 Sisomicin Sulfate (500 mg) H $144.00 test)
l « 61350-9 Sodium Ascorbate (200 G-1 $144.00 63200-4 Sulfanilamide (5 g) N $144.00
mg) 63300-7 Sulfanilamide Melting Point J-1 $69.00
I I 61360-0 Sodium Butyrate (25 mg) F $144.00 Standard (500 mg)
9 61400-2 Sodium Fluoride (1 g) H-1 $144.00 (Approximately 165
§fl 61430-8 Sodium Lactate (200 mg) H $144 .00 degree(s))
U 61450-1 Sodium Nitroprusside (500 H $144.00 63350-6 Sulfanilic Acid (200 mg) G $450.00
mg) (Limit test)
m 61460-3 Sodium Propionate (200 F-1 F (03/02) $144.00 63400-0 Sulfapyridine (200 mg) H $144.00
mg) (For Identification 63500-2 Sulfapyridine Melting Point J $85.00
Use Only) Standard (1 g)
|fl 61470-5 Sodium Stearyl Fumarate G $144.00 (Approximately 191
degree(s))
• (200 mg)
63600-5
63650-4
Sulfasalazine (125 mg)
Sulfathiazole (350 mg)
G-2
H
$114.00
$144.00
24



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63700-8 Sulfinpyrazone (200 mg) G $144.00 66710-0 Thonzonium Bromide (200 F $144.00
63800-0 Sulfisoxazole (200 mg) J $144.00 mg)
63900-3 Sulfisoxazole Acetyl (200 H-1 $144.00 66720-2 L-Threonine (200 mg) G $144.00
mg) 66727-9 Thromboplastin, Human F $144.00
64000-2 Sulfisoxazole Diolamine F $144.00 Recombinant (set) (1 vial
(500 mg) Thromboplastin and 1 vial
64200-8 Sulindac (200 mg) H 6 $144.00 Diluent)
64250-7 Suprofen (200 mg) F $144.00 66730-4 Ticarcillin Monosodium H $144.00
64300-0 Talbutal CHI (250 mg) F $166.00 Monohydrate (200 mg)
64330-6 Tamoxifen Citrate (200 H 6 $144.00 66740-6 Timolol Maleate (200 mg) G-1 $144.00
mg) 66743-9 Tioconazole (200 mg) H G (04/02) $144.00
64340-8 Temazepam CIV (200 mg) G $166.00 66745-0 Tioconazole Related G $450.00
64350-0 Terbutaline Sulfate (125 H $114.00 Compound A (25 mg)
mg) (Limit test)
64370-3 Terconazole (200 mg) G-2 $144.00 66746-1 Tioconazole Related G $450.00
64380-5 Terfenadine (200 mg) H $144 .00 Compound B (25 mg)
64390-7 Terfenadine Related G $144.00 (Limit test)
Compound A (100 mg) 66747-2 Tioconazole Related G $450.00
64392-9 Terfenadine Related F $450.00 Compound C (25 mg)
Compound B (50 mg) (Limit test)
(Limit test) 66750-8 Tobramycin (200 mg) J $144.00
64400-3 Terpin Hydrate (750 mg) G $144.00 66755-2 TocainideHCI(125mg) F-1 $114.00
64500-6 Testolactone Clll (125 mg) F-1 $133.00 66760-0 Alpha Tocopherol (250 M $144.00
64600-9 Testosterone Clll (125 mg) I $133.00 mg) (Vitamin E Alcohol)
64700-1 Testosterone Cypionate G-1 $166.00 66770-1 Alpha Tocopheryl Acetate K $144.00
Clll (200 mg) (250 mg) (Vitamin E
64800-4 Testosterone Enanthate J $166.00 Acetate)
Clll (200 mg) 66780-3 Alpha Tocopheryl Acid F-5 F-4 (01/02) $144.00
64900-7 Testosterone Propionate L 6 $166.00 Succinate (250 mg)
Clll (200 mg) (Vitamin E Succinate)
65000-6 Tetracaine HCI (200 mg) J $144.00 66800-1 Tolazamide (200 mg) G-2 $144.00
65100-9 Tetracycline HCI (200 mg) K $144.00 66900-4 Tolazoline HCI (300 mg) F $144.00
65200-1 Tetrahydrozoline HCI (200 G $144.00 67000-3 Tolbutamide (200 mg) I $144.00
mg) 67050-2 Tolmetin Sodium (1 g) H $144.00
65300-4 Theophylline (200 mg) I $144.00 67100-6 Tolnaftate (200 mg) I $144.00
65310-6 Theophylline Extended- F-1 $144.00 67200-9 Toluenesulfonamides, F-4 $450.00
Release Beads (Drug ortho and para (200 mg of
Release Calibrator, each supplied in a set)
Multiple-Unit) (20 g) (Limit test)
65500-0 Thiabendazole(100mg) F-1 $144.00 67280-3 Transplatin (25 mg) (Limit G $450.00
65600-2 Thiamine HCI (500 mg) N $144.00 test)
(Vitamin Bi Hydrochloride) 67350-0 Trazodone HCI (200 mg) F-2 $144.00
65630-8 Thiamylal Clll (200 mg) F $166.00 67400-4 Tretinoin (30 mg/amp; 5 1-1 I (01/02) $144.00
65700-5 Thiethylperazine Malate G $144.00 amps)
(200 mg) 67500-7 Triacetin (1 g) G-1 $144.00 1
65800-8 Thiethylperazine Maleate F-1 $144.00 67600-0 Triamcinolone (250 mg) H-1 $144.00 1
(200 mg) 67700-2 Triamcinolone Acetonide K $144.00 1
65900-0 Thimerosal (500 mg) H $144.00 (500 mg)
66000-0 Thioguanine (200 mg) F-1 $144.00 67800-5 Triamcinolone Diacetate G $144.00 1 1
66100-2 Thiopental Clll (250 mg) I $166.00 (200 mg)
66250-4 Thioridazine (200 mg) H $144.00 67900-8 Triamcinolone G $114.00 1 1
66300-8 Thioridazine HCI (200 mg) H $144.00 Hexacetonide (125 mg)
66370-0 Thiostrepton (200 mg) 11 F (11/02) $144.00 68000-7 Triamterene (200 mg) I $144.00 1
1
66400-0 Thiotepa (500 mg) I $144.00 68050-6 Triazolam CIV (200 mg) G-1 $166.00 1
66500-3 Thiothixene (250 mg) G $144.00 68060-8 Tributyl Citrate (500 mg) F $144.00 1
66600-6 (E)-Thiothixene(IOOmg) H $450.00 68080-1 Trichlorfon (200 mg) F $144.00 1
(Limit test) 68100-0 Trichlormethiazide (200 H $144.00 1
mg)
25


Jan-Feb. 2002 Official USP Reference Standards Catalog
Previous Previous
68300-5 Tridihexethyl Chloride (200 F-1 $144.00 70850-3 L-Valine (200 mg) F-2 F-1 (05/02) $144.00
mg) 70870-7 Valproic Acid (500 mg) J $144.00
68350-4 Trientine HCI (125 mg) F-1 (03/02) $114.00 70872-9 Valproic Acid Related F $144.00
68360-6 Triethyl Citrate (500 mg) F-1 F (03/02) $144.00 Compound A (0.25 mL)
68500-0 Trifluoperazine HCI (200 G $144.00 70900-7 Vancomycin HCI (4 vials, L 2 $144.00
mg) each vial contains 101,400
68550-0 2-[N-(2,2,2-Trifluoro- F $450.00 /jg ofvancomycin activity)
ethyl)amino-5]- 71000-6 Vanillin (200 mg) 1 $144.00
chlorobenzophenone (25 71100-9 Vanillin Melting Point 1-1 $85.00
mg) (Limit test) Standard (1 g)
68600-3 Triflupromazine HCI (200 F-1 $144.00 (Approximately 82
mg) degree(s))
68630-9 Trifluridine (200 mg) F $144.00 71120-2 Verapamil HCI (200 mg) G $144.00
68631-0 Trifluridine Related F $450.00 71130-4 Verapamil Related H $450.00
Compound A (20 mg) Compound A (50 mg)
(Limit and System (Limit test)
Suitability Test) 71140-6 Verapamil Related G $144.00
68700-6 Trihexyphenidyl HCI (200 J $144.00 Compound B (50 mg)
mg) 71150-8 Vidarabine (200 mg) G-1 $144.00
68800-9 3-(3,4,6-Trihydroxyphenyl)- J $450.00 71300-4 Vinblastine Sulfate (50 L $327.00
alanine (50 mg) (Limit mg/ampul)
test) 71400-7 Vincristine Sulfate (50 N $443.00
68900-1 Trimeprazine Tartrate (200 F-3 $144.00 mg/ampul)
mg) 71500-0 Viomycin Sulfate (200 mg) F $144.00
69000-0 Trimethadione (200 mg) G $144.00 71600-2 Vitamin A (24 capsules U $144.00
69200-6 Trimethobenzamide HCI H-2 H-1 (06/02) $144.00 each containing vitamin A
(500 mg) acetate in cottonseed oil)
69250-5 Trimethoprim (300 mg) I $144.00 XREF Vitamin Bi Hydrochloride
69300-9 Trioxsalen (200 mg) G $144.00 (Please order Cat. No.
69400-1 Tripelennamine Citrate F $144.00 65600-2)
(200 mg) XREF Vitamin B2 (Please order
69500-4 Tripelennamine HCI (200 J $144.00 Cat. No. 60300-6)
mg) XREF Vitamin B3 (Please order
69600-7 Triprolidine HCI (500 mg) I H-1 (02/02) $144.00 Cat. No. 46200-6)
69610-9 Triprolidine HCI Z Isomer G F-1 (02/02) $450.00 XREF Vitamin B5 (Please order
(100 mg) (Limit test) Cat. No. 08700-9)
69620-0 Trisalicylic Acid (100 mg) G $450.00 XREF Vitamin B6 (Please order
(Limit test) Cat. No. 58700-1)
69700-0 Troleandomycin (250 mg) F-1 $144.00 XREF Vitamin B12 (Please order
69800-2 Tromethamine(125mg) G $114.00 Cat. No. 15200-9)
69900-5 Tropicamide (125 mg) G-1 $114.00 XREF Vitamim Be (Please order
70000-2 Trypsin Crystallized (300 H $144.00 Cat. No. 28600-5)
mg) XREF Vitamin C (Please order
H | 9 70050-1 L-Tryptophan (200 mg) G-1 $144.00 Cat. No. 04300-3)
^Pjfl 70200-8 Tubocurarine Chloride K-1 $144.00 71750-4 Vitamin D Assay System F $144.00
(250 mg) Suitability (1.5 g)
• 9 70400-3 Tyloxapol (600 mg) H $144.00 XREF Vitamin 62 (Please order
^ S | f l 70450-2 Tyropanoate Sodium (500 F $144.00 Cat. No. 23900-5)
mg) XREF Vitamin D3 (Please order
H p f l 70500-6 L-Tyrosine (500 mg) J $144.00 Cat. No. 13100-9)
B I 70550-5 Undecylenic Acid (200 mg) G-1 G (01/02) $144.00
^ • | f l 70580-0 Uracil Arabinoside (50 mg) G $144.00 XREF Vitamin E Alcohol (Please
(For Non-Quantitative order Cat. No. 66760-0)
Use Only) XREF Vitamin E Acetate (Please
B 3 70600-9 Uracil Mustard (500 mg) F $144.00 order Cat. No. 66770-1)
IHH 70780-6 Ursodiol (125 mg) G 6 $144.00
70790-8 Valerenic Acid (25 mg) F $643.00
26


Previous Previous
XREF Vitamin E Acid Succinate 72042-9 Xylazine HCI F $144.00

(Please order Cat. No. 72060-0 Xylitol (1 g) 11 F-3 (11/02) $144.00
66780-3) 72100-2 Xylometazoline HCI (125 H-1 $114.00
XREF Vitamin Ki (Please order mg)
Cat. No. 53800-6) 72200-5 Xylose (1 g) F $144.00
XREF Vitamin K3 (Please order 72400-0 Yohimbine HCI (200 mg) F $144.00
Cat. No. 38100-6) 72430-6 Zalcitabine (200 mg) F $144.00
XREF Vitamin M (Please order 72450-0 Zidovudine (400 mg) G 6 $144.00
Cat. No. 28600-5) 72452-1 Zidovudine Related F-1 $144.00
71900-0 Warfarin (200 mg) H-2 6 $144.00 Compound B (25 mg)
71910-2 Warfarin Related G $144.00 72453-2 Zidovudine Related F-1 6 $450.00
Compound A (50 mg) Compound C (100 mg)
72000-0 Xanthanoic Acid (100 mg) G-1 $450.00 (Limit test)
(Limit test) 72480-5 Zolazepam HCI (500 mg) F-1 2 F (05/02) $144.00
72020-3 Xanthone (100 mg) (Limit F-1 $450.00
test)
72040-7 Xylazine (200 mg) F $144.00
27

Jan-Feb. 2002 Official USP Reference Standards Catalog
Previous Previous
GARLIC FLUIDEXTRACT
AMINO ACIDS 01305-7 S-Allyl-L-Cysteine (25 mg) F $450.00
(Limit test)
13050-5 Chlorzoxazone (500 mg) I $144.00
01250-9 L-Alanine (200 mg) F-2 $144.00
02100-0 Aminocaproic Acid (200 F-4 $144.00 GINGER
mg) 09110-8 Capsaicin (100 mg) G-1 G (03/02) $144.00
04250-0 L-Arginine (200 mg) G-1 $144.00 29150-4 Powdered Ginger (500 mg) F $144.00
04260-1 Arginine HCI (125 mg) F-1 $114.00 GINKGO
16150-9 L-Cysteine HCI (200 mg) H $144.00 60650-3 Rutin(IOOmg) F $144.00
29580-0 Glycine (200 mg) F-3 $144.00
30850-5 L-Histidine (200 mg) F-2 $144.00 MILK THISTLE
34950-2 L-lsoleucine (200 mg) 11 F-1 (09/02) $144.00 61263-0 Silybin (50 mg) F $144.00
35700-1 L-Leucine (200 mg) G-1 $144.00 61264-1 Silydianin (20 mg) F $144.00
35990-3 Levocarnitine (400 mg) F-2 $144.00 SAW PALMETTO
35992-5 Levocarnitine Related F-1 $144.00 42423-3 Methyl Caprate (300 mg) F $144.00
Compound A (100 mg) 42424-4 Methyl Caproate (300 mg) F $144.00
37150-1 L-Lysine Acetate (200 mg) F $144.00 42425-5 Methyl Caprylate (300 mg) F $144.00
37200-5 L-Lysine HCI (200 mg) H $144.00 43030-5 Methyl Laurate (500 mg) F $144.00
41150-4 L-Methionine (200 mg) G $144.00 43032-7 Methyl Linoieate (5 x 50 F $144.00
53050-3 L-Phenylalanine (200 mg) H G (02/02) $144.00 mg)
56850-6 L-Proline (200 mg) F-2 F-1 (01/02) $144.00 43034-9 Methyl Linolenate (5 x 50 F $144.00
61250-6 L-Serine (200 mg) G $144.00 mg)
66720-2 L-Threonine (200 mg) G $144.00 43150-1 Methyl Myristate (300 mg) F $144.00
70050-1 L-Tryptophan (200 mg) G-1 $144.00 43155-6 Methyl Oleate (500 mg) F $144.00
70500-6 l-Tyrosine (500 mg) J $144.00 43160-3 Methyl Palmitate (300 mg) F $144.00
70850-3 L-Valine (200 mg) F-2 F-1 (05/02) $144.00 43162-5 Methyl Palmitoleate (300 F $144.00
mg)
43750-8 Methyl Stearate (300 mg) F $144.00
BOTANICALS
VAI PQIAM
V ALCHIAIM
70790-8 Valerenic Acid (25 mg) F $643.00
CHAMOMILE
04070-8 Apigenin-7-Glucoside (30 p
i
mg) (Limit test) VITAMINS-MINERALS
CAPSAICIN/CAPSICUM
09110-8 Capsaicin (100 mg) G-1 G (03/02) $144.00 04300-3 Ascorbic Acid (1 g) P $144.00
20060-0 Dihydrocapsaicin (50 mg) F-1 $144.00 (Vitamin C)
07150-8 Biotin (200 mg) H $144.00
CRANBERRY LIQUID
08635-6 Calcium Ascorbate (200 F-1 $144.00
13436-8 Citric Acid (200 mg) F (07/02) $144.00 mg) (For Identification
18130-2 Dextrose (1 g) J-1 2 J (11/02) $114.00 Use Only)
28650-4 Fructose (125 mg) I-2 2 1-1 (11/02) $114.00 08700-9 Calcium Pantothenate N-1 $144.00
37460-1 Malic Acid (Racemic) (200 F-1 $144.00 (200 mg) (Vitamin B5)
mg) (For Identification 13100-9 Cholecalciferol (30 L $147.00
Use Only) mg/ampul; 5 ampuls)
^ m 59450-6 Quinic Acid (200 mg) F $144.00 (Vitamin D3)
H 61700-0 Sorbitol (125 mg) H $114.00 13180-3 Delta 4,6-cholestadienol F $144.00
sM 62363-7 Sucrose (100 mg) G-1 $144.00 (30 mg)
|fl GARLIC 15200-9 Cyanocobalamin (1.5 g of N $144.00
j B 01214-5 Agigenin (25 mg) F $144.00 mixture with mannitol; 10.7
I I 01295-0 Alliin (25 mg) F $1410.00 (ig/mg of mixture) (Vitamin
! • 11555-6 beta-Chlorogenin (20 mg) F $144.00 B12)
H (For Identification Use 17950-4 Dexpanthenol (500 mg) H (02/02) $148.00
£• Only)
U 29484-8 L-gamma-Glutamyl-S-allyl- F $624.00
U L-cysteine (25 mg)
H 41150-4 L-Methionine (200 mg) G $144.00 VITAMINS-MINERALS Cont.
• FEVERFEW 23900-5 Ergocalciferol (150 mg; 30 O $156.00

50040-0 Parthenolide (25 mg) F $144.00 mg/ampul; 5 ampuls)
28

Note: Where the Current Lot is blank the item is not in distribution * See page 3 for Change Code Interpretation

DIETARY SUPPLEMENT REFERENCE STANDARDS AVAILABLE FROM USP

Previous Previous
(Vitamin D2) 61350-9 Sodium Ascorbate (200 G-1 $144.00
24100-7 Ergosterol (50 mg) (For H $144.00 mg)
Identification Use Only) 61400-2 Sodium Fluoride (1 g) H-1 $144.00
28600-5 Folic Acid (500 mg) P $144.00 65600-2 Thiamine HCI (500 mg) N $144.00
(Vitamin M or Vitamin Be) (Vitamin B1 Hydrochloride)
28602-7 Folic Acid Related H-1 $144.00 66760-0 Alpha Tocopherol (250 M $144.00
Compound A (50 mg) mg) (Vitamin E Alcohol)
(Fomerly Cat. No. 08650- 66770-1 Alpha Tocopheryl Acetate K $144.00
5, Calcium Formyltetra- (250 mg) (Vitamin E
hydrofolate) Acetate)
38100-6 Menadione (200 mg) H-3 $144.00 66780-3 Alpha Tocopheryl Acid F-5 F-4 (01/02) $144.00
(Vitamin Ks) Succinate (250 mg)
46100-3 Niacin (200 mg) H-1 $144.00 (Vitamin E Succinate)
46200-6 Niacinamide (500 mg) M-1 $144.00 71600-2 Vitamin A (24 capsules U $144.00
(Vitamin B3) each containing vitamin A
49450-1 Racemic Panthenol (200 G $144.00 acetate in cottonseed oil)
mg) 71750-4 Vitamin D Assay System F $144.00
49480-7 Pantolactone (500 mg) F $450.00 Suitability (1.5 g)
(Limit test)
noDAn c <£ i A A n n
oooUU-b Phytonadione (500 mg) M-1 b $144.1)1)
(Vitamin K1)
OTHERS DIETARY SUPPLEMENTS
55000-1 Potassium Gluconate (200 G $144.00
mg) 13363-8 Chromium Picolinate (100 F 4 $144.00
58700-1 Pyridoxine HCI (200 mg) P $144.00 g) (For Identification Test
(Vitamin Be) Only)
60300-6 Riboflavin (500 mg) M-1 $144.00 15035-3 Creatinine(100mg)(For F $144.00
(Vitamin B2) Identification Test Only)
29


CONTROLLED SUBSTANCES REFERENCE STANDARDS AVAILABLE FROM USP
Previous Previous
01400-5 Alphaprodine HCI Cll (250 F $166.00 40500-2 Metharbital CHI (200 mg) F-2 $166.00
mg) 41300-0 Methohexital CIV (500 mg) F-2 $166.00
01500-8 Alprazolam CIV (200 mg) H $166.00 42500-0 4-Methyl-2,5- F $166.00
03000-1 Amobarbital Cll (200 mg) F-2 $166.00 dimethoxyamphetamine HCI
03600-8 Anileridine HCI Cll (250 mg) F $166.00 (STP) Cl (25 mg) (AS)
04200-0 Aprobarbital CHI (200 mg) F-1 $166.00 42900-0 Methylenedioxy-3,4- F-1 $166.00
(AS) amphetamine HCI (MDA) Cl
05900-3 Benzphetamine HCI CHI (200 F-1 $166.00 (25 mg) (AS)
mg)(AS) 43300-8 Methylphenidate HCI Cll (125 I $133.00
07870-0 Buprenorphine HCI CV (50 F-1 $166.00 mg)
mg) 43400-0 Methylphenidate HCI Erythro H-1 $450.00
07900-0 Butabarbital CHI (200 mg) G $166.00 Isomer (Cll) (50 mg) (Limit
08100-2 Butalbital CHI (200 mg) G-2 2 G (05/02) $166.00 Test)
08250-4 Butorphanol Tartrate CIV (500 J $166.00 43800-1 Methyltestosterone Clll (200 J 6 I (11/01) $166.00
mg) mg)
08900-4 Cannabidiol Cl (25 mg) (AS) F-2 $166.00 44700-2 Morphine Monohydrate Cll G $166.00
(For Qualitative Use Only) (50mg)(AS)
09000-3 Cannabinol Cl (25 mg) (AS) F-2 (05/02) $166.00 44800-5 Morphine Sulfate K $166.00
09680-4 Cathinone HCI Cl (50 mg) I $450.00 (Pentahydrate) Cll (500 mg)
(Limit test) (Formerly Cat. No. 45200-2 Nalorphine HCI Clll (250 mg) $166.00
02620-8, a- 45352-6 Naltrexone Related Compound F $166.00
Aminopropiophenone HCI) A Cll (30 mg) (System
10900-0 Chlordiazepoxide CIV (200 H-1 $166.00 Suitability Use Only)
mg) 45400-8 Nandrolone Clll (50 mg) F-3 $450.00
11000-9 Chlordiazepoxide HCI CIV G-4 $166.00 (Limit test)
(200 mg) 45500-0 Nandrolone Decanoate Clll I $166.00
14030-5 Clonazepam CIV (200 mg) G $166.00 (250 mg)
14050-9 Clorazepate Dipotassium CIV F-1 $166.00 45600-3 Nandrolone Phenpropionate H $166.00
(125 mg) Clll (250 mg)
14300-8 Cocaine HCI Cll (250 mg) H-2 $166.00 46840-0 Nordazepam CIV (50 mg) H $450.00
14380-2 Codeine A/-Oxide Cl (50 mg) F-1 $166.00 (Limit test) (Formerly Cat. No.
14400-0 Codeine Phosphate Cll (100 I $166.00 11400-0,7-Chloro-1,3-dihydro-
mg) 5-phenyl-2H-1,4-
14500-3 Codeine Sulfate Cll (250 mg) H-2 H-1 (01/02) $166.00 benzodiazepin-2-one)
18000-4 Dextroamphetamine Sulfate G $166.00 47300-2 Noroxymorphone HCI Cll (50 H $450.00
Cll (500 mg) mg) (Limit test)
18300-2 Diacetylmorphine HCI (Heroin J $166.00 48200-3 Oxandrolone Clll (50 mg) F-4 $166.00
HCI)CI(25mg)(AS) 48300-6 Oxazepam CIV (200 mg) G-1 $166.00
18500-8 DiazepamCIV(100mg) I 6 $166.00 48519-1 Oxycodone Cll (200 mg) H $166.00
19400-9 Diethylpropion HCI CIV (200 H $166.00 48700-7 Oxymetholone Cllf (200 mg) G $166.00
mg) 48800-0 Oxymorphone Cll (500 mg) G $166.00
20080-4 Dihydrocodeine Bitartrate Cll H $166.00 50500-7 Pentazocine CIV (500 mg) H $166.00
(200 mg) 50700-2 Pentobarbital Cll (200 mg) 11 H-1 (08/02) $166.00
21900-8 DiphenoxylateHCI Cll (200 1 H(03/02) $166.00 51600-3 Phencyclidine HCI Cll (25 mg) G $166.00
mg) (AS)
27000-5 Fentanyl Citrate Cll (100 mg) J (05/02) $166.00 51650-2 Phendimetrazine Tartrate G $166.00
28000-9 Fluoxymesterone CHI (200 G-2 $166.00 Clll (350 mg)
mg) 52300-9 Phenmetrazine HCI Cll (200 F-2 $166.00
28500-2 Flurazepam HCI CIV (200 mg) 1 $166.00 mg)
29500-6 Glutethimide Cll (500 mg) F $166.00 52400-1 Phenobarbital CIV (200 mg) J $166.00
30230-5 Halazepam CIV (200 mg) F $166.00 52850-1 Phentermine HCI CIV (200 G $166.00
30700-3 Hexobarbital CHI (500 mg) F $166.00 mg)
31500-1 Hydrocodone Bitartrate Cll 1-1 2 I (07/02) $166.00 55450-1 PrazepamCIV(500mg) F-1 $166.00
(250 mg) 57400-0 Propoxyphene HCI Cll (1 g) K $166.00
32300-0 Hydromorphone HCI Cll (50 I $166.00 57500-2 Propoxyphene Napsylate Cll H $166.00
mg) dg)
35600-9 KetamineHCI CJJI (250 mg) G-2 $166.00 59220-5 Quazepam CIV (200 mg) F $166.00
35950-6 Levmetamfetamine Cll (75 mg) F $166.00 61100-4 Secobarbital Cll (200 mg) H $166.00
36200-1 Levo-a-acetylmethadol HCI Cll F-1 $166.00 62000-5 Stanozolol Clll (200 mg) F-3 $166.00
(25 mg) 62364-8 Sufentanil Citrate Cll (25 mg) G F-1 (04/02) $166.00
36400-7 Levorphanol Tartrate Cll (500 H $166.00 64300-0 Talbutal Clll (250 mg) F $166.00
mg) 64340-8 Temazepam CIV (200 mg) G $166.00
37030-5 Lorazepam CIV (200 mg) G-2 $166.00 64500-6 Testolactone Clll (125 mg) F-1 $133.00
37100-2 Lysergic Acid Diethylamide I $166.00 64600-9 Testosterone Clll (125 mg) I $133.00
Tartrate (LSD) CI(10mg) 64700-1 Testosterone Cypionate Clll G-1 $166.00
(AS) (For Qualitative Use (200 mg)
Only) 64800-4 Testosterone Enanthate Clll J $166.00
37530-9 Mazindol CIV (350 mg) G $166.00 (200 mg)
38300-1 Meperidine HCI Cll (200 mg) I $166.00 64900-7 Testosterone Prapionate Clll L 6 $166.00
38600-0 Mephobarbital CIV (250 mg) G $166.00 (200 mg)
38900-8 Meprobamate CIV (200 mg) G-1 G (03/02) $166.00 65630-8 Thiamylal Clll (200 mg) F $166.00
39800-9 MethadoneHCICII(200mg) H-1 $166.00 66100-2 Thiopental Clll (250 mg) 1 $166.00
39900-1 Methamphetamine HCI Cll $166.00 68050-6 Triazolam CIV (200 mg) G-1 $166.00
(125 mg)
40400-0 Methaqualone Cl (500 mg) F-1 $166.00
30


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Asociacion Farmacaeutica Pharmasystems
Tel: (46) 0-33-165-317 Petah Tikva 49280
Mexicana, AC (AFM) 361 Steelcase Road West
Fax: (44) 0-33-165-310 ISRAEL
AdolfoPrieto 1649-601 10 Markham, Ontario L3R3V8
E-mail: sales@lgc.sp.se
03100 Mexico, D.F. Tel: (972) 3-931-8983
Reference Standards Fax:(972)3-930-2152 CANADA
MEXICO Tel: 888-475-2500
Prio Info AB Tel: (52) 5-524-5685 Reference Standards
Fax:888-475-7155
P.O. Box 1528 Fax: (52) 5-534-5098 Yozmot, Ltd.
Prastgardsgatan 1,14th fl. USP-NF (Print)
USP-NF (Print or Electronic); P.O. Box 56055
172 29 Sundbyberg (Stockholm) Pharmacopeial Forum Tel-Aviv 61560
SWEDEN
Proquifa, S.A. de C.V. ISRAEL ADDITIONAL
Tel: (46) 8-441-17-43 Tel: (972) 3-528-4851
Fax: (46) 8-652-81-15
Oriente 6 Mz. 26 Lote 13
Fax: (972) 3-528-5397 EXPORTERS
USP-NF (Print or Electronic); Cuchilla del Tesoro
07900 Mexico, D.F. USP-NF (Print or Electronic) Hubert Lando International, Inc.
Pharmacopeial Forum 2829 Bird Avenue
MEXICO
Promochem Standard Supplies Tel: (52) 5-799-5250 NORTH AMERICA PMB 305
A.B. Fax: (52) 5-796-6649 Miami, FL 33133
Energigatan 17 Reference Standard; USA USA
434 37 Kungsbacka USP-NF (Print or Electronic); Tel: 305-285-9513
SWEDEN National Technical Information Fax:305-285-1191
Pharmacopeial Forum; USP Service
Tel: (46) 300-568-660 Dictionary Reference Standards
Fax: (46) 300-568-669 5285 Port Royal Road
Corporation Planeta S.A. de C.V. Springfield, VA 22161 US Biological and Chemical
E-mail: info@promochem.se Standards, Inc.
Calle Maquilishuat 215 USA
Reference Standards 47 East 30th Street
Urb. Buenos Aires 3 Tel: 703-487-4825
San Salvador Fax: 703-487-4098 New York, NY 10016
LATIN AMERICA EL SALVADOR USP-NF (Print or Electronic) USA
Tel: (503 260-2860 Tel: 212-685-2985
Rittenhouse Book Distributors, Fax:212-684-3824
ARGENTINA Fax: (503) 260-2808 Inc.
USP-NF (Print or Electronic); Reference Standards
Carpe Scheider y Cia, S.A. 522 Feheley Drive
Godoy Cruz 2769, 5 Piso Pharmacopeial Forum; USP King of Prussia, PA 19406
1425 Buenos Aires Dictionary USA
ARGENTINA PARAGUAY Tel: 800-345-6425
Tel: (54) 11-477-60477 Fax: 800-223-7488
Fax: (54) 11-477-59619 Droguen'a Italqui'mica, Inc. USP-NF (Print or Electronic);
USP-NF (Print or Electronic); Calle Tercera Pharmacopeial Forum; USP
Pharmacopeial Forum; c/Corrales (Zona Norte) Dictionary
Reference Standards Fernando de la Mora
PARAGUAY
Tel: (59) 5-21-506-629
Fax: (59) 5-21-508-583
Reference Standards
33

HOW TO ORDER
DIRECT FROM USP Quantity Discounts

5% discount will be given on any assortment of 5 to 24
Telephone Orders standards per order, and 10% will be given on any assortment
of 25 or more. These discounts are subject to change without
U.S. and Canada: (800) 227-8772 notice.
International: (301) 881-0666
Please note: The quantity discount policy will soon change
Orders by telephone are accepted (except for DEA controlled to a line item discount. For example: a 5% discount will be
substances), but customers are reminded that errors may be given on 5-24 units of any one type of Reference Standard in
more frequent with verbal communications and that an order, and a 10% discount will be given on 25 or more
standards are not returnable for exchange or refund. units of any one type of Reference Standard in an order. This
new discount policy will go into effect automatically when
FAX Orders our new ERP business system is turned on in early 2002.
Fax: (301) 816-8148 Please contact Customer Service for the latest information.
FAX orders are accepted for customers (except for DEA Important Order / Policy Information
controlled substances). Customers are responsible for any A Reference Standard unit may include several individual
errors in transmission or for order duplication. containers; in such an instance, do not order in terms of the
total number of containers. Where an order contains an item
Online Orders that is not currently available, a backorder record will be
made by USP. A notice of availability will be provided to the
www.usp.org customer if the item becomes available within 6 months of
the original order (see backorder policy below). No items will
Reference Standards may be ordered online (except for DEA be shipped without prior written authorization by the
controlled substances). Go to www.usp.org. Click on customer.
"Products" and select "Reference Standards". Orders may be
charged to your USP account or by credit card via our secure
Confirmation orders may be sent and must be clearly
server. Errors in ordering are the responsibility of the
designated as such. The USP does not assume responsibility
customer.
for duplication of orders not clearly marked as confirmation.
Mail Orders
See International section for special requirements
Please send all mail orders to: pertaining to orders outside the U.S. and Canada.
U.S. Pharmacopeial Convention, Inc.
Customer Service Department DEA Requirements
12601 Twinbrook Parkway For all domestic purchases of items regulated by the Drug
Rockville, Maryland 20852 Enforcement Administration (DEA), a copy of the customer's
USA current DEA Registration Certificate must be on file with
Order forms are located in the back of this catalog. USP. In addition, customers ordering DEA Schedules III and
IV, must provide on purchase orders their DEA registration
Pricing number for the appropriate schedule. To order Schedule I and
Prices noted in individual product descriptions are effective II standards, the customer must submit with their hard copy
January 1, 2002. Please note that prices and package sizes are purchase orders a DEA Form 222-C, properly completed.
subject to change without notice. Also note that catalog items
are not returnable for exchange or refund.
Controlled substances (CI, CII, CIII, CIV, CV) shipped to
foreign address, including Canada and Puerto Rico, add
$25.00 per unit.
For additional shipping charges, see order form.
34

HOW TO ORDER
The following Reference Standards are "List Chemicals" and Canadian orders from Ontario for non-controlled substances
require certain documentation in order to be purchased: are shipped prepaid via air courier of USP's choice at a
charge of $9 (U.S. dollars) to a STREET ADDRESS ONLY
Ephedrine Sulfate (no P.O. Boxes). Shipments via air courier of the Customer's
Pseudoephedrine Sulfate choice will be at a charge of $25. Orders from all other
Pseudoephedrine HC1 Canadian Provinces are shipped by air courier at a charge of
Phenylpropanolamine Bitatrate US$60. Canadian orders for controlled substances will be
Phenylpropanolamine HC1 shipped by air courier with an additional charge of
US$195.00 per order. Appropriate import documents are
An organization in the United States seeking to purchase a required for USP to ship controlled substances to Canada.
List Chemical Reference Standard for resale to another Any fees relating to customs duties, tariffs, and other taxes
customer must have a DEA registration (either a controlled are the reponsibility of the customer.
substance or List Chemical registration). If an organization in Rush shipments, add $25.00 per order.
the United States is purchasing the List Chemical Reference
Standard for its own analytical use, the organization must International Orders
provide USP with a letter on company letterhead describing Foreign orders (orders to be shipped outside the U.S. or
the purpose for the purchase. International customers and Canada) for catalog items, except items regulated or
distributors should check with their own government controlled by the U.S. Drug Enforcement Administration
regulatory agencies to ensure compliance eith local laws. (DEA), are accepted directly by USP when customs forms
related to exporting are not required. All shipments are via
Backorder Policy air courier at a charge of US$60. The shipping charge for
All customer orders will be accepted by USP within orders involving controlled substances will be US$195.00
guidelines relating to credit approval and legal regulations. irrespective of the total cost of goods. Full payment
Reference Standards without available inventory will be in advance, in U.S. dollars drawn on a U.S. bank, is required
placed in the active backorder classification for a period of 6 for all orders from outside the United States. An additional
months. If inventory does not become available within that 6- charge may be assessed for Dangerous Goods shipments.
month period from the date of the original order, the
backorder will be canceled. The customer will need to reorder Payment Policy
the Reference Standard. All orders must be paid in advance in U.S. dollars drawn on a
U.S. bank, unless open account status has been granted by
Purchase Orders USP's Finance Department. To apply for open account status,
Official purchase orders on company letterhead must have an application can be requested through USP's Finance
billing and shipping addresses and should include the catalog Department.
number, the name of the official Reference Standard, and the USP accepts checks, money orders, credit cards (Visa,
quantity of the Reference Standard being ordered. Please do MasterCard, American Express), and electronic wire transfer
not specify lot numbers on written purchase orders; USP only (please contact USP's Finance Department regarding bank
ships official lots. information). Any bank fees are the responsibility of the
customer. Please be sure to include such fees as an addition to
Shipping the total dollar amount of the order. Any other fees, such as
Domestic orders are shipped prepaid by via air courier of customs duties, taxes, or tariffs are also the responsibility of
USP's choice at a charge of $9 to a STREET ADDRESS the customer.
ONLY (no P.O. Boxes).
Shipments via air courier of the Customer's choice will be at
a charge of $25.
An additional charge may be assessed for Dangerous Goods
shipments.
35

Official USP Reference Standards Prices Effective January 1,2002
Order Form
Below, please print names, catalog numbers, and prices as listed in the Reference Standards Catalog (for controlled
substances—Cl, CM, CHI, CIV, CV—shipping to a foreign address, please add $25.00 per unit and provide appropriate
paperwork. Call USP Customer Service at 301-881-0666 for a list of required documents).
Prices subject t o change. USP Reference Standards are not returnable f o r exchange or refund.
* Quantity discounts: 5%, any assortment of 5 to 24 standards per order; 1 0 % , any assortment of 25 or TOTAL
more per order. (Please note: Starting in early 2002, these discounts will be based on the quantity per
item, not on the total items ordered.)
TOTAL LESS DISCOUNTS*
** Maryland residents add 5 % sales tax.
*** Domestic orders are shipped via air courier (courier chosen by USP) at a charge of $9 t o a STREET
ADDRESS ONLY (no P.O. boxes). Customers may choose their own courier at a shipping charge of $25. TAX**
All shipping charges are per total order.
**** Foreign orders are shipped via air courier. Charges are per total order and in U.S. dollars.
DOMESTIC SHIPPING***
Canadian orders from Ontario for noncontrolled substances are shipped at a charge of $9 (courier
chosen by USP) to a STREET ADDRESS ONLY (no P.O. boxes). Customers may choose their own
courier at a shipping charge of $25. Orders for noncontrolled substances from all other Canadian FOREIGN SHIPPING****
provinces are shipped at a charge of $60. Canadian orders for controlled substances will be shipped
at a charge of $195.
Orders from outside the U.S. and Canada are shipped at the following charges: GRAND TOTAL
$60 for noncontrolled substances and $195 for controlled substances.
GGAZPF
NAME
TITLE
ORGANIZATION
I I USP Reference Standards Catalog on Internet:
' • " ^ www.usp.org/dsd/refstd/
ADDRESS (WE CANNOT DELIVER TO A P.O. BOX)
CITY STATE ZIP COUNTRY 800-227-8772 or 301-881-0666
( )
TELEPHONE
Fax order form to 301-816-8148
( )
FAX NUMBER E-MAIL
Completed order form with payment can be
mailed to: USP
• Charge my. • MasterCard • VISA • Amex Customer Service Department
12601 Twinbrook Parkway
Rockville, MD 20852
ACCOUNT NUMBER EXPIRATION DATE
USA
CARDHOLDER'S NAME
• I expect to be ordering drug reference standards on
CARDHOLDER'S SIGNATURE a regular basis. Please add my name to the USP
Reference Standards Catalog mailing list.
• Enclosed is my check for $_ _. Make checks payable to USP (in U.S. dollars,
microcoded, and drawn on a U.S. bank). • Please send me information on USP products.
• Bill me. (Available for U.S. orders only. Prior credit approval required for orders exceeding $1,800. For
credit approval, call 1-800-227-8772, ext. 8177; or301-881-0666, ext. 8177; ore-mail em@usp.org.)
P.O. # (REQUIRED) SIGNATURE
D Please send bank information for wire transfer.

USP Standards and Information Publications Order Form
Outside U.S.
U.S. Canada & Canada
Item No. Product Description
Unit
Qty
Total Shipping Shipping Shipping
Price Price Shipping Total
(per unit) (per unit) (per unit)
USP-NF Annual Edition, Print

(annual subscription includes hardcover and
two Supplements)
830427 1 -year USP25-NF 20 $589.00 $13.00 $33.00 $75.00
830438 2-year USP 25-NF 20 and USP 26-NF21 $1118.00 $25.00 $65.00 $150.00
($559/yr)
USP-NF Single-user CD
(annual subscription includes cumulative
CDs through Supplement Two)
852623 1 -year USP 25-NF 20 $829,00 $30.00 ...$ZQ,QO. ...1.7.0,00
852634 2-year USP 25-NF 20 and USP 26-NF 21 $1598.00 $60.00 $140.00 $140.00
($799/yr)
Call for online (Internet) and intranet pricing
Pharmacopeia! Forum (PF)

(annual subscription includes six bimonthly issues,
Jan.-Dec.)
832025 1-year 2002 $449.00 $30.00 $62.00 $150.00
832036 2-year 2002 and 2003 $858.00 $60.00 $125.00 $300.00
($429/yr)
USP Dictionary of USAN and
International Drug Names
932110 2001 Edition $269.00 $6.00 $12.00 $20.00
930228 2002 Edition (available in April) $269.00 $6.00 $12.00 $20.00
942114 Chromatographic Reagents $149.00 $4.00 $12.00 $35.00
Students, faculty, and preceptors must provide proof of status TOTAL PRICE TOTAL SHIPPING COSTS
(e.g., photocopy of valid student I.D.). 40% discounts apply only
to NEW subscriptions and exclude shipping costs.
»*- TOTAL PRICE
Prices subject to change and apply to new sales only. Prior sales excluded.
Please allow 2-4 weeks for delivery. (Total Price less discounts)
Maryland residents add 5% sates tax +$

NAME
Total Shipping Costs +$

TITLE
ORGANIZATION
GRAND TOTAL
BADZPF
CITY STATE ZIP COUNTRY

www.usp.org
TELEPHONE 800-227-8772
or 301-881-0666
FAX NUMBER E-MAIL
Fax order form to 301 -816-8148
PAYMENT OPTIONS Completed order form with payment can be
mailed to: USP
n Charge my: n MasterCard n VISA n Amex
Customer Service Department
Rockville, MD 20852
USA
CARDHOLDER'S NAME
E-mail: custsvc@usp.org
CARDHOLDER'S SIGNATURE
n Please send me information on USP products.
n Enclosed is my check for $_
microcoded, and drawn on a U.S. bank).
_. Make checks payable to USP (in U.S. dollars,
n Bill me. (Available for U.S. orders only. Prior credit approval required for orders exceeding $1,800/
w 100% Satisfaction Guarantee!
If you're not satisfied with any USP print or electronic
publication for any reason, simply return the
first shipment in resalable condition, within 30 days of
P.O. # (REQUIRED) SIGNATURE receipt, along with your invoice, for a full refund.
n Please send bank information for wire transfer.
T o r credit approval, call 1-800-227-8772, ext. 8177; or 301-881-0666, ext. 8177;

Pharmacopeial Forum NOTICE TO THE EXECUTIVE SECRETARIAT OF
Vol. 28(1) [Jan.-Feb. 2002] INTENT TO COMMENT
Date
Mail to: Executive Secretariat, USP-NF
Rockville, MD 20852
With Reference Estimated

to the Proposal(s) in Date of
Pharmacopeial Forum: Sending Comments*
Title(s) Vol. No. Page(s)
I am unable to comment at present, but please be informed of my intent to comment later,

as indicated above.
Name
(Please type or print)
Company
Address
Telephone No. ( )
(area code)
*NOTE—Specifying date(s) when you expect to submit comments to the Executive Secretariat will not necessarily
result in a deferment of the implementation of the proposal(s) referred to.
{Please fold before mailing.)
NO POSTAGE
NECESSARY
IF MAILED
IN THE
UNITED STATES
BUSINESS REPLY MAIL
FIRST CLASS PERMIT NO 566 ROCKVILLE MD.
Postage will be paid by addressee
The United States Pharmacopeial Convention, Inc.

Rockville, MD 20852
(Fold)
(Fold)
CHROMATOGRAPHIC REAGENTS
USED IN USP-NF AND
PHARMACOPEIAL FORUM
This is an update based on the proposals published in this issue of PF.
Pharmacopeial Forum
Vol. 28(1) [Jan.-Feb. 2002] CHROMATOGRAPHIC REAGENTS
Chromatographic Reagents Used in USP-NF

and Pharmacopeial Forum
January-February 2002 PF
CEFPODOXIME PROXETIL FOR ORAL SUSPENSION DSD Mgh #14112

PF LGS# Reagent Brand Type of Test Comments
23(4) L1 MicroBondapak C18 See Cefpodoxime Proxetil Assay
28(1) L1 KromasilC18 Assay 4.6-mm x 25-cm, 5 n,m, manuf. EKA Nobel.
23(4) L1 MicroBondapak C18 Identity See Assay
CEFPODOXIME PROXETIL TABLETS DSD Mgh #14113

23(4) L1 MicroBondapak C18 See Cefpodoxime Proxetil Assay
28(1) L1 Kromasil C18 Assay 4.6-mm x 25-cm, 5 fj.m, manuf. EKA Nobel.
23(4) L1 MicroBondapak C18 Identity See Assay
DIGOXIN TABLETS DSD Mgh #26030

08(2) L1 None Cited See Digoxin; reprinted 9(6), 10(3), 10(6), 11(5) 12(2)
28(1) L1 Supelcosil LC-18 Dissolution 4.6 mm x 15 cm, 5 (im, manuf. Supelco.
11(5) L1 None Cited Identity See Assay; reprinted 12(2), 13(5), 14(6)
KAVA DSD Mgh #43865

28(1) L1 YMCbasic Content of Content of kavalactones. 4.6 mm x 25 cm, manuf.
YMC.
28(1) L1 J'Sphere ODS-H80 Content of Content of kavalactones. 4.6 mm x 25 cm, manuf.
YMC.
POWDERED KAVA DSD Mgh #43868

28(1) L1 J'Sphere ODS-H80 Content of Content of kavalactones. 4.6 mm x 25 cm, manuf.
YMC.
28(1) L1 YMCbasic Content of Content of kavalactones. 4.6 mm x 25 cm, manuf.
YMC.
NYSTATIN DSD Mgh #58060

28(1) L1 Symmetry C-18 Assay 4.6-mm x 25-cm, manuf. Waters.
NYSTATIN CREAM DSD Mgh #58070

NYSTATIN LOZENGES DSD Mgh #58085

Pharmacopeia! Forum
CHROMATOGRAPHIC REAGENTS Vol. 28(1) [Jan.-Feb. 2002]
NYSTATIN OINTMENT DSD Mgh #58090

NYSTATIN TOPICAL POWDER DSD Mgh #58100

NYSTATIN ORAL SUSPENSION DSD Mgh #58120

NYSTATIN TABLETS DSD Mgh #58130

NYSTATIN AND TRIAMCINOLONE ACETONIDE CREAM DSD Mgh #58170

28(1) L1 Symmetry C-18 Assay 4.6-mm x 25-cm, manuf. Waters,
11(4) L1 None Cited Assay for triamcinolone acetonide; see Triamcinolone
Acetonide Cream
NYSTATIN AND TRIAMCINOLONE ACETONIDE OINTMENT DSD Mgh #58175

28(1) L1 Symmetry C-18 Assay 4.6-mm x 25-cm, manuf. Waters,
11(4) L1 None Cited Assay for triamcinolone acetonide; see Triamcinolone
Acetonide Cream
STREPTOMYCIN SULFATE DSD Mgh #78390

28(1) L48 CarboPac PA1 Assay 4.0-mm x 25-cm, manuf. Dionex.
STREPTOMYCIN INJECTION DSD Mgh #78398

STREPTOMYCIN FOR INJECTION DSD Mgh #78405

PHARMACOPEIA!. FORUM
U.S. PHARMACOPEIA
The Standard of QualitySM
The United States Pharmacopeia

Information and Standards Development, USP-NF
Rockville, Maryland 20852
1-301-816-8345 FAX 1-301-816-8373
M o v i n g ? To ensure prompt delivery of your PF,

please send address label with your corrections to
USPC, PF Customer Service Dept., 12601 Twinbrook
Parkway, Rockviile, MD 20852. Fax 301-816-8148
28252 14210
The Journal of Standards Development and Official-Compendia Revision
• • • ••
•
•
•
•
PHARMACOPEIAL
FORUM
NUMBER 2
BIMONTHLY: March-April 2002
HIGHLIGHTS
• Second Interim Revision Announcement

Pertaining to USP25-NF20
• Reference Standards Update
• New Labeling Requirements Proposed

for Neuromuscular Blocking Agents
U.S. PHARMACOPEIA
The Standard of QualitySM
Table of Contents*
PHARMACOPEIAL FORUM VOL. 28 No. 2 MAR -APRIL 2002

HOW TO USE PF 207
Section Descriptions 209
Staff Directory 212
Changes in Reference Standards Prices and Numbers 217
New Labeling Requirements proposed for Neuromuscular Blocking Agents (Paralyzing Agents) 218
Chromatographic Reagents Now Available 218
Pharmaceutical Education Courses 218
How to Submit Comments 219
Schedules 221
SECOND INTERIM REVISION ANNOUNCEMENT 225
Amiloxate 227
Idarubicin Hydrochloride 227
Isoamyl Methoxycinnamate 227
Menthyl Anthranilate 227
Meradimate 227
Octisalate 227
Octocrylene 227
Octyl Salicylate 228
Sulisobenzone 228
Xylazine 228
NF 20 MONOGRAPHS 228
Acetyltributyl Citrate 228
Acetyltriethyl Citrate 229
Carbomer Copolymer 229
Carbomer Interpolymer 231
Tributyl Citrate 231
Triethyl Citrate 232
(11) USP Reference Standards 232
(671) Containers Permeation 232
Preservation, Packaging, Storage, and Labeling—USP 242
Alfentanil Hydrochloride (USP 26) 244
Alprostadil (USP 26) 245
Amantadine Hydrochloride Oral Solution [new] (USP 26) 250
Amantadine Hydrochloride Syrup (USP 26) 251
Aminocaproic Acid Oral Solution [new] (USP 26) 251
Aminocaproic Acid Syrup (USP 26) 252
Aspartic Acid (USP 26) 252
Betamethasone Oral Solution [new] (USP 26) 253
Betamethasone Syrup (USP 26) 254
Bromodiphenhydramine Hydrochloride Elixir (USP 26) 254
Bromodiphenhydramine Hydrochloride Oral Solution [new] (USP 26) 255
Pharmacopeial Forum
196 Contents* Vol. 28(2) [Mar.-Apr. 2002]
Brompheniramine Maleate Elixir (USP 26) 255

Brompheniramine Maleate Oral Solution [new] (USP 26) 256
Brompheniramine Maleate and Pseudoephedrine Sulfate Oral Solution [new] (USP 26) 256
Brompheniramine Maleate and Pseudoephedrine Sulfate Syrup (USP 26) 258
Butabarbital Sodium Elixir (USP 26) 259
Butabarbital Sodium Oral Solution [new] (USP 26) 259
Calcium Polycarbophil (USP 26) 260
Cefazolin Ophthalmic Solution (USP 26) 261
Chloral Hydrate Oral Solution [new] (USP 26) 261
Choral Hydrate Syrup (USP 26) 262
Chlorpheniramine Maleate Oral Solution [new] (USP 26) 262
Chlorpheniramine Maleate Syrup (USP 26) 263
Sodium Chromate Cr 51 Injection (USP 26) 264
Ciclopirox Olamine [erratum] (USP 26) 265
Clonidine Transdermal System [new] (USP 26) 265
Clorsulon (USP 26) 269
Cocaine and Tetracaine Hydrochlorides and Epinephrine Topical Solution (USP 26) 270
Cyproheptadine Hydrochloride Oral Solution [new] (USP 26) 271
Cyproheptadine Hydrochloride Syrup (USP 26) 272
Dexchlorpheniramine Maleate Oral Solution [new] (USP 26) 272
Dexchlorpheniramine Maleate Syrup (USP 26) 273
Dexchlorpheniramine Maleate Tablets (USP 26) 273
Dextroamphetamine Sulfate Elixir (USP 26) 274
Dextroamphetamine Sulfate Oral Solution [new] (USP 26) 274
Dextroamphetamine Sulfate Tablets (USP 26) 276
Dextromethorphan Hydrobromide Oral Solution [new] (USP 26) 276
Dextromethorphan Hydrobromide Syrup (USP 26) 277
Dicyclomine Hydrochloride Oral Solution [new] (USP 26) 278
Dicyclomine Hydrochloride Syrup (USP 26) 279
Digoxin Elixir (USP 26) 279
Digoxin Injection (USP 26) 279
Digoxin Oral Solution [new] (USP 26) 279
Dimenhydrinate Oral Solution [new] (USP 26) 281
Dimenhydrinate Syrup (USP 26) 282
Diphenhydramine Hydrochloride Elixir (USP 26) 282
Diphenhydramine Hydrochloride Oral Solution [new] (USP 26) 283
Divalproex Sodium Delayed-Release Tablets (USP 26) 284
Doxazosin Mesylate [new] (USP 26) 286
Doxazosin Mesylate Tablets [new] (USP 26) 289
Doxylamine Succinate Oral Solution [new] (USP 26) 291
Doxylamine Succinate Syrup (USP 26) 292
Dyphylline Elixir (USP 26) 292
Dyphylline Oral Solution [new] (USP 26) 292
Dyphylline and Guaifenesin Elixir (USP 26) 293
Dyphylline and Guaifenesin Oral Solution [new] (USP 26) 294
Enalapril Maleate Tablets (USP 26) 295
Ephedrine Sulfate Oral Solution [new] (USP 26) 296
Ephedrine Sulfate Syrup (USP 26) 297
Erythromycin Ointment [erratum] (USP 26) 297
Ferrous Gluconate Elixir (USP 26) 297
Ferrous Gluconate Oral Solution [new] (USP 26) 297
Gabapentin Capsules [new] (USP 26) 298
Ganciclovir [new] (USP 26) 301
Guaifenesin Oral Solution [new] (USP 26) 302
Guaifenesin Syrup (USP 26) 303
Guaifenesin and Codeine Phosphate Oral Solution [new] (USP 26) 303
Guaifenesin and Codeine Phosphate Syrup (USP 26) 306
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] Contents* 197
Hydralazine Hydrochloride Oral Solution (USP 26) 306

Hydroxyzine Hydrochoride Oral Solution [new] (USP 26) 307
Hydroxyzine Hydrochoride Syrup (USP 26) 308
Iohexol Injection [erratum] (USP 26) 308
Ipecac Oral Solution [new] (USP 26) 308
Ipecac Syrup (USP 26) 310
Isoniazid Oral Solution [new] (USP 26) 310
Isoniazid Syrup (USP 26) 311
Ketoconazole Oral Suspension (USP 26) 311
Levothyroxine Sodium Tablets (Proposal for 3rd IRA) 312
Lincomycin Hydrochloride Syrup (USP 26) 313
Lincomycin Oral Solution [new] (USP 26) 313
Lithium Citrate Syrup (USP 26) 314
Lithium Oral Solution [new] (USP 26) 314
Mangafodipir Trisodium [new] (USP 26) 315
Mangafodipir Trisodium Injection [new] (USP 26) 320
Mecamylamine Hydrochloride (USP 26) 321
Mecamylamine Hydrochloride Tablets (USP 26) 322
Meperidine Hydrochloride Oral Solution [new] (USP 26) 323
Meperidine Hydrochloride Syrup (USP 26) 323
Metaproterenol Sulfate Oral Solution [new] (USP 26) 324
Metaproterenol Sulfate Syrup (USP 26) 325
Methdilazine Hydrochloride Oral Solution [new] (USP 26) 325
Methdilazine Hydrochloride Syrup (USP 26) 326
Methenamine Elixir (USP 26) 326
Methenamine Oral Solution [new] (USP 26) 327
Methenamine Tablets (USP 26) 328
Morphine Sulfate [erratum] (USP 26) 328
Morphine Sulfate Suppositories (USP 26) 328
Naloxone Hydrochloride (USP 26) 329
Naltrexone Hydrochloride (USP 26) 329
Nandrolone Decanoate Injection (USP 26) 330
Norgestimate [new] (USP 26) 331
Oxybutynin Chloride Oral Solution [new] (USP 26) 334
Oxybutynin Chloride Syrup (USP 26) 336
Paclitaxel [new] (USP 26) 336
Paromomycin Oral Solution [new] (USP 26) 341
Paromomycin Sulfate Syrup (USP 26) '. . . . . 342
Pentobarbital Elixir (USP 26) 342
Pentobarbital Oral Solution [new] (USP 26) 342
Phenobarbital Elixir (USP 26) 343
Phenobarbital Oral Solution [new] (USP 26) 344
Potassium Gluconate Elixir (USP 26) 345
Potassium Gluconate Oral Solution [new] (USP 26) 345
Prazosin Hydrochloride Capsules (USP 26) 346
Prednisolone Oral Solution [new] (USP 26) 346
Prednisolone Syrup (USP 26) 347
Probenecid Tablets (USP 26) 347
Procainamide Hydrochloride Tablets (USP 26) 347
Progesterone Vaginal Suppositories (USP 26) 348
Promethazine Hydrochloride Oral Solution [new] (USP 26) 348
Promethazine Hydrochloride Syrup (USP 26) 349
Propoxyphene Hydrochloride (USP 26) 350
Propoxyphene Napsylate (USP 26) 352
Pseudoephedrine Hydrochloride Oral Solution [new] (USP 26) 354
Pseudoephedrine Hydrochloride Syrup (USP 26) 355
Pseudoephedrine Hydrochloride Tablets (USP 26) 356
Pyridostigmine Bromide Oral Solution [new] (USP 26) 356
Pharmacopeia! Forum
Pyridostigmine Bromide Syrup (USP 26) 357

Ramipril [new] (USP 26) 357
Ranitidine Oral Solution (USP 26) 360
Reserpine Elixir (USP 26) 362
Reserpine Oral Solution [new] (USP 26) 362
Rifampin Oral Suspension (USP 26) 363
Secobarbital Elixir (USP 26) 364
Secobarbital Oral Solution [new] (USP 26) 364
Senna Oral Solution [new] (USP 26) 365
Senna Syrup (USP 26) 365
Simethicone (USP 26) 366
Sodium Hypochlorite Topical Solution (USP 26) 366
Sodium Sulfide Topical Gel (USP 26) 366
Stanozolol Tablets [erratum] (USP 26) 367
Sucralfate (USP 26) 367
Sucralfate Tablets (USP 26) 369
Terazosin Hydrochloride [new] (USP 26) 369
Terpin Hydrate Elixir (USP 26) 374
Terpin Hydrate Oral Solution [new] (USP 26) 375
Terpin Hydrate and Codeine Elixir (USP 26) 375
Terpin Hydrate and Codeine Oral Solution [new] (USP 26) 376
Tetracycline Hydrochloride Oral Suspension (USP 26) 378
Theophylline Sodium Glycinate Elixir (USP 26) 378
Theophylline Sodium Glycinate Oral Solution [new] (USP 26) 378
Thiamine Hydrochloride Elixir (USP 26) 379
Thiamine Hydrochloride Injection (USP 26) 380
Thiamine Hydrochloride Oral Solution [new] (USP 26) 380
Thiamine Mononitrate Elixir (USP 26) 381
Thiamine Mononitrate Oral Solution [new] (USP 26) 381
Torsemide (USP 26) 382
Triamcinolone Diacetate Oral Solution [new] (USP 26) 383
Triamcinolone Diacetate Syrup (USP 26) 384
Triazolam [erratum] (USP 26) 385
Tricitrates Oral Solution (USP 26) 385
Trifluoperazine Hydrochloride Syrup (USP 26) 385
Trifluoperazine Oral Solution [new] (USP 26) 385
Trihexyphenidyl Hydrochloride Elixir (USP 26) 386
Trihexyphenidyl Hydrochloride Oral Solution [new] (USP 26) 387
Trimeprazine Oral Solution [new] (USP 26) 388
Trimeprazine Tartrate Syrup (USP 26) 389
Trimethoprim (USP 26) 389
Triprolidine Hydrochloride Oral Solution [new] (USP 26) 390
Triprolidine Hydrochloride Syrup (USP 26) 391
Triprolidine Hydrochloride Tablets (USP 26) 392
Triprolidine and Pseudoephedrine Hydrochlorides Oral Solution [new] (USP 26) 392
Triprolidine and Pseudoephedrine Hydrochlorides Syrup (USP 26) 394
Triprolidine and Pseudoephedrine Hydrochlorides Tablets (USP 26) 394
Valproic Acid Oral Solution (USP 26) 395
Valproic Acid Syrup (USP 26) 396
Valsartan [new] (USP 26) 396
Valsartan Capsules [new] (USP 26) 399
MONOGRAPHS (NF) 403
Corn Syrup [new] (NF 21) 403
High Fructose Corn Syrup [new] (NF 21) 408
Dextrin (NF 21) 411
Magnesium Aluminometasilicate [new] (NF 21) 411
Magnesium Aluminosilicate [new] (NF 21) 414
Milk Thistle (NF 21) 414
Pharmacopeial Forum
Powdered Milk Thistle Extract [new] (NF 21) 417

Milk Thistle Capsules [new] (NF 21) 420
Milk Thistle Tablets [new] (NF 21) 422
Myristyl Alcohol [new] (NF 21) 424
Saw Palmetto Extract [new] (NF 21) 425
Sugar-Free Suspension Structured Vehicle (NF 21) 428
Suspension Structured Vehicle (NF 21) 429
Xanthan Gum Solution (NF 21) 429
(I) Injections (USP 26) 430
(II) USP Reference Standards (USP 26) 433
(85) Bacterial Endotoxins Test [erratum] (USP 26) 435
(563) Biological and Chemical Identification of Articles of Botanical Origin [new] (USP 26) 435
(565) Botanical Extracts (USP 26) 451
(661) Containers (USP 26) 453
(671) Containers—Permeation (USP 26) 456
(795) Pharmacy Compounding (USP 26) 458
(1146) Packaging Practice—Repackaging a Single Solid Oral Drug Product into a Unit-Dose Container [new]
(USP 26) 467
(1160) Pharmaceutical Calculations in Prescription Compounding [new] (USP 26) 476
(1186) Shipping and Storage of Labile Preparations [new] (USP 26) 495
(1206) Sterile Drug Products for Home Use (USP 26) 498
(2750) Manufacturing Practices for Nutritional Supplements (USP 26) 534
Bacterial Alkaline Protease Preparation (USP 26) 552
Bromelain [new] (USP 26) 552
4-(Butylamino)benzoic Acid [new] (USP 26) 553
Volumetric Solutions 553
Lead Perchlorate, Hundredth Molar (0.01 M) [new] (USP 26) 553
Reagent Footnotes 553
Footnote 43 (USP 26) 553
Footnote 103 [new] (USP 26) 554
Doxazosin Mesylate (USP 26) 554
Ganciclovir (USP 26) 554
Mangafodipir Trisodium (USP 26) 554
Norgestimate (USP 26) 554
PREVIOUS PF PROPOSALS STILL PENDING 555
CANCELED PROPOSALS 564
HARMONIZATION 567
Petrolatum 569
White Petrolatum 570
MONOGRAPHS (NF) 572
Butylparaben 572
Ethylparaben 574
Methylparaben 575
Polyethylene Glycol 577
Propylparaben 581
Stearic Acid 583
Pharmacopeial Forum

(601) Aerosols, Metered-Dose Inhalers, and Dry Powder Inhalers 584
(699) Density of Solids 603
(776) Optical Microscopy 606
(811) Powder Fineness 611
(846) Specific Surface Area 612
(1174) Powder Flow 618
Bismuth Subsalicylate Oral Suspension [new] 627
MONOGRAPHS (NF) 628
Ammonio Methacrylate Copolymer Dispersion [new] 628
Coriander Oil [new] 629
Corn Syrup Solids [new] 630
Lemon Tincture [new] 631
Lutein [new] 632
Lutein Preparation [new] 634
Compound Orange Spirit [new] 637
Tolu Balsam Syrup [new] 637
Tolu Balsam Tincture [new] 638
(661) Containers 639
(1075) Good Compounding Practices [new] 640
Defining Column Equivalence 652
Polypropylene Containers: Status and Comments Received 656
Review of Pharmaceutical Calculations in Prescription Compounding (1160) 661
NOMENCLATURE 675
INDEX 687
ORDER FORM
Pharmacopeial Forum
John W. Gasper, J.D. http ://www. usp.org
Jerry T. Wadsworth
Meredith Hassall; Reuben Meisel; Anthony Owens Sciences.
Editorial Coordinator
Susan Maida The United States Pharmacopeial Convention comprises represen-
Production Editors tatives from colleges and national and state organizations of med-
Erika L. Barrowclough; Evelyn Bryant icine and pharmacy. It publishes the U.S. Pharmacopeia and
Senior Editorial Assistant National Formulary, the legally recognized compendia of stan-
M. T. Samahon dards for drugs and products of other health care technologies.
Editorial Assistants The USP and NF include assays and tests for the determination
Micheline Tranquille; Milagro Welter of strength, quality, and purity and requirements for packaging
Director, Product Development and labeling.
Linda M. Guard
Debbie Miller Moving?
Production Coordinator Our subscribers' records and publication labels are computer-gen-
Celia Hamilton erated. Please send your new address, and your latest label, or an
Electronic and Desktop Publishing exact copy of it, to: USPC, PF Customer Service Dept., 12601
Debbie James; Donna A. Singh Twinbrook Parkway, Rockville, MD 20852.
Fax (301) 816-8148.
This section presents an overview of the public review and comment process, conducted through Pharmacopeial Forum
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] STANDARDS DEVELOPMENT 205

peial Previews)
3. Adopted revisions—new or revised standards that become official and binding before the publication of the next USP-
USP welcomes comments and data on potential, proposed, or official standards.* Comments, along with USP's responses,
will be published either in PF Briefings, the Commentary section of PF, the Commentary section of Supplements to USP-NF,
or the Commentary section of USP-NF.


for publication in

J_
and responds to the
USP Scientific Staff Liaison compiles and

/ Revision proposal becomes official;

/ revision published in Interim
I Revision Announcement or
\ Supplement to USP-NF; comments
\ and responses published under
\ Commentary in Supplement I
\ PF/ USP-NF
Questions on the process should be addressed to John W. Gasper, M.A., J.D., Director, Office of the Executive Secretariat,
U.S. Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852 (e-mail: jg@usp.org).
If you are not immediately able to submit comments but you intend to do
HOW TO USE PF
This section provides descriptions of the various parts of PF. It also includes Committee Designations and the StaffDirectory.
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] HOW TO USE PF 209

sues such as
study
velopment). New or revised text is marked with symbols (" B or
*. or A A ) to specify the tentative, earliest date on which the revi-
sion would be officially adopted.
Items the Pharmacopeial change or for the proposed change. The designated stage of harmo- ments to the appropriate staff liaison ci-
•For In-Process Revision, new or revised text is marked with sym-
bols (mu) to specify the tentative, earliest date on which the revi-
•If there is no proposed revision to a test or section, "No change"
precedes the text.
item. New or revised text is set off by the symbols, come official and ensure compliance.
••
Pharmacopeial Forum
210 HOW TO USE PF Vol. 28(2) [Mar.-Apr. 2002]
Other Sections
dards.
Staff Directory


Nomenclature
Revisions to existing names as a supplement to the USP Dictionary of USAN and International Drug Names
Suggested, proposed, and recommended USAN and INN
Information on how nonproprietary drug names are devised
Articles relevant to compendial nomenclature issues
Index
Cumulative directory for the content of all issues of P F beginning with P F 28(1).

Chromatographic Reagents Used in USP—NF and Pharmacopeial Forum

Pharmacopeial Forum
EXPERT COMMITTEE DESIGNATIONS

AER Aerosols
BST Biostatistics
EMC Excipient Monograph Contend
ESC Excipients—Substances and Characterization^
* HDQ Indicates USP Headquarters items.

The Expert Committee has been renamed. The old name, Excipients—Substances and Characterization (ESC) has been changed to Excipient Monograph Content (EMC).
Pharmacopeial Forum
212 HOW TO USE PF Vol. 28(2) [Mar.-Apr. 2002]
STAFF DIRECTORY
This is an updated directory that reflects assignment changes based on the reorganization of USP. The general USP telephone
number, (301) 881 -0666, may still be used for general inquiries or when a particular Committee is not identified. The FAX number is
(301)816-8373.
STAFF E-MAIL PHONE ASSIGNMENT

Clydewyn M. Anthony, cma@usp.org (301) 816-8139 Pharmaceutical Analysis (PA1)
Frank P. Barletta, Scientist fpb@usp.org (301) 816-8328 Pharmaceutical Waters (PW)
Industrial(PPI);
Charles H. Barnstein, Consultant chbarnstein@
email.msn.com (301) 774-9457 Nomenclature and Labeling (NL)
John R. Bergeron, Director jxb@usp.org
Reference Standards (301) 816-8289 USP Reference Standards
Production
Lokesh Bhattacharyya, Senior lb@usp.org (301) 816-8201 Blood and Blood Products (BBP);
Scientist Vaccines, Virology, and
Immunology (VVI)
William E. Brown, Scientist web@usp.org (301) 816-8380 Biopharmaceutics (BPC);
Biostatics (BST)
Todd L. Cecil, Director, tlc@usp.org
Non-Complex Actives (301) 816-8234 New monograph development
Elizabeth Cowley, epc@usp.org
Communications Coordinator, (301) 816-8217 Safe Medication Use (SMU)
Experience
Roger Dabbah, Director, Complex rd@usp.org (301) 816-8336 Blood and Blood Products (BBP)
Actives
Ian F. DeVeau, Scientist ifd@usp.org (301) 816-8178 Biologic, Biotechnological, and
Veterinary Product
Monographs
Shawn F. Dressman, Scientist sfd@usp.org (301) 816-8261 Pharmaceutical Analysis
6—Actives (PA6)
John L. Esker, Scientist je@usp.org (301) 816-8193 Pharmaceutical Analysis 5 (PA5)
L. Valentin Feyns, Director, lvf@usp.org (301) 816-8121 USP Reference Standards
Reference Standards Evaluation
Gabriel I. Giancaspro, Scientist gig@usp.org (301) 816-8343 Dietary Supplements—Botanicals
Supplements—
Non-Botanicals(DSN);
Bioavailability and
Elena Gonikberg, Scientist eg@usp.org (301) 816-8251 Excipient Monograph Content
(EMC)
Sue C. Harris, Director, Excipients sch@usp.org (301) 816-8275 Excipient Monograph Content
Methods (ETM)
Gloria Huang, Senior Scientific ggh@usp.org (301) 816-8183 Pharmaceutical Dosage Forms
Associate (PDF)
Pharmacopeial Forum
STAFF DIRECTORY (continued)

Associate (PA2)
Justin J. Lane, Senior Scientific jl@usp.org (301)816-8323 Excipients—Test Methods
Associate (ETM)
President Standards Operations
Azra M. Medjedovic, Scientific am@usp.org (301)816-8179 Pharmaceutical Analysis 4 (PA4)
Associate
C. David Nash, Director, dn@usp.org (301)816-8298 Veterinary Issues
Veterinary Medicine
Claudia C. Okeke, Scientist cco@usp.org (301)816-8243 Compounding Pharmacy (CRX);
Distribution (PSD)
David A. Porter, Scientist dap@usp.org (301)816-8225 Analytical Microbiology (AMB);
Salvador Salado, Scientist and ss@usp.org (301)816-8165 Pharmaceutical Analysis (PA1),
Methods (ETM)
Development
Stefan P. Schuber, Director, sps@usp.org (301)816-8551
Information and
Administration
V. Srini Srinivasan, Director, OTC vs@usp.org (301) 816-8334 Dietary Supplements—Information
Drugs and Dietary Supplements
Jerry T. Wadsworth, Manager, jtw@usp.org (301) 816-8353 Standards Publications
William W. Wright, Scientific www@usp.org (301) 816-8335 Pharmaceutical Analysis 7—
Kahkashan Zaidi, kxz@usp.org (301) 816-8269 Aerosols (AER)
POLICIES AND
ANNOUNCEMENTS
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] POLICIES AND ANNOUNCEMENTS 217
CHANGES IN REFERENCE STANDARDS PRICES New Reference Standards vials already are carrying the new
AND NUMBERS. lot numbers. You will see the expanded numbers in the cat-
alog starting with the March/April 2002 issue.
Below is an overview of four key changes taking place re-
garding USP Reference Standards. Please note that these Further changes, as listed below, will take effect as USP estab-
changes take effect on different dates. lishes its comprehensive new ERP business system designed to en-
hance customer service. We expect to convert to this system in early
2002. Please call USP Customer Service at 1-800-227-8772 or
Annual price increase 301-881-0666 for updates on when the conversion is expected to
take place.
Effective January 1, 2002, prices of USP Reference Stan-
dards increased by 4%. This price increase rate is tied to Quantity discounts by item
the Consumer Price Index (CPI) for medical commod-
ities—prescription and OTC drugs and medical supplies. Historically, USP offered discounts on the purchase of Ref-
For the one-year period ending September 2001, the average erence Standards based on the total number of all items or-
CPI for medical commodities was 4.3%. dered. In early 2002 this policy will change such that a
quantity discount will be applied based on the number of
The current prices are reflected in the Reference Standards units of all items ordered, as was previously done. This pol-
catalog. Please note that a few Reference Standards may be icy change is set to coincide with the implementation of
subject to different pricing adjustments (and not a 4% in- USP's new ERP business system mentioned above.
crease) based on market value, cost of materials, and/or ex-
traordinary expenses. Catalog numbers expanded by one digit
New system of lot numbers A leading digit " 1" will be added to all existing catalog
numbers of Reference Standards. For example, the catalog
New Reference Standards lots are identified by unique ex- number 03150-3 will become 103150-3. The old catalog
panded lot numbers that provide important information. number will be maintained as the root.
These numbers allow each Reference Standard to be easily
traced to specific lots. Until current Reference Standards lots are depleted, vials
will continue to show the old catalog number. The new cat-
The new lot numbers will have three parts as this example alog numbers will appear on all catalogs, invoices, and ship-
indicates: ping documents. As such, it is recommended that you start
Gl A 001 preparing to incorporate the new catalog numbers in your
Reference Standards ordering documents.
Current lot Calendar year Sequential
configuration (A=2001,B=2002.ect.) number
Please call USP Customer Service at 1-800-227-8772 or
301-881-0666 if you have any questions about the changes
and their impact.
Pharmacopeial Forum
218 POLICIES AND ANNOUNCEMENTS Vol. 28(2) [Mar.-Apr. 2002]
NEW LABELING REQUIREMENTS PROPOSED FOR VISIT THE USP WEB SITE AT <http://www/usp.org).
NEUROMUSCULAR BLOCKING AGENTS Various resources related to Pharmacopeial standards are
(PARALYZING AGENTS)
presented, including highlights from PF.
Over the years, serious life-threatening medication errors
have been reported with the misuse of neuromuscular block- USP-NF AVAILABLE IN THREE ELECTRONIC
ing agents (also known as paralyzing agents). Examples in- F O R M A T S . The trusted reference for official
clude the USP injections: Succinylcholine Chloride, pharmaceutical standards is available in three convenient
Tubocurarine Chloride, Atacurium Besylate, and Vecuro- electronic formats—CD, intranet, and online. The CD is
nium Bromide. Monograph proposals have been published ideal for single users who prefer to have USP—NF on their
in PF for these injections but implementation has been de-
hard drives. The intranet format allows Web browser-based
layed due to a lack of information or reference standard ma-
terial. Other NMBA injections include: Cisatracurium access to multiple users within a company, through their
Bresylate, Doxacurium Chloride, Metocurine Iodide, Miva- own intranet server. The online format can be accessed by
curium Chloride, Pancuronium Bromide, Pipecurium Bro- individual registered users through the World Wide Web.
mide, and Roncuronium Bromide. There are no USP All three electronic formats provide fast and easy access
standards for these drugs, primarily because the data needed to official USP-NF content. More information can be
to develop the monograph have not been submitted by the obtained by visiting www.usp.org/products or by calling
manufacturers. Although these drugs are not official, the USP's Customer Service Department at 1-800-227-8772
Committees hope that the FDA will extend the requirement or 301-881-0666.
to all NMBA products, for the sake of safety and consis-
tency in the marketplace. CHROMATOGRAPHIC REAGENTS NOW AVAILABLE.
A survey was conducted to determine the best way of pre- Chromatographic Reagents lists the brand names of the
column reagents cited in every proposal for new or
venting the misuse of neuromuscular blocking agents. Five
revised gas- or liquid-chromatographic test methods that
hundred pharmacists, physicians, and nurses rated the var- have been published in Pharmacopeial Forum (PF) since
ious proposals. Color coding of the vial ferrules together 1980. Chromatographic Reagents also helps to track
with a printed warning was chosen as the preferred "flag". which column reagents were used to validate methods that
There currently exists manufactured NMBA products with a have become official and are included in USP-NF. The
red ferrule, a standard warning, and a transparent clear top. branded column reagents list is updated bimonthly
The Committees, therefore, felt that this can be easily done through Pharmacopeial Forum. Chromatographic
by industry with no or minimal expenditure. Anesthesia Red Reagents can be ordered by calling USP's Customer
(Pantone 811), neon orange, was selected as being distinc- Service Department at 1-800-227-8772 or 301-881-0666.
tive. The term "Paralyzing Agent" is currently in use and is
PHARMACOPEIAL EDUCATION COURSES. USP's
considered an alert that will get the users' attention.
Pharmacopeial Education series has been developed to
Official implementation will be delayed until August 1, enhance the knowledge, skills, and expertise of
2003 (USP 26, Second Supplement) to allow manufacturers pharmaceutical industry personnel. Three interactive
to take action. This proposal is included in this number of courses are currently being offered:
PF as a revision to (1) Injections. • "Fundamentals of Dissolution" helps participants be-
come proficient in USP-NF-based dissolution equip-
UPDATE ON THE ANNUAL EDITION OF USP-NF. ment, calibration, tests, methods development, and
Starting in 2002, USP-NF will be published annually. validation.
Traditionally, USP-NF has been published every five
years with two Supplements a year. Now, one main • "Standards 100: USP-NF Overview, Applications, and
edition and two Supplements will be published every year, Development Process" provides an overview of USP-
bringing users more frequent updates—at shorter intervals- NF sections and applications, use of USP Reference
on the latest official standards and test methods. The first Standards, and participation in the official standards de-
annual edition was shipped in November 2001 and velopment process.
became official on January 1, 2002. The annual edition
will be available in hardcover and electronic formats for • "Standards 101: USP-NF Monograph Development,
user convenience. First Supplement becomes official on General Notices & Chapters" builds on Standards
April 1, 2002, and Second Supplement becomes official 100, with an in-depth review of USP-NF monographs,
on August 1, 2002 (deadline to submit comments is General Notices, and General Chapters, and focuses on
February 15, 2002). Comments on previously published the technical aspects of the monograph development
Pharmacopeial Forum proposals that are received too late
process.
to permit adequate review and evaluation will be
considered as suggestions for future revisions.
Pharmacopeial Forum
The following list indicates tentatively scheduled course

dates.

March 4 and 5 Fundamentals of Dissolution (English) USP Headquarters, Rockville, MD
March 17 Fundamentals of Dissolution (English)(one-day lec- PITTCON 2002, New Orleans, LA
ture only)
March 17-22 Analytical Method Validation (tentative) PITTCON 2002, New Orleans, LA
Titration (tentative)
April 6 Analytical Method Validation (tentative) USP Headquarters, Rockville, MD
April 15 and 16 Fundamentals of Dissolution (English) USP Headquarters, Rockville, MD
April 22 Standards 100: Fundamentals of the Use of USP-NF USP Headquarters, Rockville, MD
April 23 Standards 101: Advanced Use of USP-NF, General USP Headquarters, Rockville, MD
June 17 and 18 Titration (tentative) USP Headquarters, Rockville, MD
For further information, contact Barbara B. Hubert, Director HOW TO SUBMIT COMMENTS. The USP welcomes
Pharmacopeial Education, BBH@usp.org, 301-816-8333, and encourages interested parties to submit comments and
or Diana Lenahan, Program Associate, DPL@usp.org, data regarding potential, proposed, or adopted (official)
301-816-8530. standards. Submissions concerning a particular item that
has appeared in a PF should be submitted to the
INTERNATIONAL CORRESPONDENCE. Individuals appropriate USP scientific staff liaison identified at the
who wish to correspond with the European and Japanese end of the Briefing accompanying each item. To submit
Pharmacopoeias concerning monographs in the Official comments and data to a liaison, use the e-mail address
Inquiry and Consensus stages of international and telephone numbers listed in the Staff Directory
harmonization should address their comments to the included in every PF.
coordinating pharmacopeia for a given article. The
addresses for the European and Japanese Pharmacopoeias Please note that starting in 2002, USP-NF is being pub-
are as follows: lished in an annual edition with one main book and two Sup-
plements a year. In addition, the following schedule will
Technical Secretariat of the repeat every year so that users will know what to expect
European Pharmacopoeia Commission
B.P. 907 and become familiar with the deadlines.
F 67029 Strasbourg Cedex 1 The publication and comment schedule for USP 25-NF 20
France
is as follows:
Secretariat of the Pharmacopoeia of Japan

Safety Division, Pharmaceutical Affairs Bureau
Ministry of Health and Welfare
1-2-2, Kasumigaseki, Chiyoda-ku
Tokyo, 100-45
Japan
Pharmacopeial Forum
220 POLICIES AND ANNOUNCEMENTS Vol. 28(2) [Mar.-Apr. 2002]
Comment Deadline Publication Date Official Date

Main Book May 15, 2001 November 2001 January 2002
Supplement One October 15, 2001 February 2002 April 2002
Supplement Two February 15,2002 June 2002 August 2002
The publication and comment schedule for USP 26-NF 20

is as follows:
Supplement One October 15, 2002 February 2003 April 2003
Supplement Two February 17, 2003 June 2003 August 2003
In the future, USP anticipates including the comment sub- For general inquiries or in cases where a particular liaison is
mission deadline in each briefing of every revision proposal not identified, use the general USP telephone number (301)
when it is published for public review and comment. 881-0666 or FAX number (301) 816-8373.
Pharmacopeial Forum
All official revisions are published in Supplements to USP-NF (twice yearly). Between Supplements official revisions are
published in PF under Interim Revision Announcement', these revisions are also incorporated in the upcoming Supplement.
/st Supplement Feb. 2002* Apr. 1, 2002*
PF 28(2) [Mar-Apr. 2002] Mar. 2002* Not Applicable
nd
2 IRA [published in PF 28(2)] Mar. 2002* Apr. 1, 2002*
PF 28(3) [May-June 2002*] May 2002* Not Applicable
rd
3 IRA [published in PF 28(3)] May 2002* June 1,2002*
nd
2 Supplement June 2002* Aug. 1,2002*
PF 28(4) [July-Aug. 2002] July 2002* Not Applicable
4th IRA [published in PF 28(4)] July 2002* Aug. 1, 2002*
PF 28(5) [Sept-Oct. 2002] Sept. 2002* Not Applicable
5* IRA [published in PF 28(5)] Sept. 2002* Oct. 1, 2002*
PF 28(6) [Nov.-Dec. 2002] Nov. 2002* Not Applicable
th
6 IRA [published in PF 28(6)] Nov. 2002* Dec. 2, 2002*
Tentative
INTERIM REVISION
ANNOUNCEMENT
Symbols—Interim revisions are shown with new text (if any) enclosed in circles, *new text,. Text enclosed in squares, 'new
textB, has already been adopted in a Supplement. Where the symbols appear together with no enclosed text, such as * . or • u
it means that text has been deleted and no new text was proposed to replace it. In all revisions, the closing symbol is
accompanied by a number that indicates the IRA or Supplement in which the revision first appeared. For example, #2
indicates that the revision was officially adopted in the second interim revision announcement, and m 2 indicates that the
revision was officially adopted in the Second Supplement.
Pharmacopeial Forum
224 SECOND INTERIM REVISION ANNOUNCEMENT Vol. 28(2) [Mar.-Apr. 2002]
SECOND INTERIM REVISION ANNOUNCEMENT 225

Amiloxate 227
Idarubicin Hydrochloride 227
Isoamyl Methoxycinnamate 227
Menthyl Anthranilate 227
Meradimate 227
Octisalate 227
Octocrylene 227
Octyl Salicylate 228
Sulisobenzone 228
Xylazine 228
NF 20 MONOGRAPHS 228
Acetyltributyl Citrate 228
Acetyltriethyl Citrate 229
Carbomer Copolymer 229
Carbomer Interpolymer 231
Tributyl Citrate 231
Triethyl Citrate 232
{671) Containers—Permeation 232
Pharmacopeia! Forum
Vol. 28(2) [Mar-Apr. 2002] SECOND INTERIM REVISION ANNOUNCEMENT 225
SECOND INTERIM REVISION

ANNOUNCEMENT
to USP25mdtoNF20


Official April 1, 2002. Released March 2, 2002.
All inquiries and comments regarding USP 25 text and NF 20 text should be addressed to the Executive
Secretariat. USP-NF. 12601 Twinbrook Parkway. Rockville. MD 20852.
© 2002 The United States Pharmacopeial Convention, Inc. Alt Rights Reserved.
Pharmacopeial Forum
New USP Reference Standards USP Ginseng Extract RS

USP Gonadorelin Hydrochloride RS
The following USP Reference Standards, which were in- USP Homosalate RS
USP Hypericin RS
dicated in past Supplements to USP—NF as being not yet USP Hyperoside RS
available, have since become available. Thus, the official USP Ioversol RS
date of each USP 25 or NF 20 standard, test, or assay requir- USP Ioxaglic Acid RS
USP Ioxilan RS
ing the use of the following Reference Standards is indi- USP Isometheptene Mucate RS
cated individually in this list. USP Lactase RS
USP Lactitol RS
USP 5-Allyl-L-Cysteine RS (June 1, 2002) USP Menotropins RS
USP Chromium Picolinate RS (June 1, 2002) USP Meradimate RS
USP Iopromide RS (June 1, 2002) USP Ondansetron Hydrochloride RS
USP Iopromide Related Compound B RS (June 1, 2002) USP Ondansetron Related Compound A RS
USP Ioxilan Related Compound A RS (June 1, 2002) USP Ondansetron Related Compound B RS
USP Ondansetron Related Compound C RS
The official dates of any USP 25 or NF 20 standards, tests, USP Ondansetron Related Compound D RS
or assays requiring the use of the following new USP Ref- USP Oxfendazole RS
USP Poloxalene RS
erence Standards are postponed until further notice pending USP Potassium Perchlorate RS
availability of the respective Reference Standards. USP Pyrethrum Extract RS
USP Quercetin RS
USP Alfentanil Hydrochloride RS USP Rimexolone RS
USP Alteplase RS USP Sargramostim RS
USP Amiloxate RS USP Selenomethionine RS
USP Amitraz RS USP Sulfaquinoxaline RS
USP Positive Bioreaction RS USP Sulfaquinoxaline Related Compound A RS
USP Cefpiramide RS USP Sulisobenzone RS
USP Cinoxate RS USP A8-tetrahydrocannabinol RS
USP Decoquinate RS USP A9-tetrahydrocannabinol RS
USP Desflurane RS USP Thiacetarsamide RS
USP Desflurane Related Compound A RS USP Tiletamine Hydrochloride RS
USP Dextran 40 RS USP Tilmicosin RS
USP Dextran 40 System Suitability RS USP Tinidazole RS
USP Dextran 70 RS USP Tinidazole Related Compound A RS
USP Dextran 70 System Suitability RS USP Tinidazole Related Compound B RS
USP Dextran Calibration RS USP Trenbolone RS
USP Dextran Vo Marker RS USP Trenbolone Acetate RS
USP Dichloralphenazone rs USP Triclosan RS
USP Diethylene Glycol Monoethyl Ether RS USP Triclosan Related Compound A RS
USP Diethylstilbestrol Diphosphate RS USP Triclosan Related Compound B RS
USP Dirithromycin RS USP Tylosin RS
USP Enalapril Related Compound B RS USP Valerenic Acid RS
USP Enzacamene RS USP Powdered Valerian RS
USP Ethchlorvynol RS USP Vasopressin RS
USP Fenbendazole RS USP Zalcitabine Related Compound A RS
USP Fludeoxyglucose RS
USP Gadopentetate Monomeglumine
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] SECOND INTERIM REVISION ANNOUNCEMENT 227
USP 25 MONOGRAPHS Menthyl Anthranilate

(Current title—not to change until September 1, 2002)
Monograph title change—to become official September
1, 2002
(see Note in Introduction):
See Meradimate
Amiloxate
{Monograph under this new title—to become official Change to read:
September 1, 2002) Identification—
(Current monograph title is Isoamyl Methoxycinnamate) A: Infrared Absorption (197F).
B: Ultraviolet Absorption (197U)—
Change to read: Solution: 5.0 ug per mL.
Medium: alcohol. Absorptivities, calculated on the as-is basis,
Identification— do not differ by more than 3.0%.#2
A: Infrared Absorption (197F).
Solution: 5.0 ug per mL.
do not differ by more than 3.0%. -2
Meradimate
(Monograph under this new title—to become official
September 1, 2002)
(Current monograph title is Menthyl Anthranilate)
Idarubicin Hydrochloride
Change to read:
Add the following: Identification—
"Labeling—The amorphous form is so labeled.#2 A: Infrared Absorption (197F).
Change to read: Solution: 5.0 ug per mL.
Crystallinity (695): meets the requirements*, except where it is Medium: alcohol. Absorptivities, calculated on the as-is basis,
labeled as amorphous, most of the particles do not exhibit do not differ by more than 3.0%.#2
birefringence and extinction positions.#2
Octisalate
Isoamyl Methoxycinnamate (Monograph under this new title—to become official
(Current title—not to change until September 1, 2002 September 1,2002)
Monograph title change—to become official September (Current monograph title is Octyl Salicylate)
1, 2002
(see Note in Introduction): Change to read:
See Amiloxate
Identification—
Change to read: B: Ultraviolet Absorption (197U)—
Identification— Solution: 5.0 ug per mL.
A: Infrared Absorption (197F). Medium: alcohol. Absorptivities, calculated on the as-is basis,
B: Ultraviolet Absorption {197U)— do not differ by more than 3.0%.#2
Solution: 5.0 ug per mL.
do not differ by more than 3.0%.#2
Octocrylene
Change to read:
Identification, Ultraviolet Absorption (197U)—
Solution: 0.1 mg per mL.
Medium: methanol. Absorptivities, calculated on the as-is basis,
do not differ by more than *3.0%.. 2
Pharmacopeial Forum
Procedure—Separately inject equal volumes (about 2 uL) of the

Standard solution and the Test solution into the chromatograph,
Octyl Salicylate record the chromatograms, and measure the areas for the major
(Current title-^not to change until September 1, 2002) peaks. Calculate the percentages of acetone and isopropyl
Monograph title change—to become official September alcohol in the portion of Xylazine taken by the formula:
1, 2002 \OW){rulrs),m2
(see Note in Introduction):
See Octisalate in which C is the concentration, in jig per mL, of acetone or iso-
propyl alcohol in each mL of the Standard solution; W is the
weight, in mg, of Xylazine taken to prepare the Test solution;
Change to read: and rv and rs are the responses for the relevant analyte peak ob-
Identification— tained from the Test solution and the Standard solution, respec-
A: Infrared Absorption (197F). tively: not more than 0.02% of acetone and not more than 0.2%
B: Ultraviolet Absorption (197U)— of isopropyl alcohol are found.
Solution: 5.0 \xg per mL.
do not differ by more than 3.0%. -2
NF 20 MONOGRAPHS
Sulisobenzone
Change to read:
Identification, Ultraviolet Absorption (197U)— Acetyltributyl Citrate
Solution: 10 ug per mL.
Medium: water. Absorptivities do not differ by more than
*3.0%. -2 Change to read:
Assay—
System suitability solution—Prepare a solution in toluene
containing about 30 mg each of USP Acetyltributyl Citrate RS
and USP Tributyl Citrate RS per mL.
Assay preparation—Transfer about 300 mg of Acetyltributyl
Xylazine Citrate, accurately weighed, to a 10-mL volumetric flask,
dissolve in and dilute with toluene to volume, and mix.
Change to read: gas chromatograph is equipped with a flame-ionization detector
Limit of acetone and isopropyl alcohol— and a 0.32-mm x 30-m column bonded with a 0.5-um layer of
Diluent—Dilute 15 mL of glacial acetic acid with water to 1000 phase G42. The carrier gas is helium, flowing at a rate of about
mL, and mix. 2.3 mL per minute. The chromatograph is programmed as
follows. Initially the temperature of the column is equilibrated at
Standard solution—Transfer 10.0 uX each of acetone and about 80° for 0.5 minute, then the temperature is increased at a
isopropyl alcohol to a 500-mL volumetric flask, dilute with rate of 20° per minute to about 220°, and maintained at about
Diluent to volume, and mix. This solution contains 15.8 fig of 220° for 10 minutes. The injection port temperature is
acetone per mL and 15.7 jig of isopropyl alcohol per mL. maintained at about 85° for 0.5 minute, increased to about 225°
Test solution—Transfer about 100 mg of Xylazine, accurately at a rate of 20° per minute, and maintained at about 225° for 10
weighed, to a 10-mL volumetric flask, dissolve in and dilute minutes. The detector temperature is maintained at about 275°.
with Diluent to volume, and mix. Chromatograph the System suitability solution, and record the
Chromatographic system (see Chromatography (621))—The peak responses as directed for Procedure: the relative retention
gas chromatograph is equipped with a flame-ionization detector times are about 0.9 for tributyl citrate and 1.0 for acetyltributyl
and a 2-mm x 1.8-m column packed with 0.1% phase G25 on citrate; the resolution, R, between tributyl citrate and
80- to 100-mesh support S7. Helium is used as the carrier gas acetyltributyl citrate is not less than 1.5; and the relative standard
with a flow rate of about 30 mL per minute. The injection port deviation for replicate injections is not more than *2.0% - 2
and detector temperatures are maintained at about 240° and determined from both the tributyl citrate and acetyltributyl citrate
275°, respectively. The system is programmed according to the peaks*, based on area percent calculation...
following steps. The column temperature is maintained at 30° for
6 minutes after each injection, then increased to 100° at a rate of Procedure—Inject about *1.0 uL., of the Assay preparation
10° per minute, then increased further to 220° at a rate of 15° per into the chromatograph, record the chromatogram, and measure
minute, and maintained for 10 minutes. Chromatograph the all of the peak areas, excluding the solvent peak. Calculate the
Standard solution, and record the peak responses as directed for percentage of C2oH3408 in the portion of Acetyltributyl Citrate
Procedure: the relative retention times are about 0.75 for acetone taken by the formula:
and 1.0 for isopropyl alcohol; the resolution, R, between acetone 100,4/5,
and isopropyl alcohol is not less than 2.0; the tailing factor
determined from each analyte peak is not more than 2.0; and the in which A is the acetyltributyl citrate peak response; and B is the
relative standard deviation for replicate injections is not more than sum of the responses of all the peaks.
2.0%.
Pharmacopeial Forum
Acetyltriethyl Citrate NOTE—Different types of Carbomer Copolymers

may not have identical properties with respect to their
Change to read:
use for specific pharmaceutical purposes, e.g., as con-
Assay—
trolled-release agents, bioadhesives, topical gels,
System suitability solution—Prepare a solution in toluene thickening agents, and emulsifying agents. Therefore,
containing about 30 mg each of USP Acetyltriethyl Citrate RS different types of Carbomer Copolymers should not be
and USP Triethyl Citrate RS per mL. interchanged unless performance equivalency has
Assay preparation—Transfer about 300 mg of Acetyltriethyl been ascertained.
Citrate, accurately weighed, to a 10-mL volumetric flask,
dissolve in and dilute with toluene to volume, and mix. Packaging and storage—Preserve in tight containers, at a
Chromatographic system (see Chromatography (621))—The temperature not exceeding 45°.
gas chromatograph is equipped with a flame-ionization detector Labeling—Label it to indicate the nominal viscosity range and the
and a 0.32-mm x 30-m column bonded with a 0.5-um layer of measured viscosity, the solvent or solvents used in the
phase G42. The carrier gas is helium, flowing at a rate of about polymerization process, and the nominal and residual solvent
2.3 mL per minute. The chromatograph is programmed as levels for each solvent.
about 80° for 0.5 minute, then the temperature is increased at a Identification—
rate of 20° per minute to about 220°, and maintained at about A: Infrared Absorption (197K)—The IR spectrum exhibits
220° for 10 minutes. The injection port temperature is main bands at wavenumbers (cm"1) 2960, 1720, 1455, 1415,
maintained at about 85° for 0.5 minute, increased to about 225° 1250, 1175, and 800, with the strongest band at 1720.
at a rate of 20° per minute, and maintained at about 225° for 10 B: Add about 5 g of Carbomer Copolymer to 500 mL of water,
minutes. The detector temperature is maintained at about 275°. and stir: a dispersion is formed, with a foam layer that persists after
Chromatograph the System suitability solution, and record the allowing to stand at room temperature for 1 hour.
peak responses as directed for Procedure: the relative retention Viscosity (911)—Carefully add 5.00 g of Carbomer Copolymer,
times are about 0.9 for triethyl citrate and 1.0 for acetyltriethyl previously dried in vacuum at 80° for 1 hour, to 500 mL of
citrate; the resolution, R, between triethyl citrate and water in a 1000-mL beaker, while stirring continuously at 1000
acetyltriethyl citrate is not less than 1.5; and the relative standard ± 50 rpm, with the stirrer shaft set to one side of the beaker at
deviation for replicate injections is not more than *2.0% #2 an angle of 60° and the propeller positioned near the bottom of
determined from both the triethyl citrate and acetyltriethyl citrate the beaker. The stirrer used is a three-blade, 2-inch diameter
peaks*, based on area percent calculation... marine impeller. Add the Carbomer Copolymer at a uniform rate
Procedure—Inject about *1.0 uL.? of the Assay preparation over a period of 45 to 90 seconds, being sure that loose aggregates
into the chromatograph, record the cnromatogram, and measure of powder are broken up, and continue stirring at 1000 + 50 rpm
all of the peak areas, excluding the solvent peak. Calculate the for 15 minutes. Remove the stirrer, and place the beaker containing
percentage of CnHÔg in the portion of Acetyltriethyl Citrate the dispersion in a 25 + 2° water bath for 30 minutes. Insert a
taken by the formula: paddle stirrer to a depth necessary to ensure that air is not drawn
into the dispersion, and while stirring at 300 + 25 rpm, titrate
100A/B, potentiometrically (see Titrimetry (541)) with a calomel-glass
electrode system to a pH between 7.3 and 7.8 by adding sodium
in which A is the acetyltriethyl citrate peak response; and B is the hydroxide solution (18 in 100) below the surface. The total
sum of the responses of all the peaks. volume of sodium hydroxide solution used is about 11 mL.
Allow 2 to 3 minutes before the final pH determination.
[NOTE—If the final pH exceeds 7.8, discard the mucilage, and
prepare another using less sodium hydroxide for neutralization.]
Return the beaker containing the neutralized mucilage to the 25
Add the following: + 2° water bath for 1 hour. Using a rotational viscometer
equipped with a suitable spindle at a spindle immersion depth as
defined in the accompanying table (where A is the cylinder
•Carbomer Copolymer diameter, in cm; B is the cylinder height, in cm; C is the shaft
diameter, in cm; D is the distance, in cm, from the top of the
cylinder to the lower tip of the shaft; and E is the spindle
» Carbomer Copolymer is a high molecular weight co- immersion depth, in cm), perform the viscosity determination
without delay to avoid slight viscosity changes that occur 75
polymer of acrylic acid and a long chain alkyl metha- minutes after neutralization.
crylate cross-linked with polyalkenyl ethers of
polyalcohols.
Pharmacopeia! Forum
Vise. Ranges, in cPa Spindle No. A B C D E Multiplier

100-400 1 5.626 2.248 0.32 2.697 6.112 5
400-1,600 2 4.693 0.165 0.32 2.697 4.921 20
1,000-4,000 3 3.469 0.165 0.32 2.697 4.921 50
2,000-8,000 4 2.730 0.165 0.32 2.697 4.921 100
4,000-16,000 5 2.114 0.165 0.32 2.697 4.921 200
10,000-40,000 6 1.462 0.157 0.32 3.017 4.921 500
40,000-160,000 7 — — 0.32 — 5.037 2,000
in which Ws is the weight, in mg, of ethyl acetate or cyclohexane in

With the spindle rotating at 20 rpm, observe and record the scale the Standard solution; WT is the weight, in mg, of Carbomer Co-
reading. Calculate the viscosity, in millipascal seconds, by multi- polymer taken to prepare the Test solution; and Rv and Rs are the
plying the scale reading by the constant for the spindle used at 20 peak area ratios of the relevant analyte peak to methyl ethyl ketone
rpm. The viscosity value so obtained is within the limits specified obtained from the Test solution and the Standard solution, respec-
in the accompanying table. tively: not more than 0.5% of ethyl acetate and not more than 0.3%
Carbomer Copolymer 1% Viscosity Specification of cyclohexane is found.
Limit of acrylic acid—
4,500-13,500 pH 3.0 Phosphate buffer—Dissolve 6.80 g of monobasic
10,000-29,000 potassium phosphate in about 300 mL of water, dilute with water
25,000-45.000 to 500 mL, and mix. Dilute 100 mL of this solution with water to 1
liter, adjust with phosphoric acid to a pH of 3.0 ± 0 . 1 , and mix.
Loss on drying (731)—Dry it in vacuum at 80° for 1 hour: it loses Mobile phase—Use filtered and degassed pH 3.0 Phosphate
not more than 2.0% of its weight. buffer.
Heavy metals, Method II (231): 0.002%. Standard solution—Dissolve an accurately weighed quantity of
acrylic acid in water, and dilute quantitatively, and stepwise if
Limit of ethyl acetate and cyclohexane—NOTE—This test is necessary, to obtain a solution having a known concentration of
required only for those Carbomer Copolymers where the labeling about 0.1 mg per mL. Dilute this solution quantitatively, and
indicates that ethyl acetate or a mixture of ethyl acetate and stepwise if necessary, with water to obtain a solution having a
cyclohexane was used in the polymerization process.] known concentration of about 25 ug per mL.
Standard stock solution—Transfer 5.0 mL of methanol to a 10- Test solution—Transfer about 100 mg of Carbomer Copolymer,
mL serum vial, insert a rubber septum, and seal with a metal cap. accurately weighed, to a tared serum vial. Add water to obtain
Add 25.0 uL of ethyl acetate and 20.0 uL of cyclohexane through about 10.0 g of solution. Cap the vial, and shake by mechanical
the septum into the vial, and mix. means for 2 hours. Add 2 drops of sodium hydroxide solution (5
Standard solution—Transfer 20.0 mL of methanol to a 30-mL in 10), and shake by hand for 15 seconds. Add 1.0 mL of calcium
serum vial, insert a rubber septum, and seal with a metal cap. chloride solution (1 in 10), and shake until the gel collapses.
Through the rubber septum, add 10 uL of methyl ethyl ketone Centrifuge for 15 minutes, and use the clear supernatant.
(internal standard) and 50.0 uL of the Standard stock solution, Chromatographic system (see Chromatography (621))—The
and mix to obtain a solution containing 0.225 mg of ethyl
acetate and 0.156 mg of cyclohexane. liquid chromatograph is equipped with a 200-nm detector and an
8-mm x 10-cm column that contains packing LI. Theflowrate is
Test solution—Transfer about 50 mg of Carbomer Copolymer, about 1 mL per minute. Chromatograph the Standard solution, and
accurately weighed, to a 30-mL serum vial, add 20.0 mL of
methanol, insert a rubber septum, and seal with a metal cap. record the peak responses as directed for Procedure: the relative
Through the rubber septum, add 10 uL of methyl ethyl ketone, standard deviation for replicate injections is not more than 5%.
and mix. Procedure—Separately inject equal volumes (about 10 uL) of
the Standard solution and the Test solution into the
gas chromatograph is equipped with a flame-ionization detector
and a 2-mm x 3-m column packed with 1% liquid phase G25 responses for the acrylic acid peaks. Calculate the percentage of
on 60- to 80-mesh support SI2. The carrier gas is helium, free acrylic acid in the portion of Carbomer Copolymer taken by
flowing at a linear velocity of about 33 cm per minute. The the formula:
column temperature is maintained at 115° for 4 minutes after {C/W){rv/rs),
injection, then the temperature is increased at a rate of 6° per
minute to 175°, and maintained at 175° for 5 minutes. The in which C is the concentration, in ug per mL, of acrylic acid in the
injection port and detector temperatures are maintained at 250°. Standard solution; W'\s the weight, in mg, of Carbomer Copolymer
Chromatograph the Standard solution, and record the peak taken to prepare the Test solution; and ry and rs are the acrylic acid
responses as directed for Procedure: the relative retention times peak responses obtained from the Test solution and the Standard
are about 0.7 for methyl ethyl ketone, 0.9 for ethyl acetate, and solution, respectively: not more than 0.25% is found.
1.0 for cyclohexane; the resolution, R, between ethyl acetate and Content of carboxylic acid—Slowly add about 400 mg of
cyclohexane is not less than 1.0; and the relative standard Carbomer Copolymer, previously dried in vacuum at 80° for 1
deviation for replicate injections is not more that 2.5%. hour and accurately weighed, to 400 mL of water in a 1000-mL
Procedure—Separately inject equal volumes (about 2 uL) of the beaker, while stirring continually at about 1000 rpm, with the
Standard solution and the Test solution into the chromatograph, stirrer shaft set at an angle of about 60° and to one side of the
record the chromatograms, and measure the areas for the major beaker, with the propeller positioned near the bottom of the
peaks. Calculate the percentages of ethyl acetate and beaker. Continue stirring for 15 minutes. Reduce the stirring
cyclohexane in the portion of Carbomer Copolymer taken by the speed, and using a calomel-glass electrode system, titrate
formula: potentiometrically with 0.25 N sodium hydroxide VS to a pH of
10.0 (see Titrimetry (541)). After each addition of 0.25 N
l00(Ws/WT)(Ra/Rs), sodium hydroxide VS, allow 1 minute for mixing before
recording the pH. Calculate the percentage of carboxylic acid in
the portion of Carbomer Copolymer taken by the formula:
Pharmacopeial Forum
100(45.02 VN/W), Limit of ethyl acetate and cyclohexane—[NOTE—This test is

required only for those Carbomer Interpolymers where the
in which 45.02 is the molecular weight of the carboxylic acid labeling indicates that ethyl acetate or a mixture of ethyl acetate
(-COOH) group; V is the volume, in mL, of sodium hydroxide and cyclohexane was used in the polymerization process.]
consumed; N is the normality of the sodium hydroxide solution; Standard stock solution—Proceed as directed in the test for Limit
and W is the weight, in mg, of Carbomer Copolymer taken. The of ethyl acetate and cyclohexane under Carbomer Copolymer,
carboxylic acid content is not less than 52.0% and not more than except to use 20 uL of ethyl acetate and 10 uL of cyclohexane.
62.0%.#2 Standard solution—Proceed as directed in the test for Limit of
ethyl acetate and cyclohexane under Carbomer Copolymer to
obtain a solution containing 0.18 mg of ethyl acetate and 0.078
mg of cyclohexane.
Test solution and Chromatographic system—Proceed as directed
in the test Limit of ethyl acetate and cyclohexane under Carbomer
Add the following: Copolymer.
Procedure—Proceed as directed in the test for Limit of ethyl
•Carbomer Interpolymer acetate and cyclohexane under Carbomer Copolymer, except to
calculate the percentages of ethyl acetate and cyclohexane in the
portion of Carbomer Interpolymer taken by the formula:
» Carbomer Interpolymer is a carbomer homopolymer
or copolymer that contains a block copolymer of poly- in which WT\s the weight, in mg, of Carbomer Interpolymer taken
ethylene glycol and a long chain alkyl acid ester. to prepare the Test solution; and the other terms are as defined
NOTE—Different types of Carbomer Interpolymers therein: not more than 0.35% of ethyl acetate and not more than
may not have identical properties with respect to their 0.15% of cyclohexane is found.
use for specific pharmaceutical purposes, e.g., as tablet Limit of acrylic acid—
controlled-release agents, bioadhesives, topical gels, pH 3.0 Phosphate buffer, Mobile phase, Standard solution, Test
solution, and Chromatographic system—Proceed as directed in the
thickening agents, and emulsifying agents. Therefore, test for Limit of acrylic acid under Carbomer Copolymer.
different types of Carbomer Interpolymers should not Procedure—Proceed as directed in the test for Limit of acrylic
be interchanged unless performance equivalency has acid under Carbomer Copolymer, except to calculate the
been ascertained. percentage of free acrylic acid in the portion of Carbomer
Interpolymer taken by the formula:
Packaging and storage—Preserve in tight containers, at a (C/W)(ru/rs),
temperature not exceeding 45°.
Labeling—Label it to indicate the nominal viscosity range and the in which Wis the weight, in mg, of Carbomer Interpolymer taken
measured viscosity, the solvent or solvents used in the to prepare the Test solution; and the other terms are as defined
polymerization process, and the nominal and measured residual therein: not more than 0.25% is found.
solvent levels for each solvent. Content of carboxylic acid—Proceed as directed in the test for
Identification— Content of carboxylic acid under Carbomer Copolymer, except
A: Infrared Absorption (197K)—The IR absorption spectrum to calculate the percentage of carboxylic acid in the portion of
exhibits bands at wavenumbers (cm"1) 2960, 1720, 1455, 1415, Carbomer Interpolymer taken by the formula:
1250, 1175, and 800, with the strongest band at 1720.
B: Without mixing, add 2.5 g of Carbomer Interpolymer to 100(45.02 VN/W),
500 mL of water in an 800-mL beaker, arid allow to stand. The in which W'\s the weight, in mg, of the portion of Carbomer Inter-
powders wet out in not more than 60 minutes. polymer taken; and the other terms are as defined therein. The car-
C: Add about 5 g of Carbomer Interpolymer to 500 mL of boxylic acid content is not less than 52.0% and not more than
water, stir, and adjust with 1 N sodium hydroxide to a pH of 62.0%.. 2
about 7.5. It forms a viscous gel.
Viscosity (911)—
Carbomer Interpolymer A—Proceed as directed for Viscosity
under Carbomer Copolymer, except to perform the test on a
0.5% aqueous dispersion prepared by using 2.50 g instead of
5.00 g of copolymer.
Carbomer Interpolymer B and Carbomer Interpolymer C— Tributyl Citrate
Proceed as directed for Viscosity under Carbomer Copolymer,
except to adjust the pH of the dispersion to within the range of Change to read:
5.8 to 6.3 instead of 7.3 to 7.8. The viscosity values, determined
by the conditions specified herein, are within the limits specified in Assay—
the accompanying table. System suitability solution—Prepare a solution in toluene
containing about 30 mg each of USP Tributyl Citrate RS and
Carbomer Interpolymer Viscosity Specifications, in cP USP Acetyltributyl Citrate RS per mL.
Assay preparation—Transfer about 300 mg of Tributyl Citrate,
45,000-65,000 accurately weighed, to a 10-mL volumetric flask, dissolve in and
47,000-77,000 dilute with toluene to volume, and mix.
8.500-16.500 Chromatographic system (see Chromatography (621))—The
gas chromatograph is equipped with a flame-ionization detector
Loss on drying (731)—Dry it in vacuum at 80° for 1 hour: it loses and a 0.32-mm x 30-m column bonded with a 0.5-um layer of
not more than 2.0% of its weight. phase G42. The carrier gas is helium, flowing at a rate of about
Heavy metals, Method II (231): 0.002%. 2.3 mL per minute. The chromatograph is programmed as
Pharmacopeial Forum
about 80° for 0.5 minute, then the temperature is increased at a rate
of 20° per minute to about 220°, and maintained at about 220° for GENERAL CHAPTERS
10 minutes. The injection port temperature is maintained at about
85° for 0.5 minute, increased to about 225° at a rate of 20° per
minute, and maintained at about 225° for 10 minutes. The General Tests and Assays
detector temperature is maintained at about 275°. Chromatograph
the System suitability solution, and record the peak responses as
directed for Procedure: the relative retention times are about 0.9
for tributyl citrate and 1.0 for acetyltributyl citrate; the
resolution, R, between tributyl citrate and acetyltributyl citrate is
General Requirements for Tests and
not less than 1.5; and the relative standard deviation for replicate Assays
injections is not more than *2.0%#2 determined from both the
tributyl citrate and acetyltributyl citrate peaks*, based on area
percent calculation.-2
Procedure—Inject about *1.0 uX», of the Assay preparation (11) USP REFERENCE
into the chromatograph, record the chromatogram, and measure
all of the peak areas, excluding the solvent peak. Calculate the
STANDARDS
percentage of C18H32O7 in the portion of Tributyl Citrate taken by
the formula:
100A/B, Change to read:
in which A is the tributyl citrate peak response; and B is the sum of *USP Penicillamine RS—*Do not dry. Keep container tightly
the responses of all the peaks. closed, protected from light and store in a cold place. -2
Physical Tests and Determinations

Triethyl Citrate
(671) CONTAINERS-
Change to read: PERMEATION
Assay—
System suitability solution—Prepare a solution in toluene
containing about 30 mg each of USP Triethyl Citrate RS and The tests that follow are provided to determine the moisture per-
USP Acetyltriethyl Citrate RS per mL. meability of containers utilized for drugs being dispensed on pre-
Assay preparation—Transfer about 300 mg of Triethyl Citrate, scription * - 2 The section Multiple-Unit Containers for Capsules
accurately weighed, to a 10-mL volumetric flask, dissolve in and and Tablets applies to multiple-unit containers (see Preservation,
dilute with toluene to volume, and mix. Packaging, Storage, and Labeling under General Notices and Re-
Chromatographic system (see Chromatography (621))—The quirements). The section Single-Unit Containers and Unit-Dose
gas chromatograph is equipped with a flame-ionization detector Containers for Capsules and Tablets applies to single-unit and
and a 0.32-mm x 30-m column bonded with a 0.5-um layer of unit-dose containers (see Single-Unit Containers and Unit-Dose
phase G42. The carrier gas is helium, flowing at a rate of about Containers for Nonsterile Solid and Liquid Dosage Forms under
2.3 mL per minute. The chromatograph is programmed as Containers (661)). As used herein, the term "container" refers to
follows. Initially the temperature of the column is equilibrated at the entire system comprising, usually, the container itself, the liner
about 80° for 0.5 minute, then the temperature is increased at a (if used), the closure in the case of multiple-unit containers, and the
rate of 20° per minute to about 220°, and maintained at about lidding and blister in the case of single-unit and unit-dose contain-
220° for 10 minutes. The injection port temperature is ers.
maintained at about 85° for 0.5 minute, increased to about 225° Where the manufacturer's unopened multiple-unit, single-unit,
at a rate of 20° per minute, and maintained at about 225° for 10 or unit-dose packages are used for dispensing the drug, such con-
minutes. The detector temperature is maintained at about 275°. tainers are exempt from the requirements of this test.
Chromatograph the System suitability solution, and record the
peak responses as directed for Procedure: the relative retention Change to read:
times are about 0.9 for triethyl citrate and 1.0 for acetyltriethyl
citrate; the resolution, R, between triethyl citrate and
acetyltriethyl citrate is not less than 1.5; and the relative standard
deviation for replicate injections is not more than *2.0% - 2 MULTIPLE-UNIT CONTAINERS FOR
determined from both the triethyl citrate and acetyltriethyl citrate CAPSULES AND TABLETS
peaks*, based on area percent calculation...
Procedure—Inject a volume (about *1.0 uL. 2 ) of the Assay
preparation into the chromatograph, record the chromatogram, Desiccant—Place a quantity of 4- to 8-mesh, anhydrous calcium
and measure all of the peak areas, excluding the solvent peak. chloride1 in a shallow container, taking care to exclude any fine
Calculate the percentage of CI2H20O7 in the portion of Triethyl powder, then dry at 110° for 1 hour, and cool in a desiccator.
Citrate taken by the formula:
in which A is the triethyl citrate peak response; and B is the sum of 1

the responses of all the peaks. Suitable 4- to 8-mesh, anhydrous calcium chloride is available commer-
cially as Item JT1313-1 from VWR Scientific. Consult the VWR Scientific
catalog for ordering information or call 1-800-234-9300.
Pharmacopeial Forum
Procedure—Select 12 containers of a uniform size and type, clean

the sealing surfaces with a lint-free cloth, and close and open each Torque Applicable to Screw-Type Container
container 30 times. Apply the closure firmly and uniformly each
time the container is closed. Close screw-capped containers with Suggested Tightness Range
a torque that is within the range of tightness specified in the accom- with Manually Applied
panying table. Add Desiccant to 10 of the containers, designated Closure Diameter1 (mm) Torque;2 (inch-pounds)
test containers, filling each to within 13 mm of the closure if the
container volume is 20 mL or more, or filling each to two-thirds of 8 5
capacity if the container volume is less than 20 mL. If the interior 10 6
of the container is more than 63 mm in depth, an inert filler or 13 8
spacer may be placed in the bottom to minimize the total weight 15 5-9
of the container and Desiccant; the layer of Desiccant in such a 18 7-10
container shall be not less than 5 cm in depth. Close each immedi- 20 8-12
ately after adding Desiccant, applying the torque designated in the 22 9-14
accompanying table when closing screw-capped containers. To 24 10-18
each of"the remaining 2 containers, designated controls, add a suf- 28 12-21
ficient number of glass beads to attain a weight approximately 30 13-23
equal to that of each of the test containers, and close, applying 33 15-25
the torque designated in the accompanying table when closing 38 17-26
screw-capped containers. Record the weight of the individual con- 43 17-27
tainers so prepared to the nearest 0.1 mg if the container volume is 48 19-30
less than 20 mL; to the nearest mg if the container volume is 20 mL 53 21-36
or more but less than 200 mL; or to the nearest centigram (10 mg) if 58 23-40
the container volume is 200 mL or more; and store at 75 ± 3% 63 25^3
relative humidity and a temperature of 23 + 2°. [NOTE—A satu- 66 26-45
rated system of 35 g of sodium chloride with each 100 mL of water 70 28-50
placed in the bottom of a desiccator maintains the specified humid- 83 32-65
ity. Other methods may be employed to maintain these conditions.] 86 40-65
After 336 + 1 hours (14 days), record the weight of the individual 89 40-70
containers in the same manner. Completely fill 5 empty containers 100 45-70
of the same size and type as the containers under test with water or 110 45-70
a noncompressible, free-flowing solid such as well-tamped fine 120 55-95
glass beads, to the level indicated by the closure surface when in 132 60-95
place. Transfer the contents of each to a graduated cylinder, and
determine the average container volume, in mL. Calculate the rate
of moisture permeability, in mg per day per liter, by the formula: The torque designated for the next larger closure diameter is to be applied in testing
containers having a closure diameter intermediate to the diameters listed.
2
A suitable apparatus is available from Owens-Illinois, Toledo, OH 43666. (Model
(lO00/14V)[(Tf-ld-(Cf-Q], 25 torque tester is used for testing between 0 and 25; Model 50 for testing between 0
in which Fis the volume, in mL, of the container, (Tj— T,) is the and 50; and Model 100 for testing between 0 and 100 inch-pounds of torque.) The
difference, in mg, between the final and initial weights of each test torque values refer to application, not removal, of the closure. For further detail re-
garding instructions, reference may be made to "Standard Method of Measuring Ap-
container, and (Cj~ C,) is the difference, in mg, between the aver- plication and Removal Torque of Threaded Closures," ASTM Designation D 3198-
age final and average initial weights of the 2 controls. For contain- 73, published by the American Society for Testing and Materials, 1916 Race St., Phi-
ers used for drugs being dispensed on prescription, the containers ladelphia, PA 19103.
so tested are tight containers if not more than one of the 10 test
containers exceeds 100 mg per day per liter in moisture permeabil-
ity, and none exceeds 200 mg per day per liter. * #2
For containers used for drugs being dispensed on prescription,
the containers are well-closed containers if not more than one of
the 10 test containers exceeds 2000 mg per day per liter in moisture
permeability, and none exceeds 3000 mg per day per liter.
IN-PROCESS REVISION
to official status.
BRIEFING
*new text.
A
new
•new textB
if slated for a Supplement to USP-NF. The same symbols not set off by an extra paragraph break and enclosing text with no
increase in type size indicate recent revisions that are already official. Where the symbols appear together with no enclosed
text, such as or # . or • m or AA, it means that text has been deleted and no new text was proposed to replace it. In all revisions,
the closing symbol is accompanied by an identifier that indicates the particular IRA or Supplement or indicates the USP or NF,
as the publication where the revision will appear if approved. For example, #2 indicates that the revision is proposed for the
Second Interim Revision Announcement, and m2 indicates that the proposed revision is slated for the Second Supplement, and
AUSP26 a n d ANF2I indicate that the revisions are proposed for USP 26 and NF 21, respectively.
Experts. Changes based on these Errata will appear in the next published Supplement and become official with that
Supplement.
Pharmacopeial Forum
236 IN-PROCESS REVISION Vol. 28(2) [Mar.-Apr. 2002]

Preservation, Packaging, Storage, and Labeling—USP 242
Alfentanil Hydrochloride (USP 26) 244
Alprostadil (USP 26) 245
Amantadine Hydrochloride Oral Solution [new] (USP 26) 250
Arnantadine Hydrochloride Syrup (USP 26) 251
Aminocaproic Acid Oral Solution [new] (USP 26) 251
Aminocaproic Acid Syrup (USP 26) 252
Aspartic Acid (USP 26) 252
Betamethasone Oral Solution [new] (USP 26) 253
Betamethasone Syrup (USP 26) 254
Bromodiphenhydramine Hydrochloride Elixir (USP 26) 254
Bromodiphenhydramine Hydrochloride Oral Solution [new] (USP 26) 255
Brompheniramine Maleate Elixir (USP 26) , 255
Brompheniramine Maleate Oral Solution [new] (USP 26) 256
Brompheniramine Maleate and Pseudoephedrine Sulfate Oral Solution [new] (USP 26) 256
Brompheniramine Maleate and Pseudoephedrine Sulfate Syrup (USP 26) 258
Butabarbital Sodium Elixir (USP 26) 259
Butabarbital Sodium Oral Solution [new] (USP 26) 259
Calcium Polycarbophil (USP 26) 260
Cefazolin Ophthalmic Solution (USP 26) 261
Chloral Hydrate Oral Solution [new] (USP 26) 261
Choral Hydrate Syrup (USP 26) 262
Chlorpheniramine Maleate Oral Solution [new] (USP 26) 262
Chlorpheniramine Maleate Syrup (USP 26) 263
Sodium Chromate Cr 51 Injection (USP 26) 264
Ciclopirox Olamine [erratum] (USP 26) 265
Clonidine Transdermal System [new] (USP 26) 265
Clorsulon (USP 26) 269
Cocaine and Tetracaine Hydrochlorides and Epinephrine Topical Solution (USP 26) 270
Cyproheptadine Hydrochloride Oral Solution [new] (USP 26) 271
Cyproheptadine Hydrochloride Syrup (USP 26) 272
Dexchlorpheniramine Maleate Oral Solution [new] (USP 26) 272
Dexchlorpheniramine Maleate Syrup (USP 26) 273
Dexchlorpheniramine Maleate Tablets (USP 26) 273
Dextroamphetamine Sulfate Elixir (USP 26) 274
Dextroamphetamine Sulfate Oral Solution [new] (USP 26) 274
Dextroamphetamine Sulfate Tablets (USP 26) 276
Dextromethorphan Hydrobromide Oral Solution [new] (USP 26) 276
Dextromethorphan Hydrobromide Syrup (USP 26) 277
Dicyclomine Hydrochloride Oral Solution [new] (USP 26) 278
Dicyclomine Hydrochloride Syrup (USP 26) 279
Digoxin Elixir (USP 26) 279
Digoxin Injection (USP 26) 279
Digoxin Oral Solution [new] (USP 26) 279
Dimenhydrinate Oral Solution [new] (USP 26) 281
Dimenhydrinate Syrup (USP 26) 282
Diphenhydramine Hydrochloride Elixir (USP 26) 282
Diphenhydramine Hydrochloride Oral Solution [new] (USP 26) 283
Divalproex Sodium Delayed-Release Tablets (USP 26) 284
Doxazosin Mesylate [new] (USP 26) 286
Doxazosin Mesylate Tablets [new] (USP 26) 289
Doxylamine Succinate Oral Solution [new] (USP 26) 291
Doxylamine Succinate Syrup (USP 26) 292
Dyphylline Elixir (USP 26) 292
Pharmacopeia! Forum
Vol. 28(2) [Man-Apr. 2002] IN-PROCESS REVISION 237
Dyphylline Oral Solution [new] (USP 26) 292

Dyphylline and Guaifenesin Elixir (USP 26) 293
Dyphylline and Guaifenesin Oral Solution [new] (USP 26) 294
Enalapril Maleate Tablets (USP 26) 295
Ephedrine Sulfate Oral Solution [new] (USP 26) 296
Ephedrine Sulfate Syrup (USP 26) 297
Erythromycin Ointment [erratum] (USP 26) 297
Ferrous Gluconate Elixir (USP 26) 297
Ferrous Gluconate Oral Solution [new] (USP 26) 297
Gabapentin Capsules [new] (USP 26) 298
Ganciclovir [new] (USP 26) 301
Guaifenesin Oral Solution [new] (USP 26) 302
Guaifenesin Syrup (USP 26) 303
Guaifenesin and Codeine Phosphate Oral Solution [new] (USP 26) 303
Guaifenesin and Codeine Phosphate Syrup (USP 26) 306
Hydralazine Hydrochloride Oral Solution (USP 26) 306
Hydroxyzine Hydrochoride Oral Solution [new] (USP 26) 307
Hydroxyzine Hydrochoride Syrup (USP 26) 308
Iohexol Injection [erratum] (USP 26) 308
Ipecac Oral Solution [new] (USP 26) 308
Ipecac Syrup (USP 26) 310
Isoniazid Oral Solution [new] (USP 26) 310
Isoniazid Syrup (USP 26) 311
Ketoconazole Oral Suspension (USP 26) 311
Levothyroxine Sodium Tablets (Proposal for 3rd IRA) 312
Lincomycin Hydrochloride Syrup (USP 26) 313
Lincomycin Oral Solution [new] (USP 26) 313
Lithium Citrate Syrup (USP 26) 314
Lithium Oral Solution [new] (USP 26) 314
Mangafodipir Trisodium [new] (USP 26) 315
Mangafodipir Trisodium Injection [new] (USP 26) 320
Mecamylamine Hydrochloride (USP 26) 321
Mecamylamine Hydrochloride Tablets (USP 26) 322
Meperidine Hydrochloride Oral Solution [new] (USP 26) 323
Meperidine Hydrochloride Syrup (USP 26) 323
Metaproterenol Sulfate Oral Solution [new] (USP 26) 324
Metaproterenol Sulfate Syrup (USP 26) 325
Methdilazine Hydrochloride Oral Solution [new] (USP 26) 325
Methdilazine Hydrochloride Syrup (USP 26) 326
Methenamine Elixir (USP 26) 326
Methenamine Oral Solution [new] (USP 26) 327
Methenamine Tablets (USP 26) 328
Morphine Sulfate [erratum] (USP 26) 328
Morphine Sulfate Suppositories (USP 26) 328
Naloxone Hydrochloride (USP 26) 329
Naltrexone Hydrochloride (USP 26) 329
Nandrolone Decanoate Injection (USP 26) 330
Norgestimate [new] (USP 26) 331
Oxybutynin Chloride Oral Solution [new] (USP 26) 334
Oxybutynin Chloride Syrup (USP 26) 336
Paclitaxel [new] (USP 26) 336
Paromomycin Oral Solution [new] (USP 26) 341
Paromomycin Sulfate Syrup (USP 26) 342
Pentobarbital Elixir (USP 26) 342
Pentobarbital Oral Solution [new] (USP 26) 342
Phenobarbital Elixir (USP 26) 343
Phenobarbital Oral Solution [new] (USP 26) 344
Potassium Gluconate Elixir (USP 26) 345
Pharmacopeial Forum
Potassium Gluconate Oral Solution [new] (USP 26) 345

Prazosin Hydrochloride Capsules (USP 26) 346
Prednisolone Oral Solution [new] (USP 26) 346
Prednisolone Syrup (USP 26) 347
Probenecid Tablets (USP 26) 347
Procainamide Hydrochloride Tablets (USP 26) 347
Progesterone Vaginal Suppositories (USP 26) 348
Promethazine Hydrochloride Oral Solution [new] (USP 26) 348
Promethazine Hydrochloride Syrup (USP 26) 349
Propoxyphene Hydrochloride (USP 26) 350
Propoxyphene Napsylate (USP 26) 352
Pseudoephedrine Hydrochloride Oral Solution [new] (USP 26) 354
Pseudoephedrine Hydrochloride Syrup (USP 26) 355
Pseudoephedrine Hydrochloride Tablets (USP 26) 356
Pyridostigmine Bromide Oral Solution [new] (USP 26) 356
Pyridostigmine Bromide Syrup (USP 26) 357
Ramipril [new] (USP 26) 357
Ranitidine Oral Solution (USP 26) 360
Reserpine Elixir (USP 26) 362
Reserpine Oral Solution [new] (USP 26) 362
Rifampin Oral Suspension (USP 26) 363
Secobarbital Elixir (USP 26) 364
Secobarbital Oral Solution [new] (USP 26) 364
Senna Oral Solution [new] (USP 26) 365
Senna Syrup (USP 26) 365
Simethicone (USP 26) 366
Sodium Hypochlorite Topical Solution (USP 26) 366
Sodium Sulfide Topical Gel (USP 26) 366
Stanozolol Tablets [erratum] (USP 26) 367
Sucralfate (USP 26) 367
Sucralfate Tablets (USP 26) 369
Terazosin Hydrochloride [new] (USP 26) 369
Terpin Hydrate Elixir (USP 26) 374
Terpin Hydrate Oral Solution [new] (USP 26) 375
Terpin Hydrate and Codeine Elixir (USP 26) 375
Terpin Hydrate and Codeine Oral Solution [new] (USP 26) 376
Tetracycline Hydrochloride Oral Suspension (USP 26) 378
Theophylline Sodium Glycinate Elixir (USP 26) 378
Theophylline Sodium Glycinate Oral Solution [new] (USP 26) 378
Thiamine Hydrochloride Elixir (USP 26) 379
Thiamine Hydrochloride Injection (USP 26) 380
Thiamine Hydrochloride Oral Solution [new] (USP 26) 380
Thiamine Mononitrate Elixir (USP 26) 381
Thiamine Mononitrate Oral Solution [new] (USP 26) 381
Torsemide (USP 26) 382
Triamcinolone Diacetate Oral Solution [new] (USP 26) 383
Triamcinolone Diacetate Syrup (USP 26) 384
Triazolam (USP 26) 385
Tricitrates Oral Solution (USP 26) 385
Trifluoperazine Hydrochloride Syrup (USP 26) 385
Trifluoperazine Oral Solution [new] (USP 26) 385
Trihexyphenidyl Hydrochloride Elixir (USP 26) 386
Trihexyphenidyl Hydrochloride Oral Solution [new] (USP 26) 387
Trimeprazine Oral Solution [new] (USP 26) 388
Trimeprazine Tartrate Syrup (USP 26) 389
Trimethoprim (USP 26) 389
Triprolidine Hydrochloride Oral Solution [new] (USP 26) 390
Triprolidine Hydrochloride Syrup (USP 26) 391
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] IN-PROCESS REVISION 239
Triprolidine Hydrochloride Tablets (USP 26) 392

Triprolidine and Pseudoephedrine Hydrochlorides Oral Solution [new] (USP 26) 392
Triprolidine and Pseudoephedrine Hydrochlorides Syrup (USP 26) 394
Triprolidine and Pseudoephedrine Hydrochlorides Tablets (USP 26) 394
Valproic Acid Oral Solution (USP 26) 395
Valproic Acid Syrup (USP 26) 396
Valsartan [new] (USP 26) 396
Valsartan Capsules [new] (USP 26) 399
MONOGRAPHS (NF) 403
Corn Syrup [new] (NF 21) 403
High Fructose Corn Syrup [new] (NF 21) 408
Dextrin (NF 21) 411
Magnesium Aluminometasilicate [new] (NF 21) 411
Magnesium Aluminosilicate [new] (NF 21) 414
Milk Thistle (NF 21) 414
Powdered Milk Thistle (NF 21) 417
Powdered Milk Thistle Extract [new] (NF 21) 417
Milk Thistle Capsules [new] (NF 21) 420
Milk Thistle Tablets [new] (NF 21) 422
Myristyl Alcohol [new] (NF 21) 424
Saw Palmetto Extract [new] (NF 21) 425
Sugar-Free Suspension Structured Vehicle (NF 21) 428
Suspension Structured Vehicle (NF 21) 429
Xanthan Gum Solution (NF 21) 429
(I) Injections (USP 26) 430
(II) USP Reference Standards (USP 26) 433
(85) Bacterial Endotoxins Test [erratum] (USP 26) 435
(563) Biological and Chemical Identification of Articles of Botanical Origin [new] (USP 26) 435
(565) Botanical Extracts (USP 26) 451
(661) Containers (USP 26) .* 453
(671) Containers—Permeation (USP 26) 456
(795) Pharmacy Compounding (USP 26) 458
(1146) Packaging Practice—Repackaging a Single Solid Oral Drug Product into a Unit-Dose Container [new]
(USP 26) 467
(1160) Pharmaceutical Calculations in Prescription Compounding [new] (USP 26) 476
(1186) Shipping and Storage of Labile Preparations [new] (USP 26) 495
(1206) Sterile Drug Products for Home Use (USP 26) 498
(2750) Manufacturing Practices for Nutritional Supplements (USP 26) 534
Bacterial Alkaline Protease Preparation (USP 26) 552
Bromelain [new] (USP 26) 552
4-(Butylamino)benzoic Acid [new] (USP 26) 553
Volumetric Solutions 553
Lead Perchlorate, Hundredth Molar (0.01 M) [new] (USP 26) 553
Reagent Footnotes 553
Doxazosin Mesylate (USP 26) 554
Ganciclovir (USP 26) 554
Mangafodipir Trisodium (USP 26) 554
Norgestimate (USP 26) 554
Pharmacopeial Forum
when the article is recognized in the USP. The standards apply

GENERAL NOTICES AND equally to articles bearing the official titles or names derived by
transposition of the definitive words of official titles or transposi-
REQUIREMENTS tion in the order of the names of two or more active ingredients in
Names considered to be synonyms of the official titles may not be
they remain separate compendia. The designation USP-NF or sim-
BRIEFING ilar combination may be used on the label of an article, provided
the label also bears a statement such as "Meets NF standards as
General Notices and Requirements, USP 25 page 1 and page 32 published by the USP", indicating the particular compendium to
of PF 28(1) [Jan.-Feb. 2002]. It is proposed to clarify the beyond- which the article purports to apply.
use date requirements for nonsterile dosage forms in the Labeling Where an article differs from the standards of strength, quality,
section under Preservation, Packaging, Storage, and Labeling. and purity, as determined by the application of the assays and tests
Also, in a proposal for the general tests chapter Pharmaceutical set forth for it in the Pharmacopeia, its difference shall be plainly
Compounding (795), which appears elsewhere in this number of stated on its label. Where an article fails to comply in identity with
PF, the chapter title is being changed to Pharmaceutical Com- the identity prescribed in the USP, or contains an added substance
pounding—Nonsterile Preparations (795). Accordingly, the that interferes with the prescribed assays and tests, such article
cross-references to this chapter are being updated under Ingredi- shall be designated by a name that is clearly distinguishing and dif-
ents and Processes and under Preservation, Packaging, Storage, ferentiating from any name recognized in the Pharmacopeia.
and Labeling. Articles listed herein are official and the standards set forth in the
monographs apply to them only when the articles are intended or
(PSD:C. Okeke; CRX: C. Okeke) RTS—34757-1; 36442-1 labeled for use as drugs, as nutritional or dietary supplements, or as
medical devices and when bought, sold, or dispensed for these pur-
An article is deemed to be recognized in this Pharmacopeia
Change to read: when a monograph for the article is published in it, including its
supplements, addenda, or other interim revisions, and an official
"OFFICIAL" AND "OFFICIAL ARTICLES' The following terminology is used for distinguishing the articles
for which monographs are provided: an official substance is an ac-
The word "official", as used in this Pharmacopeia or with ref- dient, or a pharmaceutic ingredient (see also NF 20) or a
erence hereto, is synonymous with "Pharmacopeial", with component of a finished device for which the monograph title in-
"USP", and with "compendial". cludes no indication of the nature of the finished form; an official
The designation "USP" in conjunction with the official title or preparation is a drug product, a nutritional supplement, a dietary
elsewhere on the label of an article moano that tho artiolo supplement or a finished device. It is the finished or partially fin-
ished (e.g., as in the case of a sterile solid to be constituted into a
îndicates that a monograph is included in the USP and that solution for administration) preparation or product of one or more
official substances formulated for use on or for the patient or con-
the article_AUSP26 sumer; an article is an item for which a monograph is provided,
purports to comply with whether an official substance or an official preparation.
AUSP26 'Products Not Marketed in the United States—Interest in

USP standards.
A
Any language modifying or limiting this representation the USP outside the United States has always existed. From
shall be accompanied by a statement that the article is time to time, monographs may be adopted for articles not
legally marketed in the United States as a service to autho-
auoh apooifio rities in other countries where USP standards are recognized
AU2 and applied. Appearance of any such monograph does not
designation
AUSP26 grant any marketing rights whatsoever, and the status of the
on the label
A article in the United States must be checked with the U.S.
may not a A U s r e t f
does not constitute a representation, endorsement, or incorporation Food and Drug Administration in the event of any ques-
by the manufacturer's labeling of the informational material con-
tained in the USP monograph, nor does it constitute assurance by tion.B1
USP that the article is known to comply with USP standards. An
article may only purport to comply with a USP standard Nutritional and Other Dietary Supplements—The designation
of an official preparation containing one or more recognized nutri-
A
or other requirements AUSP26 ents as "USP" or the use of the designation "USP" in conjunction
with the title of such nutritional or dietary supplement preparation
may be made only if the preparation meets
Pharmacopeial Forum
AUSP26 and other specifications relating to the article, whether incorporated

the applicable requirements contained in the individual monograph in the monograph itself, in the General Notices and Requirements,
and general chapters. Any additional ingredient in such article that or in the section General Chapters.
is not recognized in the Pharmacopeia and for which nutritional Water—Water used as an ingredient of official preparations
value is claimed shall not be represented nor imply that such ingre- meets the requirements for Purified Water, for Water for Injection,
dient is of USP quality or recognized by USP. If a preparation does or for one of the sterile forms of water covered by a monograph in
not comply with this Pharmacopeia.
Potable water meeting the requirements for drinking water as set
a
forth in the regulations of the U.S. Environmental Protection
ÂUSP26 . . . . Agency may be used in the preparation of official substances.
applicable requirements but contains nutrients or dietary supple- Alcohol—All statements of percentages of alcohol, such as un-
ment ingredients that are recognized in the USP, the article may not der the heading Alcohol content refer to percentage, by volume, of
designate the individual nutrients or ingredients as complying with C2H5OH at 15.56°. Where reference is made to "C 2 H 5 OH," the
USP standards or being of USP quality without designating on the chemical entity possessing absolute (100 percent) strength is in-
label that the article itself does not comply with USP standards. tended.
Change to read: Alcohol—Where "alcohol" is called for in formulas, tests, and
assays, the monograph article Alcohol is to be used.
Dehydrated Alcohol—Where "dehydrated alcohol" (absolute
alcohol) is called for in tests and assays, the monograph article De-
INGREDIENTS AND PROCESSES hydrated Alcohol is to be used.
Denatured Alcohol—Specially denatured alcohol formulas are
Official drug products and finished devices are prepared from available for use in accordance with federal statutes and regulations
ingredients that meet the requirements of the compendial mono- of the Internal Revenue Service. A suitable formula of specially
graphs for those individual ingredients for which monographs denatured alcohol may be substituted for Alcohol in the manufac-
are provided (see also NF 20). Generally, nutritional and dietary ture of Pharmacopeial preparations intended for internal or topical
supplements are prepared from ingredients that meet requirements use, provided that the denaturant is volatile and does not remain in
of the compendial monographs for those ingredients for which the finished product. A finished product that is intended for topical
monographs are provided, except that substances of acceptable application to the skin may contain specially denatured alcohol,
food grade quality may be utilized in the event of a difference. provided that the denaturant is either a normal ingredient or a per-
Official substances are prepared according to recognized princi- missible added substance; in either case the denaturant must be
ples of good manufacturing practice and from ingredients comply- identified on the label of the topical preparation. Where a process
ing with specifications designed to assure that the resultant is given in the individual monograph, the preparation so made must
substances meet the requirements of the compendial monographs be identical with that prepared by the given process.
(see also Foreign Substances and Impurities under Tests and As-
says). Added Substances—An official substance, as distinguished
from an official preparation, contains no added substances except
Preparations for which a complete composition is given in this where specifically permitted in the individual monograph. Where
Pharmacopeia, unless specifically exempted herein or in the indi- such addition is permitted, the label indicates the name(s) and
vidual monograph, are to contain only the ingredients named in the amount(s) of any added substance(s).
formulas. However, there may be deviation from the specified pro-
cesses or methods of compounding, though not from the ingredi- Unless otherwise specified in the individual monograph, or else-
ents or proportions thereof, provided the finished preparation where in the General Notices and Requirements, suitable sub-
conforms to the relevant standards laid down herein and to prepara- stances such as antimicrobial agents, bases, carriers, coatings,
tions produced by following the specified process. colors, flavors, preservatives, stabilizers, and vehicles may be
added to an official preparation to enhance its stability, usefulness,
The tolerances specified in individual monographs and in the or elegance or to facilitate its preparation. Such substances are re-
general chapters for compounded preparations are based on those garded as unsuitable and are prohibited unless (a) they are harmless
attributes of quality as might be expected to characterize an article in the amounts used, (b) they do not exceed the minimum quantity
compounded from suitable bulk drug substances and ingredients in required to provide their intended effect, (c) their presence does not
accordance with the procedures provided or under recognized prin- impair the bioavailability or the therapeutic efficacy or safety of the
ciples of good pharmaceutical practice as described in this Pharma- official preparation, and (d) they do not interfere with the assays
copeia (see Pkamtacy Compounding Pmctiecs (1161) and tests prescribed for determining compliance with the Pharma-
A
Pharmaceutical Compounding—Nonsterile Preparations copeial standards.
Nutritional and Dietary Supplements—Unless otherwise speci-
\))xUSP26 fied in the individual monograph, or elsewhere in the General No-
and elsewhere. tices and Requirements, consistent with applicable regulatory
Monographs for preparations intended to be compounded pur- requirements, suitable added substances such as bases, carriers,
suant to prescription may contain assay methods under the heading coatings, colors, flavors, preservatives, and stabilizers may be
Compliance assay. Assay methods under this heading are not in- added to a nutritional supplement preparation to enhance its stabi-
tended for evaluating a compounded preparation prior to dispen- lity, usefulness, or elegance, or to facilitate its preparation. Such
sing. Compliance assay methods are intended to serve as the added substances shall be regarded as suitable and shall be per-
official test methods in the event of a question or dispute as to mitted unless they interfere with the assays and tests prescribed
whether or not the compounded preparation complies with official for determining compliance with Pharmacopeial standards.
standards. Additional Ingredients—Additional ingredients, including exci-
Where a monograph on a preparation calls for an ingredient in pients, may be added to nutritional supplement preparations con-
an amount expressed on the dried basis, the ingredient need not be taining recognized nutrients, consistent with applicable regulatory
dried prior to use if due allowance is made for the water or other requirements, provided that they do not interfere with the assays
volatile substances present in the quantity taken. and tests prescribed for determining compliance with Pharmaco-
Unless specifically exempted elsewhere in this Pharmacopeia, peial standards.
the identity, strength, quality, and purity of an official article are Inert Headspace Gases—The air in a container of an article for
determined by the definition, physical properties, tests, assays, parenteral use may be evacuated or be replaced by carbon dioxide,
helium, or nitrogen, or by a mixture of these gases, which fact need
not be declared in the labeling.
Pharmacopeial Forum
Colors—Added substances employed solely to impart color shipment, storage, and distribution, and is capable of tight reclo-
may be incorporated into official preparations, except those in- sure. Where a tight container is specified, it may be replaced by
tended for parenteral or ophthalmic use, in accordance with the a hermetic container for a single dose of an article.
regulations pertaining to the use of colors issued by the FDA pro- A gas cylinder is a metallic container designed to hold a gas un-
vided such added substances are otherwise appropriate in all re- der pressure. As a safety measure, for carbon dioxide, cyclopro-
spects. (See also Added Substances under Injections (1).) pane, helium, nitrous oxide, and oxygen, the Pin-index Safety
Ointments and Suppositories—In the preparation of ointments System of matched fittings is recommended for cylinders of Size
and suppositories, the proportions of the substances constituting E or smaller.
the base may be varied to maintain a suitable consistency under NOTE—Where packaging and storage in a tight container or a
different climatic conditions, provided the concentrations of active well-closed container is specified in the individual monograph,
ingredients are not varied and the bioavailability, therapeutic effi- the container utilized for an article when dispensed on prescription
cacy or safety of the preparation is not impaired. meets the requirements under Containers—Permeation (671).
Hermetic Container—A hermetic container is impervious to air
Change to read: or any other gas under the ordinary or customary conditions of
handling, shipment, storage, and distribution.
Single-Unit Container—A single-unit container is one that is de-
PRESERVATION, PACKAGING, STORAGE, AND LABELING signed to hold a quantity of drug product intended for administra-
tion as a single dose or a single finished device intended for use
Containers—The container is that which holds the article and is promptly after the container is opened. Preferably, the immediate
or may be in direct contact with the article. The immediate contain- container and/or the outer container or protective packaging shall
er is that which is in direct contact with the article at all times. The be so designed as to show evidence of any tampering with the con-
closure is a part of the container. tents. Each single-unit container shall be labeled to indicate the
Prior to its being filled, the container should be clean. Special identity, quantity and/or strength, name of the manufacturer, lot
precautions and cleaning procedures may be necessary to ensure number, and expiration date of the article.
that each container is clean and that extraneous matter is not intro- Single-Dose Container (see also Containers for Injections under
duced into or onto the article. Injections (1))—A single-dose container is a single-unit container
The container does not interact physically or chemically with the for articles intended for parenteral administration only. A single-
article placed in it so as to alter the strength, quality, or purity of the dose container is labeled as such. Examples of single-dose contain-
article beyond the official requirements. ers include pre-filled syringes, cartridges, fusion-sealed containers,
The Pharmacopeial requirements for the use of specified con- and closure-sealed containers when so labeled.
tainers apply also to articles as packaged by the pharmacist or other Unit-Dose Container—A unit-dose container is a single-unit
dispenser, unless otherwise indicated in the individual monograph. container for articles intended for administration by other than
Tamper-Resistant Packaging—The container or individual car- the parenteral route as a single dose, direct from the container.
ton of a sterile article intended for ophthalmic or otic use, except Unit-of-Use Container—A unit-of-use container is one that con-
where extemporaneously compounded for immediate dispensing tains a specific quantity of a drug product and that is intended to be
on prescription, shall be so sealed that the contents cannot be used dispensed as such without further modification except for the addi-
without obvious destruction of the seal. tion of appropriate labeling. A unit-of-use container is labeled as
Articles intended for sale without prescription are also required such.
to comply with the tamper-resistant packaging and labeling re- Multiple-Unit Container—A multiple-unit container is a con-
quirements of the FDA where applicable. tainer that permits withdrawal of successive portions of the con-
Preferably, the immediate container and/or the outer container or tents without changing the strength, quality, or purity of the
protective packaging utilized by a manufacturer or distributor for remaining portion.
all dosage forms that are not specifically exempt is designed so as Multiple-Dose Container (see also Containers for Injections un-
to show evidence of any tampering with the contents. der Injections (1))—A multiple-dose container is a multiple-unit
Light-Resistant Container (see Light Transmission under Con- container for articles intended for parenteral administration only.
tainers (661))—A light-resistant container protects the contents Storage Temperature and Humidity—Specific directions are
from the effects of light by virtue of the specific properties of the stated in some monographs with respect to the temperatures and
material of which it is composed, including any coating applied to humidity at which Pharmacopeial articles shall be stored and dis-
it. Alternatively, a clear and colorless or a translucent container tributed (including the shipment of articles to the consumer) when
may be made light-resistant by means of an opaque covering, in stability data indicate that storage and distribution at a lower or a
which case the label of the container bears a statement that the higher temperature and a higher humidity produce undesirable re-
opaque covering is needed until the contents are to be used or ad- sults. Such directions apply except where the label on an article
ministered. Where it is directed to "protect from light" in an indi- states a different storage temperature on the basis of stability stu-
vidual monograph, preservation in a light-resistant container is dies of that particular formulation. Where no specific storage direc-
intended. tions or limitations are provided in the individual monograph, but
Where an article is required to be packaged in a light-resistant the label of an article states a storage temperature that is based on
container, and if the container is made light-resistant by means of stability studies of that particular formulation, such labeled storage
an opaque covering, a single-use, unit-dose container or mnemonic directions apply (see also Stability under Pharmaceutical Dosage
pack for dispensing may not be removed from the outer opaque Forms (1151).) The conditions are defined by the following terms.
covering prior to dispensing. Freezer—A place in which the temperature is maintained ther-
Well-Closed Container—A well-closed container protects the mostatically between -25° and -10° (-13° and 14 °F).
contents from extraneous solids and from loss of the article under Cold—Any temperature not exceeding 8° (46 °F). A refrigera-
the ordinary or customary conditions of handling, shipment, sto- tor is a cold place in which the temperature is maintained thermo-
rage, and distribution. statically between 2° and 8° (36° and 46 °F).
Tight Container—A tight container protects the contents from Cool—Any temperature between 8° and 15° (46° and 59 °F). An
contamination by extraneous liquids, solids, or vapors, from loss article for which storage in a cool place is directed may, alterna-
of the article, and from efflorescence, deliquescence, or evapo- tively, be stored and distributed in a refrigerator, unless otherwise
ration under the ordinary or customary conditions of handling, specified by the individual monograph.
Room Temperature—The temperature prevailing in a working
Pharmacopeial Forum
Controlled Room Temperature—A temperature maintained ther- A shipping container containing a single article, unless such
mostatically that encompasses the usual and customary working container is also essentially the immediate container or the outside
environment of 20° to 25° (68° to 77 °F); that results in a mean of the consumer package, is labeled with a minimum of product
kinetic temperature calculated to be not more than 25°; and that identification (except for controlled articles), lot number, expira-
allows for excursions between 15° and 30° (59° and 86 °F) that tion date, and conditions for storage and distribution.
are experienced in pharmacies, hospitals, and warehouses. Pro- Articles in this Pharmacopeia are subject to compliance with
vided the mean kinetic temperature remains in the allowed range, such labeling requirements as may be promulgated by governmen-
transient spikes up to 40° are permitted as long as they do not ex- tal bodies in addition to the Pharmacopeial requirements set forth
ceed 24 hours. Spikes above 40° may be permitted if the manufac- for the articles.
turer so instructs. Articles may be labeled for storage at "controlled Amount of Ingredient per Dosage Unit—The strength of a drug
room temperature" or at "up to 25°", or other wording based on product is expressed on the container label in terms of micrograms
the same mean kinetic temperature. The mean kinetic temperature or milligrams or grams or percentage of the therapeutically active
is a calculated value that may be used as an isothermal storage tem- moiety or drug substance, whichever form is used in the title, un-
perature that simulates the nonisothermal effects of storage tem- less otherwise indicated in an individual monograph. Both the ac-
perature variations. (See also Stability under Pharmaceutical tive moiety and drug substance names and their equivalent
Dosage Forms (1151).) amounts are then provided in the labeling.
An article for which storage at Controlled room temperature is Pharmacopeial articles in capsule, tablet, or other unit dosage
directed may, alternatively, be stored and distributed in a cool form shall be labeled to express the quantity of each active ingre-
place, unless otherwise specified in the individual monograph or dient or recognized nutrient contained in each such unit; except
on the label. that, in the case of unit-dose oral solutions or suspensions, whether
Warm—Any temperature between 30° and 40° (86° and 104 °F). supplied as liquid preparations or as liquid preparations that are
Excessive Heat—Any temperature above 40° (104 °F). constituted from solids upon addition of a designated volume of
Protection from Freezing—Where, in addition to the risk of a specific diluent, the label shall express the quantity of each active
breakage of the container, freezing subjects an article to loss of ingredient or recognized nutrient delivered under the conditions
strength or potency, or to destructive alteration of its characteris- prescribed in Deliverable Volume (698). Pharmacopeial drug pro-
tics, the container label bears an appropriate instruction to protect ducts not in unit dosage form shall be labeled to express the quan-
the article from freezing. tity of each active ingredient in each milliliter or in each gram, or to
express the percentage of each such ingredient (see Percentage
Measurements), except that oral liquids or solids intended to be
'Dry Place—The term "dry place" denotes a place that constituted to yield oral liquids may, alternatively, be labeled in
terms of each 5-milliliter portion of the liquid or resulting liquid.
does not exceed 40% average relative humidity at Con- Unless otherwise indicated in a monograph or chapter, such de-
clarations of strength or quantity shall be stated only in metric units
trolled Room Temperature or the equivalent water vapor (see also Units of Potency in these General Notices and Require-
ments).
pressure at other temperatures. The determination may be Use of Leading and Terminal Zeros—In order to help minimize
the possibility of errors in the dispensing and administration of
made by direct measurement at the place or may be based drugs, the quantity of active ingredient when expressed in whole
numbers shall be shown without a decimal point that is followed by
on reported climatic conditions. Determination is based on a terminal zero (e.g., express as 4 mg [not 4.0 mg]). The quantity of
active ingredient when expressed as a decimal number smaller than
not less than 12 equally spaced measurements that encom- one shall be shown with a zero preceding the decimal point (e.g.,
express as 0.2 mg [not .2 mg]).
pass either a season, a year, or, where recorded data demon- Labeling of Salts of Drugs—It is an established principle that
Pharmacopeial articles shall have only one official name. For pur-
strate, the storage period of the article. There may be values poses of saving space on labels, and because chemical symbols for
the most common inorganic salts of drugs are well known to prac-
of up to 45% relative humidity provided that the average titioners as synonymous with the written forms, the following al-
ternatives are permitted in labeling official articles that are salts:
value is 40% relative humidity. HC1 for hydrochloride; HBr for hydrobromide; Na for sodium;
and K for potassium. The symbols Na and K are intended for
Storage in a container validated to protect the article from use in abbreviating names of the salts of organic acids; but these
symbols are not used where the word Sodium or Potassium appears
moisture vapor, including storage in bulk, is considered a at the beginning of an official title (e.g., Phenobarbital Na is accep-
table, but Na Salicylate is not to be written).
dry place.B1 Labeling Vitamin-Containing Products—The vitamin content of
an official drug product shall be stated on the label in metric units
Storage under Nonspecific Conditions—For articles, re- per dosage unit. The amounts of vitamins A, D, and E may be sta-
gardless of quantity, where no specific storage directions or limita- ted also in USP Units. Quantities of vitamin A declared in metric
tions are provided in the individual monograph, it is to be units refer to the equivalent amounts of retinol (vitamin A alcohol).
understood that conditions of storage and distribution include pro- The label of a nutritional supplement shall bear an identifying lot
tection from moisture, freezing, and excessive heat. number, control number, or batch number.
Labeling—The term "labeling" designates all labels and other Labeling Parenteral and Topical Preparations—The label of a
written, printed, or graphic matter upon an immediate container of preparation intended for parenteral or topical use states the names
an article or upon, or in, any package or wrapper in which it is en- of all added substances (see Added Substances in these General
closed, except any outer shipping container. The term "label" des- Notices and Requirements, and see Labeling under Injections
ignates that part of the labeling upon the immediate container. (1)), and, in the case of parenteral preparations, also their amounts
or proportions, except that for substances added for adjustment of
pH or to achieve isotonicity, the label may indicate only their pre-
sence and the reason for their addition.
Pharmacopeial Forum
Labeling Electrolytes—The concentration and dosage of elec- dispensed, whichever is earlier. For nonsterile solid and liquid do-
trolytes for replacement therapy (e.g., sodium chloride or potassi- sage forms that are packaged in single-unit and unit-dose contain-
um chloride) shall be stated on the label in milliequivalents (mEq). ers, the beyond-use date shall be one year l
The label of the product shall indicate also the quantity of ingredi- A
ents) in terms of weight or percentage concentration. from the date the drug is packaged into the single-unit or
Labeling Alcohol—The content of alcohol in a liquid prepara- unit-dose container or the expiration date on the manufac-
tion shall be stated on the label as a percentage (v/v) of C2H5OH. turer's container, whichever is earlier, . ^ ^
Special Capsules and Tablets—The label of any form of Cap-
sule or Tablet intended for administration other than by swallowing unless stability data or the manufacturer's labeling indicates other-
intact bears a prominent indication of the manner in which it is to wise. For all other typoo of nonatorilo dooago forms, tho boyond
be used. uoo dato ia ono yoar or tho timo remaining of tho expiration dato,
Expiration Date and Beyond-Use Date—The label of an official whiohovor ia Ioo9:
drug product, nutritional or dietary supplement product shall bear
an expiration date. All articles shall display the expiration date so •
AUSP26
that it can be read by an ordinary individual under customary con-
ditions of purchase and use. The expiration date shall be promi- The dispenser must maintain the facility where the dosage forms
nently displayed in high contrast to the background or sharply are packaged and stored, at a temperature such that the mean ki-
embossed, and easily understood (e.g., "EXP 6/89," "Exp. June netic temperature is not greater than 25°. The plastic material used
89," "Expires 6/89"). NOTE—For additional information and gui- in packaging the dosage forms must afford better protection than
dance, refer to the Nonprescription Drug Manufacturers Associa- poly vinyl chloride, which does not provide adequate protection
tion's Voluntary Codes and Guidelines of the OTC Medicines against moisture permeation. Records must be kept of the tempera-
Industry. ture of the facility where the dosage forms are stored, and of the
plastic materials used in packaging.
The monographs for some preparations state how the expiration
date that shall appear on the label is to be determined. In the ab- Pharmacy
sence of a specific requirement in the individual monograph for a *Pharmaceutical. USP26
drug product or nutritional supplement, the label shall bear an ex- Compounding—The label on the container or package of an offi-
piration date assigned for the particular formulation and package of cial compounded preparation shall bear a beyond-use date. The be-
the article, with the following exception: the label need not show yond-use date is the date after which a compounded preparation is
an expiration date in the case of a drug product or nutritional sup- not to be used. Because compounded preparations are intended for
plement packaged in a container that is intended for sale without administration immediately or following short-term storage, their
prescription and the labeling of which states no dosage limitations, beyond-use dates may be assigned based on criteria different from
and which is stable for not less than 3 years when stored under the those applied to assigning expiration dates to manufactured drug
prescribed conditions. products.
Where an official article is required to bear an expiration date, The monograph for an official compounded preparation typi-
such article shall be dispensed solely in, or from, a container la- cally includes a beyond-use requirement that states the time period
beled with an expiration date, and the date on which the article following the date of compounding during which the preparation,
is dispensed shall be within the labeled expiry period. The expira- properly stored, is to be used. In the absence of stability informa-
tion date identifies the time during which the article may be ex- tion that is applicable to a specific drug and preparation, recom-
pected to meet the requirements of the Pharmacopeial mendations for maximum beyond-use dates have been devised
monograph provided it is kept under the prescribed storage condi- for nonsterile compounded drug preparations that are packaged
tions. The expiration date limits the time during which the article in tight, light-resistant containers and stored at controlled room
may be dispensed or used. Where an expiration date is stated only temperature unless otherwise indicated (see Stability Criteria and
in terms of the month and the year, it is a representation that the Beyond-Use Dating under Stability of Compounded Preparations
intended expiration date is the last day of the stated month. The in the general tests chapter Pharmacy Compounding (49)}
beyond-use date is the date after which an article must not be used.
The dispenser shall place on the label of the prescription container ^Pharmaceutical Compounding—Nonsterile Preparations
a suitable beyond-use date to limit the patient's use of the article
based on any information supplied by the manufacturer and the (795)).
General Notices and Requirements of this pharmacopeia. The be-
yond-use date placed on the label shall not be later than the expira-
tion date on the manufacturer's container.
For articles requiring constitution prior to use, a suitable be-
yond-use date for the constituted product shall be identified in
the labeling.
For all other dosage forms, in determining an appropriate period MONOGRAPHS (USP)
of time during which a prescription drug may be retained by a pa-
tient after its dispensing, the dispenser shall take into account, in
addition to any other relevant factors, the nature of the drug; the
container in which it was packaged by the manufacturer and the
expiration date thereon; the characteristics of the patient's contain-
er, if the article is repackaged for dispensing; the expected storage
conditions to which the article may be exposed; any unusual sto- BRIEFING
rage conditions to which the article may be exposed; and the ex-
pected length of time of the course of therapy. The dispenser shall,
on taking into account the foregoing, place on the label of a multi- Alfentanil Hydrochloride, USP 25 page 61 and page 2508 of
ple-unit container a suitable beyond-use date to limit the patient's PF 27(3) [May-June 2001]. On the basis of comments received, it
use of the article. Unless otherwise specified in the individual is proposed to delete the test for Melting range because in this case
monograph, or in the absence of stability data to the contrary, such the melting range only differentiates manufacturing processes.
beyond-use date shall be not later than (a) the expiration date on the
manufacturer's container, or (b) one year from the date the drug is
Pharmacopeial Forum
Since crystallization procedures may differ, which can result in dif- \iL of a freshly prepared 1 in 50 solution of ot bromo 2
ferent degrees of hydration in the product and different melting aootonaphthono in aootonitrilo. Swirl to wash down tho sidos of
ranges, the test does not reflect a purity standard. the vial. Add 100 uL of a froshly prepared 1 in 100 solution of
diisopropylothylamino in aootonitrilo, swirl again, and allow to
(PA2: J. Kelly) RTS—36140-1 stand at room temperature for not Ioa3 than 90 minutos.
Evaporate with tho aid of a stroam of nitrogon to drynoosradd
20.0 mL of Internal standard solution, and mix.
Test preparation—Aoourately weigh about 2 mg of Alprostadil,
dissolve in about 2 mL of dehydrated alooholv and gently evaporate
Change to read: to drynoss using nitrogon. Prooood as dirootod for Standard
preparation beginning with "Add 200 uL of a froshly prepared
Packaging and storage—Preserve in woll closed 1 in 50 solution " Dissolvo the residue in 2.0 mL of Internal
standaini solution.
containers Chromatographic system (soo Chromatography (624))—Tfee
liquid ohromatograph is equipped with a 251 nm detootor and a
A
, and store at controlled room temperature. A[/5W6 4 mm x 30 em oolumn that contains paoking L3. Tho flow rate
is about 2 mL por minuto. Chromatograph tho Standard
preparation, and rooord tho peak responses as dirootod under
Delete the following: Procedure: tho resolution; R, between the USP Prostaglandin At
A
McIting range, Class I (744); between 136° and 111°, over a 3
C RS and internal standard poaks ia not I033 than 1.0, and tho
range or looB.At/iff2ff rolativo standard doviation for roplioato injootions is not more
than 2.5%.
Procedure—NOTE—Whore poak responses are indioatod, use
peak heights.Separately injeot equal volumos (about 25 uL) of
tho Standard preparation and the Test preparation into tho
ohromatograph, rooord tho ohromatograms, and measure tho
rosponsoa for tho poaks. Tho rolativo rotontion timos aro about
1.3 and 1.1 for prostaglandin A+ and B^, respectively, and 1.0 for
tho internal standard. Prostaglandin 64. 00 olutos with 13,11
dihydroprostaglandin E^.. Caloulato tho quantity, in mg, of
prostaglandin A+ takon by tho formula:
BRIEFING
in whioh Cg is tho oonoontration of USP Prostaglandin A+ RS, in
Alprostadil, USP 25 page 65 and page 2509 of PF 27(3) [May- mg por mL in tho Standard stock solution, and Ry and R^ aro the
June 2001]. Based on comments received, further clarification of ratios of tho peak responses for prostaglandin Af and internal stan
the redaction in Test 1 and Test 2 in the previously proposed Limit dard poaks obtained from tho Test preparation and tho Standai'd
of foreign protaglandins test is made. preparation, rospootivoly. Not moro than 1.5% of prostaglandin
(PA1: C. Anthony) RTS—34880-1; 33797-1 Caloulato the quantity, in mg; of prostaglandin B+ and 13,11 di
hydroprostaglandin E+, as a summation, from tho formula:
whoro F is a rosponso factor dofinod as tho ratio of rotontion timo of

Change to read: prostaglandin At. to prostaglandin B^. Tho other terms aro as pro-
Packaging and storage -Preserve in tight containers, viously dofinod. A total content of not moro than 0.5% is
found.
"and stqre B1
in a refrigerator. Add the following:
Change to read: "Limit of chromium—
Standard solution—^Dissolve an accurately weighed quantity of
USP Reference standards {11)—USP Alprostadil RS. USP Pros- chromium trichloride in 0.05 M nitric acid, and dilute, stepwise if
taglandin Ax RS. necessary, with 0.05 M nitric acid to obtain a solution having a
A
USP Prostaglandin Bx RS.AUSP26 known concentration of about 3.04 ug per mL. Transfer 2 mL of
this solution to a 100-mL volumetric flask, dilute with alcohol to
volume, and mix. This solution contains 20 ng of chromium per
Delete the following: mL.
A Test solution—Transfer about 10 mg of Alprostadil, accurately
P r o s t a g l a n d i n A^., p r o s t a g l a n d i n Bj., a n d 1 3 , 1 4 - weighed, to a 10-mL volumetric flask, dissolve in and dilute
dihydroprostaglandin E+— with alcohol to volume, and mix.
Internal standard solution—Proparo a solution in mothylono Procedure—Separately inject equal volumes (about 20 uL) of
ohlorido containing about 0.02 mg of mothyltostostorono per mL. the Standard solution and the Test solution into a suitable
Mobile phase—Add 1.0 mL of wator to 7.5 mL of ten amyl graphite furnace atomic absorption spectrophotometer (see
aloohol. Add thio solution to lflOO mL of mothylono ohlorido; Spectrophotometry and Light-Scattering (851)), equipped with a
mix, and filter boforo UBO. chromium hollow-cathode lamp, with a drying temperature of
Standard preparation—Dissolve an accurately weighed quantity 100°, an ashing temperature of 1000°, and an atomization
of USP Prostaglandin At. RS in mothyleno ohlorido, and diluto temperature of 2700°. Use alcohol as the blank. Concomitantly
quantitatively with mothylono ohlorido to obtain a Standard stock determine the absorbances at the chromium emission line at
solution having a known concentration of about 0.1 mg per mL. 357.9 nm, and calculate the percentage of chromium (Cr) in the
Evaporate a 2.0 mL aliquot to drynoss using nitrogen. Add 200 portion of Alprostadil taken by the formula:
Pharmacopeial Forum
absorbances obtained from the Test solution and the Stan-

in which Cs is the concentration, in mg per mL, of chromium in the dard solution, respectively: not more than 0.002% is
Standard solution; CA is the concentration, in mg per mL, of Al-
prostadil in the Test solution; and Av and As are the absorbances found.B1
obtained from the Test solution and Standard solution, respec-
tively: not more than 0.002% is found.B1 Change to read:
Add the following: Limit of foreign prostaglandins—
Mobile phase—Prepare a oolution oontaining mothylono
•Limit of rhodium— ohlorido, 1,3 butanodiol, and water (995:5:0.5).
Test preparation—Dissolve about 2 mg of Alprostadil,
Standard solution—Dissolve an accurately weighed accurately weighed, in 2 mL of dohydratod aloohol, and gently
evaporate to dryness using nitrogen.
quantity of rhodium chloride hydrate in 1.2 M Chromatographie system—Tho liquid ohromatograph is oapablo
of providing oolumn prosauro up to about 2000 psi and is equipped
hydrochloric acid, and dilute, stepwise if necessary, with with a ouitablo rooordor; a detector for monitoring ultraviolet light
at 254 nm and a 4 mm x 30 em stainless stool oolumn oontaining
1.2 M hydrochloric acid to obtain a solution having a paoking L3i
Procedure—Add 200 uL of a 1 in 50 solution of oe bromo 2'
known concentration of 100 ug of rhodium per mL. aoetonaphthono in aoetonitrile to tho Test preparation washing
the sides of tho oontainor, and swirl. Add 100 uL of a 1 in 100
Transfer 5 mL of this solution to a 100-mL volumetric solution of diisopropylothylamino in aootonitrilo in a similar
manner. Heat tho oontainor at 45° for about 60 minutes and
flask, dilute with alcohol to volume, and mix. Transfer 2 ovaporato to drynoss using nitrogen. Add 10 mL of mothylono
ohlorido to dissolve the residue. Injoot approximately 10 uL of
mL of this solution to a 200-mL volumetric flask, dilute tho resulting solution. Adjust the attonuation for adequate
rooordor detection. NOTE—Allow eaoh ohromatogram to run not
with alcohol to volume, and mix. This solution contains loss than 30 minutos boforo another injection. Nogloot peaks
oluting in tho firat 8 minutes after injection (prostaglandin A^-eftd
50 ng of rhodium per mL. prostaglandin B^). Normalize areao for tho alprostadil peak
rooordor attonuation. Caloulato tho poroontago of oaoh foroign
prostaglandin takon by tho formula:
Test solution—Transfer about 20 mg of Alprostadil,
acccurately weighed, to a 10-mL volumetric flask,
in whioh A4 is tho area of oaoh individual poak, A^-A-^ oto.v ore tho
dissolve in and dilute with alcohol to volume, and mix. areas of tho foroign prostaglandin peaks, and AA is the area of tho
alprootadil peak. Not more than 3.0% total is found; and no single
Procedure—Separately inject equal volumes (about 20 foroign prostaglandin is greater than 2.0%.
A
uL) of the Standard solution and the Test solution into a TEST 1—
suitable graphite furnace atomic absorption spec- N O T E S — U s e freshly prepared solutions. Measure the
trophotometer (see Spectrophotometry and Light- peak responses at the following wavelengths: prostaglandin
Scattering (851)), equipped with a rhodium hollow- Aj at 224 nm; prostaglandin Bj at 280 nm; and all other for-
cathode lamp, with a drying temperature of 100°, an eign prostaglandin impurities at 200 nm.
ashing temperature of 1000°, and an atomization Mobile phase, System suitability solution, Standard
temperature of 2800°. Use alcohol as the blank. preparation; fmd Chromatographiesystem—Proceed as
Concomitantly determine the absorbances at the rhodium directed in the Assay.
emission line at 343.5 nm, and calculate the percentage of Standard solution—Dissolve accurately weighed
rhodium (Rh) in the portion of Alprostadil taken by the quantities of USP Alprostadil RS, USP Prostaglandin A,
formula: RS, and USP Prostaglandin Bj RS in a mixture of
methanol and water (9:1), and dilute quantitatively, and
stepwise if necessary, with a mixture of methanol and
in which Cs is the concentration, in mg per mL, of rhodium
water (9:1) to obtain a solution having known con-
in the Standard solution; CA is the concentration, in mg per
centrations of about 300 6 jig per mL, AS 15 ug per mL,
mL, of Alprostadil in the Test solution; and Av and As are the
and 0^- 6 ug per mL, respectively.
Pharmacopeia! Forum
Test solution—Uao tho Assay preparation: occurring at 200 nm and eluting before prostaglandin A] e?e
Test solution—Dissolve about 15 mg of Alprostadil, oluding prootaglandin At and prostaglandin B^ in the por-
accurately weighed, in 5 mL of a mixture of methanol and tion of Alprostadil taken by the formula:
water (9:1), and mix. 1 C\C\(C JC.'Sfr
Chromatographic system—Proceed as directed in the

Assay. Chromatograph the Standard solution, and record
the peak responses as directed for Procedure: the
resolution between prostaglandin A, and alprostadil is not
less than 7.5, and the relative standard deviation from the in which Cs is the concentration, in mg per mL, of USP Al-
peaks at their respective wavelength for replicate prostadil RS in the Standard solution; r, is the peak response
injections is not more than 4.0%. for each impurity obtained from the Test solution; rs is the
Procedure—Separately inject equal volumes (about 20 peak response for alprostadil obtained from the Standard so-
uL) of the Standard solution and the Test solution into the lution; and the other terms are as defined herein: not more
chromatograph, record the chromatograms, and measure the than 0.9% of any foreign prostaglandin impurity is found.
peak responses at 200 nm, 224 nm, and 280 nm. Calculate Calculate the percentage of any impurity having a relative
the percentage of prostaglandin A! and prostaglandin BiO* retention time of 0.6, relative to the prostaglandin Ai peak
224 nm and 280 nm, respectively, in the portion of detected at 224 nm, in the portion of Alprostadil taken by
Alprostadil taken by the formula: the formula:
1 r\r\rn in
500(Cs/W)(rt/rs),
in which Cs is the concentration, in mg per mL, of USP in which Cs is the concentration, in mg per mL, of USP
Prostaglandin A, RS or USP Prostaglandin B, RS in the Prostaglandin Ai RS or USP Proataglandin B^-ftS in the
Standard solution; G¥ W is the oonoontration weight, in Standard solution; rt is the peak response for any impurity
mg, per mL, of Alprostadil taken for the Test solution; r, having a relative retention time of 0.6, relative to the pros-
is the peak response for prostaglandin Ai or prostaglandin taglandin Ai peak, obtained from the Test solution; rs is the
B, obtained from the Test solution; and rs is the peak re- peak response of prostaglandin A] obtained from the Stan-
sponse of prostaglandin A] or prostaglandin B\ obtained dard solution; and the other terms are as defined herein: not
from the Standard solution: not more than 1.5% of prosta- more than 0.9% of any impurity having a relative retention
glandin Aj is found; and not more than 0.1% of prostaglan- time of 0.6, relative to the prostaglandin Aj peak, is found.
din Bi is found. Calculate the percentage of each impurity
Pharmacopeial Forum
TEST 2— detecting UV wavelengths between 200 nm and 300 nm
Mobile phase—Prepare a filtered and degassed mixture of and a 4.6-mm x 25-cm column that contains packing LI.
methanol, acetonitrile, and 0.02 M monobasic potassium The flow rate is about 1.2 mL per minute. Chromatograph
phosphate (2:1:1), and adjust with phosphoric acid to a the Identification solution as directed for Procedure: the
pH of 3. Make adjustments if necessary (see System relative retention times for prostaglandin Ai and
Suitability under Chromatography (621)). alprostadil are about 1.2 and 1.0, respectively; the
System suitability solution—Prooocd ao dirootod in tho resolution between prostaglandin Aj and alprostadil is not
less that 4.0. Chromatograph the Standard solution, and
Standard solution—Uoo tho Standard preparation, record the peak responses as directed for Procedure: the
prepared as dirootod in tho Assay. relative standard deviation determined from the main peak
Test solution—Uao tho Assay preparation. for replicate injections is not less than 2.0%.
Identification solution—Disoolvo aoouratoly weighed Procedure—Separately inject equal volumes (about 20
amounto of USP Alproatadil RS, USP Proataglandin B» uL) of the Standard solution and the Test solution into the
RS, and USP Prostaglandin A4. RS in mothanol, and chromatograph, record the chromatograms, and measure the
dilute^ stopwiso if nooo39ary;with methanol to obtain a peak responses oluting aftor proataglandin A4 at 200 nm,
oolution having -known concentrations of about 0:6 mg per Calculate tho percentage of oaoh impurity, excluding
mL, 0.6 mg por mL, and 1.5 mg por mL, ro3pootivoly. prostaglandin A+ and prostaglandin 64., whioh have boon
Transfer 1 mL of this solution to a 100 mL volumotrio identified in tho ohromatogram of tho Identification
flaok, and diluto with a mixture of mothanol and wator solution, in the* portion of Alprostadil takon by tho formula:
(9:1) to volume:
Chromatographic system—Prooeedao dirooted in tho
224 nm, and 280 nm. Calculate the percentage of each im-
Assay. Injoot tho Identification solution ao dirootod for
purity occurring at 200 nm and eluting after prostaglandin
Procedwc, and identify tho poaks.
Al5 excluding prostaglandin Bj, in the portion of Alprostadil
taken by the formula:
quantity of USP Alprostadil RS in a mixture of
acetonitrile and water (1:1) to obtain a solution having a
known concentration of about 10 ug per mL. in which Cs is the concentration, in mg per mL, of USP Al-
Test solution—Dissolve about 25 mg of Alprostadil, prostadil RS in the Standard solution; G¥ W is the oonoon
accurately weighed, in 5 mL of a mixture of acetonitrile tration weight, in mg, por mL, of Alprostadil taken for the
and water (1:1), using ultrasound if necessary. Test solution; r, is the peak response for each impurity ob-
Identification solution—Use the Standard solution under tained from the Test solution; and rs is the peak response for
Test 1. alprostadil obtained from the Standard solution: the sum of
Chromatographic system (see Chromatography the peaks having relative retention times of 2.0 and 2.3 is not
(621))—The liquid chromatograph is equipped with a more than 0.6%; not more than 0.9% of any other foreign
photodiode array detector or equivalent capable of
Pharmacopeial Forum
prostaglandin impurity is found; and not more than 2.0% of Mobile phase—Prepare a filtered and degassed mixture of
total impurities is found, the results for Test 1 and Test 2 methanol, 0.1 M monobasic potassium phosphate and
being added.AUSp26 acetonitrile (2:2:1), and adjust with phosphoric acid to a
Add the following: pH of 3.0. Make adjustments if necessary (see System

"Organic volatile impurities, Method IV (467): meets the
Internal standard solution—Dissolve an accurately
requirements^ j
weighed quantity of ethylparaben in a mixture of
Change to read:
methanol and water (9:1), and dilute quantitatively, and
Assay—
Mobile-phase—Proparo a filtered and degassed mixture of stepwise if necessary, with a mixture of methanol and
mothylono ohlorido, 1;3 butanediol, and water (1000:6:0.5).
•Make adjustments if necessary (aoo System Suitability under water (9:1) to obtain a solution having a known
Chromatography (654-)}?
Internal standard solution—Dissolve othylparabon in mothylono concentration of about 0.05 mg per mL.
ehlorido to obtain a solution containing about 0.05 mg per mL.
Standard stock preparation—Disoolvo an aoouratoly woighod
quantity of USP Alprostadil RS in abaoluto aloohol, and diluto Standard preparation—Dissolve an accurately weighed
quantitatively with absolute aloohol to obtain a solution having a
known oonoontration of about 0.5 mg per mL. quantity of USP Alprostadil RS in a mixture of methanol
Standard preparation—Gently evaporate a 0.5 mL portion of and water (9:1), and dilute quantitatively, and stepwise if
tho Standard stock preparation to drynoss using nitrogen.
Proceed as directed under -Assay preparation beginning with necessary, with a mixture of methanol and water (9:1) to
—Add 150 uL of a 1 in 25 freshly prepared solution "
Assay preparation—Transfer about 5 mg of Alprostadil, obtain a solution having a known concentration of about
accurately woighod, to a 10 mL volumotrio flask and dissolve in
and diluto with absolute aloohol to volume. Gently evaporate a 0.3 mg per mL. To 2.0 mL of this solution, add 1.0 mL of
0:5 mL aliquot to drynooo using nitrogen. Add 150 uL of a 1 in
35 freshly prepared solution of ot bromo 2' aootonaphthono in
ftootonitrilo^ wash down tho inside of the container, and swirl. Internal standard solution, and mix.
Add 150 uL of a froohlyprepared 1 in 200 solution of
diisopropylothylamino in aootonitrilo to tho oontainer in a similar System suitability solution—Dilute an accurately
manner. Cap and hoat tho container at 45° for 45 minutes, swirling
occasionally. NOTE—If tho entire sample docs not dissolve^ tho measured amount of USP Prostaglandin A! RS with
apooimon should bo discarded Evaporato tho solution using a
stream of nitrogen, add 2.0 mL of Internal standard solution, Standard preparation to obtain a solution having a
and mix. Sonicate to effect dissolution if undissolvod drug is
observed. NOTE—If incomplete dissolution is still observed, concentration of 4.5 ug of prostaglandin Ai per mL. To
discard tho spooimon.
2.0 mL of this solution, add 1.0 mL of Internal standard
Chromatographic system (soo Chromatography (££4-))—:¥he
liquid ohromatograph is equipped with a 254 nm dotoetor and a solution, and mix.
4:1mm x 25 om column that contains packing LI8. Tho flow
rato is about 1.5 mL per minute. Chromatograph tho Standard
preparation, and record tho peak responses as directed under Assay preparation—Transfer about 7.5 mg of Alprostadil,
Procedure: the relative retention times arc about 0.4 and l.Oi, for
ethylparabon and alprostadil, respectively, tho resolution, R, accurately weighed, to a 25-mL volumetric flask, dissolve in
botwoon tho poaks foralprostadil and the internal standard is not
loss than 9:0, and tho rolativo standard deviation for replicate and dilute with a mixture of methanol and water (9:1) to
injections of tho Standardpreparation is not greater than 2.5%.
volume, and mix. To 2.0 mL of this solution, add 1.0 mL
Procedure—Separately inject equal volumes of tho Standard
preparation and tho Assay preparation into tho ohromatograph, of Internal standard solution, and mix.
record the ohromatograms, and measure tho responses for tho
major peaks. Caloulato tho quantity, in mg, ofC^HÔ^ in tho
portion of Alprostadil taken by tho formula: Chromatographic system (see Chromatography (621))—
The liquid chromatograph is equipped with a photodiode
in whioh G is tho oonoontration, in mg por mL, of USP xMprostadil array detector or equivalent capable of detecting UV
RS in tho Standard stoekpreparation, and Ry and Rg are tho ratios
ef the peak responses for tho alprostadil and internal standard wavelengths between 200 nm and 300 nm and a 4.6-mm
peaks obtained from the Assay piiparation and the Standard-pro
paration, respectively. x 25-cm column that contains packing LI. The column
•NOTE—Use freshly prepared solutions. temperature is maintained at 40°. The flow rate is about 1
Pharmacopeia! Forum
mL per minute. Chromatograph the System suitability Add the following:

solution, and record the peak responses as directed for A
Amantadine Hydrochloride Oral
Procedure: the resolution, R, between prostaglandin A] Solution
and alprostadil is not less than 7.5, and between {Monograph under this new title—to become official
June 1, 2005)
prostaglandin Ai and ethylparaben is not less than 2.0; {Current monograph title is Amantadine Hydrochloride
Syrup)
and the relative standard deviation determined from the
peak area ratio of alprostadil to ethylparaben for replicate
» Amantadine Hydrochloride Oral Solution con-
injections is not more than 2.0%.
tains not less than 95.0 percent and not more than
uL) of the Standard preparation and the Assay prep- 105.0 percent of the labeled amount of amanta-
aration into the chromatograph, record the chromatograms dine hydrochloride (C10H17N • HC1).
at 200 nm, and measure the responses areas for the major
peaks. Calculate the quantity, in mg, of C2oH3405 in the
USP Reference standards (11)—USP Amantadine Hydro-
portion of Alprostadil taken by the formula:
chloride RS.
Identification, Infrared Absorption (197S)—
in which C is the concentration, in mg per mL, of USP Al- Cell: 1 mm.
prostadil RS in the Standard preparation; and Rv and Rs are Solution—Place a volume of Oral Solution, equivalent to
the peak responses area ratios of alprostadil to ethylparaben about 200 mg of amantadine hydrochloride, in a vessel,
obtained from the Assay preparation and the Standard pre- dissolve in 0.1 N hydrochloric acid, and filter. Transfer the
paration, respectively.B1 filtrate to a separator, add 10 mL of 0.5 N sodium hydroxide,
and extract with 5 mL of methylene chloride. Filter the
extract through anhydrous sodium sulfate, and rinse the
anhydrous sodium sulfate with 2 mL of methylene chloride.
Assay—
Internal standard solution, Standard preparation, and
BRIEFING
Assay under Amantadine Hydrochloride Capsules.
Amantadine Hydrochloride Oral Solution—See briefing un-
der Amantadine Hydrochloride Syrup. Assay preparation—Pipet 5.0 mL of the Oral Solution
(NL: C. Barnstein; PA7: W. Wright) RTS—35939-1 into a 250-mL conical flask, and add 45 mL of 1.0 N
sodium hydroxide and 50.0 mL of Internal standard
solution. Shake for 60 minutes, and collect the hexane
layer (Assay preparation).
Pharmacopeia! Forum
Procedure—Proceed as directed in the Assay under The revisions are proposed for publication in USP 26-NF 21,
which is to become official January 1, 2003, but with June 1,
Amantadine Hydrochloride Capsules. Calculate the 2005 designated as the official date for the name changes. Use of
the revised names would be permitted as of the January 1, 2003
quantity, in mg, of amantadine hydrochloride official date of USP 26-NF 21, but use of the revised names would
not become mandatory until June 1, 2005. The thirty-month post-
(C10H17N • HC1) in the portion of Oral Solution taken by ponement of the official date for the name changes is intended to
allow for product label changes to be made and for health practi-
the formula: tioners and consumers to become familiar with the revised termi-
nology.
50C(Ru/Rs),
(NL: C. Barnstein; PA7: W. Wright) RTS—35939-1
Amantadine Hydrochloride RS in the Standard prepara-
Amantadine Hydrochloride Syrup
tion; and RJJ and Rs are the peak response ratios obtained (Current title—not to change until June 1,2005)
Monograph title change—to become official June 1,
from the Assay preparation and the Standard preparation, 2005
(see Official Title Changes on the first page of fa'Pro-
respectively.^/^ cess Revision):
(Official June 1,2005) See Amantadine Hydrochloride Oral Solution
BRIEFING BRIEFING
Amantadine Hydrochloride Syrup, USP 25, page 103. It is Aminocaproic Acid Oral Solution—See briefing under Aman-
proposed to change the title of this monograph to Amantidine Hy- tadine Hydrochloride Syrup.
drochloride Oral Solution. Revisions are proposed by the Expert
Committee on Nomenclature and Labeling to change the titles of
58 USP monographs from [DRUG] Elixir and [DRUG] Syrup to (NL: C. Barnstein; PA5: J. Esker) RTS—35940-1
[DRUG] Oral Solution or [DRUG] Oral Suspension, as appropri-
ate. The change of terminolgy proposed for these older Elixir and
Syrup monograph titles is consistent with the nomenclature that
has been applied over the past several years whereby Oral Solution Add the following:
and Oral Suspension terminology has been applied to naming new
A
oral liquid preparations of therapeutic substances that were, and are
being, added to the USP. It follows the policy established by a for-
Aminocaproic Acid Oral Solution
mer USP Drug Nomenclature Committee, and continued in effect (Monograph under this new title—to become official
by the present Expert Committee on Nomenclature and Labeling, June 1, 2005)
whereby these oral liquid preparations are to be named in the gen- (Current monograph title is Aminocaproic Acid Syrup)
eral form [DRUG NAME] [ROUTE OF ADMINISTRATION]
[DOSAGE FORM], e.g., [Acetaminophen] [Oral] [Solution].
The decision to move away from traditional Elixir and Syrup ter-
minology came about because it was observed that there have been » Aminocaproic Acid Oral Solution contains not
discrepancies in uses of the traditional Elixir and Syrup terms. In
the beginning, oral liquid pharmaceutical preparations containing
alcohol were designated Elixirs, and those containing sucrose and less than 95.0 percent and not more than 115.0
no alcohol were designated Syrups. That distinction has become
less clear over the years, however, such that there are products con- percent of the labeled amount of aminocaproic
taining no alcohol marketed as elixirs, while a number of those
marketed as syrups contain varying amounts, some quite high, of acid (C6H13NO2).
alcohol and/or excipients such as non-sucrose polyols or glycerin.
Revisions are proposed also for nine USP monographs on Injec-
tions or Tablets in which references currently made to Elixir or Syr- Packaging and storage—Preserve in tight containers.
up monographs would necessarily be changed concomitantly to
ensure that reference is made to the correctly titled oral liquid do- USP Reference standards (11)—USP Aminocaproic Acid
sage forms.
RS.
Pharmacopeial Forum
Identification—Mix about 1 g of ion-exchange resin

(strongly acidic styrene-divinylbenzene cation-exchange BRIEFING
resin) with about 10 mL of 1 N hydrochloric acid in a Aminocaproic Acid Syrup, USP 25 page 113. It is proposed to
change the title of this monograph to Aminocaproic Acid Oral So-
100-mL beaker. Decant and discard the hydrochloric acid, lution. See also briefing under Amantadine Hydrochloride Syrup.
and wash the resin with five 10-mL portions of water, (NL: C. Bamstein; PA5: J. Esker) RTS—35940-1
decanting and discarding the liquid following each
washing. Place the washed resin in a glass-stoppered, 125-
Aminocaproic Acid Syrup
mL conical flask, and add a volume of Oral Solution,
{Current title--not to change until June 1, 2005)
equivalent to about 250 mg of aminocaproic acid, and 10 Monograph title change—to become official June 1,
2005
mL of water. Insert the stopper in the flask, and shake by (see Official Title Changes on the first page of In-Pro-
cess Revision):
mechanical means for 30 minutes. Transfer the resin See Aminocaproic Acid Oral Solution
slurry to a medium-porosity, sintered-glass funnel, wash
with about 100 mL of water, apply suction to filter, and
discard the washing. Place a 100-mL beaker under the
stem of the funnel, add 10 mL of 1 N hydrochloric acid to
the resin, stir for 4 to 5 minutes, and filter by applying
suction. Evaporate the filtrate on a steam bath to dryness, BRIEFING
dry at 105° for 1 hour, and cool: the residue so obtained Aspartic Acid, USP 25 page 164 and page 1269 of PF 26(5)
meets the requirements for the Identification test under [Sept.-Oct. 2001]. Based on comments received, it is proposed
to clarify the concentration of the reagent, 17% ammonia solution,
Aminocaproic Acid. and include its preparation in the test for Chromatographic purity.
pH (791): between 6.0 and 6.5. (DSN: J. Esker) RTS—36137-1
Assay—Transfer an accurately measured volume of Oral

Solution, equivalent to about 250 mg of aminocaproic Add the following:
acid, to a 250-mL beaker, add 80 mL of glacial acetic A
acid, and mix. Add 10 drops of a 1 in 500 solution of containers, protected from light.AUSP26
crystal violet in chlorobenzene, and titrate with 0.1 N Change to read:
perchloric acid in dioxane VS to a blue endpoint. Perform Chromatographic purity—
Adsorbent: 0.25-mm layer of chromatographic silica gel
a blank determination, and make any necessary correction. mixture.
System suitability solution—Dissolve 10 mg each of USP
Each mL of 0.1 N perchloric acid is equivalent to 13.12 mg Aspartic Acid RS and glutamic acid, each accurately weighed, in
2 mL of ammonia TS, dilute with water to 25.0 mL, and mix.
of aminocaproic acid (C6B.l3NO2).AUSP26 Test solution—Transfer 0.1 g of Aspartic Acid to a 10-mL
volumetric flask, dissolve in 2 mL of 17% ammonium hydroxide;
(Official June 1,2005) A
ammonia solution (prepared by diluting ammonium hy-
droxide, 6 in IO),AUSP26
Standard solution—Transfer 5 mg of USP Aspartic Acid RS to a
100-mL volumetric flask, dissolve in 2 mL of 17% ammonium
hydroxide;
A
ammonia solution (prepared by diluting ammonium hy-
droxide, 6 in 10),AUSP26
Pharmacopeial Forum
dilute with water to volume, and mix. Proceed as directed for Identification test B under
Application volume: 5 uL.
Developing solvent system: a mixture of butyl alcohol, glacial Betamethasone, beginning with "Apply 10 uL of this
acetic acid, and water (6:2:2).
Spray reagent—Dissolve 0.2 g of ninhydrin in 100 mL of a solution."
mixture of butyl alcohol and 2 N acetic acid (95:5).
Procedure—Proceed as directed for Thin-Layer Chromato- Assay—
graphy under Chromatography (621), except to dry the plate at
80° for 30 minutes, spray with Spray reagent, and heat at 80° for Developing solvent—Prepare a mixture of chloroform,
30 minutes. Examine the plate under white light. The
chromatogram obtained from the System suitability solution methanol, and ammonium hydroxide (175:20:1).
exhibits two clearly separated spots, and no secondary spot in
the chromatogram of the Test solution is larger or more intense Tetramethylammonium hydroxide reagent—Dilute 20 mL
than the principal spot in the chromatogram of the Standard
solution: not more than 0.5% of any individual impurity is of tetramethylammonium hydroxide TS with alcohol to
found; and not more than 2.0% of total impurities is found.
make 100 mL.
Standard preparation—Dissolve a suitable quantity of
USP Betamethasone RS, accurately weighed, in a mixture
of chloroform and methanol (1:1) to obtain a solution
having a known concentration of about 0.6 mg per mL.
BRIEFING Assay preparation—Use a pipet calibrated to contain a

suitable volume, and transfer to a 50-mL centrifuge tube
Betamethasone Oral Solution—See briefing under Amanta-
dine Hydrochloride Syrup. an accurately measured volume of Oral Solution,
(NL: C. Barnstein; PA1: C. Anthony) RTS—35941-1 equivalent to about 1.2 mg of Betamethasone. Rinse the
pipet with 15 mL of 0.1 N hydrochloric acid, then with 20
Add the following: mL of ethyl acetate, and add the rinsings to the centrifuge
A tube. Rotate for about 10 minutes, or shake manually for
Betamethasone Oral Solution
(Monograph under this new title—to become official about 1 minute. (Do not use a mechanical shaker.)
June 1, 2005)
(Current monograph title is Betamethasone Syrup) Centrifuge to separate the phases. Transfer the upper
phase (ethyl acetate) to a small, pear-shaped flask. Extract
the aqueous phase twice more with 20-mL portions of
» Betamethasone Oral Solution contains not less
ethyl acetate, and add the extracts to the pear-shaped
flask. Evaporate the combined extracts on a steam bath
of the labeled amount of betamethasone
under a gentle stream of nitrogen to dryness. Allow to
(C22H29FO5).
cool to room temperature. Dissolve the residue in about
Packaging and storage—Preserve in well-closed 0.5 mL of chloroform and methanol (1:1) using a vortex
containers. mixer. Transfer the solution to a 2-mL volumetric flask
USP Reference standards (11)—USP Betamethasone RS. with small portions of chloroform and methanol (1:1),
dilute with chloroform and methanol (1:1) to volume, and
Identification—Evaporate 25 mL of the Assay preparation,
mix.
prepared as directed in the Assay, on a steam bath just to
dryness, and dissolve the residue in 0.5 mL of alcohol.
Pharmacopeial Forum
Procedure—Apply 200-uL portions of the Assay

preparation and the Standard preparation to a suitable
BRIEFING
thin-layer chromatographic plate (see Chromatography
Betamethasone Syrup, USP 25 page 221. It is proposed to
(621)) coated with a 0.25-mm layer of chromatographic change the title of this monograph to Betamethasone Oral Solu-
tion. See also briefing under Amantadine Hydrochloride Syrup.
silica gel. Allow the spots to dry, and develop the
(NLfC. Barnstein; PA1: C. Anthony) RTS—35941-1
chromatogram, using the Developing solvent, until the
solvent front has moved about 15 cm. Remove the plates
from the developing chamber, and allow them to dry for Betamethasone Syrup
about 15 minutes. Mark the betamethasone bands, using (Current title—not to change until June 1, 2005)
short-wavelength UV light, to include similar zones of 2005
(see Official Title Changes on the first page of In-Pro-
silica gel for the Assay preparation, the Standard cess Revision)
See Betamethasone Oral Solution
preparation, and a zone containing no betamethasone for
the blank. Scrape off these zones, and transfer them to
separate, 50-mL centrifuge tubes. Add 15.0 mL of alcohol
to each, and rotate for 20 minutes. Centrifuge to clarify.
Transfer 10.0-mL portions of the supernatant to separate,
stoppered tubes. To each tube add 1.0 mL of blue
BRIEFING
tetrazolium TS, followed by 1.0 mL of Tetrameth-
Bromodiphenhydramine Hydrochloride Elixir, USP 25 page
ylammonium hydroxide reagent, and mix. Heat in a 35° 254. It is proposed to change the title of this monograph to Bromo-
diphenhydramine Oral Solution. See also briefing under Amanta-
water bath for about 1 hour. Remove from the water bath, dine Hydrochloride Syrup.
add 1.0 mL of glacial acetic acid to each tube, and mix.
(NL: C. Barnstein; AER: K. Zaidi) RTS—35942-1
Cool to room temperature. Concomitantly determine the
absorbances of the solutions in 1-cm cells at the
wavelength of maximum absorbance at about 525 nm,
Bromodiphenhydramine Hydrochloride
Elixir
with a suitable spectrophotometer. Calculate the quantity,
(Current title—not to change until June 1, 2005)
in mg, of betamethasone (C22H29FO5) in each mL of the Monograph title change—to become official June 1,
2005
Oral Solution taken by the formula: (see Official Title Changes on the first page of In-Pro-
cess Revision):
See Bromodiphenhydramine Hydrochloride Oral Solu-
2(C/V)(Av-AB)/(As-AB), tion
in which C is the concentration, in mg per mL, of USP Be-
tamethasone RS in the Standard preparation; V is the vol-
ume, in mL, of Oral Solution taken; and Av, As, and AB
are the absorbances of the solutions from the Assay prepara-
tion, the Standard preparation, and the blank, respective-
(Official June 1,2005)
Pharmacopeial Forum
shake with 100 mL of ether, and drain the aqueous layer into
BRIEFING
a second separator containing 50 mL of ether. Shake, and
Bromodiphenhydramine Hydrochloride Oral Solution—See discard the aqueous layer. Wash the ether solutions with
briefing under Amantadine Hydrochloride Syrup.
two 20-mL portions of water, shaking each aqueous portion
successively in the two separators, and then discard the
aqueous solutions. Extract the ether solutions successively
Add the following:
with 10.0 mL of 0.1 N sulfuric acid VS, followed by two
A
Bromodiphenhydramine 5-mL portions of water, and collect the aqueous extracts
Hydrochloride Oral Solution in a conical flask. Add methyl red TS to the solution in
June 1, 2005) the flask, and titrate the excess acid with 0.02 N sodium hy-
{Current monograph title is Bromodiphenhydramine Hy-
drochloride Elixir) droxide VS. Perform a blank determination (see Residual
Titrations under Titrimetry (541)). Each mL of 0.1 N sul-
furic acid is equivalent to 37.07 mg of bromodiphenhydra-
» Bromodiphenhydramine Hydrochloride Oral
mine hydrochloride (C17H20BrNO •
Solution contains not less than 93.0 percent and
HC1).AusP26
not more than 107.0 percent of the labeled amount
of bromodiphenhydramine hydrochloride
(C17H20BrNO-HCl).
containers.
USP Reference standards (11)—USP Bromodiphenhydra-
BRIEFING
mine Hydrochloride RS.
Brompheniramine Maleate Elixir, USP 25 page 254. It is pro-
Identification—It meets the requirements for the posed to change the title of this monograph to Brompheniramine
Maleate Oral Solution. See also briefing under Amantadine Hydro-
Identification test under Bromodiphenhydramine chloride Syrup.
Hydrochloride Capsules. (NL: C. Barnstein; AER: K. Zaidi) RTS—35943-1
Alcohol content, Method I (611): between 12.0% and
15.0%ofC 2 H 5 OH.
Brompheniramine Maleate Elixir
Assay—Evaporate an accurately measured volume of Oral (Current title—not to change until June 1,2005)
Solution, equivalent to about 250 mg of bromo- 2005
diphenhydramine hydrochloride, to about half the original cess Revision):
See Brompheniramine Maleate Oral Solution
volume, using a suitable vacuum evaporator. Transfer the
concentrated solution to a 250-mL separator, with the aid
of sufficient warm water to bring the volume to the
original volume. Add 20 g of sodium chloride, and shake
until dissolved. Add 5 mL of 1 N sodium hydroxide,
Pharmacopeial Forum
pH (791): between 2.5 and 3.5.

BRIEFING
Alcohol content, Method I (611): between 2.7% and 3.3%
Brompheniramine Maleate Oral Solution—See briefing un- ofC2H5OH.
der Amantadine Hydrochloride Syrup.
Solution, equivalent to about 20 mg of brompheniramine
maleate, to a separator, render distinctly alkaline with 1 N
Add the following:
sodium hydroxide, and extract with ten 10-mL portions of
A
Brompheniramine Maleate Oral chloroform, shaking gently to avoid emulsification. Wash
Solution
the combined chloroform extracts with 10 mL of water,
June 1, 2005) wash the latter with 20 mL of chloroform, and discard the
(Current monograph title is Brompheniramine Maleate
Elixir) aqueous phase. Quantitatively filter the combined
chloroform extracts and washings into a conical flask, and
» Brompheniramine Maleate Oral Solution con- evaporate the solvent on a steam bath, with the aid of a
tains not less than 95.0 percent and not more than current of air. To the residue add 25 mL of glacial acetic
105.0 percent of the labeled amount of bromphe- acid and 5 mL of acetic anhydride, agitate, and allow to
stand for about 15 minutes. Add 1 drop of crystal violet
niramine maleate (C16H19BrN2 • C4H4O4).
TS, and titrate with 0.01 N perchloric acid VS to a blue-
Packaging and storage—Preserve in well-closed, light- green endpoint. Perform a blank determination, and make
resistant containers. any necessary correction. Each mL of 0.01 N perchloric
USP Reference standards (11)—USP Brompheniramine acid is equivalent to 2.177 mg of brompheniramine
Maleate RS. maleate (C16H19BrN2 • C4E4O4).AUSP26
Identification—Transfer a volume of Oral Solution, (Official June 1,2005)
equivalent to about 50 mg of brompheniramine maleate,

to a separator, render distinctly alkaline with 1 N sodium
hydroxide, and extract with two 50-mL portions of
chloroform, shaking gently to avoid emulsification. Wash
the combined chloroform extracts with 10 mL of water,
BRIEFING
and discard the aqueous phase. Filter the combined
chloroform extracts into a conical flask, and evaporate the Brompheniramine Maleate and Pseudoephedrine Sulfate
Oral Solution—See briefing under Amantadine Hydrochloride
solvent on a steam bath, with the aid of a current of air. Syrup.
To the residue add 25 mL of dilute hydrochloric acid (1 in (NL: C. Barnstein; PA2: J. Kelly) RTS—35944-1
1200), and proceed as directed under Identification—
Organic Nitrogenous Bases (181), beginning with
"Transfer the liquid to a separator." The Oral Solution
meets the requirements of the test.
Pharmacopeial Forum
Add the following: ethyl ether, methanol, and ammonium hydroxide (16:3:1)
until the solvent front has moved about three-fourths of
^Brompheniramine Maleate and
Pseudoephedrine Sulfate Oral Solution the length of the plate. Remove the plate from the
{Monograph under this new title—to become official developing chamber, mark the solvent front, and allow the
June 1, 2005)
{Current monograph title is Brompheniramine Maleate solvent to evaporate. Locate the spots on the plate by
and Pseudoephedrine Sulfate Syrup)
examination under short-wavelength UV light: the RF
values of the two principal spots obtained from the test
» Brompheniramine Maleate and Pseudo- solution correspond to those obtained from the Standard
ephedrine Sulfate Oral Solution contains not less solutions.
than 90.0 percent and not more than 110.0 percent Assay—
of the labeled amounts of brompheniramine male- Mobile phase—Prepare a mixture of water, acetonitrile,
ate (C10H15BrN2 • C4H4O4) and pseudoephedrine methanol, and tetrahydrofuran (550:320:80:50). Transfer
sulfate (C10H15NO)2 • H2SO4. 1.0 mL of phosphoric acid, followed by 4.33 g of sodium
lauryl sulfate to this mixture, and mix. Adjust with
USP Reference standards (11)—USP Brompheniramine
ammonium hydroxide to a pH of 3.50 ± 0.05, filter, and
Maleate RS. USP Pseudoephedrine Sulfate RS.
degas. Make adjustments if necessary (see System
Identification—
Suitability under Chromatography (621)). [NOTE—The
A: The retention times of the major peaks in the
pH of the Mobile phase is critical and may cause 1 to 4
chromatogram of the Assay preparation correspond to
minutes of differences in the retention times of internal
those in the chromatogram of the Standard preparation,
standard and brompheniramine maleate.]
Internal standard solution—Transfer about 50 mg of
B: A solution of it meets the requirements of the test for
naphazoline hydrochloride to a 100-mL volumetric flask,
Sulfate (191).
add Mobile phase to volume, and mix.
C: Transfer a volume of Oral Solution, equivalent to
about 6 mg of brompheniramine maleate, to a separator,
quantity of USP Brompheniramine Maleate RS in Mobile
add 0.5 mL of ammonium hydroxide and 5 mL of
phase, and quantitatively dilute with Mobile phase to
methylene chloride, shake for 1 minute, and allow the
obtain a solution having a known concentration of about
layers to separate. Use the clear, lower layer as the test
6000/ ug per mL, J being the ratio of the labeled amount,
solution. Prepare separate Standard solutions in methanol
in mg, of brompheniramine maleate to the labeled amount,
containing, respectively, 1.2 mg of USP Brompheniramine
in mg, of pseudoephedrine sulfate per mL (Solution P).
Maleate RS and 9 mg of USP Pseudoephedrine Sulfate RS
Transfer about 30 mg of USP Pseudoephedrine Sulfate
per mL. Separately apply 5 uL of each solution to a suitable
RS, accurately weighed, to a 25-mL volumetric flask, add
thin-layer chromatographic plate (see Chromatography
5.0 mL each of Solution P and Internal standard solution,
(621)) coated with a 0.25-mm layer of chromatographic
dilute with Mobile phase to volume, and mix to obtain a
silica gel mixture. Allow the spots to dry, and develop the
Standard preparation having known concentrations of
chromatogram in a solvent system consisting of a mixture of
Pharmacopeia! Forum
about 1200/ug of USP Brompheniramine Maleate RS per in which C is the concentration, in mg per mL, of USP
mL and about 1.2 mg of USP Pseudoephedrine Sulfate RS Brompheniramine Maleate RS in the Standardpreparation;
per mL. Fis the volume, in mL, of Oral Solution taken; and Rv and
Assay preparation—Using a "To contain" pipet transfer Rs are the peak response ratios obtained for bromphenira-
an accurately measured volume of Oral Solution, equivalent mine maleate and naphazoline hydrochloride from the As-
to about 30 mg of Pseudoephedrine Sulfate, to a 25-mL say preparation and the Standard preparation, re-
volumetric flask. Rinse the pipet with about 5 mL of spectively. Calculate the quantity, in mg, of pseudo-
Mobile phase, collecting the rinse in the volumetric flask. ephedrine sulfate (C10H15NO)2 • H2SO4 in each mL of the
Add 5.0 mL of Internal standard solution, dilute with Oral Solution taken by the same formula, changing the
Mobile phase to volume, and mix. terms to refer to pseudoephedrine sulfate.AUSP26
Chromatographic system (see Chromatography (621))— (Official June 1, 2005)

detector and a 4-mm x 30-cm column that contains
packing LI 1. The flow rate is about 1.5 mL per minute.
Chromatograph the Standard preparation, and record the
peak responses as directed for Procedure: the resolution,
BRIEFING
R, between the pseudoephedrine sulfate and naphazoline
hydrochloride peaks is not less than 3, and the resolution, Brompheniramine Maleate and Pseudoephedrine Sulfate
Syrup, USP 25 page 255. It is proposed to change the title of this
R, between the brompheniramine maleate and naphazoline monograph to Brompheniramine Maleate and Pseudoephedrine
Sulfate Oral Solution. See also briefing under Amantadine Hydro-
hydrochloride peaks is not less than 3, and the relative chloride Syrup.
standard deviation for replicate injections is not more than (NL: C. Barnstein; PA2: J. Kelly) RTS—35944-1
2.0%.
Brompheniramine Maleate and
uL) of the Standard preparation and the Assay pre- Pseudoephedrine Sulfate Syrup
paration into the chromatograph, record the chro- (Current title—-not to change until June 1,2005)
matograms, and measure the responses for the major 2005
peaks. The relative retention times are about 1.0 for cess Revision):
See Brompheniramine Maleate and Pseudoephedrine
pseudoephedrine sulfate, 1.5 for naphazoline hydro- Sulfate Oral Solution
chloride, and 2.5 for brompheniramine maleate. Calculate
the quantity, in mg, of brompheniramine maleate
(C 16 H 19 BrN 2 -C 4 H 4 O 4 ) in each mL of the Oral Solution
Pharmacopeial Forum
Identification, Infrared Absorption (197K)—Prepare the

BRIEFING
test specimen as follows. Place a volume of Oral Solution,
Butabarbital Sodium Elixir, USP 25 page 264. It is proposed equivalent to about 150 mg of butabarbital sodium, in a
to change the title of this monograph to Butabarbital Sodium Oral
Solution. See also briefing under Amantadine Hydrochloride Syr- separator, render it distinctly alkaline by the addition of 1
up.
N sodium hydroxide, and saturate it with sodium chloride.
(NL: C. Barnstein; PA3: S. Salado) RTS—35945-1
Extract the mixture with two 15-mL portions of ether, and
discard the ether. Acidify the solution with hydrochloric
Butabarbital Sodium Elixir acid, and render it just alkaline to litmus by adding small
(Current title-^not to change until June 1, 2005) portions of sodium bicarbonate (carbonate-free). Extract
2005 the liberated acid barbiturate, using five 20-mL portions of
cess Revision): chloroform. Wash the combined chloroform extracts with
See Butabarbital Sodium Oral Solution
10 mL of water acidified with 1 drop of hydrochloric acid,
then extract the water with 10 mL of chloroform, adding the
latter to the main chloroform solution. Filter the chloroform
solution through a pledget of cotton or other suitable filter,
previously washed with chloroform, into a tared beaker, and
finally wash the separator and the filter with three 5-mL
BRIEFING
portions of chloroform. Evaporate the combined
Butabarbital Sodium Oral Solution—See briefing under
Amantadine Hydrochloride Syrup. chloroform solution and washings on a steam bath with
the aid of a current of air to dryness, and dry the residue
at 105° for 2 hours.
Add the following: Alcohol content, Method II (611): between 95.0% and
A 115.0% of the labeled amount of C2H5OH.

Butabarbital Sodium Oral Solution
(Monograph under this new title—to become official Assay—
June 1, 2005) Internal standard solution—Dissolve an accurately
(Current monograph title is Butabarbital Sodium Elixir)
weighed quantity of secobarbital in chloroform, and
quantitatively dilute with chloroform to obtain a solution
» Butabarbital Sodium Oral Solution contains not
less than 90.0 percent and not more than 110.0
Standard preparation—Dissolve accurately weighed
percent of the labeled amount of butabarbital so-
quantities of USP Butabarbital RS and secobarbital in
dium (C10H15N2NaO3). chloroform, and quantitatively dilute with chloroform to
Packaging and storage—Preserve in tight containers. obtain a solution that contains, in each mL, known
USP Reference standards (11)—USP Butabarbital RS. amounts of about 1 mg of USP Butabarbital RS and about
1.4 mg of secobarbital.
Pharmacopeial Forum
Assay preparation—[NOTE—This preparation includes a in which 234.23 and 212.25 are the molecular weights of
bromination step for elimination of parabens and a butabarbital sodium and butabarbital, respectively; Fis the
carbonate-chloroform extraction for elimination of benzoic volume, in mL, of Oral Solution taken; and the other terms
acid.] Transfer an accurately measured volume of Oral are as defined therein.Aas.w<s
Solution, equivalent to about 30 mg of butabarbital (Official June 1,2005)
sodium, to a separator, add 1 mL of bromine water

(prepared by dissolving 2.0 mL of bromine and 10 g of
potassium bromide in 60 mL of water), and swirl. Allow
to stand for 5 minutes, add 1 mL of sodium metabisulfite
solution (1 in 10), and swirl. Add 300 mg of sodium
BRIEFING
bicarbonate in small portions, with mixing, and extract
with four 10-mL portions of chloroform. Filter the Calcium Polycarbophil, USP 25 page 293 and page 3261 of
PF 27(6) [Nov.-Dec. 2001]. To improve the titration method in the
extracts through about 15 g of anhydrous sodium sulfate test for Calcium content, it is proposed to ash the sample first, spec-
ify an appropriate pH of the test solution prior to titration, and omit
that is supported on a runnel by a small pledget of glass the filtration step that could have contributed to the variability of
the test.
wool. Collect the combined filtrates in a 50-mL
volumetric flask, wash the sodium sulfate with 5 mL of
chloroform, collecting the washing with the filtrate, dilute
with chloroform to volume, and mix. Combine 2.0 mL of Change to read:
Content of calcium—Transfer about 2 g of Calcium Poly-
this solution with 2.0 mL of Internal standard solution in carbophil, accurately weighed, to a 250 mL boaker, add 100.0
mL of dilute hydrochloric aoid (1 in 5), atir for 15 minutoa, and
a suitable container, and reduce the volume to about 1 mL filter, diaoarding tho firot 15 mL of thofiltrato.Pipot 15 mL of
the filtrato
by evaporation, with the aid of a stream of dry nitrogen, at
A
to a tared crucible. Cover, leaving the lid slightly ajar, and
room temperature.
place in a muffle furnace. Heat to 600° over 2 hours, in-
Chromatographic system and System suitability—Proceed
crease the temperature to 1000° over 1 hour, and maintain
as directed for Chromatographic System and System
at 1000° for 1 hour. Allow to cool slowly. Dissolve the re-
Suitability under Barbiturate Assay (361), the resolution,
sidue in dilute hydrochloric acid (1 in 5), quantitatively
R, between butabarbital and secobarbital being not less
transfer with the aid of dilute hydrochloric acid (1 in 5) to
than 2.4. [NOTE—Relative retention times are approx-
a 100-mL volumetric flask, and dilute with dilute hydro-
imately 0.6 for butabarbital and 1.0 for secobarbital.]
chloric acid (1 in 5) to volume. Pipet 15 mL of this solu-
Procedure—Proceed as directed for Procedure under
tion AUSP26
Barbiturate Assay (361). Calculate the quantity, in mg, of into a 2 50-mL beaker, and add, while stirring with a magnetic stir-
rer, 100 mL of water, 20.0 mL of 0.05 M edetate disodium VS, 30
butabarbital sodium (C10H15N2NaO3) in each mL of the mL of 1 N aodium hydroxide,
Oral Solution taken by the formula: A.USP26

and 300 mg of hydroxy naphthol blue, trituration.
(234.23 /212.25)(5O)(RU)(QS)(Q/ V(RS), •
Ada additional aodium hydroxide dropwiao until tho color of tho
solution ohangoa from rod to bluo and then to violet, and add an
additional 0.5 mL of oodium hydro?cide. Continue titrating

Pharmacopeial Forum
A
Adjust with 1 N sodium hydroxide solution to a pH of 9.0 Cefazolin Sodium 35 mg
to 9.5. Adjust with about 10 mL of 2 N sodium hydroxide to Thimerosal 0.2 mg
Sodium Chloride Injection (0.9%), a 10.0 mL
a pH of 12.4. Titrate. VSP26 sufficient quantity to make
with 0.05 M edetate aisodium VS to a persistent blue endpoint.
Each mL of 0.05 M edetate disodium is equivalent to 2.004 mg
of calcium (Ca). The content of Ca found is not less than 18.0% Dissolve accurately weighed quantities of Cefazolin
and not more than 22.0%, calculated on the dried basis. Sodium and Thimerosal in Sodium Chloride Injection
(0.9%), and dilute quantitatively, and stepwise if nec-
essary, with Sodium Chloride Injection (0.9%) to ob-
tain a solution containing, in each mL, 3.5 mg of
Cefazolin Sodium and 0.02 mg of Thimerosal. Filter
a 10.0-mL portion of the resulting solution to produce
a clear and sterile Ophthalmic Solution. If Cefazolin
for Injection is used, prepare the Ophthalmic Solution
as follows. Dissolve an accurately weighed quantity of
Thimerosal in Sodium Chloride Injection (0.9%), and
BRIEFING
Sodium Chloride Injection (0.9%) to obtain a solution
Cefazolin Ophthalmic Solution, USP 25 page 333 and page
3262 of PF21(6) [Nov.-Dec. 2001]; Cocaine and Tetracaine containing 0.3 mg of Thimerosal per mL. Add 9.8 mL
Hydrochlorides and Epinephrine Topical Solution, USP 25 of the resulting solution to a vial of Cefazolin for In-
page 467 and page 3269 of PF 27(6) [Nov.-Dec. 2001]; Hydrala- jection, containing 500 mg of cefazolin, and mix to ob-
zine Hydrochloride Oral Solution, USP 25 page 847 and page tain a stock solution. Transfer 3.3 mL of the stock
3301 of PF 27(6) [Nov.-Dec. 2001]; Ketoconazole Oral Suspen- solution to a 50-mL volumetric flask, dilute with So-
sion, USP 25 page 976 and page 3313 of PF 27(6) [Nov.-Dec.
2001]; Morphine Sulfate Suppositories, USP 25 page 1175 and dium Chloride Injection (0.9%) to volume, and mix.
page 3318 of PF 27(6) [Nov.-Dec. 2001]; Progesterone Vaginal Filter a 10.0-mL portion of the resulting solution to
Suppositories, USP 25 page 1455; Rifampin Oral Suspension, produce a clear and sterile Ophthalmic Solution.
USP 25 page 1533 and page 3327 of PF 27(6) [Nov.-Dec.
2001]; Sodium Hypochlorite Topical Solution, USP 25 page
1585 and page 3329 of PF 27(6) [Nov.-Dec. 2001]; Suspension Change to read:
Structured Vehicle, NF 20 page 2632 and page 3346 of P F 27(6) Packaging and storage—Preserve in
[Nov.-Dec. 2001]; Sugar-Free Suspension Structured Vehicle,
NF20 page 2632 and page 3346 of P F 27(6) [Nov.-Dec. 2001]; •tight5|11
Tetracycline Hydrochloride Oral Suspension, USP 25 page sterile ophthalmic containers. Store in a refrigerator.
1678 and page 3333 of PF 27(6) [Nov.-Dec. 2001]; Xanthan
Gum Solution, NF 20 page 2644 and page 3347 of PF 27(6) Change to read:
[Nov.-Dec. 2001]. Sterility—See Sterility under Pharmacy Compounding '(•&§•)
It is proposed to revise these new title references of Pharmacy A
Compounding—Nonsterile Preparations (795) to agree with the Pharmaceutical Compounding—Nonsterile Preparations
new proposed change of Pharmaceutical Compounding—Nonster-
ile preparations (795).
(CRX: C. Okeke) RTS—35643-5
Change to read:
» Cefazolin Ophthalmic Solution contains an amount

of Cefazolin Sodium equivalent to not less than 29.7
mg and not more than 36.3 mg of cefazolin
(C14H14N8O4S3) in 10.0 mL of Ophthalmic Solution. BRIEFING
Use Cefazolin Sodium or Cefazolin for Injection that
contains the designated amount of cefazolin, and pre- Chloral Hydrate Oral Solution—See briefing under Amanta-
dine Hydrochloride Syrup.
pare the Ophthalmic Solution as follows (see Phar
inacy Compounding ( ) (NL: C. Barnstein; PA3: S. Salado) RTS—35947-1
^Pharmaceutical Compounding—Nonsterile Pre-
parations (795)):A.USP26
Pharmacopeial Forum
Add the following:

BRIEFING
A
Chloral Hydrate Oral Solution
Choral Hydrate Syrup, USP 25 page 376. It is proposed to
{Monograph under this new title—to become official change the title of this monograph to Chloral Hydrate Oral Solu-
June 1, 2005) tion. See also briefing under Amantadine Hydrochloride Syrup.
(Current monograph title is Chloral Hydrate Syrup)
» Chloral Hydrate Oral Solution contains not less

than 95.0 percent and not more than 110.0 percent Chloral Hydrate Syrup
of the labeled amount of chloral hydrate Monograph title change—to become official June 1,
2005
(C2H3C13O2). (see Official Title Changes on the first page of In-Pro-
cess Revision):
See Chloral Hydrate Oral Solution
containers.
Identification—It meets the requirements for the
Identification test under Chloral Hydrate.
Assay—Transfer 25.0 mL of Oral Solution to a 250-mL
conical flask with the aid of several portions of water.
BRIEFING
Add 30.0 mL of 1 N sodium hydroxide VS, and mix.
After the mixture has stood for 2 minutes, add 5 drops of Chlorpheniramine Maleate Oral Solution—See briefing un-
phenolphthalein TS, and immediately titrate the excess
sodium hydroxide with 1 N sulfuric acid VS. Designate
the volume of 1 N sodium hydroxide VS consumed as A.
Add the following:
Transfer 5.0 mL of Oral Solution to a second 250-mL
A
conical flask with the aid of several portions of water. Chlorpheniramine Maleate Oral
Solution
Add 10 drops of phenolphthalein TS, and titrate with 0.1
N sodium hydroxide VS. Designate the volume of 0.1 N June 1,2005)
(Current monograph title is Chlorpheniramine Maleate
sodium hydroxide VS consumed as B. Calculate the Syrup)
weight, in mg, of chloral hydrate (C2H3C13O2) in the
amount of Oral Solution taken by the first titration by the » Chlorpheniramine Maleate Oral Solution con-
formula: tains not less than 90.0 percent and not more than
165A(A-O.5B).AUSP26 110.0 percent of the labeled amount of chlorphe-
(Official June 1,2005) niramine maleate (C,6H19C1N2 • C4H4O4).

containers.
USP Reference standards (11)—USP Chlorpheniramine
Maleate RS.
Pharmacopeial Forum
Identification— acid phases through paper, discarding the first few mL of

A: Evaporate the remaining extract from the Assay on a each filtrate, and determine the absorbances of the
steam bath to a small volume, then transfer it to a smaller, solutions obtained from the Oral Solution and the
more suitable vessel, and evaporate just to the point where Standard solution in 1-cm cells at the wavelength of
hexane vapors are no longer perceptible. Transfer the oily maximum absorbance at about 264 nm, with a suitable
residue, with the aid of four 3-mL portions of spectrophotometer, using the extracted acid as the blank.
dimethylformamide, to a suitable glass-stoppered Calculate the quantity, in jig, of chlorpheniramine maleate
graduated cylinder, dilute with dimethylformamide to 15.0 (C16H19C1N2-C4H4O4) in each mL of the Oral Solution
mL, and mix: the optical rotation of the solution so obtained, taken by the formula:
in a 100-mm tube, after correcting for the blank, is not more
C{AV/AS),
than +0.01° {distinction from dexchlorpheniramine
in which C is the concentration, in ug per mL, of USP
maleate).
Chlorpheniramine Maleate RS in the Standard solution;
and Av and As are the absorbances of the solutions from
Solution: the solution employed for measurement of
the Oral Solution and the Standard solution, respective-
absorbance in the Assay.
Alcohol content {ifpresent) (611): between 6.0% and 8.0%
ofC2H5OH.
Assay—Transfer 10 mL of Oral Solution, accurately
measured, to a separator. Transfer about 40 mg of USP
Chlorpheniramine Maleate RS, accurately weighed, to a
100-mL volumetric flask, dilute with water to volume,
mix, and pipet 10 mL of this Standard solution into a BRIEFING
separator similar to that containing the Oral Solution.

Chlorpheniramine Maleate Syrup, USP 25 page 399. It is pro-
Treat each solution as follows. Add 10 mL of sodium posed to change the title of this monograph to Chlorpheniramine
Maleate Oral Solution. See also briefing under Amantadine Hydro-
hydroxide solution (1 in 10), and extract with two 50-mL chloride Syrup.
portions of solvent hexane. Combine the extracts in a (NL: C. Barnstein; AER: K. Zaidi) RTS—35948-1
second separator, wash with 10 mL of sodium hydroxide
solution (1 in 250), and discard the washing. Extract the
Chlorpheniramine Maleate Syrup
hexane solution with two 40-mL portions of dilute (Current title—not to change until June 1, 2005)
hydrochloric acid (1 in 100), collect the extracts in a 100- 2005
mL volumetric flask, add the same dilute acid to volume, (see Official Title Changes on the first page of In-Pro-
cess Revision):
and mix. Wash 50-mL portions of each solution, and of See Chlorpheniramine Maleate Oral Solution
dilute hydrochloric acid (1 in 100), respectively, with

three 30-mL portions of chloroform and then with 50 mL
of solvent hexane, and discard the washings. Filter the
Pharmacopeia! Forum
mL of 0.1 N sodium bicarbonate, and dilute with water to volume

BRIEFING to obtain solutions having final concentrations of 0.25, 0.50, 0.75,
Sodium Chromate Cr 51 Injection, USP 25 page 415 and page 1.00, 1.25, and 1.50 ug of chromium per mL.
2526 of PF 27(3) [May-June 2001]. In response to comments re-
ceived, the Expert Committee on Radiopharmaceuticals and Med- Assay preparation—Use the Injection.
ical Imaging Agents reviewed the revised Assay for sodium
chromate that was proposed in PF 27(3) [May-June 2001] and Blank preparation—Transfer 0.42 mL of 0.1 N sodium
decided to keep the revised version. The decision was based on
the judgment that the revised Assay, an atomic absoption ion-spe- bicarbonate to a 100-mL volumetric flask, and dilute with
cific test, together with the test for Radiochemical purity that dis-
tinguishes and quantifies the relative proportion of chromium in the water to volume.
Cr(III) and Cr(VI) oxidative states, provide a very meaningful and
appropriate standard for the quality of the Injection. Procedure—Concomitantly determine the absorbances of
the Assay preparation, the Standard preparations, and the
Blank preparation at the chromium emission line at 357.7
A
357.9 AC ,^ 2(5 nm with a suitable atomic absorption
Change to read: spectrophotometer (see Spectrophotometry and Light-
Assay for sodium chromate—Prepare a Standard solution of
aodium ohromato adjusted with sodium bicarbonate solution (1 Scattering {851}) equipped with a chromium hollow-
in 100) to a pH of 8.0 + 0.5 and containing 1.4 jxg of sodium
ohromato por mL. Dotormino the absorbanoos of tho Standard cathode lamp and an air-acetylene (fuel-rich) flame using
solution and of the Injootion, respectively, in 5 om oolls at tho
wavolongth of maximum aboorbanoo at about 370 nm, with a water to set the instrument to zero. Plot the absorbances
suitable spootrophotomotor, using water as tho blank. If tho
absorbanoo of tho Injootion ia not within 10% of that of tho of the Standard preparations and the Blank preparation
Standard solution, appropriately dilute oithor tho Injootion or tho
Standard solution. If tho Injootion is diluted, caloulate tho versus concentration, in ug per mL, of chromium, and
quantity', in u,g, of Naa€fQ4 per mL of tho Injootion taken by tho
perform a regression analysis. A suitable standard curve
1. '\D will have an intercept between -0.002 and +0.002, and a
in whioh D# is tho dilution faotor for tho Injootion and A# and As
aro tho absorbanooo of the Injootion and tho Standard solution, ro regression coefficient of not less than 0.99. Using the
apootivoly: If tho Standard solution is diluted, uoo \/D# in whioh Ds
is tho dilution faotor for tho Standard, in plaoe of D^ standard curve so obtained, determine the concentration,
m
Standard stock preparation—Dissolve 3.735 g of C, in ug per mL, of chromium in the Injection taken.
potassium chromate in 1000 mL of water to obtain a Calculate the quantity of sodium chromate, in ug per mL,
solution having a known concentration of 1.0 mg per mL by the formula:
of chromium. 3.115C,
A
Standard preparation—Pipet 0.25, 0.50, 0.75, 0.025,
in which 3.115 is the conversion factor.-,
0.050, Q.015,AUSP26 0.100, 0.125, and 0.150 mL of the
Standard stock preparation, accurately measured, into
separate 100-mL volumetric flasks. To each flask add 0.42
Pharmacopeial Forum
.2.0 mg and not more than 3.0 mg

BRIEFING of clonidino, if labeled to deliver 0.1 mg of oloni
Ciclopirox Olamine, USP 25 page 418. dine per day for one week; not loss than 4.0 mg
(PA7: S. Dressman) RTS—35816-1 and not more than 6.0 mg of olonidinc, if labeled
to deliver 0.2 mg of olonidino per day for one
Erratum: week; and not less than 6.0 mg and not more than
Monoethanolamine content, line 6: Change "anhydrous" to:
dried 9.0 mg of clonidino, if labeled to deliver 0.3 mg of
clonidino per day for ono wook. 80.0 percent and
of clonidine (C9H9C12N3).
Packaging and storage—Preserve in sealed, single-dose
BRIEFING containers at a temperature not exceeding 30°.
Labeling—The label states the total amount of clonidine in

Clonidine Transdermal System, page 1766 ofPF 27(1) [Jan.-
Feb. 2001 ]. Based on comments received that the overly restrictive
requirements in the Definition would hinder the development of the Transdermal System and the release rate, in mg per day,
other suitable transdermal systems, it is proposed to change the
limits back to a percentage of the total labeled content of clonidine for the duration of the application of one system.
in the transdermal system. In addition, Labeling requirements are
proposed to include the total content of clonidine in the transder- USP Reference standards (11)—USP Clonidine Hydro-
mal system in addition to the release rate. Several modifications are
being proposed for the Drug release test to be in accordance with chloride RS.
the approved NDA. Also, the Tolerances are expressed in intervals
to indicate that the specified release rate is in effect during the en- Identification—The retention time of the major peak in the
tire time interval and not just at a single point. Recent comments
received regarding the Assay and Chromatographic purity proce- chromatogram of the Assay preparation corresponds to that
dures are still under deliberation by the Expert Committee. Inter-
ested parties should be aware that a USP monograph for Clonidine in the chromatogram of the Standard preparation, as
(free-base) is under development and is necessary before adoption
of the monograph for Clonidine Transdermal System. obtained in the Assay.
(PA5: J. Esker,; NL: L. Paul; BPC: M. Marques) RTS— Uniformity of dosage units (905): meets the re-
31592-1 ; 34457-1; 34393-1; 33859-9; 33859-10
quirements.
Drug release (724)—

Add the following:
A Medium: 0.001 M phosphoric acid; 80 mL for systems
Clonidine Transdermal System
containing 5 mg or less of clonidine; 160 mL 200 mL for
systems containing more than 5 mg of clonidine.

» Clonidine Transdermal System contains not less
of t h e l a b e l e d a m o u n t of c l o n i d i n o
Pharmacopeial Forum
Times: 8, 24,96, and 168 hours. Solvent—Diosolve 2.01 g of monobasic potassium
Apparatus 7—Proceed asdircotod in the ohaptor. [Siso of phosphate and 2:88 g of 1 pontanosulfonio aoid aodium 1
aomplo holder to oomo.] pontano3ulfonato in 300 mL of water. Adjust with
Apparatus 7—Proceed as directed in the chapter, using phosphorio aoid to a pH of 3.5.
the transdermal system holder-angled disk (see Figure 7a). Mobile phase—Proparo a filtered and degassed mixture of
The appropriate size of the holder, 1.42" or 1.98", should be Solvent and mothanol (26:M). Make adjustments if
chosen based on the size of the system to prevent overhang. nooossary (see System Suitability under Chromatography
Use 100-mL beakers for Medium volumes of 80 mL and (634-)}r Use a filtered and degassed 0.1% solution of
300-mL beakers for Medium volumes of 200 mL. Gently triethylamine in a mixture of water and methanol (70:30),
press the transdermal system to a dry, smooth, square adjust with phosphoric acid to a pH of 6.0 + 0.2. Make
piece of cellulose membrane*, or equivalent, with the adjustments if necessary (see System Suitability under
adhesive side against the membrane. Attach the Chromatography (621)).
membrane/system to a suitable inert sample holder with a Test solution—At oaoh of the tost timo3, withdraw a 10-
Viton O-ring, or equivalent, such that the backing of the mL aliquot of the solution from eaoh container.
system is adjacent to, and centered on, the bottom of the Standai«d solution—Prepare a solution of USP Clonidino
sample holder. Trim the excess of cellulose membrane Hydroohlorido RS in 0.001 M phosphoric aoid having a
with scissors. Suspend each sample holder from the arm known oonoontration of olonidino similar to that of tho
of a reciprocating shaker such that each system is Test solution.
continuously immersed in a beaker containing the System suitability solution—Prepare a solution of USP
specified volume of Medium. The filled beakers are Clonidine Hydrochloride RS in 0.001 M phosphoric acid
weighed and pre-equilibrated to 32.0 + 0.3° prior to having a known concentration of about 10 ug per mL.
immersing the test sample. Agitate the sample in an up- Standard solutions—Prepare a minimum of four standard
down motion at a frequency of 30 cycles per minute with solutions of USP Clonidine Hydrochloride RS in 0.001 M
an amplitude of 2.0 + 0.1 cm. The Medium must be phosphoric acid having known concentrations of clonidine
added daily to the beakers during each interval to similar to those of the Test solutions.
maintain sample immersion. At the end of each time Test solutions—At the end of each release interval, allow
interval, transfer the test sample to a fresh beaker the beakers to cool to room temperature and make up for
containing the appropriate volume of Medium, weighed evaporative Medium losses by adding Medium to obtain
and pre-equilibrated to 32.0 + 0.3°. the original weight. Mix.
Determine the amount of C9H9CI2N3 released by employ- Chromatographic system (see Chromatography (621))—
ing the following method. The liquid chromatograph is equipped with a 210 nm 220-
nm detector and a 4,0 mm x 30 cm 4.6-mm x 15-cm
column that contains packing LI. The flow rate is about
1.5 mL per minute. Chromatograph the System suitability
* A suitable cellulose membrane is available as Cuprophan solution, and record the peak responses as directed for
80M, from Membrana GmbH, Ohder Strasse 28, D-42289,
Wuppertal, fax number +49 02 02 60 57 15. Procedure: the tailing factor is not more than £ 2.0; the
Pharmacopeia! Forum
capacity factor is not less than 0.5; the column efficiency is

•XATTTW Amount dissolved
not less than 2000 theoretical plates; and the relative
(ug/h cma)
standard deviation for replicate injections is not more than
& botwoon 7.5 and 16.0
2.0%.
34 botwoon 1.5 and 6.0
Procedure—Separately inject equal volumes (about §Q
96 botwoon 1.5 and 1.6
ph 25 uL) of filtered portions of the Standard solution
4r6& botwoon 1.5 and 3.3
and the Test solution into the chromatograph, record the
The amount of C 9 H 9 C1 2 N 3 released, as a percentage of the
labeled amount of the dose absorbed in vivo, as ug per hour
peaks. Construct a standard curve of concentration (ug per
per cm 2 , at the times specified conforms to Acceptance Table
mL) of clonidine in the Standard solutions versus peak area
4.
by linear regression analysis. The correlation coefficient is
not less than 0.995. Calculate the release rate of clonidine by
Time Time for sampling Amount dissolved
the formula:
(hours)
CV/TA, 0-8 between 7.5 and
in which C is the concentration, ug per mL, of clonidine in 16.0
the sample obtained from the standard curve; Fis the vol- 8-24 24 between 1.5 and
ume, in mL, of the Medium; Tis the time, in hours; and A is 4.6
the area, in cm2, of the transdermal system. 24-96 96 between 1.5 and
Tolerances—Tho amount of C9a9.Gix&i. roloaood,ao a 4.6
porocntago of tho labeled amount of tho doso absorbed in 96-168 168 between 1.5 and
vivo, as |ig por hour per om^ at the times speoified 3.3
oonforms to Acceptance Table 4. Chromatographic purity—
Buffer solution—Dissolve 2.0 g of sodium 1-pent-
Amount dig
anesulfonate, 13.61 g of monobasic potassium phosphate,
and 2 mL of triethylamine in about 1000 mL of water in a
botwoon 28% 2-liter volumetric flask, adjust with phosphoric acid to a pH
of 4.0 + 0.1, dilute with water to volume, and mix.
botwoon 116%
and 288%
Buffer solution and acetonitrile (1:1), and, if necessary,
T w botwoon 170%
adjust with phosphoric acid to a pH of 4.5 ± 0 . 1 . Make
and 357%
Pharmacopeial Forum
Diluent 1—Dissolve 1 mL of triethylamine in about 800 combine this aqueous supernatant layer with the first
mL of water in a 1-liter volumetric flask, adjust with aqueous layer in the 150-mL polytef-lined screw-cap tube.
phosphoric acid to a pH of 10.0 + 0.1, dilute with water [NOTE—The total length of time of extraction with 0.01 N
to volume, and mix. Transfer this solution to a 2-liter sulfuric acid should not exceed 1 hour to avoid degradation
volumetric flask, dilute with acetonitrile to volume, and of any related impurity that may be present.] Extract the
mix. aqueous layer by shaking vigorously for 2 minutes with
Diluent 2—Dissolve 1 mL of triethylamine and 4.36 g of each of two 30-mL portions of chloroform, collecting the
dibasic potassium phosphate in about 800 mL of water in a chloroform extracts in a 150-mL polytef-lined screw-cap
1-liter volumetric flask, adjust with phosphoric acid to a pH tube. Evaporate the chloroform extracts under nitrogen to
of 10.0 ± 0 . 1 , dilute with water to volume, and mix. dryness, and dissolve the residue in 15.0 mL of Diluent 2.
Transfer this solution to a 2-liter volumetric flask, dilute Chromatographic system (see Chromatography (621))—
with acetonitrile to volume, and mix. The liquid chromatograph is equipped with a 210-nm
Standard solution—Dissolve an accurately weighed detector and a 4.6-mm x 25-cm column that contains
quantity of USP Clonidine Hydrochloride RS in Diluent 1 packing L10. The flow rate is about 1 mL per minute.
to obtain a solution having a known concentration of about Chromatograph the Standard solution, and record the peak
0.1 mg per mL. Quantitatively dilute an accurately responses as directed for Procedure: the column efficiency
measured volume of this solution with Diluent 2 to obtain is not less than 4000 theoretical plates; the tailing factor is
a solution having a known concentration of about 16.2 ug not more than 1.5; and the relative standard deviation for
of USP Clonidine Hydrochloride RS per mL (equivalent to replicate injections is not more than 2.0%.
about 14.0 jig of clonidine per mL). Procedure—Separately inject equal volumes (about 20
Test solution—Carefully peel the release liner from each uL) of the Standard solution and the Test solution into the
Transdermal System, and place a number of Transdermal chromatograph, record the chromatograms, and measure the
Systems, equivalent to about 15 mg of clonidine, into a peak responses. Calculate the percentage of each impurity in
150-mL polytef-lined screw-cap tube. Add 30 mL of n- the Transdermal Systems taken by the formula:
heptane, cap, and mix on a vortex mixer for 2 minutes.
Allow to stand for about 3 hours, but every 30 minutes
during this period mix on a vortex mixer until the
clonidine and clonidine hydrochloride, respectively; C is
Transdermal Systems are delaminated. Add 0.3 mL of
the concentration, in ug per mL, of USP Clonidine Hydro-
methanol and 45 mL of 0.01 N sulfuric acid, shake for at
chloride RS in the Standard solution; N is the number of
least 2 minutes, and centrifuge. Retain the n-heptane
Transdermal Systems taken to prepare the Test solution; L
layer, and transfer the aqueous supernatant layer to a
is the labeled amount, in mg, of clonidine in each Transder-
second 150-mL polytef-lined screw-cap tube. Add 9 mL
mal System taken; rv is the peak response for each impurity
of ammonium hydroxide to the aqueous supernatant layer,
obtained from the Test solution; and rs is the clonidine peak
and mix. Extract the n-heptane layer with an additional 45
response obtained from the Standard solution: not moro
mL of 0.01 N sulfuric acid for at least 2 minutes, and
Pharmacopeia! Forum
than 1.4% of total impurities is found; not more than 1.4% packing LI. The flow rate is about 1.5 mL per minute.
of any impurity is found; and not more than 2.4% of total Chromatograph the Standard preparation, and record the
impurities is found. peak responses as directed for Procedure: the tailing
Assay— factor is not more than 2.0; and the relative standard
Mobile phase—Prepare a filtered and degassed mixture of deviation for replicate injections is not more than 2.0%.
sodium 1-pentanesulfonate and methanol (63:36). Make Procedure—Separately inject equal volumes (about 50
adjustments if necessary (see System Suitability under uL) of the Standard preparation and the Assay
Chromatography (621)). preparation into the chromatograph, record the
Standard preparation—Dissolve an accurately weighed chromatograms, and measure the responses for the major
quantity of USP Clonidine Hydrochloride RS in 0.01 N peaks. Calculate the quantity, in ug, of clonidine
sulfuric acid, and dilute quantitatively, and stepwise if (C9H9CI2N3) in the Transdermal System taken by the
necessary, with 0.01 N sulfuric acid to obtain a solution formula:
having a known concentration of about 46 ug per mL.
0.0467 per mL (equivalent to about 0.040T of clonidine
per mL), T being the total amount, in mg, of clonidine in
(230.10/266.56)(25 Q ^ / rs),
each Transdermal System.
Assay preparation—Carefully peel the release liner from
clonidine and clonidine hydrochloride, respectively; C is the
1 Transdermal System, and cut the Transdermal System into
concentration, in jig per mL, of USP Clonidine Hydrochlor-
segments. Quantitatively transfer the segments into an
ide RS in the Standard preparation; and rv and rs are the
appropriate polytef-lined screw-cap centrifuge tube, add
peak responses obtained from the Assay preparation and
10 mL of 0.01 N sulfuric acid saturated with n-heptane,
the Standard preparation, respectively. AUSP26
accurately measured, cap, and heat to 60° for 3 hours.
Add 10 mL of «-heptane, cap, shake vigorously for 1
minute, and heat to 60° for about 16 hours. Allow the
solution to cool to room temperature, add 15 mL of 0.01
N sulfuric acid saturated with n-heptane, cap, and mix in
a vortex mixer for about 2 minutes. Allow to separate,
BRIEFING
and filter the aqueous layer. [NOTE—If backing membrane
Clorsulon, USP 25 page 457 and page 55 of PF 28(1) [Jan.-
has not delaminated, repeat with a new Transdermal Feb. 2002]. On the basis of data received, in the test for Chromato-
graphic purity it is proposed to store the Standard solutions and
System.] Use the aqueous layer as the Assay preparation. Test Solution in low-actinic glassware. In the Assay, it is also pro-
posed to store the Standard preparation and the Assay preparation
Chromatographic system (see Chromatography (621))— in low-actinic glassware.
(VET: I. DeVeau) RTS—35776-1
detector, a 3.9-mm x 2-cm guard column that contains
packing L2, and a 3.9-mm x 30-cm column that contains
Pharmacopeia! Forum
in which C is the concentration, in mg per mL, of USP Clorsulon

Change to read: RS in the Standard preparation; and rv and rs are the clorsulon
Chromatographic purity— peak responses obtained from the Assay preparation and the Stan-
A dard preparation, respectively.
[NOTE—The Standard solutions and Test solutions should
be stored in low-actinic glassware.]Al/5F2(5

Prepare a solution of Clorsulon in methanol containing 10.0 mg per
mL (Test solution). Prepare a solution of USP Clorsulon RS in
methanol containing 10.0 mg per mL (Standard solution A). Trans-
fer 1.0 mL of Standard solution A to a 100-mL volumetric flask,
dilute with methanol to volume, and mix (Standard solution B).
Apply 10-uL portions of the Test solution and of Standard solution
A, and 5- and 10-uL portions of Standard solution B to a suitable
thin-layer chromatographic plate (see Chromatography (621)),
coated with a 0.25-mm layer of chromatographic silica gel mixture. BRIEFING
Allow the spots to dry, and develop the chromatograms in a solvent
system consisting of a mixture of chloroform and methanol (4:1)
until the solvent front has moved about three-fourths of the length Cocaine and Tetracaine Hydrochlorides and Epinephrine
of the plate. Remove the plate from the developing chamber, mark Topical Solution, USP 25 page 467 and page 3269 of PF 27(6)
the solvent front, allow the solvent to evaporate, and examine the [Nov.-Dec. 2001]—See briefing under Cefazolin Ophthalmic So-
plate under short-wavelength UV light: the chromatograms show lution.
principal spots at about the same RF value. Estimate the amounts of
any additional spots observed in the chromatogram of the Test so- (CRX: C. Okeke) RTS—35643-3
lution by comparing them with the spots in the two chromatograms
obtained from Standard solution B, corresponding to 0.5% and
1.0% of impurity: no spot, other than the principal spot, in the chro-
matogram of theTest solution is larger or more intense than that of Change to read:
the principal spot in the chromatogram obtained from the 5-uL por-
tion of Standard solution B (0.5%), and the sum of all such impu-
rities is not more than 2.0%. » Cocaine and Tetracaine Hydrochlorides and Epi-
nephrine Topical Solution contains not less than 3.6
Change to read: g and not more than 4.4 g of Cocaine Hydrochloride,
Assay— not less than 0.90 g and not more than 1.10 g of Tetra-
Mobile phase—Prepare a filtered and degassed mixture of water, caine Hydrochloride, and not less than 20 mg and not
acetonitrile, and glacial acetic acid more than 30 mg of Epinephrine in 100 mL of Topical
"(70:30:0.1).B2 Solution prepared as follows (see Pharmacy
Make adjustments if necessary (see System Suitability under Compounding ( )
Standard preparation—Dissolve an accurately weighed quantity ^Pharmaceutical Compounding—Nonsterile Pre-
of USP Clorsulon RS in Mobile phase to obtain a solution having a
known concentration of about 0.1 mg per mL. parations (795:)):AUSP26
A
Store the solution in low-actinic glassware.AUSp26
Assay preparation—Transfer about 50 mg of Clorsulon,
accurately weighed, to a 50-mL volumetric flask, dilute with Cocaine Hydrochloride 4.0 g
Mobile phase to volume, and mix. Transfer 5.0 mL of this Tetracaine Hydrochloride 1.0 g
solution to a second 50-mL volumetric flask, dilute with Mobile Epinephrine Injection (1:1000) 25.0 mL
phase to volume, and mix. Benzalkonium Chloride 10 mg
A
Store the solution in low-actinic glassware.. ro p Edetate Disodium 6.4 mg
Chromatographic system (see Chromatography (621))—The Sodium Chloride Injection (0.9%) 35 mL
4.6-mm x 25-cm column that contains packing L7. The flow Purified Water, a sufficient quantity to
rate is about 1 mL per minute. Chromatograph the Standard make 100 mL
Procedure: the column efficiency is not less than 7400
theoretical plates; the tailing factor is not more than 1.4; and the Dissolve the Cocaine and Tetracaine Hydrochlor-
relative standard deviation for replicate injections is not more ides in about 25 mL of Purified Water, and add the Epi-
than 1.0%. nephrine Injection (1:1000). Separately dissolve an
Procedure—Separately inject equal volumes (about 30 uL) of accurately weighed quantity of Edetate Disodium in
the Standard preparation and the Assay preparation into the Sodium Chloride Injection (0.9%), and dilute quantita-
responses for the major peaks. Calculate the quantity, in mg, of tively, and stepwise if necessary, with Sodium Chlo-
C8H8C13N3O4S2 in the portion of Clorsulon taken by the formula: ride Injection (0.9%) to obtain 35 mL of a solution
containing 6.4 mg of Edetate Disodium. Similarly,
and separately, dissolve an accurately weighed quan-
tity of Benzalkonium Chloride in Purified Water (or
use an accurately measured volume of Benzalkonium
Chloride Solution), and dilute quantitatively, and step-
Pharmacopeial Forum
wise if necessary, with Purified Water to obtain 10 mL disulfide, filtering if necessary. Determine the IR
of a solution containing 10 mg of Benzalkonium Chlo-
ride. Combine the three solutions, add sufficient Puri- absorption spectrum as directed under Identification—
fied Water to make the product measure 100 mL, and Organic Nitrogenous Bases (181), obtaining the spectrum
mix to produce the Topical Solution.
of USP Cyproheptadine Hydrochloride RS as directed: the
Oral Solution meets the requirements of the test.
Assay—
Methanesulfonic acid solution, Mobile phase, and

BRIEFING
Assay under Cyproheptadine Hydrochloride Tablets.
Cyproheptadine Hydrochloride Oral Solution—See briefing
under Amantadine Hydrochloride Syrup. Standard preparation—Dissolve an accurately weighed
(NL: C. Bamstein; AER: K. Zaidi) RTS—35949-1 quantity of USP Cyproheptadine Hydrochloride RS in

Add the following: concentration of about 0.02 mg per mL.
A Assay preparation—Transfer an accurately measured

Cyproheptadine Hydrochloride Oral
Solution volume of Oral Solution, equivalent to about 2 mg of
(Monograph under this new title—to become official cyproheptadine hydrochloride, to a 100-mL volumetric
June 1, 2005)
(Current monograph title is Cyproheptadine Hydrochlor- flask. Dilute with Mobile phase to volume, and mix. Pass
ide Syrup)
the solution through a filter having a 0.45-urn or finer
porosity.
» Cyproheptadine Hydrochloride Oral Solution Procedure—Separately inject equal volumes (about 10
contains not less than 90.0 percent and not more uL) of the Standard preparation and the Assay
than 110.0 percent of the labeled amount of cypro- preparation into the chromatograph, record the
heptadine hydrochloride (C21H21N • HC1). chromatograms, and measure the responses for the major
peaks. Calculate the quantity, in mg, of cyproheptadine
hydrochloride (C2IH21N-HC1) in the portion of Oral
USP Reference standards (11)—USP Cyproheptadine
Solution taken by the formula:
Hydrochloride RS.
l00C(ru/rs),
Identification—Place about 50 mL of Oral Solution in a
separator, add 25 mL of sodium bicarbonate solution (2 in in which C is the concentration, in mg per mL, of USP Cy-
100), and extract with three 15-mL portions of isooctane. proheptadine Hydrochloride RS in the Standard prepara-
Wash the combined isooctane extracts with 15 mL of tion; and rv and rs are the cyproheptadine peak responses
sodium bicarbonate solution (2 in 100), and discard the obtained from the Assay preparation and the Standard pre-
washing. Evaporate the isooctane solution on a steam bath paration, respectively.A6OT2<s
to dryness, and dissolve the residue in 1 mL of carbon (Official June 1,2005)
Pharmacopeia! Forum
USP Reference standards (11)—USP Dexchlorphenira-
BRIEFING
mine Maleate RS.
Identification—
Cyproheptadine Hydrochloride Syrup, USP 25 page 497. It is
proposed to change the title of this monograph to Cyproheptadine A: Evaporate the remaining extract from the Assay on a
Hydrochloride Oral Solution. See also briefing under Amantadine
Hydrochloride Syrup. steam bath to a small volume, then transfer it to a smaller,
(NL: C. Bamstein; AER: K. Zaidi) RTS—35949-1 more suitable vessel, and evaporate just to the point where
hexane vapors are no longer perceptible. Transfer the oily
residue, with the aid of four 3-mL portions of dimethyl-
Cyproheptadine Hydrochloride Syrup
{Current title--not to change until June 1,2005) formamide, to a suitable glass-stoppered graduated
2005 cylinder, dilute with dimethylformamide to 15.0 mL, and
cess Revision): mix: the optical rotation of the solution so obtained, in a
See Cyproheptadine Hydrochloride Oral Solution
100-mm tube, after correcting for the blank, is between
+0.06° and +0.11° (distinction from chlorpheniramine
maleate).
B: Ultraviolet Absorption (197U): Assay preparation
compared to Standard preparation from Assay.
Alcohol content (611): between 5.0% and 7.0% of
BRIEFING
C2H5OH.
Dexchlorpheniramine Maleate Oral Solution—See briefing Assay—
under Amantadine Hydrochloride Syrup.
Dexchlorpheniramine Maleate RS, accurately weighed, to
a 100-mL volumetric flask, add water to volume, and mix.
Add the following:
Transfer 10.0 mL of this solution to a separator, adjust with
A
Dexchlorpheniramine Maleate Oral 1 N sodium hydroxide to a pH of 11, and cool. Extract with
Solution
two 50-mL portions of solvent hexane, shaking each portion
June 1, 2005) for 2 minutes before separating the phases, and combining
(Current monograph title is Dexchlorpheniramine Male-
ate Syrup) the hexane extracts in a second separator. Extract the hexane
solution with two 40-mL portions of dilute hydrochloric
» Dexchlorpheniramine Maleate Oral Solution acid (1 in 120), combine the acid extracts in a 100-mL
contains not less than 90.0 percent and not more volumetric flask, add dilute hydrochloric acid (1 in 120)
than 110.0 percent of the labeled amount of dex- to volume, and mix. Filter the solution into a glass-
stoppered conical flask, discarding the first few mL of the
chlorpheniramine maleate (C16H19C1N2 • C4H4O4).
filtrate. The concentration of USP Dexchlorpheniramine
Packaging and storage—Preserve in tight, light-resistant Maleate RS in the Standard preparation is about 40 ug
containers. per mL.
Pharmacopeial Forum
Assay preparation—Transfer an accurately measured in which C is the concentration, in jig per mL, of USP Dex-
volume of Oral Solution, equivalent to about 40 mg of chlorpheniramine Maleate RS in the Standard prepara-
dexchlorpheniramine maleate, to a 250-mL separator, tion; V is the volume, in mL, of Oral Solution taken; and
using a pipet calibrated "to contain" the required volume. Ay and As are the absorbances of the Assay preparation
Rinse the pipet with small portions of water, add the and the Standard preparation, respectively.A[/Sp2(5
rinsings to the separator, adjust with 1 N sodium (Official June 1,2005)
hydroxide to a pH of 11, and cool. Extract with five 70-

mL portions of solvent hexane, combine the hexane
extracts in a 500-mL separator, and wash the hexane
solution with two 10-mL portions of sodium hydroxide
solution (1 in 250). Extract the combined alkaline
BRIEFING
washings with two 20-mL portions of solvent hexane, and
add these extracts to the bulk of the alkali-washed hexane Dexchlorpheniramine Maleate Syrup, USP 25 page 529. It is
proposed to change the title of this monograph to Dexchlorphenir-
solution. Filter the hexane solution through a pledget of amine Maleate Oral Solution. See also briefing under Amantadine
Hydrochloride Syrup.
cotton that previously has been saturated with solvent
hexane into a 500-mL volumetric flask, rinse the separator
with portions of solvent hexane, pass the rinsings through
the filter to add to volume, and mix. Transfer 50.0 mL of Dexchlorpheniramine Maleate Syrup
this solution to a separator (retain the remaining extract (Current title—not to change until June 1,2005)
for Identification test A), and proceed as directed for 2005
Standard preparation, beginning with "Extract the hexane cess Revision):
See Dexchlorpheniramine Maleate Oral Solution
solution."
Procedure—Concomitantly determine the absorbances of
the Standard preparation and the Assay preparation in 1-cm
cells at the wavelength of maximum absorbance at about
264 nm, using dilute hydrochloric acid (1 in 120) as the
blank. Calculate the quantity, in mg, of dexchlor-
BRIEFING
pheniramine maleate (C16H19C1N2-C4H4O4) in each mL
Dexchlorpheniramine Maleate Tablets, USP 25 page 530.
of the Oral Solution taken by the formula: Editorial revisions are indicated to conform with the title change
proposed for Dexchlorpheniramine Maleate Syrup. See briefing
(C/V)(Aa/As),
Pharmacopeial Forum
Change to read:
Assay—
Standard preparation—Prepare as directed in the Assay under BRIEFING
Dexchlorpheniramine Maleate Syimp
A
Oral Solution AUSP26 Dextroamphetamine Sulfate Oral Solution—See briefing un-
. The concentration of USP Dexchlorpheniramine Maleate RS in der Amantadine Hydrochloride Syrup.
the Standard preparation is about 40 ug per mL.
Assay preparation—Weigh and finely powder not fewer than 20 (NL: C. Bamstein; PA3: S. Salado) RTS—35952-1
Tablets. Transfer an accurately weighed portion of the powder,
equivalent to about 8 mg of dexchlorpheniramine maleate, to a
250-mL separator, mix with 50 mL of water for 10 minutes,
adjust with sodium hydroxide solution (1 in 10) to a pH of 11, Add the following:
and cool to room temperature. Extract the mixture with two 75-
mL portions of solvent hexane, and combine the extracts in a A
second separator. Extract the solvent hexane solution with three Dextroamphetamine Sulfate Oral
50-mL portions of dilute hydrochloric acid (1 in 120),
combining the acid extracts in a 200-mL volumetric flask. Add Solution
dilute hydrochloric acid (1 in 120) to volume, and mix. (Monograph under this new title—to become official
Procedure—Concomitantly determine the absorbances of the June 1, 2005)
Assay preparation and the Standard preparation in 1-cm cells at (Current monograph title is Dextroamphetamine Sulfate
the wavelength of maximum absorbance at about 264 nm, with a Elixir)
suitable spectrophotometer, using dilute hydrochloric acid (1 in
120) as the blank. Calculate the quantity, in mg, of
dexchlorpheniramine maleate (C| 6 H 1 9 C1N 2 -C 4 H 4 O 4 ) in the
portion of Tablets taken by the formula: » Dextroamphetamine Sulfate Oral Solution con-
0.2C(Ay/As),
tains, in each 100 mL, not less than 90.0 mg and
in which C is the concentration, in jig per mL, of USP Dexchlor-
pheniramine Maleate RS in the Standard preparation; and Av and
As are the absorbances of the Assay preparation and the Standard not more than 110.0 mg of dextroamphetamine
preparation, respectively.
sulfate [(C9H13N)2-H2SO4].
containers.
USP Reference standards (11)—USP Dextroampheta-

mine Sulfate RS.
Identification—Transfer 25 mL of Oral Solution to a 250-

BRIEFING
mL separator, add 25 mL of water and 5 mL of 2.5 N
Dextroamphetamine Sulfate Elixir, USP 25 page 537. It is sodium hydroxide, mix, and extract with 60 mL of ether.
proposed to change the title of this monograph to Dextroampheta-
mine Sulfate Oral Solution. See also briefing under Amantadine Wash the ether extract with two 5-mL portions of 0.25 N
sodium hydroxide, and discard the washings. Filter the
(NL: C. Bamstein; PA3: S. Salado) RTS—35952-1
ether extract through a pledget of cotton, previously
saturated with ether, into a 100-mL beaker, and evaporate
Dextroamphetamine Sulfate Elixir on a steam bath in a current of air to about 1 mL.
(Current title—not to change until June 1,2005)
Monograph title change—to become official June 1, Dissolve the residue in 3 mL of alcohol, and transfer to a
2005
(see Official Title Changes on the first page of In-Pro- glass-stoppered, 125-mL conical flask containing 25 mL
cess Revision):
See Dextroamphetamine Sulfate Oral Solution of water. Rinse the beaker with 3 mL of alcohol, and
transfer to the flask. Cool to about 15°, add 3 mL of 1 N
sodium hydroxide, then add 1 mL of a mixture of 1
Pharmacopeial Forum
volume of benzoyl chloride and 2 volumes of anhydrous pledget of filter cotton into a 100-mL beaker, rinse the
ethyl ether, and shake for 2 minutes. Filter the precipitate, cotton with a small amount of chloroform, and evaporate
wash with about 15 mL of cold water, and recrystallize on a steam bath in a current of air or nitrogen to dryness.
twice from diluted alcohol: the benzoyl derivative of Heat and triturate the residue until the odor of chloroform
dextroamphetamine so obtained, after being dried at 105° is no longer perceptible. Allow the residue to cool,
for 1 hour, melts between 154° and 160°. inducing it to crystallize. Reduce the crystals to a fine
Alcohol content (611): between 9.0% and 11.0% of powder, heat at 80° for 30 minutes, and cool: the specific
C2H5OH. rotation of the acetylamphetamine so obtained, determined

in a solution in chloroform containing 20 mg per mL, a 200-
Isomeric purity—Transfer 150 mL of Oral Solution to a
mm semimicro polarimeter tube being used, is between
500-mL separator, add 15 mL of 2.5 N sodium hydroxide,
-37.5° and -44.0°.
and extract with one 60-mL and two 40-mL portions of
Assay—
ether. Wash the combined ether extracts with two 10-mL
portions of 0.25 N sodium hydroxide. Wash the aqueous Chromatographic column—Proceed as directed for
alkaline extracts with 20 mL of ether, adding the ether Column Partition Chromatography under Chro-
washing to the combined ether extracts. Filter the ether matography (621), packing a chromatographic tube with a
extracts through a pledget of cotton, previously saturated mixture of 2 g of Solid Support and 1 mL of 0.06 N
with ether, into a 250-mL beaker, rinse the cotton with a hydrochloric acid.
small amount of ether, and evaporate on a steam bath in a Standard preparation—Dissolve an accurately weighed
current of air to about 2 mL. Dissolve the residue in 20 mL quantity of USP Dextroamphetamine Sulfate RS in 1.8 N
of chloroform, and transfer to a separator containing 35 mL sulfuric acid (previously saturated with chloroform), and
of 0.1 N sulfuric acid. Complete the transfer with two dilute quantitatively and stepwise with the same solvent to
additional 20-mL portions of chloroform. Shake the obtain a solution having a known concentration of about 0.5
separator vigorously for 1 minute, allow the layers to mg per mL.
separate, and discard the chloroform. Add to the liquid in Assay preparation—Pipet 5 mL of Oral Solution into a
the separator 2.5 g of sodium bicarbonate, preventing it 100-mL beaker, add 1 drop of 3 N hydrochloric acid, and
from coming in contact with the mouth of the separator, swirl to mix. Add 6 g of purified siliceous earth, and mix
and swirl until most of the bicarbonate has dissolved. By with a glass rod until a fluffy mixture is obtained.
means of a 1-mL syringe, rapidly inject 1.0 mL of acetic Procedure—Transfer the Assay preparation to the
anhydride directly into the contents of the separator. Chromatographic column, and complete the preparation
Immediately insert the stopper in the separator, and shake of the column. Wash the prepared column with 100 mL of
vigorously until the evolution of carbon dioxide has chloroform that previously has been saturated with water,
ceased, releasing the pressure as necessary through the and discard the washing. Arrange to collect the eluate in a
stopcock. Allow to stand for 5 minutes, and extract the separator containing 10.0 mL of 1.8 N sulfuric acid that
solution with 50 mL of chloroform, shaking vigorously previously has been saturated with chloroform. Pass
for 1 minute. Pass the chloroform extract through a through the column 60 mL of a freshly prepared
Pharmacopeial Forum
ammoniacal chloroform solution, made by shaking 50 Change to read:

Identification—
volumes of chloroform with 1 volume of ammonium A: Transfer a portion offinelyground Tablets, equivalent to
about 50 mg of dextroamphetamine sulfate, to a suitable
hydroxide for 1 to 2 minutes and discarding the aqueous centrifuge tube. Add 25 mL of water, shake vigorously, and
centrifuge until clear. Decant the clear solution into a 250-mL
phase. Complete the elution with 60 mL of chloroform separator, add 5 mL of 2.5 N sodium hydroxide, mix, and
proceed as directed for the Identification test under
(previously saturated with water). Shake the separator Dextroamphetamine Sulfate Elixir
A
vigorously for 1 minute, allow the layers to separate, and Oral Solution. USP26
, beginning with and extract with 60 mL of ether."
discard the chloroform. Concomitantly determine the B: The retention time of the major peak in the chromatogram
of the Assay preparation corresponds to that in the chromatogram
absorbances of the Standard preparation and the Assay of the Standard preparation, as obtained in the Assay.
(Official June 1, 2005)
preparation in 1-cm cells at 280 nm and at the maximum
Change to read:
at about 257 nm, with a suitable spectrophotometer, using Isomeric purity—Pack a pledget of fine glass wool in the base of a
200- x 2 5-mm chromatographic tube, with the aid of a tamping
1.8 N sulfuric acid (previously saturated with chloroform) rod. Add 5 g of chromatographic siliceous earth, and tampfirmlyto
compress the material to a uniform mass.
as the blank. Calculate the quantity, in mg, of Finely powder a number of Tablets, equivalent to about 130 mg
dextroamphetamine sulfate [(C 9 H 13 N) 2 -H 2 SO 4 ] in the of dextroamphetamine sulfate, mix the powder in a mortar with 5 g
of chromatographic siliceous earth, add 1 mL of methanol and 0.5
mL of ammonium hydroxide, and triturate to a uniform mixture.
portion of Oral Solution taken by the formula: Transfer the mixture without delay to the chromatographic tube,
and tamp as before. Wipe the mortar and pestle with a small
amount of glass wool, and insert it into the tube on top of the col-
umn. Arrange a 125-mL separator containing 35 mL of 0.1 N sul-
furic acid to receive the effluent. Pass 60 mL of chloroform through
in which C is the concentration, in mg per mL, of USP Dex- the column. Proceed as directed in the test for Isomeric purity un-
der Dextroamphetamine Sulfate Elixir
troamphetamine Sulfate RS in the Standard preparation; A
Oral Solution. USP26
and the parenthetic expressions are the differences in the ab- , beginning with Shake the separator vigorously."
sorbances of the two solutions at the wavelengths indicated
by the subscripts, for the Assay preparation (U) and the
Standard preparation (5), respectively.At/5W5
BRIEFING
Dextromethorphan Hydrobromide Oral Solution—See

(NL: C. Barnstein; PA2: J. Kelly) RTS—35954-1

BRIEFING
Dextroamphetamine Sulfate Tablets, USP 25 page 537. Edi-

torial revisions are indicated to conform with the title change pro- Add the following:
posed for Dextroamphetamine Sulfate Elixir. See also briefing
under Amantadine Hydrochloride Syrup. A
Dextromethorphan Hydrobromide
(NL: C. Barnstein; PA3: S. Salado) RTS—35953-1 Oral Solution
June 1, 2005)
(Current monograph title is Dextromethorphan Hydro-
bromide Syrup)
Pharmacopeial Forum
» Dextromethorphan Hydrobromide Oral Solu- Assay preparation—Pipet, using a to-contain pipet, a
tion contains not less than 90.0 percent and not volume of Oral Solution, equivalent to about 10 mg of
dextromethorphan hydrobromide, into a 100-mL
more than 110.0 percent of the labeled amount
of dextromethorphan hydrobromide (C18H25
Chromatographic system and Procedure (see
NOHBrH 2 O).
Chromatography (621))—Proceed as directed in the
Packaging and storage—Preserve in tight, light-resistant Assay under Dextromethorphan Hydrobromide. Calculate
containers. the quantity, in mg, of dextromethorphan hydrobromide
USP Reference standards (11)—USP Dextromethorphan (C 18 H 25 NO-HBr-H 2 O) in the volume of Oral Solution
Hydrobromide RS. taken by the formula:
Identification— (370.33 /352.32)(100C)(r(,/rs),

A: Transfer about 50 mL of Oral Solution to a 250-mL
separator, add 20 mL of water, 5 mL of 2.5 N sodium
dextromethorphan hydrobromide and anhydrous dextro-
hydroxide, and 40 mL of solvent hexane, and shake
methorphan hydrobromide, respectively; C is the concentra-
thoroughly. Remove the solvent hexane layer, and filter
tion, in mg per mL, of USP Dextromethorphan
through anhydrous sodium sulfate into a 150-mL beaker.
Hydrobromide RS, on the anhydrous basis, in the Standard
Repeat the solvent hexane extraction, using two 40-mL
preparation; and rv and rs are the peak responses obtained
portions and collecting the extracts in the beaker after
filtering. Evaporate the combined extracts at 50° under
respectively.^^
nitrogen to dryness, and dissolve the residue in, and dilute
with, 10 mL of chloroform: the solution is dextrorotatory
(see Optical Rotation (781)). Retain the chloroform
solution for Identification test B.
BRIEFING
B: Evaporate the chloroform solution from
Dextromethorphan Hydrobromide Syrup, USP 25 page 539.
Identification test A on a steam bath to dryness, dissolve It is proposed to change the title of this monograph to Dextro-
methorphan Hydrobromide Oral Solution. See also briefing under
the residue in 2 mL of 2 N sulfuric acid, and add 1 mL of Amantadine Hydrochloride Syrup.
a freshly prepared solution of mercuric nitrate (prepared by
dissolving 700 mg of mercuric nitrate in 4 mL of water,
adding 100 mg of sodium nitrate, mixing, and filtering):
no red color is produced immediately, but after heating, a Dextromethorphan Hydrobromide
Syrup
yellow to red color develops in about 15 minutes.
(Current title—-not to change until June 1, 2005)
Assay— Monograph title change—to become official June 1,
2005
Mobile phase and Standard preparation—Prepare as (see Official Title Changes on first page of In-Process
Revision):
directed in the Assay under Dextromethorphan See Dextromethorphan Hydrobromide Oral Solution
Hydrobromide.
Pharmacopeial Forum
BRIEFING
Dicyclomine Hydrochloride Oral Solution—See briefing un-
der Amantadine Hydrochloride Syrup. obtained in the Assay.
(NL: C. Bamstein; PA4: A. Medjedovic) RTS—35955-1 Assay—

Add the following: Chromatographic system—Prepare as directed in the
A Assay under Dicyclomine Hydrochloride Capsules.
Dicyclomine Hydrochloride Oral
Solution Assay preparation—Transfer an accurately measured
(Monograph under this new title—to become official volume of Oral Solution, equivalent to 5.0 mg of
June 1, 2005)
(Current monograph title is Dicyclomine Hydrochloride dicyclomine hydrochloride, to a solid-phase extraction
Syrup)
cartridge. Elute with 4 mL of chloroform and then elute
with three 2-mL portions of chloroform, collecting the
» Dicyclomine Hydrochloride Oral Solution con-
eluates in a 25-mL volumetric flask. Add 5.0 mL of
tains not less than 95.0 percent and not more than Internal standard solution, dilute with methanol to
105.0 percent of the labeled amount of dicyclo- volume, and mix.
mine hydrochloride (C19H35NO2 • HC1). Procedure—Proceed as directed in the Assay under
Dicyclomine Hydrochloride Capsules. Calculate the
quantity, in mg, of dicyclomine hydrochloride
USP Reference standards (11)—USP Dicyclomine Hy-
(C19H35NO2 -HC1) in the portion of Oral Solution taken
drochloride RS.
by the formula:
Identification—
A: Transfer a portion of the Oral Solution, equivalent to
about 100 mg of dicyclomine hydrochloride, to a separator in which C is the concentration, in mg per mL, of USP Di-
containing 10 mL of water and 1 mL of hydrochloric acid. cyclomine Hydrochloride RS in the Standard preparation;
Extract with two 30-mL portions of ether, and discard the and the other terms are as defined therein.AUSP26
ether. Proceed as directed in Identification test A under (Official June 1, 2005)
Dicyclomine Hydrochloride Capsules, beginning with

"Extract the aqueous acid solution."
Pharmacopeial Forum
Change to read:
BRIEFING Identification—
A: Injection meets the requirements for Identification test A
under Digoxin Elixir
Dicyclomine Hydrochloride Syrup, USP 25 page 558. It is
A
proposed to change the title of this monograph to Dicyclomine Hy- Oral Solution. ±VSP26
drochloride Oral Solution. See also briefing under Amantadine B: Chloramine T-trichloroacetic acid reagent, Spotting
Hydrochloride Syrup. solvent, and Standard solution—Proceed as directed for
Identification test B under Digoxin Elixir
(NL: C. Barnstein; PA4: A. Medjedovic) RTS—35955-1 A
Oral Solution.AfjSP26
Test solution—Pipet a volume of Injection, equivalent to 0.5 mg
of digoxin, into a separator, and add 5 mL of water. Extract with
three 10-mL portions of chloroform, combining the extracts in a
Dicyclomine Hydrochloride Syrup conical flask. Evaporate the combined chloroform extracts on a
steam bath with the aid of a current of air to dryness. (If traces
(Current title—not to change until June 1,2005) of water or propylene glycol remain, dry the flask in vacuum at
Monograph title change—to become official June 1, 100° for 30 minutes.) Dissolve the residue in 2 mL of Spotting
2005 solvent.
(see Official Title Changes on the first page of In-Pro- Procedure—Proceed as directed for Procedure in the test for
cess Revision): Related glycosides under Digoxin, except to omit the use of the
See Dicyclomine Hydrochloride Oral Solution Gitoxin standard solution. Examine the plate under long-
wavelength UV light: the RF value of the principal spot in the
chromatogram of the Test solution corresponds to that of the
Standard solution.
BRIEFING
Digoxin Elixir, USP 25 page 572. It is proposed to change the

title of this monograph to Digoxin Oral Solution. See also briefing
under Amantadine Hydrochloride Syrup. BRIEFING
(NL: C. Barnstein; DSB: G. Giancaspro) RTS—35956-1 Digoxin Oral Solution—See briefing under Amantadine Hy-
drochloride Syrup.
(NL: C. Barnstein; DSB: G. Giancaspro) RTS—35956-1

Digoxin Elixir
(Current title—-not to change until June 1,2005)
Monograph title change—to become official June 1, Add the following:
2005 A
(see Official Title Changes on the first page of In-Pro- Digoxin Oral Solution
cess Revision):
See Digoxin Oral Solution (Monograph under this new title—to become official
June 1, 2005)
(Current monograph title is Digoxin Elixir)
» Digoxin Oral Solution contains, in each 100 mL,

BRIEFING
not less than 4.50 mg and not more than 5.25 mg
Digoxin Injection, USP 25 page 572. Editorial revisions are in-
dicated to conform with the title change proposed for Digoxin Elix- of digoxin (C41H64O14).
ir. See also briefing under Amantadine Hydrochloride Syrup.
(NL: C. Barnstein; DSB: G. Giancaspro) RTS—35957-1 Packaging and storage—Preserve in tight containers, and
avoid exposure to excessive heat.
USP Reference standards (11 }—USP Digoxin RS.
Pharmacopeial Forum
Identification— Assay—
A: The retention time of the major peak in the Mobile phase—Prepare a filtered and degassed mixture of
chromatogram of Oral Solution corresponds to that in the water, acetonitrile, and isopropyl alcohol (70:27.5:2.5).
chromatogram of the Standard preparation, as obtained in Make adjustments if necessary (see System Suitability
the Assay. under Chromatography (621)).
B: Chloramine T-trichloroacetic acid reagent—Mix 10 Standard preparation—Dissolve an accurately weighed
mL of a freshly prepared solution of chloramine T (3 in 100) quantity of USP Digoxin RS in diluted alcohol, and dilute
and 40 mL of a 1 in 4 solution of trichloroacetic acid in quantitatively and stepwise with diluted alcohol to obtain a
dehydrated alcohol. solution having a known concentration of about 20 ug per
Spotting solvent—Prepare a mixture of chloroform and mL.
methanol (2:1). Assay preparation—Transfer an accurately measured
Standard solution—Dissolve an accurately weighed volume of Oral Solution, equivalent to about 500 ug of
quantity of USP Digoxin RS in Spotting solvent to obtain digoxin, to a 25-mL volumetric flask, dilute with diluted
a solution containing 0.25 mg per mL. alcohol to volume, and mix.
Test solution—Pipet a volume of Oral Solution, System suitability preparation—Prepare as directed in the
equivalent to 0.5 mg of digoxin, into a separator. Add Assay under Digoxin.
sufficient water to obtain a final volume of approximately Chromatographic system (see Chromatography (621))—
50 mL. Extract the aqueous layer with three 30-mL The liquid chromatograph is equipped with a 218-nm
portions of chloroform, combining the extracts in a detector and a 4.6-mm x 15-cm column that contains
conical flask. Evaporate the combined chloroform extracts packing LI. The flow rate is about 0.5 mL per minute.
on a steam bath with the aid of a current of air to dryness. Chromatograph the System suitability preparation, and
Add 2 mL of Spotting solvent to the residue, and shake for 2 record the peak responses as directed for Procedure: the
minutes. resolution, R, between the digoxin and digoxigenin
Procedure—Proceed as directed for Procedure in the test bisdigitoxoside peaks is not less than 2.0; the tailing
for Related glycosides under Digoxin, except to omit the use factor for the analyte peak is not more than 2.0; and the
of the Gitoxin standard solution. Examine the plate under relative standard deviation for replicate injections is not
long-wavelength UV light: the RF value of the principal more than 2.0%.
spot in the chromatogram of the Test solution corresponds Procedure—Separately inject equal volumes (about 10
to that in the chromatogram of the Standard solution. uL) of the Standard preparation and the Assay
Alcohol content (611): between 90.0% and 115.0% of the preparation into the chromatograph, record the
labeled amount of C2H5OH. chromatograms, and measure the responses for the major
peaks. Calculate the quantity, in ug, of digoxin
(C41H64O14) in each mL of the Oral Solution taken by the
formula:
(l00C/V)(ru/rs),
Pharmacopeial Forum
in which C is the concentration, in \ag per mL, of USP Di-

goxin RS in the Standard preparation; Vis the volume, in BRIEFING
mL, of Oral Solution taken; and rv and rs are the digoxin Dimenhydrinate Oral Solution—See briefing under Amanta-
peak responses obtained from the Assay preparation and
(NL: C. Barnstein; PA4: A. Medjedovic) RTS—35959-1
the Standard preparation, respectively.AUSP26
Add the following:
A
Dimenhydrinate Oral Solution
June 1, 2005)
(Current monograph title is Dimenhydrinate Syrup)
BRIEFING
» Dimenhydrinate Oral Solution contains not less
Digoxin Tablets, USP 25 page 573. Editorial revisions are indi- than 90.0 percent and not more than 110.0 percent
cated to conform with the title change proposed for Digoxin Elixir.
See also briefing under Amantadine Hydrochloride Syrup.
of the labeled amount of dimenhydrinate
(C17H21NO • C7H7C1N4O2).

Change to read: USP Reference standards (11 )—USP Dimenhydrinate RS.
Identification—
A: The retention time of the major peak in the chromatogram USP Diphenhydramine Hydrochloride RS.
of the Standard preparation, as obtained in the Assay. Identification—The relative retention times of the major
B: Chloramine T-trichloroacetic acid reagent, Spotting
solvent, and Standard solution—Proceed
1
as directed for peaks for 8-chlorotheophylline and diphenhydramine in
Identification test B under Digoxin Elixir
A
Oral Solution. ±USP26 the chromatogram of the Assay preparation correspond to
Test solution—Transfer an accurately weighed portion of finely
powdered Tablets, equivalent to 0.5 mg of digoxin, to a 10-mL those in the chromatogram of the Standard preparation,
centrifuge tube. Add 2 mL of Spotting solvent, shake for 10
minutes, and centrifuge. Decant the supernatant, and use it as the as obtained in the Assay.
Test solution.
Procedure—Proceed as directed for Procedure in the test for Content of 8-chlorotheophylline—
Related glycosides under Digoxin, except to omit the use of the
Gitoxin standard solution. Examine the plate under long- Ammonium bicarbonate solution, Diluent solution,
wavelength UV light: the RF value of the principal spot in the
chromatogram of the Test solution corresponds to that of the Mobile phase A, Mobile phase B, Internal standard
Standard solution.
(Official June 1,2005) solution, Standard preparation, Assay preparation,
Chromatographic system, and Procedure—Proceed as
directed in the Assay. An amount of 8-chlorotheophylline
that is between 43.4% and 47.9% of the amount of
dimenhydrinate is found.
C2H5OH.
Pharmacopeial Forum
Assay—
BRIEFING
Ammonium bicarbonate solution, Diluent solution,
Mobile phase A, Mobile phase B, Internal standard Dimenhydrinate Syrup, USP 25 page 586. It is proposed to
change the title of this monograph to Dimenhydrinate Oral Solu-
preparation, Standard preparation, and Chromatographiction. See also briefing under Amantadine Hydrochloride Syrup.
system—Proceed as directed in the Assay under (NL: C. Barnstein; PA4: A. Medjedovic) RTS—35959-1
Dimenhydrinate Tablets.
Assay preparation—Pipet 5.0 mL of Oral Solution into a
Dimenhydrinate Syrup
suitable container, add 5.0 mL of Internal standard solution, (Current title—-not to change until June 1, 2005)
and mix. Transfer about 1 mL of this solution into a suitable Monograph title change—to become official June 1,
2005
container, add about 5 mL of Diluent solution, and mix. (see Official Title Changes on the first page of In-Pro-
cess Revision):
Procedure—Proceed as directed for Procedure in the See Dimenhydrinate Oral Solution
Assay under Dimenhydrinate Tablets. Calculate the

quantity, in mg per mL, of dimenhydrinate
(C17H21NO -C7H7C1N4O2) in the portion of Oral Solution
Q.Q5W(RV/RS),
BRIEFING
in which FFis the weight, in mg, of USP Dimenhydrinate RS
Diphenhydramine Hydrochloride Elixir, USP 25 page 592. It
in the Standard preparation; and Rv and Rs are the diphen- is proposed to change the title of this monograph to Diphenhydra-
mine Hydrochloride Oral Solution. See also briefing under Aman-
hydramine peak area ratios obtained from the Assay pre- tadine Hydrochloride Syrup.
paration and the Standard preparation, respectively. (NL: C. Barnstein; AER: K. Zaidi) RTS—35963-1
Calculate the quantity, in mg per mL, of C7H7C1N4O2 in
the portion of Oral Solution taken by the formula:
Diphenhydramine Hydrochloride Elixir
(0.4567)(0.05) W(RV/RS), (Current title—not to change until June 1, 2005)
2005
in which Wis the weight, in mg, of USP Dimenhydrinate RS (see Official Title Changes on the first page of In-Pro-
cess Revision):
in the Standard preparation; and Rv and Rs are the 8-chlor- See Diphenhydramine Hydrochloride Oral Solution
otheophylline peak area ratios obtained from the Assay pre-
paration and the Standard preparation, respectively.±VSp26
Pharmacopeial Forum
with "Determine the absorption spectra of the filtered solu-

BRIEFING tions": the Oral Solution meets the requirements of the test.
Diphenhydramine Hydrochloride Oral Solution—See brief- B: The retention time of the major peak in the
ing under Amantadine Hydrochloride Syrup.
Add the following:
Alcohol content (611): between 90.0% and 110.0% of the
A
Diphenhydramine Hydrochloride labeled amount of C2H5OH.
Oral Solution
Assay—
June 1, 2005) Mobile phase, Standard preparation, System suitability
(Current monograph title is Diphenhydramine Hydro-
chloride Elixir) solution, and Chromatographic system—Prepare as
directed in the Assay under Diphenhydramine Hydro-
» Diphenhydramine Hydrochloride Oral Solution chloride.
contains not less than 90.0 percent and not more Assay preparation—Transfer an accurately measured
than 110.0 percent of the labeled amount of di- volume of Oral Solution, equivalent to about 50 mg of
diphenhydramine hydrochloride, to a 100-mL volumetric
phenhydramine hydrochloride (C17H21NO • HC1).
flask, dilute with water to volume, and mix.
Packaging and storage—Preserve in tight, light-resistant Procedure—Proceed as directed for Procedure in the
containers. Assay under Diphenhydramine Hydrochloride. Calculate
USP Reference standards (11)—USP Diphenhydramine the quantity, in mg, of diphenhydramine hydrochloride
Hydrochloride RS. (C17H21NO HC1) in each mL of the Oral Solution taken
Identification— by the formula:
A: Place a portion of Oral Solution, equivalent to 50 mg
l00(C/V)(ru/rs),
of diphenhydramine hydrochloride, in a separator, add 0.5
mL of 2 N sulfuric acid, and extract with three 15-mL in which C is the concentration, in mg per mL, of USP Di-
portions of ether, discarding the extracts. Add 5 mL of phenhydramine Hydrochloride RS in the Standard prepara-
water. In a second separator dissolve 50 mg of USP tion; Fis the volume, in mL, of Oral Solution taken; and rv
Diphenhydramine Hydrochloride RS in 25 mL of water. and rs are the peak responses obtained from the Assay pre-
Treat each solution as follows. Add 2 mL of 1 N sodium paration and the Standard preparation, respectively.AUSP26
hydroxide, and extract with 75 mL of n-heptane. Wash the
H-heptane extract with 10 mL of water, evaporate the extract
to dryness, and dissolve the residue in 4 mL of carbon
disulfide. Pass through a dry filter to clarify the solution,
if necessary, and proceed as directed under Iden-
tification—Organic Nitrogenous Bases (181), beginning
Pharmacopeial Forum
acid peak to that of biphenyl in the chromatograms of the solutions

obtained from the Test solution and the Standa\«d solution, respec-
BRIEFING tively.
Divalproex Sodium Delayed-Release Tablets, USP 25 page ^Citrate buffer—Dissolve 0.5 g of citric acid mono-
603 and page 1781 of PF 27(1) [Jan.-Feb. 2001]. In the test for
Drug release and in the Assay, it is proposed to replace the current hydrate and 4.0 g of dibasic sodium phosphate in 1.0 liter
analytical GC methods with HPLC methods to avoid tedious sam-
ple preparation and the use of methylene chloride. The validation of water.
work was made using a 4 urn, 150 x 3.9 mm Waters Nova-Pack
Phenyl brand of LI 1 column. The retention times for valproic acid Potassium phosphate buffer—Dissolve 6.8 g of
are about 8.5 minutes and 6.7 minutes for the Assay and the test for
Drug release, respectively. monobasic potassium phosphate and 1.7 g of sodium
hydroxide in 1.0 liter of water. Adjust with phosphoric

(PA3:S. Salado) RTS—35344-1
acid to a pH of 7.4 ± 0 . 1 .
Mobile phase—Prepare a mixture of Citrate buffer,

Change to read: Potassium phosphate buffer, and acetonitrile (35:35:30).
containers? Adjust with phosphoric acid to a pH of 3.0 ± 0 . 1 , and
A
, at controlled room temperature. AUSP26 mix. Filter and degas. Make adjustments if necessary (see
System Suitability under Chromatography (621)).

Change to read:
Drug release, Method B (724)— Standard solution—Prepare a solution of USP Valproic
pH 1.2, 0.08 N Hydrochloric acid—Add 40 mL of Hydrochloric
acid to 5000 mL of water. Adjust with 2 N hydrochloric acid to a Acid RS in the pH 7.5 Phosphate buffer used in the
pH of 1.2, dilute with water to 6.0 liters, and mix.
pH 7.5 Phosphate buffer—Dissolve 40.83 g of monobasic Buffer Stage, having a known concentration of about 0.12
potassium phosphate and 9.84 g of sodium hydroxide in 5000
mL of water. Adjust with/?// 1.2, 0.08 N Hydrochloric acid to a mg per mL. [ N O T E — A volume of acetonitrile not
pH of 7.5, dilute with water to 6.0 liters, and mix.
Medium—Proceed as directed for Method B, observing the exceeding the 10.0% of the total volume may be used to
following exceptions. Perform Acid Stage testing, using 900 mL
of/?// 1.2, 0.08 N Hydrochloric acid, for 1 hour; and perform dissolved the USP Valproic Acid RS.]
Buffer Stage testing, using 900 mL of pH 7.5 Phosphate buffer,
for not less than 1 hour. Test solution—If necessary, dilute a portion of each
Times: 1 and 2 hours. filtered solution under test with pH 7.5 Phosphate buffer
Determine the amount of C 8 H 16 O 2 dissolved by employing the
following method. used in the Buffer Stage to obtain a solution having a
Internal standard solution—Dissolve an accurately weighed
quantity of biphonyl in mothylcno chloride to obtain a solution concentration of about 0.12 mg per mL.
having a known oonoontration of about 187.5 ug por mL.
Standard solution—Prepare a solution of USP Valproio Aoid RS Chromatographic system (see Chromatography
in a mixture of water and 1 N oodium hydroxide (5:1) containing
about 24 mg por mL: Quantitatively dilute an aoouratoly measured (621))—The liquid chromatograph is equipped with a
volume of this solution with pH 7.5 Phosphate buffer to obtain a
solution having a known oonoontration of about 141 p,g por mL. 210-nm detector and a 3.9-mm x 15-cm column that
•Test solutions—If necessary; dilute a portion of each filtered
solution under tost with pM 7.5 Phosphate buffer to obtain contains 4-um packing LI 1. The flow rate is about 1.2
solutions having oonoontrations of about 141 ug por mL.
Chromatographic system—Prepare as directed in the Assay: mL per minute. Chromatograph the Standard solution,
Procedure—Transfer 6.0 mL of the Test solution and the
Standard solution, eaoh to a separate 20 mL glass tost tube. Add and record the peak responses as directed for Procedure:
1.0 mL of 2 N hydrochloric aoid and 5.0 mL of Internal standard
solution. Mix vigorously^ allow the layers to separate, and aspirate the column efficiency is not less than 1000 theoretical
and disoard the uppor layor. Proceed as directed for Procedure in
the Assay. Dotcrmino the quantity, in mg, of CgH^Q 3 dissolved by plates; the tailing factor is not more that 2.0; and the
the formula:
in which G is the oonoontration, in mg per mL, of USP Valproio more than 2.0%.
Acid in the solution obtained from the Standard solution; D is
the dilution factor usod to prepare the solution obtainod from the
Test solution; and R# and R& are the response ratios of the valproio
Pharmacopeial Forum
A
Procedure—Separately inject equal volumes (about 50 Citrate buffer—Dissolve 2.0 g of citric acid
jiL ) of the Standard solution and the Test solution into monohydrate and 1.6 g of dibasic sodium phosphate, in
the chromatograph, record the chromatograms, and 4.0 liters of water.
measure the responses for the major peaks. Calculate the Mobile phase—Prepare a mixture of Citrate buffer and
quantity, in mg, of valproic acid (C8H16O2) dissolved by acetonitrile (7:3). Adjust with phosphoric acid to a pH of
the formula: 3.0 ± 0.1 , and mix. Filter and degas. Make adjustments
if necessary (see System Suitability under Chro-
900CD(RU/RS\
matography (621)).
in which C is the concentration, in mg per mL, of USP Val-
Standard preparation—Prepare a solution of USP
proic Acid RS in the Standard solution; D is the dilution
Valproic Acid RS in Mobile phase having a known
factor used to prepare the Test solution; and Rv and Rs are
the peak area ratios of valproic acid obtained from the Test
Assay preparation—Transfer a number of whole Tablets
solution and the Standard solution, respectively.ÛSP26
containing the equivalent of about 2500 mg of valproic
Tolerances—Not less than 80% (Q) of the labeledamount of
C g H, 6 O 2 is dissolved in 2 hours. acid into a 250-mL volumetric flask. Add 150 mL of
Change to read:
Assay—
Mobile phase, and sonicate with frequent swirling for 30
Internal standard solution—Dissolvean aoouratoly woighod minutes or until the Tablets completely disintegrate. Allow
quantity of biphonylin mothylono ohlorido to obtain a solution
having a known concentration of about 2.5 mg per mL. the solution to cool down to room temperature, and then
Standard preparation—Prepare a solution of USP Valproio Aoid
RS in Internal standard solution having a known oonoontration of dilute with Mobile phase to volume. Transfer 5.0 mL of
about 2 mg per mL.
Assay-preparation—Transfer an amount of whole Tablets the resulting solution to a 100-mL volumetric flask. Dilute
containing tho equivalent of botwoon 625 mg and 1250 mg of
valproio aoid into a aoparatory funnel containing 50.0 mL of with Mobile phase to volume, and mix.
Internal standard solution. Shako by moohanioal moano for 1
hour, and then add about 40 mL of dilute hydrochloric aoid (1 in Chromatographic system (see Chmmatography (621))—
20): Shako for 2 minutes^ allow to atand for 15 minutes, and then
flhako again for 2 minutes. Allow tho phaaoa to separate The liquid chromatograph is equipped with a 210-nm
(approximately 30 minutoa). Tako an aliquot from tho bottom
layor, and diluto quantitatively Withlntcrnal standard solution to detector and a 3.9-mm x 15-cm column that contains 4-
obtain a final concentration of about 2 mg per mL of valproio aoid.
Ghromatographic system (soo Chmmatography (6£j-))—¥fee um packing LI 1. The flow rate is about 0.9 mL per
gaa ohromatograph is equipped with a flame ionization detector
and a 2 mm x 1,8 m glass column paokod with 10% phase G34 minute. Chromatograph the Standard preparation, and
on 80 to 100 moan support S1 A. Tho oarrior gao ia helium, flowing
at a rate of 40 mL por minute: Tho oolumn temperature is record the peak responses as directed for Procedure; the
maintained at150°, the dotootor temperature at 300°, and tho
injection port temperature at 250°. Chromatograph the Standard column efficiency is not less than 1000 theoretical plates;
preparation, and rooord tho poak rooponsoo as direotedfor
Procedure.1 tho resolution, R, between valproio aoid and biphonyl the tailing factor is not more than 2.0; and the relative
ia not losa than 3.0; and tho relative standard deviation of tho ratio
of tho poak responses for replicate injections is not more than 2.0%. standard deviation for replicate injections is not more than
Procedure—Separately injoot equal volumes (about 2 uL) of tho
Standard preparation and the Assay preparation into tho 2.0%.
ohromatograph, rooord tho ohromatograma, and measure tho
responses for tho major peaks. Calculate the quantity, in mg, of Procedure—Separately inject equal volumes (about 15
valproio aoid (CgH^Q^) in tho portion of Tablets taken by the
|xL) of the Standard preparation and the Assay
in whioh C is tho oonoontration, in mg por mL, of USP Valproio
Aoid RS in tho Standard preparation; D is tho dilution faotor usod
to prepare tho Assay preparation; and Ry and R^ are tho response
ratios of valproio aoid to those of biphonyl obtained from tho Assay
preparation and tho Standard preparation; respectively.
Pharmacopeial Forum
chromatograms, and measure the responses for the major 1 -(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(l ,4-benzo-
peaks. Calculate the quantity, in mg, of valproic acid dioxan-2-ylcarbonyl)piperazine monomethanesulfo-
(C8H16O2) in the portion of Tablets taken by the formula: nate [77883-43-3]
in which C is the concentration, in mg per mL, of USP Val- » Doxazosin Mesylate contains not less than 98.0
proic Acid RS in the Standard preparation; and Rv and Rs p e r c e n t and n o t m o r e than 102.0 p e r c e n t of
are the peak area ratios of valproic acid obtained from the C 2 3 H 2 5 N 5 O 5 • CH 4 SO 3 , calculated on the anhy
Assay preparation and the Standard preparation, respecti- drous dried basis.

containers.
USP Reference standards (11)—USP Doxazosin Mesy-
late RS. USP Terazosin Related Compound A RS. USP Ter-
azosin Related Compound C RS.
Identification—
BRIEFING
A: Infrared Absorption (WM) (197K).
Doxazosin Mesylate, page 8044 ofPF25(3) [May-June 1999].
This monograph, which first appeared in Pharmacopeial Previews, B: The retention time of the major peak in the
is now forwarded to In-Process Revision with the following
changes, based on comments received: the Definition requirements chromatogram of the Assay preparation corresponds to
are based on the dried basis; the infrared identification procedure is
revised; the test for Water is replaced by a Loss on drying test; a that in the chromatogram of the Standard preparation, as
Chromatographic purity test is added; and a new stability-indicat-
ing Assay procedure is proposed. The molecular weight has also obtained in the Assay.
been updated to agree with the sum of revised atomic weights pub-
lished in USP 25. The Chromatographic purity procedure is based Loss on drying (731)—Dry it at 105° under vacuum for 4
on analyses performed using a Zorbax SB-C8 brand of L7 column;
and the retention times for terazosin related compound A, terazosin hours: it loses not more than 1.0% of its weight.
related compound C, and doxazosin are about 4.5, 8.3, and 9.5
minutes, respectively. The Assay procedure is based upon analyses Water, Method I (934-): not more than 1.0%.
performed using a Luna C18 brand of L1 column; and the retention
time for doxazosin is about 9.5 minutes. Residue on ignition (281): not more than 0.1%.
(PA5: J. Esker) RTS—24017-1; 31970-1 ; 32474-1; 35018-1 Heavy metals, MethodII (231): 20 ug per g.
Chromatographic purity—[To como.j
Add the following: Solution A—Dissolve 17.3 g of sodium 1-octanesulfonate
A
Doxazosin Mesylate and 5.4 mL of phosphoric acid in 4 liters of water. Adjust
C23H25N5O5 • CH4SO3 &&S2 547.58 with 1 M sodium hydroxide to a pH of 2.5, and mix.
Piperazine, 1 -(4-amino-6.7-dimethoxy-2-quinazolinyl)-4- Solution B—Use acetonitrile.
[(2,3-dihydro-l ,4-benzodioxin-2-yl)carbonyl]-, mono- Mobile phase—Use variable mixtures of Solution A and
methanesulfonate. Solution B as directed for Chromatographic system. Make

Pharmacopeial Forum
Diluent—Dissolve 2.7 mL of phosphoric acid in 2 liters of

water. Adjust with 1 M sodium hydroxide to a pH of 2.5,
(min.) Elution
and mix.
Blank solution—Prepare a solution of dimethyl sulfoxide 0-20 75->45 25->55 linear gradient
and Diluent (1 in 100). 20-35 45 55 isocratic
System suitability solution—Prepare a solution containing 35-36 45->75 55->25 linear gradient
about 1.5 ug of USP Terazosin Related Compound A RS per 36-47 75. 25 isocratic
mL, 0.5 ug of USP Terazosin Related Compound C RS per Chromatograph the System suitability solution: the resolu-
mL, and 0.5 ug of USP Doxazosin Mesylate RS per mL in tion between terazosin related compound C and doxazosin
Blank solution. is not less than 2.0. Chromatograph the Standard solution,
Standard stock solution—To an accurately weighed and record the peak responses as directed for Procedure: the
quantity of USP Doxazosin Mesylate RS, add a volume of tailing factor is not more than 2.0; and the relative standard
dimethyl sulfoxide, equivalent to about 1% of the flask deviation for replicate injections for the main peak is not
volume, sonicate for 1 minute, and dilute quantitatively, more than 5.0%.
and stepwise if necessary, with Diluent to obtain a Procedure—Separately inject equal volumes (about 10
solution having a known concentration of about 0.1 mg uL) of the Standard solution and the Test solution into the
per mL. Sonicate, if necessary, until dissolved. chromatograph, record the chromatograms, and measure the
Standard solution—Quantitatively, and stepwise if responses for all peaks. Calculate the percentage of each
necessary, dilute a volume of Standard stock solution with impurity in the portion of Doxazosin Mesylate taken by
Blank solution to obtain a solution containing 0.5 (ig of the formula:
doxazosin mesylate per mL.

Test solution—Transfer about 50 mg of Doxazosin
in which the response factor F is 0.6 for terazosin related
Mesylate, accurately weighed, to a 100-mL volumetric
compound A and 0.55 for terazosin related compound C;
flask, add 1 mL of dimethyl sulfoxide, and sonicate for 1
Cs is the concentration, in ug per mL, of USP Doxazosin
minute. Dilute with Diluent to volume and sonicate, if
Mesylate RS in the Standard solution; C, is the concentra-
necessary, until dissolved.
tion, in ug per mL, of doxazosin mesylate in the Test solu-
tion; /*, is the peak response for each individual impurity,
The liquid chromatographic system is equipped with a 245-
excluding solvent peaks, obtained from the Test solution;
nm detector and a 4.0-mm x 80-mm column that contains
and rs is the peak response obtained from the Standard solu-
packing L7. The flow rate is about 1 mL per minute. The
tion: not more than 0.3% of terazosin related compound A is
chromatograph is programmed as follows:
Pharmacopeial Forum
found; not more than 0.1% of any other individual impurity Procedure—Separately injoot equal volumes (about 10
is found; and not more than 1.0% of total impurities is uL) of tho Standard preparation and tho Assay preparation
found. into the ohromatograph; rooord the ohromatograms, and
Assay— measure the responses for the major peaks. Caloulato tho
Buffer solution—Prepare a 0.05 M solution of monobaoio quantity, in mg, of C^ft^N^,—Gft 4 SQ^ in tho portion of
potassium phosphate by disolving 0:68 g of monobasio Doxazooin Mosylato taken by tho formula:
potassium phosphatein 100 mL of water. Adjust with

phoaphorio acid to a pH of 3.0 + 0.1.
in whioh C is tho oonoontration, in ug per mL; of USP Dox
azosin Mooylato RS in tho Standard preparation; and r^rmd
Buffer solution, mothanol, and aootonitrilo (6:4:1.5). Make
i*g are the peak responses obtained from tho Assay pmpara
adjustments if noooosary (see System suitability under
iion and tho Standard preparation; rospootivoly.
Chromatography (€H)}T
Buffer solution—Transfer 3.4 g of monobasic potassium
Standard pwparation—Dissolve an aoouratoly weighed
phosphate into a 1-liter flask, add 800 mL of water and
quantity of USP DoxazosinMooylato R.S in methanol to
4.0 mL of triethylamine to dissolve. Adjust with
phosphoric acid to a pH of 4.5, and dilute with water to
0.30 mg per mL. Quantitatively dilute a volume of this
volume .
solution with Mobile phase to obtain a solution having a
known concentration of about 15.0 jig of USP Doxazosin
methanol and Buffer solution (11:9). Make adjustments if
Mosylato RS per mL.
Assay preparation—Transfer about 75 mg of Doxazosin
(621)).
Mesylato, aoouratoly weighed, to a 250 mL volumotrio
Diluent—Dissolve 2.7 mL of phosphoric acid in 2 liters of
flask, dissolve in and dilute with mothanol to volume, and
water. Adjust with 1 M sodium hydroxide to a pH of 2.5,
mix. Quantitatively dilute a known volume of this solution
and mix.
with Mobile phase to obtain a solution having a
concentration of about 15.0 ug per mL.
quantity of USP Doxazosin Mesylate RS in Diluent, and
Chmmatographic system (sQQChromat&graphy {€H))—
The liquid ohromatograph io equipped with a 216 nm
Diluent to obtain a solution having a final concentration
dotootor and a 3:9 mm x 15.0 cm oolumn that oontains
of about 49 ug per mL.
Assay preparation—Transfer about 98 mg of Doxazosin
Chromatograph the Standard preparation, and rooord the
Mesylate to a 200-mL volumetric flask, dissolve in and
peak responses ao directed for Procedure: tho oapaoity
dilute with Diluent to volume. Transfer 10.0 mL of this
faotorj k', is not loss than1.5; the tailing faotor is not
solution to a 100-mL volumetric flask, dilute with Diluent
more than 2.0; and tho relative standard deviation for
to volume, and mix.
roplioato injections io not more than 2.0%.
Pharmacopeia! Forum
Chromatographic system—The liquid chromatograph is indicating Assay procedure is proposed. The Assay procedure is
based upon analyses performed using a Luna C18 brand of LI col-
equipped with a 245-nm detector and a 4.6-mm x 25-cm umn; and the retention time for doxazosin is about 9.5 minutes.
column that contains 5-um packing LI. The flow rate is (PAS: J. Esker; NL: C. Barnstein) - RTS—24017-2;
31970-2
about 1 mL per minute, and the column temperature is
maintained at 40°. Chromatograph the Standard
Add the following:
Procedure: the capacity factor, K, for doxazosin is not less Doxazosin Mesylate Tablets
than 2.0; the column efficiency is not less than 1000
theoretical plates; the tailing factor is not more than 2.0; » Doxazosin Mcsylato Tablets contain not loss
and the relative standard deviation for replicate injections
is not more than 2.0%.
of the labeled amount of doxazosin mosylatc
{ G ^ f t ^ O ^ - G J ^ S Q ^ Doxazosin Tablets con-
tain an amount of doxazosin mesylate equivalent
to not less than 90.0 percent and not more than
doxazosin peaks. Calculate the quantity, in mg, of 110.0 percent of the labeled amount of doxazosin
C 23 H 25 N 5 O 5 CH4SO3 in the portion of Doxazosin (C23H25N5O5).

Mesylate taken by the formula:
USP Reference standards (11)—USP Doxazosin Mesy-
in which C is the concentration, in ug per mL, of USP Dox- late RS.
azosin Mesylate RS in the Standard preparation; and rv and Thin Layer Chromatographie Identification Test
rs are the peak responses obtained from the Assay prepara-
tion and Standard preparation, respectively. Test solution—Finely powder not fewer than 5 Tablets,
and transfer an accurately weighed portion of tho powder^
equivalent to not loss than 2 mg of doxaaooin mooylato, to
a centrifuge tube-: Add 4 mL of a mixture of mothanol and
glaoial aoetio aoid (1:1), mix on a vortex mixer for about 3
minutOG, and extract. Filter tho extract, and use tho filtrate:
BRIEFING Standard solution—Dissolve an aoouratoly weighed
Doxazosin Mesylate Tablets, page 3275 of PF 27(6) [Nov.- quantity of USP Doxazosin Mosylato RS in a mixture of
Dec. 2001]. Based on comments received, revisions to this mono-
graph are proposed. The Definition identifies the labeled amount of mothanol and glaoial aootio aoid (1:1) to obtain a solution
doxazosin; therefore, the monograph title is changed to reflect the
active moiety, which is consistent with the established policy of having a known concentration of about 0:5 mg per mL.
naming the active moiety in the title where the active moiety is
used to express the strength of the product. The TLC identification Application volume: 20 uL.
procedure is replaced by an HPLC method. And a new stability-
Pharmacopeial Forum
Developing solvcnt system—Prepare a mixture of 4 Uniformity of dosage units (905): meet the requirements.
methyl 2 pontanono; aootic acid, and water (2:1:1). Assay—
Separate, and use the upper layer: Standard preparation—Dissolve an accurately weighed
Spray wagent—Dissolve a quantity of platinio chloride^ quantity of USP Doxazosin Mosylato RS in 0.01 N
equivalent to about 0.3 g of anhydrous platinio ohloride; mothanolio hydroohlorio aoid; and dilute quantitatively^
in 5 mL of 1 N hydrochloric acid (Solution 1). Dissolve 5 and stopwiso if necessary;with 0.1 N mothanolio
g of potassium iodide in 50 mL of water (Solution 2). hydroohlorio acid to obtain a solution having a known
Transfer 5 mL of Solution 1 and <15 mL of Solution 2 toa concentration of about 5 -ug per mL.
150 mL volumetric flaok, dilute with water to volume, and Assay preparation—Finely powder not fewer than 20
TTTTzvT
Tablets. Transfer an accurately weighed portion of tho
Procedure—Proceed as directed in the ohaptor, and then powder, equivalent to about 100 mg of doxazosin
plaoo the plate in an air oven at 100° for 10 minutes: mosylato, to a 200 mL volumetric flask, add 10 mL of
Remove the plate from the oven; eool; and 3pray the plate water, dilute with 0.01 N mothanolio hydroohlorio acid to
with the freshly prepared Spray reagent: the principal volume, and mix: Stir for 30 minutes;using a magnotio
reddish brown spot obtained from the Test solution stirror: Transfer 15 mL of this solution to a suitable
corresponds in color and j?^ value to that obtained from container, insert a stopper, and centrifuge for 15 minutes.
the Standard solution. Transfer 1.0 mL of tho supernatant to a 100 mL
Identification—The retention time for the major peak in the volumetric flask; dilute with 0.01 N mothanolio
chromatogram of the Assay preparation corresponds to that hydroohlorio aoid to volume; and mix.
in the chromatogram of the Standard preparation, as Procedure—Conoomitantly determine the absorbanoos of
obtained in the Assay. tho Standard preparation and tho Assay preparation, at tho
Dissolution (711)— wavelength of maximum absorbanoo at about 246 nm, in 1
Medium: 0.1 N 0.01 N hydrochloric acid; 900 mL. em cells, with a suitable spootrophotomotor; using 0.01 N
Apparatus 2: 50 rpm 75 rpm. mothanolio hydroohlorio acid as the blank: Caloulato tho
Time: 30 minutes. q u a n t i t y , in m g , of d o x a z o f l i n mosylato
Procedure—Determine the amount of C23H25 (€3jBajN»Q»-€H4SQ») in the portion of Tablets taken by
N5O5 • CH4SO3 dissolved by employing UV absorption at the formula:
the wavelength of maximum absorbance at about 246 nm
on filtered portions of the solution under test, suitably
in which O is tho concentration^ in ug per mL; of USP Box
diluted with Dissolution Medium, if necessary, in
azosin Mosylato RS in the Standard preparation; and Av
comparison with a Standard solution having a known
and Ag are the abaorbanooa obtained from tho Assay pro
concentration of USP Doxazosin Mesylate RS in the
paration and the Standard preparation, respectively.
same Medium.
Buffer solution, Mobile phase, Diluent, Standard
Tolerances—Not less than «0% 75%(0 of the labeled
preparation, and Chromatographic system—Proceed as
amount of C23H25N5O5 • CH4SO3 is dissolved in 30 minutes.
directed in the Assay under Doxazosin Mesylate.

Pharmacopeial Forum
Assay preparation—Transfer 10 Tablets, whole or

BRIEFING
ground, into a 250-mL volumetric flask, add 10 mL of
water, and sonicate until the Tablets are disintegrated. Add Doxylamine Succinate Oral Solution—See briefing under
Amantadine Hydrochloride Syrup.
150 mL of Diluent, sonicate for 30 minutes, dilute with
(NL: C. Barnstein; AER: Z. Zaidi) RTS—35964-1
Diluent to volume, and mix. Quantitatively dilute a
portion of the supernatant with Diluent to obtain a
Add the following:
solution having a concentration of about 0.04 mg of
A
doxazosin per mL. Doxylamine Succinate Oral Solution
{Monograph under this new title—to become official
Procedure—Separately inject equal volumes (about 20 June 1, 2005)
(Current monograph title is Doxylamine Succinate Syr-
uL) of the Standard preparation and the Assay up)
» Doxylamine Succinate Oral Solution contains
doxazosin peaks. Calculate the quantity, in mg, of
doxazosin (C23H25N5O5) in the portion of Tablets taken by
108.0 percent of the labeled amount of doxyla-
the formula:
mine succinate (C17H22N2O • C4H6O4).
(451.48/547.58) CD Packaging and storage—Preserve in tight, light-resistant
containers.
in which 451.48 and 547.58 are the molecular weights of USP Reference standards (11)—USP Doxylamine Succi-
doxazosin and doxazosin mesylate, respectively; C is the nate RS.
concentration, in mg per mL, of USP Doxazosin Mesylate Identification—Use a volume of Oral Solution equivalent
RS in the Standard preparation; D is the dilution volume, in to about 50 mg of doxylamine succinate, and proceed as
mL, considering the initial 250-mL flask and any subse- directed under Identification—Organic Nitrogenous Bases
quent dilution used to prepare the Assay preparation; and (181), beginning with "Transfer the liquid to a separator."
rv and rs are the peak responses obtained from the Assay The Oral Solution meets the requirements of the test.
preparation and Standard preparation, respectively.AUSP26 Assay—Proceed with Oral Solution as directed under Salts
of Organic Nitrogenous Bases (501), determining the
absorbance at the wavelength of maximum absorbance at
about 262 nm. Calculate the quantity, in mg, of
doxylamine succinate (C 17 H 22 N 2 O-C 4 H 6 O 4 ) in each mL
of the Oral Solution taken by the formula:
Pharmacopeial Forum
in which C is the concentration, in jig per mL, of USP Dox-

ylamine Succinate RS in the Standard Preparation; and Fis BRIEFING
the volume, in mL, of Oral Solution taken.. ±VSP26
Dyphylline Oral Solution—See briefing under Amantadine
(Official June 1, 2005) Hydrochloride Syrup.
Add the following:

A
Dyphylline Oral Solution
(Monograph under this new title—to become Official
BRIEFING June 1, 2005)
(Current monograph title is Dyphylline Elixir)
Doxylamine Succinate Syrup, USP 25 page 623. It is proposed
to change the title of this monograph to Doxylamine Succinate
Oral Solution. See also briefing under Amantadine Hydrochloride
Syrup. » Dyphylline Oral Solution contains not less than
(NL: C. Barnstein; AER: Z. Zaidi) RTS—35964-1 90.0 percent and not more than 110.0 percent of
the labeled amount of dyphylline (C10H14N4O4).
Doxylamine Succinate Syrup Packaging and storage—Preserve in tight containers.
Monograph title change—to become official June 1, USP Reference standards {11)—USP Dyphylline RS.
2005
(see Official Title Changes on the first page of In-Pro- Identification—The retention time of the major peak in the
cess Revision):
See Doxylamine Succinate Oral Solution chromatogram of the Assay preparation corresponds to that
in the chromatogram of the Standard preparation, as
Alcohol content—
Standard preparation—Pipet 5 mL of dehydrated alcohol
and 5 mL of acetone into a 200-mL volumetric flask
BRIEFING containing 50 mL of water, add water to volume, and mix.
Dyphylline Elixir, USP 25 page 628. It is proposed to change Pipet 10 mL of this solution into a 200-mL volumetric flask,
the title of this monograph to Dyphylline Oral Solution. See also
briefing under Amantadine Hydrochloride Syrup. add water to volume, and mix.
(NL: C. Barnstein; AER: K. Zaidi) RTS—35965-1 Test preparation—Transfer an accurately measured

volume of Oral Solution, equivalent to about 5 mL of
alcohol, to a 200-mL volumetric flask containing about 30
Dyphylline Elixir
mL of water. Pipet 5 mL of acetone into the flask, add water
Monograph title change—to become official June 1, to volume, and mix. Pipet 10 mL of this solution into a 200-
2005
(see Official Title Changes on the first page of In-Pro- mL volumetric flask, add water to volume, and mix.
cess Revision):
See Dyphylline Oral Solution
Pharmacopeial Forum
Chromatographic system—The gas chromatograph is Assay preparation—Transfer an accurately measured

equipped with a flame-ionization detector and contains a volume of Oral Solution, equivalent to about 100 mg of
75-cm x 4-mm column packed with 20% phase G20 on dyphylline, to a 200-mL volumetric flask, add Mobile
s u p p o r t S 1 A B , c o n d i t i o n e d as d i r e c t e d (see phase to volume, and mix.
Chromatography (621)). The column is maintained at a Procedure—Separately inject equal volumes (about 10
temperature of about 85°, and the injection port and |j.L), of the Standard preparation and the Assay
detector block are maintained at about 175° and 225°, preparation into the chromatograph, record the
respectively. Nitrogen is used as the carrier gas at a flow chromatograms, and measure the responses for the major
rate of about 18 mL per minute. Chromatograph the peaks. Calculate the quantity, in mg, of dyphylline
Standard preparation, and record the peak responses as (C10H14N4O4) in the volume of Oral Solution taken by the
directed for Procedure: the resolution, R, is not less than formula:
2.0; the tailing factor of the alcohol peak is not greater
02C(rulrs\
than 1.5; and the relative standard deviation for replicate
injections is not more than 2.0% in the ratio of the peak in which C is the concentration, in ug per mL, of USP Dy-
of alcohol to the peak of acetone. phylline RS in the Standard preparation; and rv and rs are
Procedure—Separately inject equal volumes (about 4 uL) the dyphylline peak responses obtained from the Assay pre-
of the Test preparation and the Standard preparation, in paration and the Standard preparation, respectively. AUSP26
duplicate, into the gas chromatograph, record the
peaks. Calculate the percentage of alcohol in the specimen
in which Fis the volume, in mL, of Oral Solution taken, and BRIEFING
Rv and Rs are the peak response ratios of alcohol to that of Dyphylline and Guaifenesin Elixir, USP 25 page 630. It is pro-
posed to change the title of this monograph to Dyphylline and
acetone obtained from the Assay preparation and the Stan- Guaifenesin Oral Solution. See also briefing under Amantadine
dard preparation, respectively: the alcohol content, ob-
tained as the average of the calculated results, is between
90.0% and 110.0% of the labeled amount of C2H5OH.
Assay— Dyphylline and Guaifenesin Elixir
Mobile phase and Chromatographic system—Prepare as (Current title—not to change until June 1,2005)
2005
directed in the Assay under Dyphylline Tablets. (see Official Title Changes on the first page of In-Pro-
cess Revision)
Standard preparation—Dissolve an accurately weighed See Dyphylline and Guaifenesin Oral Solution
quantity of USP Dyphylline RS in Mobile phase to obtain
a solution having a known concentration of about 500 ug
per mL.
Pharmacopeial Forum
C: The retention times of the major peaks in the

BRIEFING
chromatogram of the Assay preparation correspond to
Dyphylline and Guaifenesin Oral Solution—See briefing un-
der Amantadine Hydrochloride Syrup. those in the chromatogram of the Standard preparation,
Alcohol content—
Add the following:
A Standard preparation, Test Preparation, Chro-
Dyphylline and Guaifenesin Oral
Solution matographic system, and Procedure—Proceed as directed
{Monograph under this new title—to become official in Alcohol content under Dyphylline Oral Solution: the
June 1, 2005)
(Current monograph title is Dyphylline and Guaifenesin alcohol content is between 90.0% and 110.0% of the
Elixir)
labeled amount of C2H5OH.
Assay—
» Dyphylline and Guaifenesin Oral Solution con-
Mobile phase—Prepare a suitable filtered and degassed
tains not less than 90.0 percent and not more than mixture of 0.01 M monobasic potassium phosphate and
110.0 percent of the labeled amounts of dyphyl- methanol (79:21). Make adjustments if necessary (see
line (C10H14N4O4) and guaifenesin (C10H14O4). System Suitability under Chromatography (621)).
quantities of USP Dyphylline RS and USP Guaifenesin
USP Reference standards {11 )—USP Dyphylline RS. USP
RS in Mobile phase, and dilute quantitatively, and
Guaifenesin RS.
stepwise if necessary, with Mobile phase to obtain a
Identification—
solution having known concentrations of about 0.1 mg of
A: To an amount of the Oral Solution equivalent to
guaifenesin and about 0.1J mg of dyphylline per mL, J
about 100 mg of dyphylline, add water to make 20 mL,
being the ratio of the labeled amount of dyphylline to that
mix, and add 2.0 mL of 2 N sodium hydroxide and 2
of guaifenesin.
drops of potassium permanganate TS: a green color is
Resolution solution—Prepare a solution in Mobile phase
produced.
containing in each mL about 0.1 mg each of dyphylline and
B: Transfer a volume of Oral Solution, equivalent to
guaifenesin and about 0.01 mg of guaiacol.
about 100 mg of guaifenesin, to a 60-mL separator, add
Assay preparation—Transfer an accurately measured
10 mL of chloroform, shake for 30 seconds, and allow the
volume of Oral Solution, equivalent to about 100 mg of
layers to separate. Decant the lower (chloroform) layer
guaifenesin, to a 100-mL volumetric flask, dilute with
through chloroform-washed cotton into a small beaker.
Mobile phase to volume, and mix. Transfer 5.0 mL of this
Evaporate 1 mL of the extract, on a watch glass, on a
solution to a 50-mL volumetric flask, dilute with Mobile
steam bath to dryness. To the residue add 1 drop of
phase to volume, and mix.
formaldehyde TS and a few drops of sulfuric acid: a deep
cherry-red to purple color is produced.
Pharmacopeial Forum

BRIEFING
Enalapril Maleate Tablets, USP 25 page 650 and page 2541 of
detector, a guard column that contains packing LI, and a PF 27(3) [May-June 2001]. Comments have been received regard-
ing confusion as to the use of both a ratio of molecular weights and
4.6-mm x 15-cm column that contains packing LI. The a response factor in the calculation of enalapril diketopiperazine in
the test for Related compounds. Based on further comments re-
flow rate is about 2 mL per minute. Chromatograph the ceived supporting the equation for calculation of the diketopiper-
azine impurity as percent enalapril maleate, the definition of the
Resolution solution, and record the peak responses as response factor is clarified. This equation is intended to calculate
the percent of enalapril maleate degraded to yield the amount of
directed for Procedure: the resolution, R, between the diketopiperazine observed as required for the limits. In addition,
the molecular weights used in the calculation are updated to agree
guaiacol and guaifenesin peaks is not less than 1.8, and with the sum of atomic weights for Enalapril Maleate.
the resolution, R, between the guaiacol and dyphylline
(PA5:J. Esker) RTS—35905-1
peaks is not less than 9.0. The relative retention times are
about 0.25 for dyphylline, 0.7 for guaiacol, and 1.0 for
guaifenesin. Chromatograph the Standard preparation, Change to read:
and record the peak responses as directed for Procedure: Medium: water
the relative standard deviation for replicate injections is •pH 6.8 phosphate buffer (see Buffer Solutions in the sec-
tion Reagents, Indicators, and Solutions);m
not more than 2.0% for both dyphylline and guaifenesin.
900 mL.
Procedure—Separately inject equal volumes (about 20 Apparatus 2: 50 rpm.
Time: 30 minutes.
|j.L) of the Standard preparation and the Assay prep- Procedure—Determine the amount of C 2 oH 28 N20 5 • C 4 H 4 O 4
dissolved as directed for Procedure for content uniformity under
aration into the chromatograph, record the chro- Uniformity of dosage units except to (a) U30 water instead of tho
Buffet4 solution to prepare the Standard preparation, (b)
matograms, and measure the responses for the major
peaks. Calculate the quantities, in mg, of dyphylline use afilteredportion of the solution under test as the Test prepara-
tion, and {e)
(C10H14N4O4) and guaifenesin (C10H14O4) in each mL of •to f l
make any necessary modifications for appropriate sample and
the Oral Solution taken by the formula: standard concentrations.
l000C/V(ra/rs), ^20^28^2^*5' C4H4O4 is dissolved in 30 minutes.
Change to read:
in which C is the concentration, in mg per mL, of the appro- Related compounds—
Buffer solution, Mobile phase, Enalaprilat standard solution,
priate USP Reference Standard in the Standard preparation, Enalapril diketopiperazine solution, System suitability solution,
Standard preparation, and Chromatographic system—Proceed as
Fis the volume, in mL, of Oral Solution taken; and rv and rs directed in the Assay.
Test preparation—Use the Assay preparation.
are the peak responses of the corresponding analyte ob- Related compounds standard solution—Transfer 1.0 mL of the
Standard preparation to a 100-mL volumetric flask, dilute with
tained from the Assay preparation and the Standard pre- Buffer solution to volume, and mix.
paration, respectively.AUSP26 the Standard preparation, the Test preparation, the Related
compounds standard solution, and the Buffer solution, into the
(Official June 1,2005) chromatograph, record the chromatograms, and measure the
responses for all of the peaks in the Test preparation greater than
0.1% of the response of the enalapril peak that are not observed in
the Buffer solution. Calculate the percentage of anhydrous
Pharmacopeial Forum
enalaprilat (as enalapril

enalap maleate) present in the portion of Tablets
taken hv
talfftn by thp formula1
the formula:
BRIEFING
(•192.53/3 48.39
Ephedrine Sulfate Oral Solution—See briefing under A man ta-
A
(492.52/348.39)(CF/iV)(r [/ /r 5 )(100/L), Al/ , P2(J (NL: C. Barnstein; AER: K. Zaidi) RTS—35967-1
in which 492.53
Add the following:
and 348.39 are the molecular weights of enalapril maleate and an-
hydrous enalaprilat, respectively; C is the concentration, in mg per A
mL, of USP Enalaprilat RS in the Standard preparation; Fis the Ephedrine Sulfate Oral Solution
nominal capacity, in mL, of the volumetric flask containing the Test (Monograph under this new title—to become official
preparation; N'is the number of Tablets taken for the Test prepara- June 1, 2005)
tion; rv and rs are the enalaprilat peak responses obtained from the (Current monograph title is Ephedrine Sulfate Syrup)
Test preparation and the Standard preparation, respectively; and L
is the labeled amount of enalapril maleate in the Tablet.
Calculate the percentage of enalapril diketopiperazine (as enala-
pril maleate) present in the portion of Tablets taken by the formula:
» Ephedrine Sulfate Oral Solution contains, in
N)(^/1.25 ^
each 100 mL, not less than 360 mg and not more
A
than 440 mg of ephedrine sulfate [(C 10 H 15
(492.52/358.44)(C'P7iV)(/y 1.25 rs)(l00/L),AUSP26
NO) 2 H 2 SO 4 ].
in which 192.53
492.52A[M Packaging and storage—Preserve in tight, light-resistant
and 358.44 are the molecular weights of enalapril maleate and en-
alapril diketopiperazine, respectively; C is the concentration, in containers, and avoid exposure to excessive heat.
mg per mL, of USP Enalapril Maleate RS in the Related com-
pounds standard solution; V is the nominal capacity, in mL, of USP Reference standards (11)—USP Ephedrine Sulfate
the volumetric flask containing the Test preparation; Nis the num-
ber of Tablets taken for the Test preparation; rv is the enalapril di- RS.
ketopiperazine peak response obtained from Test preparation; 1.25
is the response for enalapril diketopiperazine relative to that for en- Identification—The 0.1 N sulfuric acid extract of the
alapril
chloroform solution obtained as directed under Assay
; rs is the enalapril peak response obtained from the Related com-
pounds standard solution; and L is the labeled amount, in mg, of preparation meets the requirements of Identification test C
enalapril maleate in the Tablet.
Calculate the percentage of any other related compound by the under Ephedrine Sulfate Injection.
formula:
(CV/N)(rR/rs)(100/L),
in which rR is the sum of the responses of any related compound,
C2H5OH.
other than those from maleic acid, enalapril, enalaprilat, and ena-
lapril diketopiperazine obtained from the Test preparation; rs is the Assay—
enalapril peak response obtained from the Related compounds
standard solution; and C, V, N, and L are as defined above: the Standard preparation—Dissolve an accurately weighed
sum of all related compounds including those from enalaprilat
and enalapril diketopiperazine is not greater than 5.0%. quantity of USP Ephedrine Sulfate RS in 0.1 N sulfuric
acid to obtain a solution having a known concentration of
about 20 ug per mL.
Assay preparation—Transfer 5 mL of Oral Solution to a
separator, add 1 mL of 1 N sulfuric acid, and extract with 10
mL of chloroform. Discard the extract, and add 5 mL of
potassium carbonate solution (1 in 5). After gas evolution
has ceased, extract the solution with three 10-mL portions
Pharmacopeia! Forum
of chloroform, and combine the extracts in a second

BRIEFING
separator. Extract the chloroform solution with 50.0 mL of
Erythromycin Ointment, USP 25 page 678 and page 3278 of
0.1 N sulfuric acid. Filter the acid layer through paper, and PF 27(6) [Nov.-Dec. 2001].
dilute 5.0 mL of it with 0.1 N sulfuric acid to 100.0 mL.
Procedure—Proceed as directed for Procedure in the
Assay under Ephedrine Sulfate Capsules. Calculate the
Erratum:
quantity, in mg, of ephedrine sulfate [ ( C 1 0 H 1 5 Assay, line 4 under Assay preparation: Change "separate por-
tions" to: separate 20-mL portions
NO)2 • H2SO4]in the portion of Oral Solution taken by the
formula:

Ephedrine Sulfate RS in the Standard preparation, andAy
BRIEFING
and As are the absorbances of the solutions from the Assay
preparation and the Standard preparation, respective- Ferrous Gluconate Elixir, USP 25 page 732. It is proposed to
change the title of this monograph to Ferrous Gluconate Oral So-
ly- A USP26 lution. See also briefing under Amantadine Hydrochloride Syrup
(Official June 1,2005) (NL: C. Barnstein; DSN: G. Giancaspro) RTS—35968-1
Ferrous Gluconate Elixir

2005
cess Revision):
BRIEFING See Ferrous Gluconate Oral Solution
Ephedrine Sulfate Syrup, USP 25 page 657. It is proposed to

change the title of this monograph to Ephedrine Sulfate Oral Solu-
Ephedrine Sulfate Syrup

BRIEFING
2005 Ferrous Gluconate Oral Solution—See briefing under Aman-
(see Official Title Changes on the first page of In-Pro- tadine Hydrochloride Syrup
cess Revision)
See Ephedrine Sulfate Oral Solution (NL: C. Barnstein; DSN: G. Giancaspro) RTS—35968-1
Pharmacopeial Forum
Add the following:

BRIEFING
A
Ferrous Gluconate Oral Solution
Gabapentin Capsules, page 2160 of PF 27(2) [Mar.-Apr.
{Monograph under this new title—to become official 2001]. It is proposed to revert to the previously proposed limit
June 1, 2005) for gabapentin related compound A in the test for Related com-
{Current monograph title is Ferrous Gluconate Elixir) pounds, because this limit has been approved and demonstrated
to be safe.

» Ferrous Gluconate Oral Solution contains not
Add the following:
percent of the labeled amount of ferrous gluconate A
Gabapentin Capsules
(C12H22FeO142H2O.)
Packaging and storage—Preserve in tight, light-resistant » Gabapentin Capsules contain not less than 95.0
containers. percent and not more than 105.0 percent of the la-
Labeling—Label the Oral Solution in terms of the content beled amount of gabapentin (C9H17NO2).
of ferrous gluconate (C12H22FeO14 • 2H2O) and in terms of
the content of elemental iron.
containers.
USP Reference standards (11)—USP Potassium Gluco-
USP Reference standards (II)—USP Gabapentin RS.
nate RS.
USP Gabapentin Related Compound A RS.
Identification—A volume of Oral Solution diluted, where
Identification—
necessary, with water meets the requirements of the
A: Infrared Absorption (197K)—
Identification tests under Ferrous Gluconate.
Test specimen—Use the contents of three Capsules or a
portion of the dry, powdered Capsule contents as prepared
in the Assay, equivalent to about 156 mg of gabapentin.
C2H5OH.
Solution, equivalent to about 1.2 g of ferrous gluconate, to
that in the chromatogram of Standard preparation I, as
a flask containing a cooled mixture of 80 mL of recently
boiled water and 80 mL of 2 N sulfuric acid. Add
orthophenanthroline TS, and immediately titrate with 0.1
Medium: 0.06 N hydrochloric acid; 900 mL.
N eerie sulfate VS. Perform a blank determination, and
make any necessary correction. Each mL of 0.1 N eerie
Time: 20 minutes.
sulfate is equivalent to 48.22 mg of ferrous gluconate
Determine the amount of C9H17NO2 dissolved by employ-
(Official June 1,2005) ing the following method.
Pharmacopeia! Forum
Mobile phase—Prepare a filtered solution of 5.75 g of Procedure—Inject equal volumes (about 25 uL) of the
monobasic ammonium phosphate and 1 g of sodium 1- Standard solution and the filtered portion of the solution
decanesulfonate in 575 mL of water. Add 390 mL of under test into the c h r o m a t o g r a p h , record the
methanol, 110 mL of acetonitrile, and 5 mL of phosphoric chromatograms, and measure the areas for the major
acid. Mix, and adjust with triethylamine to a pH of 4.4. Do peaks. From the measured peak areas, calculate the
not degas. quantity, in mg, of C9Hi7NO2 dissolved.
Standard stock solution—Dissolve an accurately weighed Tolerances—Not less than 80% (Q) of the labeled amount
quantity of USP Gabapentin RS in Medium to obtain a of C9HI7NO2 is dissolved in 20 minutes.
solution having a known concentration of about 1.1 mg Uniformity of dosage units (905): meet the requirements.
per mL. Sonicate to dissolve. Related compounds—
Standard solution—Dilute the Standard stock solution Phosphate buffer solution, Mobile phase, Standard
quantitatively, and stepwise if necessary, with Medium to preparation 1, Standai<vi preparation-2, System suitability
obtain a solution with a concentration similar to that of solution, and Chromatographic system—Proceed as
the solution under test. directed in the Assay.
Resolution solution—Dissolve an accurately weighed Standard solution 1—Use Standard preparation 2, as
quantity of USP Gabapentin Related Compound A RS in prepared in the Assay.
Medium to obtain a s o l u t i o n h a v i n g a known Standard solution 2—Transfer 5.0 mL of Standard
concentration of about 0.2 mg per mL. Transfer 4.0 mL of solution 7 to a 50-mL volumetric flask, dilute with Mobile
this solution and 15.0 mL of the Standard stock solution to a phase to volume, and mix.
50-mL volumetric flask, dilute with Medium to volume, and Test solution—Use the Assay preparation.
mix. Procedure—Separately inject equal volumes (about 50
Chromatographic system (see Chromatography (621))— uL) of Standard solution 2 and the Test solution into the
The liquid chromatograph is equipped with a 210-nm chromatograph, record the chromatograms, and measure
detector and a 4.6-mm x 25-cm column that contains 5- the areas for the major peaks. Calculate the quantity, in
um packing LI. The flow rate is about 1.0 mL per minute. mg, of oaoh impurity gabapentin related compound A in
Chromatograph the Standard solution, and record the peak the portion of Capsules taken by the formula:
responses as directed for Procedure: the column efficiency
25C(r,/r,),
is not less than 6000 theoretical plates; the tailing factor for
gabapentin is not more than 2.0; and the relative standard in which C is the concentration, in mg per mL, of USP Ga-
deviation for replicate injections is not more than 1.0%. bapentin Related Compound A RS in Standard solution 2; *,
Chromatograph the Resolution solution, and record the is the peak response for oaoh impurity obtained from tho
peak responses as directed for Procedure: the resolution, Test preparation; and i'£ is the peak response obtained from
R, between gabapentin and gabapentin related compound and r, and rs are the peak areas for gabapentin related com-
A is not less than 1.5. pound A obtained from the Test solution and Standard solu-
tion 2, respectively: not more than 0.4% 0.5% 0.4% of
Pharmacopeial Forum
gabapentin related compound A is found. Calculate the per- volumetric flask. Add about 15 mL of Mobile phase,
centage of any other unknown impurity in the portion of dissolve by stirring, and dilute with Mobile phase to
Capsules taken by the formula: volume.
100(r,/r,)f
in which rt is the peak area for each impurity obtained from
the Test solution; and rs is the sum of the areas of all the
um packing LI. The flow rate is about 1.0 mL per minute.
peaks obtained from the Test solution: tho sum of all impu
Chromatograph Standard preparation 1, and record the
ritios 19 not moro than 0.6%. not more than 0.2% of any
peak responses as directed for Procedure: tho oolumn
other unknown impurity is found; and not more than 1.0%
efficiency ianot looo than 1600 thoorotical plates; tho
of total impurities is found.
tailing faotor is not moro than 2.0; and the relative
Assay—
Phosphate buffer solution—Dissolve 3.52 g of monobasic 1.0%. Chromatograph the System suitability solution, and
potassium phosphate and 7.27 g of dibasic sodium record the peak responses as directed for Procedure: the
phosphate in 1000 mL of water. Adjust with phosphoric resolution, R, between gabapentin and gabapentin related
acid or potassium hydroxide to a pH of 7.0. compound A is not less than 8.0; the column efficiency is
Mobile phase—Prepare a filtered and degassed mixture of not less than 1600 theoretical plates, determined from
water, methanol, acetonitrile, and Phosphate buffer solution gabapentin, and not less than 3000 theoretical plates,
(55:35:10:0.1). Make adjustments if necessary (see System determined from gabapentin related compound A; and the
Suitability under Chromatography (621)). tailing factors for the gabapentin and gabapentin related
Standard preparation 1—Dissolve an accurately weighed compound peaks are not more than 2.0 and 1.8, respectively.
quantity of USP Gabapentin RS in Mobile phase to obtain a Procedure—Separately inject equal volumes (about 50
solution having a known concentration of about 6.25 mg per uL) of Standard preparation 1 and the Assay preparation
mL. into the chromatograph, record the chromatograms, and
Standard preparation 2—Dissolve an accurately weighed measure the areas for the major peaks. Calculate the
quantity of USP Gabapentin Related Compound A RS in quantity, in mg, of gabapentin (C9Hi7NO2) in the portion
Mobile phase to obtain a solution having a known of Capsules taken by the formula:
System suitability solution—Transfer 5.0 mL of Standard
preparation 1 and 25.0 mL of Standard preparation 2 to a in which C is the concentration, in mg per mL, of USP Ga-
100-mL volumetric flask, dilute with Mobile phase to bapentin RS in Standard preparation 1; and rv and rs are the
volume, and mix. peak areas obtained from the Assay preparation and Stan-
Assay preparation—Combine and finely powder the dard preparation 1, respectively.AUSP2IJ
contents of not fewer than 20 Capsules. Transfer an

accurately weighed portion of the Capsule contents,
equivalent to about 156 mg of gabapentin, to a 25-mL
Pharmacopeia! Forum
BRIEFING
Mobile phase, System suitability solution, and
Ganciclovir, page 358 of PF 26(2) [Mar.-Apr. 2000]. This new Chromatographic system—Proceed as directed in the Assay.
monograph, which previously appeared in Pharmacopeial Pre-
views, is now forwarded to In-Process Revision with minor Test solution—Transfer about 5 mg 11 mg of Ganciclovir,
changes in the tests for Related compounds and the Assay.
accurately weighed, to a 50-mL volumetric flask, dissolve in
(PA7: S. Dressman) RTS—35617-1
and dilute with Mobile phase to volume, and mix.
Add the following:
A solution into the c h r o m a t o g r a p h , r e c o r d the
GancicIovir
chromatogram, and measure the peak responses. Calculate
(Chemical structure to come) the percentage of each impurity in the portion of
Ganciclovir taken by the formula:
C9H13N5O4 255.23
6/f-Purin-6-one, 2-amino-l,9-dihydro-9-[[2-hydroxy-l-
(hydroxymethyl)ethoxy]methyl]-.
in which r, is the peak response for each impurity in the Test
9-[[2-Hydroxy-1 -(hydroxymethyl)ethoxy]methyl]gua-
solution, and rs is the sum of the responses of all the peaks:
nine [82410-32-0]
not more than 0.5% of ganciclovir related compound A is
found, and not more than 1.5% of total impurities is found.
» Ganciclovir contains not less than 98.0 percent Assay—
and not more than 102.0 percent of C9H13N5O4, Trifluoroacetic acid solution—Transfer about 0.5 mL of
calculated on the dried basis. trifluoroacetic acid to a 1000-mL volumetric flask, dilute
with water to volume, and mix.
Mobile phase—Prepare afilteredand degassed mixture of
containers.
Trifluoroacetic acid solution and acetonitrile (1:1). Make
USP Reference standards (11)—USP Ganciclovir RS.
USP Ganciclovir Related Compound A RS.
Identification— System suitability solution—Dissolve accurately weighed
A: Infrared Absorption (197K). quantities of USP Ganciclovir RS and USP Ganciclovir
B: Ultraviolet Absorption (197U)— Related Compound A RS in Mobile phase, sonicating if
Solution: 10 u,g per mL. necessary, to obtain a solution having a known
Medium: methanol. concentration of about 0.1 mg of each per mL.
Water, Method I (921): not more than 6.0%. [NOTE— Standard preparation—Dissolve an accurately weighed
Ganciclovir is extremely hygroscopic] quantity of USP Ganciclovir RS, previously dried under
Residue on ignition (281): not more than 0.1%. vacuum at 80° for 3 hours, in Mobile phase, and dilute
Heavy metals, Method II (231): 0.002%. quantitatively, and stepwise if necessary, with Mobile
phase to obtain a solution having a known concentration
of about 0.22 mg per mL.
Pharmacopeial Forum
Assay preparation—Transfer about 11 mg of Ganciclovir,

BRIEFING
previously dried under vacuum at 80° for 3 hours and
accurately weighed, to a 50-mL volumetric flask, dissolve Guaifenesin Oral Solution—See briefing under Amantadine
in and dilute with Mobile phase to volume, and mix.
Chromatographicsystem (see Chromatography (621))—
Add the following:
detector and a 4.6-mm x 25-cm column that contains
A
packing L9. The flow rate is about 1.5 mL per minute. Guaifenesin Oral Solution
The column temperature is 40°. Chromatograph the June 1,2005)
(Current monograph title is Guaifenesin Syrup)
System suitability solution, and record the peak responses
as directed for Procedure: the relative retention times are
about 0.9 for ganciclovir related compound A and 1.0 for » Guaifenesin Oral Solution contains not less than
ganciclovir; the resolution, R, between ganciclovir and 90.0 percent and not more than 110.0 percent of
ganciclovir related compound A is not less than 1.4; the the labeled amount of guaifenesin (C10H14O4).
column efficiency is not less than 5000 theoretical plates;
the tailing factor is not more than 4r3f 1.4; and the relative
USP Reference standards (11)—USP Guaifenesin RS.
Identification—The retention time of the guaifenesin peak
1.0%.
in the chromatogram of the Assay preparation corresponds
to that in the chromatogram of the Standard preparation, as
chromatograms, and measure the responses for the major pH (791): between 2.3 and 3.0.
peaks. Calculate the quantity, in mg, of C9H13N5O4 in the Alcohol content, Method I (611) (if present): between
portion of Ganciclovir taken by the formula: 90.0% and 115.0% of the labeled amount of C2H5OH.
Assay—
Mobile phase, Benzoic acid solution, Resolution solution,
in which C is the concentration, in mg per mL, of USP Gan-
Standard preparation, and Chromatographic system—
ciclovir RS in the Standard preparation; and rv and rs are
Proceed as directed in the Assay under Guaifenesin Tablets.
the peak responses obtained from the Assay preparation and
the Standard preparation, respectively.
guaifenesin, to a 100-mL volumetric flask, dilute with
water to volume, and mix. Transfer 2.0 mL of this
solution to a 100-mL volumetric flask, add 45 mL of
methanol, dilute with water to volume, and mix.
Pharmacopeial Forum
Procedure—Proceed as directed in the Assay under Add the following:

Guaifenesin Tablets. Calculate the quantity, in mg, of A
Guaifenesin and Codeine Phosphate
guaifenesin (C10H14O4) in each mL of the Oral Solution Oral Solution
taken by the formula: (Monograph under this new title—to become official
June 1, 2005)
(Current monograph title is Guaifenesin and Codeine
5C/V(ro/rs), Phosphate Syrup)
in which Fis the volume, in mL, of Oral Solution taken; and

the other terms are as defined therein.AasP2(S » Guaifenesin and Codeine Phosphate Oral Solu-
(Official June 1,2005) tion contains not less than 90.0 percent and not
more than 110.0 percent of the labeled amounts
of guaifenesin (C10H14O4) and codeine phosphate
(C18H21NO4-H3PO4.1/2H2O).

BRIEFING containers, at controlled room temperature.
Guaifenesin Syrup, USP 25 page 821. It is proposed to change USP Reference standards (11 >—USP Codeine Phosphate
the title of this monograph to Guaifenesin Oral Solution. See also
briefing under Amantadine Hydrochloride Syrup. RS. USP Guaifenesin RS.
(NL: C. Barnstein; PA2: J. Kelly) RTS—35969-1 Identification—
A: The retention time of the codeine peak in the
Guaifenesin Syrup chromatogram of the Assay preparation corresponds to

(Current title--not to change until June 1,2005) that in the chromatogram of the Standard preparation, as
2005 obtained in the Assay for codeine phosphate.
cess Revision): B: The retention time of the guaifenesin peak in the
See Guafenesin Oral Solution
obtained in the Assay for guaifenesin.
pH (791): between 2.3 and 3.0 if it contains alcohol, 5.0 to
5.5 if it does not contain alcohol.
Alcohol content (if present)—
BRIEFING
Standard stock solution—Dilute 10.0 mL of dehydrated
Guaifenesin and Codeine Phosphate Oral Solution—See
alcohol with water to 100.0 mL.
Internal standard solution—Dilute 10 mL of acetone with
water to 100 mL.
Standard preparation—Transfer 10.0 mL of Standard
stock solution and 8.0 mL of Internal standard solution to
a 100-mL volumetric flask, dilute with water to volume, and
Pharmacopeial Forum
mix. Transfer 5.0 mL of this solution to a 250-mL

in which P is the percentage (v/v) of alcohol (C2H5OH) in
This solution contains 0.02% (v/v) of alcohol.
the Standard preparation; Fis the volume, in mL, of Oral
Test preparation—Transfer 251k mL of Syrup (k being the
Solution taken to prepare the Test preparation; and Rv and
labeled percentage (v/v) of C2H5OH in the Oral Solution),
Rs are the peak response ratios of alcohol to that of acetone
accurately measured, to a 25-mL volumetric flask, add 2.0
obtained from the Test preparation and the Standard pre-
mL of Internal standard solution, dilute with water to
paration, respectively: between 90.0% and 115.0% of the
volume, and mix. Transfer 5.0 mL of this solution to a
labeled amount of alcohol (C2H5OH) is found.
250-mL volumetric flask, dilute with water to volume, and
Assay for codeine phosphate—
mix.
Internal standard solution—Place about 45 mg of
hydrocodone bitartrate in a flask containing about 5 mL of
The gas chromatograph is equipped with a flame-ionization
water, add 1 mL of 0.5 N sodium hydroxide and 50 mL of
detector and a 2-mm x 1.8-m column that contains 5%
chloroform, insert the stopper into the flask, and shake by
liquid phase G16 on 100- to 120-mesh support SI A, and
mechanical means for about 20 minutes. Allow the layers
is programmed to maintain the column temperature at 50°
to separate, and filter the chloroform layer.
for 5 minutes after injection, to increase to 100° at the rate
Standard preparation—Prepare a Standard stock solution
of 20° per minute, to maintain the temperature at 100° for 2
of USP Codeine Phosphate RS in 0.1 N hydrochloric acid
minutes, and then return to 50° before the next injection.
having a known concentration of about 2 mg per mL.
The injection port is maintained at about 200°, and the
Transfer 5.0 mL of this Standard stock solution to a
detector block is maintained at about 250°. The carrier gas
suitable flask. Add 2 mL of 2.5 N sodium hydroxide, 8.0
is dry helium flowing at a rate of about 30 mL per minute.
mL of Internal standard solution, and 40 mL of
chloroform, insert the stopper, and shake by mechanical
chromatogram as directed for Procedure: the relative
means for 1 hour. Allow the layers to separate, and collect
retention times are about 0.3 for acetone and 1.0 for
the chloroform layer.
alcohol (C2H5OH); the resolution, R, between the acetone
and alcohol peaks is not less than 2; the tailing factors for
the acetone and alcohol peaks are not more than 1.5; and the
codeine phosphate, to a 200-mL flask containing about 5
mL of water, and swirl. Add 2 mL of 2.5 N sodium
more than 2%.
hydroxide, 8.0 mL of Internal standard solution, and 40
Procedure—Separately inject equal volumes (about 2 uL)
mL of chloroform, insert the stopper, and shake by
of the Test preparation and the Standard preparation into
mechanical means for 1 hour. Allow the layers to
the chromatograph, record the chromatograms, and
separate, and collect the chloroform layer.
measure the responses for the major peaks. Calculate the
percentage (v/v) of alcohol (C2H5OH) in the portion of
Oral Solution taken by the formula:
Pharmacopeia! Forum
liquid phase G3 on 100- to 120-mesh support SI A, and is Standard preparation—Prepare a Standard stock solution
stabilized for isothermal operation. The column temperature of USP Guaifenesin RS in 0.1 N hydrochloric acid having a
is maintained at about 210°, the injection port temperature at known concentration of about 4 mg per mL. Transfer 5.0
about 250°, and the detector block temperature is mL of this Standard stock solution to a suitable glass-
maintained at about 300°. The carrier gas is dry helium stoppered flask, add 2 mL of 2.5 N sodium hydroxide, 8.0
flowing at a rate of about 25 mL per m i n u t e . mL of Internal standard solution, and 40 mL of chloroform,
Chromatograph the Standard preparation, and record the insert the stopper, and shake by mechanical means for 1
chromatogram as directed for Procedure: the relative hour. Allow the layers to separate, and collect the
retention times are about 0.75 for codeine and 1.0 for chloroform layer. Extract the aqueous layer with two 20-
hydrocodone; the resolution, R, between the codeine and mL portions of chloroform, and combine the three
hydrocodone peaks is not less than 1; and the relative chloroform extracts. Transfer 5.0 mL of the combined
standard deviation for replicate injections is not more than chloroform extracts to a suitable glass-stoppered flask, add
2%. 1 mL of trifluoroacetic anhydride, and allow to stand for not
Procedure—Separately inject equal volumes (about 2 uL) less than 1 hour.
of the Assay preparation and the Standard preparation into Assay preparation—Transfer an accurately measured
the chromatograph, record the chromatograms, and measure volume of Oral Solution, equivalent to about 20 mg of
the responses for the major peaks. Calculate the quantity, in guaifenesin, to a 200-mL flask containing about 5 mL of
mg, of codeine phosphate hemihydrate (C 1 8 H 2 i water, and swirl. Add 2 mL of 2.5 N sodium hydroxide,
NO 3 • H 3 PO 4 • y2H2O) in each mL of the Oral Solution 8.0 mL of Internal standard solution, and 40 mL of
taken by the formula: chloroform, insert the stopper, and shake by mechanical
(406.37 / 397.37)(5C/ V){RV/RS), means for 1 hour. Allow the layers to separate, and collect
the chloroform layer. Extract the aqueous layer with two 20-
mL portions of chloroform, and combine the three
codeine phosphate hemihydrate and anhydrous codeine
chloroform extracts. Transfer 5.0 mL of the combined
phosphate, respectively; C is the concentration, in mg per
chloroform extracts to a suitable glass-stoppered flask, add
mL, of USP Codeine Phosphate RS in the Standard stock
1 mL of trifluoroacetic anhydride, and allow to stand for not
solution used to prepare the Standard preparation; V is
less than 1 hour.
the volume, in mL, of Oral Solution taken to prepare the As-
say preparation; and Rv and Rs are the peak response ratios
of the codeine peak to the hydrocodone peak obtained from
the Assay preparation and the Standard preparation, re-
liquid phase G6 on 100- to 120-mesh support SI A. The
spectively.
column temperature is maintained at about 170°, the
Assay for guaifenesin—
injection port temperature is maintained at about 250°,
Internal standard solution—Prepare a solution of
and the detector block temperature is maintained at about
dipropyl phthalate in chloroform containing about 12.5
300°. The carrier gas is dry helium flowing at a rate of
mg per mL.
Pharmacopeial Forum
about 45 mL per minute. Chromatograph the Standard Guaifenesin and Codeine Phosphate
preparation, and record the chromatogram as directed for Syrup
Procedure: the relative retention times are about 0.6 for (Current title--not to change until June 1,2005)
the trifluoroacetyl derivative of guaifenesin and 1.0 for the 2005
trifluoroacetyl derivative of dipropyl phthalate; the cess Revision):
See Guaifenesin and Codeine Phosphate Oral Solution
resolution, R, between the guaifenesin and dipropyl
phthalate peaks is not less than 1; and the relative
2%.
of the Assay preparation and the Standard preparation into
BRIEFING
the chromatograph, record the chromatograms, and measure
Hydralazine Hydrochloride Oral Solution, USP 25 page 847
the responses for the major peaks. Calculate the quantity, in and page 3301 of PF 27(6) [Nov.-Dec. 2001]—See briefing under
Cefazolin Ophthalmic Solution.
mg, of guaifenesin (C 10 H 14 O 4 ) in the portion of Oral
Solution taken by the formula: (CRX: C. Okeke) RTS—35643-10
Change to read:
in which W is the quantity, in mg, of USP Guaifenesin RS
» Hydralazine Hydrochloride Oral Solution contains
taken to prepare the Standard preparation; Fis the volume, not less than 90.0 percent and not more than 110.0 per-
cent of the labeled content of hydralazine hydrochlor-
in mL, of Oral Solution taken to prepare the Assay prepara-
ide ( C 8 H 8 N 4 - H C 1 ) . P r e p a r e H y d r a l a z i n e
tion; and Rv and Rs are the peak response ratios of the guai- Hydrochloride Oral Solution of the designated percen-
tage strength as follows (see Pharmacy Compounding
fenesin peak to the dipropyl phthalate peak obtained from {)
the Assay preparation and the Standard preparation, re- ^Pharmaceutical Compounding—Nonsterile
spectively.AKSPM Preparations (795)):AUSP26
NOTE—Hydralazine reacts with many flavors; do

not add flavors when compounding.
Hydralazine Hydrochloride
for 0.1% Oral Solution 100 mg
for 1.0% Oral Solution 1.0 g
Sorbitol Solution (70%) 40 g
BRIEFING Methylparaben 65 mg
Propylparaben 35 mg
Guaifenesin and Codeine Phosphate Syrup, USP 25 page Propylene Glycol 10 g
822. It is proposed to change the title of this monograph to Guai-
fenesin and Codeine Phosphate Oral Solution. See also briefing Aspartame 50 mg
under Amantadine Hydrochloride Syrup. Purified Water, a sufficient
quantity to make 100 mL
Pharmacopeial Forum
Dissolve the Hydralazine Hydrochloride in 30 mL solution and 100 \iL of a solution in the same medium
of Purified Water, add the Aspartame, and shake or stir
until the solids have dissolved. Add the Sorbitol Solu- containing about 350 f*g of USP Hydroxyzine
tion. In a separate container, dissolve an aliquot por- Hydrochloride RS per mL to a suitable thin-layer
tion of an intimate homogeneous mixture of
accurately weighed quantities of Methylparaben and chromatographic plate (see Chromatography (621)),
Propylparaben in the Propylene Glycol, and, with stir-
coated with a 0.25-mm layer of chromatographic silica gel
ring, add this mixture to the solution containing the
Hydralazine Hydrochloride. Add sufficient Purified and dried in air for 30 minutes followed by drying in
Water to make the product measure 100 mL, and mix.
vacuum at 140° for 30 minutes. Allow the spots to dry,
and develop the chromatogram in a solvent system
consisting of a mixture of toluene, alcohol, and
ammonium hydroxide (150:95:1) until the solvent front
has moved about three-fourths of the length of the plate.
Remove the plate from the developing chamber, mark the
BRIEFING
solvent front, and allow the solvent to evaporate. Locate
Hydroxyzine Hydrochoride Oral Solution—See briefing un- the spots by lightly spraying with potassium iodoplatinate
TS: the RF value of the principal spot obtained from the
test solution corresponds to that obtained from the
Standard solution.
Add the following:
Assay—
A
Hydroxyzine Hydrochloride Oral Mobile phase and Chromatographic system—Proceed as
Solution
directed in the Assay under Hydroxyzine Hydrochloride
Monograph under this new title—to become official
June 1, 2005 Tablets.
(Current monograph title is Hydroxyzine Hydrochloride
Syrup) Standard preparation—Dissolve a suitable quantity of
USP Hydroxyzine Hydrochloride RS, accurately weighed,
» Hydroxyzine Hydrochloride Oral Solution con- in water to obtain a s o l u t i o n having a known
tains not less than 90.0 percent and not more than concentration of about 100 (ig per mL.
110.0 percent of the labeled amount of hydroxy- Assay preparation—Transfer an accurately measured
zine hydrochloride (C21H27C1N2O2 • 2HC1).
hydroxyzine hydrochloride, to a 200-mL volumetric flask,
Packaging and storage—Preserve in tight, light-resistant dilute with water to volume, mix, and pass a portion
containers. through a polytef membrane filter having a 5-ym or finer
USP Reference standards {11 )—USP Hydroxyzine Hy- porosity.
drochloride RS.
Identification—Dilute a volume of Oral Solution,
equivalent to about 20 mg of hydroxyzine hydrochloride,
with 50 mL of methanol, and mix. Apply 100 uL of this
Pharmacopeial Forum

Assay under Hydroxyzine Hydrochloride Tablets. BRIEFING
Calculate the quantity, in mg, of h y d r o x y z i n e Iohexol Injection, USP 25 page 931.

hydrochloride (C21H27C1N2O2 • 2HC1) in each mL of the (RMI: F. Barletta) RTS—36099
02(C/V)(ru/rs), Erratum:
Other requirements, line 2: Change "Chromatographic purity"
to: Related compounds
in which C is the concentration, in ug per mL, of USP Hy-
droxyzine Hydrochloride RS in the Standardpreparation, V
is the volume, in mL, of Oral Solution taken; and rv and rs
are the peak responses obtained from the Assay preparation
and the Standard preparation, respectively.AUSP26
BRIEFING
Ipecac Oral Solution—See briefing under Amantadine Hydro-

chloride Syrup.
BRIEFING
Add the following:
A
Hydroxyzine Hydrochoride Syrup, USP 25 page 876. It is Ipecac Oral Solution
proposed to change the title of this monograph to Hydroxyzine Hy- Monograph under this new title—to become official
drochloride Oral Solution. See also briefing under Amantadine
Hydrochloride Syrup. June 1, 2005
(Current monograph title is Ipecac Syrup)
(NL: C. Barnestein; PA3: S. Salado) RTS—35971-1
» Ipecac Oral Solution yields, from each 100 mL,

Hydroxyzine Hydrochloride Syrup not less than 123 mg and not more than 157 mg of
(Current title—not to change until June 1, 2005) the total ether-soluble alkaloids of ipecac.
2005
(see Official Title Changes on the first page of In-Pro- The content of emetine (C29H40N2O4) and ce-
cess Revision)
See Hydroxyzine Hydrochloride Oral Solution phaeline (C28H38N2O4) together is not less than
90.0 percent of the amount of the total ether-solu-
ble alkaloids. The content of cephaeline varies
Pharmacopeia! Forum
from an amount equal to, to an amount not more Alcohol content (611): between 1.0% and 2.5% of
than 2.5 times, the content of emetine. C2H5OH.

Assay for total ether-soluble alkaloids—[NOTE—It is
Powdered Ipecac 70 g important that the ether used in this assay shall have been
1QQ mL shown by test to be free from peroxides within 24 hours
Glycerin
prior to use.] Transfer about 50 mL, accurately measured,
Syrup, a sufficient quantity, to
of Oral Solution to a liquid-liquid automatic extractor, add
make 1000 mL
water, if necessary, to reduce the viscosity, render the liquid
Exhaust the powdered Ipecac by percolation, distinctly alkaline with ammonium hydroxide, and extract
using a mixture of 3 volumes of alcohol and 1 vol- with ether for at least 4 hours or until the extraction is
ume of water as the menstruum, macerating for 72 complete. Use a water bath to boil the ether. Frequently
disconnect the extractor from the condenser, and agitate
hours, and percolating slowly. Reduce the entire
the lower layer by raising and lowering the center tube or
percolate to a volume of 70 mL by evaporation
by other suitable manipulation. At the conclusion of the
at a temperature not exceeding 60° and preferably
extraction period, transfer the ether extract to a separator,
in vacuum, and add 140 mL of water. Allow the
and rinse the extraction flask with 2 or more small
mixture to stand overnight, filter, and wash the re- volumes of ether, adding the rinsings to the separator.
sidue on the filter with water. Evaporate the filtrate Complete the assay as directed in the Assay for total
and washings to 40 mL, and to this add 2.5 mL of ether-soluble alkaloids under Ipecac, beginning with
hydrochloric acid and 20 mL of alcohol, mix, and "Extract the alkaloids from the ether."
filter. Wash the filter with a mixture of 30 volumes Assay for emetine and cephaeline—
of alcohol, 3.5 volumes of hydrochloric acid, and Standard preparation, Phosphate buffer, and Citric acid
66.5 volumes of water, using a volume sufficient buffer—Prepare as directed in the Assay for emetine and
cephaeline under Ipecac.
to produce 70 mL of the filtrate. Add 100 mL of
Assay preparation—Pipet 10 mL of water into a 25-mL
Glycerin and enough Syrup to make the product
volumetric flask. With the aid of a 20-mL pipet, add Oral
measure 1000 mL, and mix.
Solution to volume, taking care to prevent contact of the
Packaging and storage—Preserve in tight containers, Oral Solution with the neck of the flask above the
preferably at a temperature not exceeding 25°. Containers graduation line. Insert the stopper, and mix.
intended for sale to the public without prescription contain Chromatographic columns—Pack a pledget of fine glass
not more than 30 mL of Oral Solution. wool in the base of a chromatographic tube (25-mm x 200-
USP Reference standards (11)—USP Emetine Hydro- mm test tube to which is fused a 5-cm length of 7-mm
chloride RS. tubing) with the aid of a tamping rod having a disk with a
Microbial limits (61)—It meets the requirements of the diameter about 1 mm less than that of the tube.
tests for absence of Escherichia coli.
Pharmacopeial Forum
To prepare Column I, transfer 4.0 mL of the Assay pre-

BRIEFING
paration to a 150-mL beaker, add about 1 g of sodium bi-
Ipecac Syrup, USP 25 page 945. It is proposed to change the
carbonate, and mix. Then proceed as directed for title of this monograph to Ipecac Oral Solution. See also briefing
Chromatographic columns in the Assay for emetine and ce-
phaeline under Ipecac, beginning with "add 6 g of purified (NL: C. Barnstein; DSB: G. Giancaspro) RTS—35972-1
siliceous earth," and prepare Columns II, III, and IVas di-
rected therein. Ipecac Syrup
Procedure—Proceed as directed for Procedure in the (Current title—not to change until June 1, 2005)
Assay for emetine and cephaeline under Ipecac. 2005
Calculate the quantity, in mg, of emetine in each 100 mL cess Revision)
See Ipecac Oral Solution
of Oral Solution taken by the formula:
2.08C(y4 2 8 3 — ^35o)(/'(^283 ~~ -^35o)s>
in which the parenthetic expressions are the differences in

the absorbances of the solution of emetine from the Assay
preparation (U) and the Standard preparation (S), respec-
tively, at the wavelengths indicated by the subscripts, and BRIEFING
C is as defined in the Procedure. Isoniazid Oral Solution—See briefing under Amantadine Hy-
drochloride Syrup.
Calculate the quantity, in mg, of cephaeline in each 100
mL of Oral Solution taken by the formula: (NL: C. Barnstein; PA7: W. Wright) RTS—35973-1
0.971(2.08Q(^283 - ^ 3 5 0 V G 4 2 8 3 - ^ 3 5 0 ) , ,
Add the following:
in which 0.971 is the ratio of the molecular weight of ce- A
Isoniazid Oral Solution
phaeline to that of emetine, the parenthetic expressions are
the differences in the absorbances of the solution of cephae- June 1, 2005)
(Current monograph title is Isoniazid Syrup)
line from the Assay preparation (V) and the Standard pre-
paration (S), respectively, at the wavelengths indicated by
» Isoniazid Oral Solution contains, in each 100
the subscripts, and C is as defined in the Procedure.AUSP26
(Official June 1,2005) mL, not less than 0.93 g and not more than 1.10
g of isoniazid (C6H7N3O).

containers.
USP Reference standards (11)—C/SP Isoniazid RS.
Identification—A volume of Oral Solution, equivalent to

about 50 mg of isoniazid, meets the requirements of
Identification test B under Isoniazid.
Pharmacopeial Forum
Assay—Transfer an accurately measured volume of Oral Change to read:
Solution, equivalent to about 100 mg of isoniazid, to a » Ketoconazole Oral Suspension contains not less than
100-mL beaker. Add 50 mL of a mixture of 1 part of 1.8 g and not more than 2.2 g of Ketoconazole in 100
mL of Oral Suspension.
potassium bromide in 10 parts of dilute hydrochloric acid Use Ketoconazole or the number of Ketoconazole
(1 in 6), and proceed as directed under Nitrite Titration Tablets that contain the designated amount of Ketoco-
nazole, and prepare Ketoconazole Oral Suspension as
(451), beginning with "cool to 15°." Each mL of 0.1 M follows (see Pharmacy Compounding ( )
sodium nitrite is equivalent to 13.71 mg of isoniazid ^Pharmaceutical Compounding—Nonsterile
(C6H7N3O).AWSpM Preparations (795)):AWSMd
Ketoconazole 2.0 g
Cetylpyridinium Chloride 10 mg
Xanthan Gum 0.15 g
Purified Water 30 mL
Suspension Structured Vehicle or
Sugar-Free Suspension Structured Vehi-
cle, a sufficient quantity, to m a k e . . . 100 mL
BRIEFING
Transfer the Ketoconazole, or Ketoconazole Ta-
blets, to a glass mortar. If Tablets are used, finely pow-
Isoniazid Syrup, USP 25 page 956. It is proposed to change the
title of this monograph to Isoniazid Oral Solution. See also briefing der the Tablets such that they pass through a 40-mesh
under Amantadine Hydrochloride Syrup. or 45-mesh sieve, and place the sieved portion in the
glass mortar. Dissolve an accurately weighed quantity
(NL: C. Barnstein; PA7: W. Wright) RTS—35973-1 of Cetylpyridinium Chloride in Purified Water, and di-
lute quantitatively, and step wise if necessary, with Pur-
ified Water to obtain 10 mL of a solution containing 10
mg of Cetylpyridinium Chloride. Transfer this solu-
Isoniazid Syrup tion, in divided portions, to the mortar containing the
{Current title—not to change until June 1,2005) powder, and mix to form a smooth paste. Place 20 mL
(Monograph title change—to become official June 1, of Purified Water in a beaker. Using moderate heat, stir
2005) to form a vortex, and slowly sprinkle the Xanthan Gum
(see Official Title Changes on the first page of In-Pro- into the vortex to obtain a uniform dispersion. Add the
cess Revision): dispersion to the wetted powder paste, and mix until
See Isoniazid Oral Solution
smooth. Add a sufficient quantity of the Suspension
Structured Vehicle or Sugar-Free Suspension Struc-
tured Vehicle to make a final volume of 100 mL, and
mix.
Change to read:
amber containers. Store at a temperature bolow 25°.
BRIEFING •controlled room temperature. B1
Ketoconazole Oral Suspension, USP 25 page 976 and page

3313 ofPF27(6) [Nov.-Dec. 2001]—See briefing under Cefazolin
Ophthalmic Solution.
Pharmacopeial Forum
*Test 2: If tho produot oomplies with this toot; tho labeling

BRIEFING
indicates that it moots USP Dissolution Tost 2.
Levothyroxine Sodium Tablets, USP 25 page 1002 and page Medium: 0:01 N hydroohlorio aoid containing 0.2%
1048 of PF 26(4) [July-Aug. 2000]. Because FDA recently ap-
proved an NDA for an additional manufacturer of Levothyroxine dodooyl sodium sulfato (olootrophoroois grade); 500 mL.
Sodium Tablets, it is proposed to add a Test 2 to the test for Dis-
solution. This new product has a different dissolution rate in vitro Apparatus, Mobile phase, and Test solution—Prooood as
and does not comply with the current test for Dissolution. In the
absence of any adverse comment, it is proposed to implement this dirootod for Test 1.
revision via the Third Interim Revision Announcement, pertaining
to USP 25-NF20, with an official date of June 1, 2002. lime: SO minutoo.
(BPC: M. Marques) RTS—34999; 35502 Determine tho amount of C^Hî 4 NNaO 4 dissolved by
Standard solution—Prepare a stock solution of USP
Add the following:
Lovothyroxino RS in 0.01 N mothanolio sodium
•Labeling—Tho labeling indicator? tho Dissolution Test
hydroxide having a"known concentration of about 0.5 mg
with whioh tho product oomplios. When more than one
per mL. Dilute this stock solution with Dissolution
Dissolution test is given, the labeling states the
Medium to obtain a solution having a concentration
Dissolution test used only if Test 1 is not used.#3
similar to that oxpootod in tho Test solution.
Change to read:
Dissolution (711)—[NOTE—All containers that are in contact with Chromatographic system (soo Chromatography (€34-))—
solutions containing levothyroxine sodium are to be made of
glass.] Tho liquid ohromatograph io equipped with a 229 nm
*Test 1:
If tho product oomplioa with thio tost, tho labeling indioatog dotootor and a 4.6 mm x 25 om column that contains
that it moots USP Dissolution Tost 1.•3 paoking LI: Tho flow rate is about 2 mL per minute.
Medium: 0.01 N hydrochloric acid containing 0.2% sodium
dodecyl sulfate; 500 mL. Chromatograph tho StandaM solution, and record the peak
Time: 45 minutes. responses a3 dirootod for Pmccdurc: the tailing factor is not
Determine the amount of C15H10I4NNaO4 dissolved by employ-
ing the following method. more than 1:5; and tho relative standard deviation is not
methanol and 0.1% phosphoric acid (60:40). more than 4.0%.
Standard solution—Prepare a stock solution of USP Pmccdwc—Separately inject equal volumes (about 400
Levothyroxine RS in methanol having a known concentration of
about 0.1 mg per mL. Dilute this stock solution with Dissolution
Medium to obtain a solution having a concentration similar to that uL). of tho Standard solution and the Test solution into the
expected in the Test solution.
Test solution—[NOTE—Prior to use, check the filters for
ohromatograph, record tho ohromatograms, and measure tho
absorptive loss of drug.] Use a filtered portion of the solution
under test. responses for tho major poak3: Calculate the amount of
liquid chromatograph is equipped with a 225-nm detector and a dissolved.
4.6-mm x 25-cm column that contains packing LI. The flow
rate is about 2 mL per minute. Chromatograph the Standard Tolerances Not less than 55% (Q) of tho labeled amount
Procedure: the tailing factor is not more than 1.5; and the ^ ^ i 4 N N a 0 4 is dissolved in 80 minutes; If the product
relative standard deviation is not more than 4.0%.
complies with this test, the labeling indicates that it meets
the Standard solution and the Test solution into the chromatograph,
record the chromatograms, and measure the responses for the USP Dissolution Test 2.
major peaks. Calculate the amount of C 15 H, 0 I 4 NNaO 4 dissolved.
C15H10I4NNaO4 is dissolved in 45 minutes.
©2002 The United States Pharmacopeial Convention, Inc. All Rights Reserved
Pharmacopeial Forum
Medium, Apparatus, Mobile phase, Standard solution,

Test solution, Chromatographic system, and Procedure— BRIEFING
Proceed as directed for Test 1.

Lincomycin Oral Solution—See briefing under Lincomycin
Time: 15 minutes. Hydrochloride Syrup.
Tolerances—Not less than 80% (Q) of the labeled amount (NL: C. Bamstein; PA7:W. Wright) RTS—35845-1
of C15H10I4NNaO4 is dissolved in 15 minutes.#3

Add the following:
A
Lincomycin Oral Solution
June 1, 2005)
(Current monograph title is Lincomycin Hydrochloride
Syrup)
BRIEFING
» Lincomycin Oral Solution contains an amount
Lincomycin Hydrochloride Syrup, USP 25 page 1009;
Lithium Citrate Syrup, USP 25 page 1016; Paromomycin Sul- of l i n c o m y c i n h y d r o c h l o r i d e (C 1 8 H 3 4 -
fate Syrup, USP 25 page 1312; Trifluoperazine Hydrochloride
Syrup, USP 25 page 1759; Trimeprazine Tartrate Syrup, USP N2O6S • HC1 • H2O) equivalent to not less than
25 page 1766.
Revisions are proposed by the Expert Committee on Nomencla- 90.0 percent and not more than 120.0 percent of
ture and Labeling to change the titles of these monographs on oral
liquid preparations to be in conformance with USP policy. A pre- the labeled amount of lincomycin (C18H34N2O6S),
vious USP Nomenclature Committee adopted a policy to"name
the active moiety in the title if the strength is expressed in terms
of active moiety, and name the derivative in the title if the strength and one or more suitable colors, flavors, preserva-
is expressed in terms of the derivative." The nomenclature pro-
posed for these five monograph titles accordingly change from tives, and sweeteners in water.
naming the drug ingredient as the salt to naming the active moiety
for each to be consistent with policy. Also, revisions are proposed
to change the Elixir and Syrup terminology in the titles to Oral So- Packaging and storage—Preserve in tight containers.
lution terminology (see briefing under Amantadine Hydrochloride
Syrup). USP Reference standards (11)—USP Lincomycin Hydro-
The revisions are proposed for publication in USP 26-NF 21,
which is to become official January 1, 2003, but with June 1, chloride RS.
2005 designated as the official date for the name changes. Use of
the revised names would be permitted as of the January 1, 2003 Uniformity of dosage units (905)—
official date of USP 26-NF 21, but use of the revised names would
not become mandatory until June 1, 2005. The thirty-month post- F O R ORAL SOLUTION PACKAGED IN SINGLE-UNIT
ponement of the official date for the name changes is intended to
allow for product label changes to be made and for health practi-
tioners and consumers to become familiar with the revised termi- CONTAINERS: meets the requirements.
nology
(NL: C. Barnstein; PA7: W. Wright) RTS—35845-1 pH (791): between 3 and5.5.
Assay—
Lincomycin Hydrochloride Syrup Mobile phase, Standard preparation, and
(Current title—not to change until June 1, 2005) Chromatographic system—Proceed as directed in the
2005 Assay under Lincomycin Hydrochloride.
cess Revision): Assay preparation—Transfer an accurately measured
See Lincomycin Oral Solution
volume of Oral Solution, freshly mixed and free of air
bubbles, equivalent to about 100 mg of lincomycin, to a
Pharmacopeia! Forum
suitable container. Add 0.5 mL of sodium carbonate

solution (3 in 10), and swirl for 30 seconds, noting that a
BRIEFING
precipitate forms. Add 1.0 mL of 0.2 N sodium
Lithium Oral Solution—See briefing under Lincomycin Hy-
hydroxide, swirl for 30 seconds, add 10.0 mL of drochloride Syrup.
chloroform, and shake by mechanical means for 10 (NL: C. Barnstein; PA3: S. Salado) RTS—35920-1
minutes. Centrifuge, and remove the upper aqueous layer
by suction. Transfer 1.0 mL of the clear chloroform layer Add the following:
to a suitable container, and evaporate under a stream of A
Lithium Oral Solution
nitrogen to dryness. Add 10.0 mL of Mobile phase to the
residue, and dissolve by swirling, sonicating if necessary. June 1, 2005)
(Current monograph title is Lithium Citrate Syrup)
Lincomycin Hydrochloride, recording the chromatogram
» Lithium Oral Solution is prepared from Lithium
over a period seven times the retention time of
Citrate or Lithium Hydroxide to which an excess
lincomycin. Calculate the quantity, in mg, of lincomycin
of Citric Acid has been added. It contains not less
(C18H34N2O6S) in each mL of the Oral Solution taken by
the formula: than 90.0 percent and not more than 110.0 percent
of the labeled amount of lithium (Li).

the other terms are as defined therein. AUSP26 USP Reference standards (11)—USP Lithium Carbonate
(Official June 1,2005) RS.
Identification—
A: When diluted with an equal volume of 3 N
hydrochloric acid, it imparts an intense crimson color to a
nonluminous flame.
B: It meets the requirements of the test for Citrate
BRIEFING (191).
Lithium Citrate Syrup, USP 25 page 1016. It is proposed to pH (791): between 4.0 and 5.0.
change the title of this monograph to Lithium Oral Solution. See
also briefing under Lincomycin Hydrochloride Syrup. Assay—
(NL: C. Barnstein; PA3: S. Salado) RTS—35920-1 Standard preparation—Prepare as directed in the Assay
under Lithium Citrate. Determine its pH.
Lithium Citrate Syrup Assay preparation—Transfer an accurately measured

{Current title—not to change until June 1, 2005) volume of Oral Solution, equivalent to about 60 mg of
2005 lithium, to a 1000-mL volumetric flask, dilute with water
cess Revision):
See Lithium Oral Solution
Pharmacopeia! Forum
to volume, and mix. Pipet 20 mL of the resulting solution Trisodium trihydrogen (0C-6-13)-[|W,AM,2-ethanediyl-
into a 1000-mL volumetric flask, add about 950 mL of bis[W-[[3-hydroxy-2-methyl-5-[(phosphonooxy)-
water, 2 mL of 1 N hydrochloric acid, and 20 mL of a sur- methyl]-4-pyridinyl]methyl]glycinato]](8-)] manga-
factant solution, and mix. Adjust with 1 N hydrochloric acid nate(6-).
or 1 N sodium hydroxide to the same pH ( + 0.1 pH unit) as Trisodium trihydrogen (0C-6-13)-[|W,iV'-ethylenebis[J/V"-
that of the Standard preparation, dilute with water to vol- [[3-hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridyl]-
ume, and mix. methyl]glycine] 5,5'-bis(phosphato)](8-)]manganate
Procedure—Employ a suitable flame photometer, and (6-) [140678-14-4].
adjust the instrument with the surfactant solution. Aspirate
into the photometer the Standard preparation and the Assay
» Mangafodipir Trisodium contains not less than
preparation, and measure the emission at about 671 nm.
97.0 percent and not more than 103.0 percent of
Calculate the quantity, in mg, of lithium in each mL of the
C22H27MnN4Na3Oi4P2, calculated on the anhy-
drous basis.
(13.88 /73.S9)(50C/V)(A/S),
in which 13.88 is twice the atomic weight of lithium; 73.89
containers.
is the molecular weight of lithium carbonate; C is the con-
USP Reference standards (11 )—USP Endotoxin RS. USP
centration, in jig per mL, of USP Lithium Carbonate RS in
Mangafodipir Trisodium RS. USP Mangafodipir Related
the Standard preparation; V is the volume, in mL, of Oral
Compound A RS. USP Mangafodipir Related Compound
Solution taken; and A and S are the photometer readings
B RS. USP Mangafodipir Related Compound C RS.
of the Assay preparation and the Standard preparation, re-
spectively.^^ Identification—
(Official June 1,2005) A: Infrared Absorption (197K).
B: It meets the requirements of the tests for Sodium
(191) and Manganese (191).
Microbial limits (61)—The total aerobic microbial count is
BRIEFING
not more than 500 cfu per g.
Mangafodipir Trisodium, page 3146 of PF 27(5) [Sept.-Oct.
2001]. This new monograph, which previously appeared in Phar- Bacterial endotoxins (85): not more than 0.13 USP
macopeia! Previews, is now forwarded to In-Process Revision with
several editorial changes, clarifications, and corrections as recom- Endotoxin Unit per mg.
mended by the innovator company.
pH (791): between 5.5 and 7.0, in a solution (1 in 100).
(RMI: F. Barletta) RTS— 36043-1
Water, Method I (921): not more than 20%.
Add the following: Limit of residual solvents—

A Internal standard solution—Transfer 600 uL of methyl
Mangafodipir Trisodium
ethyl ketone to a 100-mL volumetric flask, dilute with
water to volume, and mix to obtain a solution having a
a30i4P2 757.33 concentration of about 5 mg per mL. Transfer 2 mL of
Pharmacopeial Forum
this solution to a 100-mL volumetric flask, dilute with water peak responses as directed for Procedure: the resolution,
to volume, and mix to obtain a solution having a known R, between alcohol and acetone is not less than 5; and the
concentration of about 0.1 mg per mL. relative standard deviation for replicate injections,
Standard stock solution—Transfer about 1 g of determined from the peak response ratios of the analyte to
dehydrated alcohol and 1 g of acetone, both accurately the internal standard, is not more than 2.0%. Calculate the
weighed, to a 100-mL volumetric flask, and dilute with peak response ratios of the analyte to the internal standard,
water to volume. Transfer 10.0 mL of this solution to a and plot the results. Determine the linear regression
100-mL volumetric flask, dilute with water to volume, and equation of the standards by the mean-square method, and
mix to obtain a solution having a known concentration of record the linear regression equation and the correlation
about 1 mg each of alcohol and acetone per mL. coefficient. A suitable system is one that yields a line
Standard solutions—Transfer 10.0 mL of Internal having a correlation coefficient of not less than 0.990.
standard solution to each of four 100-mL volumetric Procedure—Separately inject equal volumes (about 1
flasks. Separately add 0 mL, 1.0 mL, 5.0 mL, and 10.0 mL) of the gaseous headspace of each of the Standard
mL of Standard stock solution to the volumetric flasks, solutions and the Test solution into the chromatograph,
and dilute each with water to volume to obtain solutions record the chromatograms, and measure the peak
having known concentrations of 0.0 ug per mL and about responses. Calculate the percentages (w/w) of alcohol and
10 ug per mL, 50 ug per mL, and 100 ug per mL each of acetone in the portion of Mangafodipir Trisodium taken
alcohol and acetone, respectively. Add 7.0 mL of each by the formula:
Standard solution to separate headspace sample vials, and
7(10,000)(CTO>
cap.
Test solution—Transfer about 1 g of Mangafodipir
(7/lO,000)(OW),
Trisodium, accurately weighed, to a sample vial, add 7.0
mL of the Standard solution having a concentration of 0.0 in which C is the concentration, in ug per mL, of alcohol or
ug per mL, cap, and swirl to dissolve. acetone in the Test solution, as determined from the relevant
Chromatographic system (see Chromatography (621))— standard response line; and Wis the weight, in g, of Manga-
The gas chromatograph is equipped with a flame-ionization fodipir Trisodium taken: not more than 0.1% of alcohol is
detector, a 32 mm 0.32-mm x 30-m fused silica column found, and not more than 0.01% of acetone is found, both
coated with 1.8-um G43 stationary phase. The carrier gas calculated on the anhydrous basis.
is helium, flowing at a rate of 1.5 mL per minute. The Limit of free manganese and free fodipir—
temperatures of the injection port and the oven are Ascorbic acid solution—Dissolve 0.5 g of ascorbic acid in
maintained at 150° and 50°, respectively. The bath 10 mL of water.
temperature for the headspace sample vials is maintained Manganese solution—Transfer about 3.6 g of manganese
at 90°, the valve/loop temperature is maintained at 130°, chloride, accurately weighed, to a 1000-mL volumetric
and the sample thermostating time is 15 minutes. flask, dissolve in and dilute with 0.1 N hydrochloric acid
Chromatograph the Standard solutions, and record the
Pharmacopeial Forum
to volume, and mix. Transfer 100.0 mL of this solution to a in which 100.09 is the molecular weight of calcium carbon-
500-mL volumetric flask, dilute with water to volume, and ate; W'\s the weight, in mg, of the calcium carbonate taken;
mix. and Fis the final titration volume, in mL, of Edetate titrant
Edetate titrant solution—Transfer about 37 g of edetate solution.
disodium, accurately weighed, to a 1000-mL volumetric Procedure—Transfer about 1 g of Mangafodipir
flask, dilute with water to volume, and mix. Transfer 36 Trisodium, accurately weighed, to a suitable beaker, add
mL of this solution to a 1000-mL volumetric flask, dilute about 100 mL of water, 1.0 mL of Ascorbic acid solution,
with water to volume, and mix to obtain a solution having 10 mL of ammonia-ammonium chloride buffer TS, 0.1 mL
a concentration of 0.0036 moles per liter. of eriochrome black TS, and 1.0 mL of Manganese solution,
STANDARDIZATION OF 0.0036 M EDETATE TITRANT and record the color. If the color is yellow to green, add
S O L U T I O N — A c c u r a t e l y weigh about 200 mg of additional 1.0-mL increments of Manganese solution until
chelometric standard calcium carbonate, previously dried the color is red. Record the volume added. Titrate with the
at 110° for 2 hours and cooled in a desiccator, transfer to Edetate titrant solution, determining the endpoint
a 100-mL volumetric flask, and add 10 mL of water and photometrically. Perform a blank determination, and make
about 4 mL of diluted hydrochloric acid. Swirl the flask to any necessary correction (see Titrimetry (541)). Calculate
dissolve, dilute with water to volume, and mix. Transfer 5.0 the percentage of free manganese in the portion of
mL of this solution to a beaker while stirring, preferably Mangafodipir Trisodium taken by the formula:
with a magnetic stirrer, add about 15 mL of sodium
5A9V(M/W),
hydroxide TS and enough hydroxynaphthol blue indicator
in which Fis the volume, in mL, of the Edetate titrant solu-
to achieve a percent transmission of about 95%, using a
tion; Mis the molarity of the Edetate titrant solution; and W
suitable autotitrator at a wavelength of 620 nm, calibrated
is the weight, in g, of Mangafodipir Trisodium taken. Cal-
to 100% transmission with water. Add 20.0 mL of Edetate
culate the percentage of free fodipir in the portion of Man-
titrant solution, and continue to titrate until 3 mL of titrant
gafodipir Trisodium taken by the formula:
have been added beyond the sharp break point, as
determined from the titration curve obtained by plotting 63.85 V{MIW),
relative transmittance versus volume, in mL, of titrant
in which V, M, and Ware as defined herein: not more than
added. Determine the endpoint volume from the titration
0.03% of free manganese is found; and not more than 0.5%
curve. The final titration volume is the sum of the
of free fodipir is found, both calculated on the anhydrous
endpoint volume and the 20.0 mL of Edetate titrant
basis.
solution initially added. Calculate the molarity of the
Edetate titrant soluton by the formula:
Ascorbic acid solution—Dissolve 0.4 g of ascorbic acid in
100 mL of water.
(100.09)(5 00(100 TO
Phosphate buffer—Prepare as directed in the Assay.
(5/100.09)(FF)/(100K),
Pharmacopeial Forum
Mobile phase—Prepare as directed in the Assay. [NOTE— the mangafodipir related compound C peak, if present, in
Increasing the proportion of acetonitrile will decrease the the chromatogram of System suitability solution 1.
retention times]. Chromatograph System suitability solution 1, and record
System suitability stock solution—Prepare as directed for the peak responses as directed for Procedure: the retention
Standard stock preparation in the Assay. time for mangafodipir is between 18 and 30 minutes. The
System suitability solution 1—Prepare a solution of USP peak area for mangafodipir related compound C is less
Mangafodipir Trisodium RS having a known concentration than 0.1%. [NOTE—If the peak area is more than 0.1% of
of about 4.0 mg per mL. Transfer 5.0 mL of this solution to a the total of all peak areas, prepare fresh quantities of
50-mL volumetric flask, add 5.0 mL of System suitability Ascorbic acid solution and System suitability solution 1,
stock solution, 5.0 mL of Phosphate buffer, and 5.0 mL of and repeat the test. If the peak area of mangafodipir
Ascorbic acid solution. Dilute with nitrogen-purged water to related compound C is still greater than 0.1%, repeat the
volume, and mix to obtain a solution having a concentration test using another column. A contaminated column can
of about 0.4 mg eaefe of USP Mangafodipir Trisodium RS, result in oxidation of Mn(II) to Mn(III), forming related
and about 0.01 mg each of USP Mangafodipir Related compound C ] The tailing factor for the mangafodipir
Compound A RS and USP Mangafodipir Related peak is not more than $S 2.3; the column efficiency is not
Compound B RS per mL. [NOTE—Store in a refrigerator less than 1000 theoretical plates; the resolution, R, between
and under nitrogen to avoid excessive exposure to heat, mangafodipir related compound B and mangafodipir is not
air, and light.] less than 1.5; and the relative standard deviation for
System suitability solution 2—Transfer about 10 mg of replicate injections is not more than 10% for each peak.
USP Mangafodipir Related Compound C RS to a 100-mL [NOTE—If the resolution is less than 1.5, adjust the
volumetric flask, dilute with water to volume, and mix. Mobile phase by increasing the concentration of
Transfer 5.0 mL of this solution to a 50-mL volumetric tetrabutylammonium hydrogen sulfate.]
flask, and add 5.0 mL of Phosphate buffer. Procedure—Inject about 10 jiL of the Test solution into
Test solution—Transfer an accurately weighed quantity of the chromatograph, record the chromatogram, and
Mangafodipir Trisodium, equivalent to about 100 mg of measure the areas for all of the major peaks. The relative
mangafodipir trisodium, to a 50-mL volumetric flask, retention times for ascorbic acid, mangafodipir related
dilute with water to volume, and mix. Transfer 10.0 mL c o m p o u n d A, M n ( I I ) - 5 - m e t h y l dipyridoxal
of this solution to a second 50-mL volumetric flask, add monophosphate (Mn(II)-5-methyl DPMP) if present,
5.0 mL of Phosphate buffer, dilute with water to volume, mangafodipir related compound C, mangafodipir related
and mix. [NOTE—Store in a refrigerator and under compound B, and mangafodipir are about 0.1, 0.3, 0.4,
nitrogen to avoid excessive exposure to heat, air, and light.] 0.6, 0.8, and 1.0, respectively. Calculate the percentages
Chromatographic system (see Chromatography {621))— of mangafodipir related compound A, mangafodipir
Prepare as directed in the Assay. Chromatograph System related compound B, mangafodipir related compound C,
suitability solution 2, and record the peak responses as and Mn(II)-5-methyl DPMP in the portion of
directed for Procedure: note the elution time to identify Mangafodipir Trisodium taken by the formula:
Pharmacopeial Forum
buffer, dilute with water to volume, and mix. [NOTE—

Store in a refrigerator under nitrogen to avoid exposure to
in which r, is the peak area of each impurity; and rs is the
excessive heat, air, or light.]
sum of the areas of all of the peaks: not more than 0.5% each
of mangafodipir related compound A and mangafodipir re-
quantity of Mangafodipir Trisodium, equivalent to about
lated compound B is found; not more than 0.6% of manga-
100 mg of mangafodipir trisodium, to a 50-mL volumetric
fodipir related compound C is found; not more than 0.3% of
flask, dilute with water to volume, and mix. Transfer 10.0
Mn(II)-5-methyl DPMP is found; not more than 0.1% of
mL of this solution to a 50-mL volumetric flask, add 5.0
any other impurity is found; and not more than a total of
mL of Phosphate buffer, dilute with water to volume, and
0.5% of tetel other impurities is found.
mix. [NOTE—Store in a refrigerator under nitrogen to
Assay—
avoid exposure to excessive heat, air, or light.]
Phosphate buffer—Transfer about 26.8 g of dibasic
sodium phosphate to a 1000-mL volumetric flask, add 900
mL of water, and adjust with 1 N sodium hydroxide or 1 N
hydrochloric acid to a pH of about 8.0. Dilute with water to
um packing L21. The chromatograph is maintained at
volume, filter, and degas.
about 20°. The flow rate is 0.8 mL per minute.
Mobile phase—Transfer about 0.61 g of boric acid and 9.2
g of tetrabutylammonium hydrogen sulfate to a 1000-mL
peak responses as directed for Procedure: the resolution,
volumetric flask, add 640 mL water, and mix. Adjust with
R, between mangafodipir related compound A and
3 N sodium hydroxide to a pH of about 9.3, add 250 mL of
mangafodipir related compound B is not less than 1.5; the
acetonitrile, dilute with water to volume, and mix. Adjust
with 3 N hydrochloric acid or 3 N sodium hydroxide to a
and the tailing factor is not more than 2.3.
pH of about 10.5, filter, and degas. Make adjustments if
(621)).
Standard stock preparation—Transfer about 10 mg each
of USP Mangafodipir Related Compound A RS and USP
peaks. Calculate the percentage of C22H27MnN4Na3O14P2
Mangafodipir Related Compound B RS, both accurately
in the portion of Mangafodipir Trisodium taken by the
weighed, to a 100-mL volumetric flask, dilute with water
formula:
to volume, and mix.
Mangafodipir Trisodium RS to a 50-mL volumetric flask, in which C is the concentration, in mg per mL, of USP Man-
dilute with water to volume, and mix. Transfer 10.0 mL gafodipir Trisodium RS in the Standard preparation; Wis
of this solution to a 50-mL volumetric flask, add 5.0 mL the weight, in mg, of the Mangafodipir Trisodium taken;
of Standard stock preparation and 5.0 mL of Phosphate
Pharmacopeia! Forum
and rv and rs are the peak responses obtained from the Assay USP Reference standards (1 l)ÛSPEndotoxin RS. USP
preparation and the Standard preparation, respective- Mangafodipir Trisodium RS.
•AUSP26 Identification—
A: The retention time of the major peak in the
B: It meets the requirements of the tests for Sodium
BRIEFING
(191) and Manganese (191).
Mangafodipir Trisodium Injection, page 3151 of PF 27(5) Bacterial endotoxins (85): not more than 0.66 USP
[Sept.-Oct. 2001]. This new monograph, which previously ap-
peared in Pharmacopeial Previews, is now forwarded to In-Pro-
cess Revision. The Definition has been changed to reflect Endotoxin Unit per mg of mangafodipir trisodium.
quantitative limits as recommended by the Expert Committee on
Nomenclature and Labeling. pH (791): between 8.4 and 9.2.
(RMI: F. Barletta) RTS—34167 Osmolarity (785): between 244 and 330 mOsmol per kg of
water.
Add the following: Other requirements—It meets the requirements under
A Injections {1).
Mangafodipir Trisodium Injection
Assay—
Phosphate buffer and Mobile phase—Proceed as directed
» Mangafodipir Trisodium Injection is a sterile so-
in the Assay under Mangafodipir Trisodium.
lution of Mangafodipir Trisodium in Water for In- Standard preparation—Prepare a solution of USP
jection, ft Each mL contains not less than 9Q& Mangafodipir Trisodium RS in water having a known
percent 6.81 mg and not more than 110.0 percent concentration of about 2 mg per mL. Transfer 10.0 mL of
8.33 mg of the labeled amount of mangafodipir this solution to a 50-mL volumetric flask, add 5.0 mL of
trisodium (C22H27MnN4Na3Oi4P2). It may contain Phosphate buffer, dilute with water to volume, and mix.
[NOTE—Store under nitrogen to avoid excessive exposure
stabilizers and buffers. It contains no antimicro-
to air and light.]
bial agents.
Packaging and storage—Preserve in single-dose volume of Injection, equivalent to about 100 mg of
containers of Type I glass. Store at controlled room mangafodipir trisodium, to a 50-mL volumetric flask,
temperature, with containers on their sides in the original dilute with water to volume, and mix. Transfer 10.0 mL
carton. of this solution to a 50-mL volumetric flask, add 5.0 mL
Labeling—Label it to indicate that the maximum dose does of Phosphate buffer, dilute with water to volume, and
not exceed 15 mL. mix. [NOTE—Store under nitrogen to avoid excessive
exposure to air and light.]
Pharmacopeial Forum
Chromatographic system—Prepare as directed in the Delete the following:

A
Assay under Mangafodipir Trisodium. Chromatograph the MccamyIamine Hydrochloridc
Standard preparation, and record the peak responses as
than 1000 theoretical plates; and the tailing factor is not
more than 2.3.

203.7:
Procedure—Separately inject equal volumes (about 10 ioyolo[2.2.1]heptan 2 amino, Ar,2,3,3 totramothyl , hydroohlor
|^L) of the Standard preparation and the Assay iV,2,3,3 Totramothyl 2 norbornanamino hydroohlorido \826-
39-4]
chromatograms, and measure the responses for the major » Mooamylomino Hydroohlorido contains not losa than
peaks. Calculate the quantity, in mg, of mangafodipir 95,0 poroont and not moro than 100.5 porcont of
O M ^ H ^ " HC1, calculated on tho driod baaia.
trisodium (C22H27MnN4Na3Oi4P2) in each mL of the
Packaging and storage—Preserve in tight containers^
Injection taken by the formula: USP Reference standards (44-) USP Mecamylamine Hydro
chloride RS.
250{CIV)(rulrs), Identification—
Ai Infrared Absorption ( 4 ^ K ) T
Ui—It responds to tho toota for Chloride (491)?
in which C is the concentration, in mg per mL, of the USP Acidity—Dioaolvo 5.0 g in 100 mL of mothanol, and titrate
potontiomotrioally with 0.10 N alooholio potaaaium hydroxide to
Mangafodipir Trisodium RS in the Standard preparation; V an apparent pH of 5.5, using a oalomol glaoo olootrodo oyotom
and a potentiometer provioualy atandardizod with pH 5.0
is the volume, in mL, of Injection taken to prepare the Assay neutralized phthalato buffer (BOO Solutiona in tho oootion
Roagento, Indioatoro, and Solutiona): after oorrootion for tho
preparation; and rv and rs are the mangafodipir peak re- volume of alkali consumed by 100 mL of mothanol, not moro
than OJ55 mL of 0:10 N alooholio potaaaium hydroxide is required.
sponses obtained from the Assay preparation and the Stan- Loss on drying (3^4-)—Dry it at a prooauro not oxoooding 5 mm
of mercury at 105° for 1 hour; it loses not moro than 1.0% of ita
dard preparation, respectively.
Residue on ignition (SM): not moro than 0.5%.
Heavy metals» Method I (334-) Diooolvo 100 mg in 20 mL of
water, add 2 mL of 1 N acetic aoid, and dilute with water to 25
mL: tho limit ia 0.005%.
Organic volatile impurities, Method I {44rf): moota tho
requirements.
Chloride content—Diosolvo about 500 mg, aoouratoly woighod,
in 5 mL of watorj Add 5 mL of glacial aoetio aoid, 50 mL of
mothanol, and 1 drop of oooin YTS, and titrate with 0.1N oilvor
BRIEFING nitrate VS. Each mL of 0.1 N oilvor nitrate io equivalent to 3.545
mg of Cl: tho content is between 17.0% and 17.8%.
Assay—Into oovon tarod, marked, scrupulously oloanod glass
Mecamylamine Hydrochloride, USP 25 page 1057; Mecamy- ampul3, place about 50, 100, 110, 175, 200, 225, and 250 mg,
lamine Hydrochloride Tablets, USP 25 page 1057. Because there respectively, of Mooamylamino Hydroohlorido, and again weigh
are no approved products on the market at this time, it is proposed tho ampuls and their contents (BOO Phase solubility Analysis
to omit the monographs under Mecamylamine Hydrochloride and (44^4-)). To oaoh add 5.0 mL of freshly distilled iaopropyl
Mecamylamine Hydrochloride Tablets from USP 27, effective Jan- aloohol, cool tho ampuls in a dry ioo acetone mixture, and flame-
uary 1, 2004. Parties interested in maintaining these monographs seal them; retaining individually any separated glass. Weigh oaoh
are requested to provide updated specifications and validation to of the scaled ampuls, with tho corresponding separated glaos.
support any proposed procedures.
Agitato tho ampuls vigorously by moohanieal moans in a bath
maintained at 25 + 0.5° for a poriod of not loss than 16 hours
(PA5: J. Esker) RTS—36176-1 but sufficiently long to ensure equilibrium: Support tho ampuls vor
tioally in the bath; the nooks being above tho lovol of tho water, and
allow tho solid phaso to settle completely. Qpon the ampuls, and
remove about 2 mL of tho supernatant liquid from oaoh; using a
pipot the tip of whioh is wrapped with ootton to servo ao a filter-
Remove tho cotton, and transfer tho oloar liquid from oaoh ampul
to separate, tarod pyonomotor flasks. Weigh immediately to deter
Pharmacopeial Forum
mino tho weight of oolution transferred. Cool tho flasks in a dry ioo Apparatus-2: 50 rpm.
aootono mixture^ transfer thorn to a vaouum ovonând ovQporato Time: 30 minutes.
tho solvent at a pressure not oxoooding 5 mm of moroury. Thoro Determine the amount of C^H^N- HC1 dissolved using the fol-
aftor inoroaso tho temperature to 100°, and heat tho flasks to con lowing proooduro.
otant weight Diluent—Prepare a solution of triothylamino in alcohol (1:100).
Plot aa ordinato tho woight of rooiduo obtained por g of solvent Internal standard solution—Prepare a oolution of biphonyl in
for oaoh ampul, and as abscissatho corresponding weight of Mo Diluent having a oonoontration of 82:5 ug por mL.
oamylamino Hydroohlorido added por g of solvent. Tho firat point Standard solution—Prepare a solution of USP Meoamylamino
(for tho solution prepared from 50 mg of Mooamylamino Hydro Hydroohlorido RS and biphonyl in Diluent having concentrations
ohlorido and 5 mL of solvent) represents an unsaturatod solution of 8.25 u.g per mL of oaoh.
and falls on a lino of slope 1 passing through the origin:1 Tho points Test solution—[NOTE—Condition tho 3olid phase oxtraotion
corresponding to saturated solutions fall on another straight lino oolumn specified in this proooduro in tho following manner.
whoso slopo represents tho fraction of impurity in tho samplo. Wash tho oolumn with 5 mL of wator, thon with 5 mL of
(Failure of tho points to fall on a straight lino indioatos that oquili Diluent, and finally with two 5 mL portions of water.] Transfer
brium has not been attained;) Caloulato tho poroontago of by pipetting 25.0 mL of the solution under toot through a freshly
€j^tfgi.M" HC1 in tho Mooamylamino Hydroohlorido taken by tho conditioned solid phase oxtraotion oolumn containing LI packing
with a sorbent maoo to oolumn volume ratio of 360 mg por 5 mL,
or equivalent. Wash tho pipot and tho solid phase oxtraotion
•WO—100S C, oolumn with two 5 mL portions of water. Discard tho filtrate.
Eluto tho solid phase oxtraotion oolumn with two <\ mL portions
in whioh S is the slope of tho lino representing tho fraotion of im of'Diluent, and oolloot tho oluato in a 10 mL volumetric flask
purity, and C is tho poroontago of loss on drying. containing 1.0 mL of Internal standard solution. Dilute with
(Official January 1, 2004) Diluent to volume, and mix.
Chromatographic system (soo Chromatography {634-))—¥he
gas ohromatograph is equipped with a flame ionization detector;
a splitlo33 injection system, and a 30 m x 0.53 mm analytical
oolumn coated with a 1 5 am layor of phaoo G27. Tho carrier
ga3 is helium at a flow rate of 5.2 mL por minute. Tho dotootor
and oolumn aro maintained at 250° and 150°, roopootivoly.
Chromatograph roplioato injections of the Standard solution, wad
rooord tho peak responses as dirooted under Procedure: the
oolumn efficiency is not Ios3 than 4000 thoorotioal plates, tho
tailing factor is not more than 2, and the relative standard
deviation is not more than 2.0%.
BRIEFING Procedure—Separately injoot equal volumes (about 2uL) of tho
Standard solution and tho Test solution into tho ohromatograph,
Mecamylamine Hydrochloride Tablets, USP 25 page 1057— rooord tho ehromatogram3; and measure the responses for tho
See briefing under Mecamylamine Hydrochloride major poako. Caloulato tho amount in mg, of Cj4.H-a4N--44£l
dissolved by tho formula:
in whiohC is the concentration; in ug por mL, of USP Mooamyla-

mino Hydroohlorido RS in ik® Standard solution, and R# and R^ aro
Delete the following: tho peak response ratios of the mooamylamino hydrochlorido peak
to tho internal standard poak obtained from tho Test solution and
Standard solution, respectively.
Mecamylamine Hydrochloride Tablets Tolerances—Not loss than 75% ( 0 of tho labolod amount of
H N H C l is dissolved in 30 minutos.
Uniformity of dosage units (9Q&): moot tho roquiromonts.
» Mooamylamino Hydroohlorido Tablets contain not Procedure for content uniformity—Plaoo 1 Tablot in tho
loss than 90.0 poroont and not more than 110.0 porcont digestion fla3k, and proceed as directed under Nitrogen
of tho labolod amount of C^B^N-- HC1. Determination, Method II (464-). Each mL of 0.01 N oulfurio
aoid is equivalent to 2.038 mg of mooamylamine hydroohlorido.
Packaging and storage—Preserve in wall olosod containers. Assay—Weigh and finely powdor not loso than 30 Tablets-
USP Reference standards (44-)—USP Mecamylamine Hydro Transfer an aoouratoly weighed portion of tho powder, equivalent
chloride RS. to about 50 mg of mooamylamino hydroohlorido, to a glass
Identification— stoppered, 125 mL conical flask. Add about 25 mL of wator,
At—To a quantity of powdered Tablets, equivalent to about 75 insert tho stopper in tho flask, and shako by moohanioal moans
mg of mooamylamino hydroohlorido, add 50 mL of ohlorofomfr for 20 minutos: Transfer tho oontonta of tho flaok to a 250 mL
and triturate tho mixture for 5 minutes. Filter, and evaporate the separator with tho aid of small portiono of water. Add 1 mL of 1
filtrate on a steam bath with the aid of a ourront of air to N sodium hydroxide and 5 g of aodium ohlorido, and oxtraot tho
drynoss; tho infrared absorption spootrum of a potassium mixture successively with two 50 mL and three 25 mL portions
bromido dispersion of a portion of tho residue so obtained of other. Wash the oombinod othor ox tracts withthroo 10 mL
exhibits maxima only at the same wavolongtho as that of a portions of water, and wash, in turn, tho combined wrator washos
similar preparation of USP Mooamylamino Hydroohlorido RS. with a 10 mL portion of othor, adding it to tho washed oombinod
Bi A portion of the residue obtained in Identification tost A othor oxtraots. Transfer the other phase to a 250 mL oonioal flask
responds to tho tosto for Chloride ( # ) containing 25.0 mL of 0.02 N sulfurio aoid VS, and evaporate tho
ether on a steam bath. Cool tho solution, add mothyl rod TS, and
Dissolution (W)—
Pharmacopeial Forum
titrate tho oxoooo aoid with 0.02 N oodium hydroxide VS. Eaoh mL the extracts to a 100-mL volumetric flask, dilute with 0.1
of 0.02 N aulfurio aoid ia oquivalont to 1.075 mg of
r^ ysP26 N hydrochloric acid to volume, and mix: the UV
(Official January 1,2004) absorption spectrum of this solution exhibits maxima and
minima at the same wavelengths as that of a similar
preparation of USP Meperidine Hydrochloride RS,
concomitantly measured.

BRIEFING
Solution, equivalent to about 250 mg of meperidine
Meperidine Hydrochloride Oral Solution—See briefing un-
der Amantadine Hydrochloride Syrup. hydrochloride, to a separator, and add 3 mL of 1 N
(NL: C. Barnstein; PA2: J. Kelly) RTS—35974-1 sodium hydroxide. Extract with five 20-mL portions of
chloroform, and filter the extracts through a pledget of
cotton into a 250-mL conical flask. Wash the cotton with
Add the following:
A 5 mL of chloroform, and add the washing to the
Meperidine Hydrochloride Oral
combined filtrates. Add 10 mL of glacial acetic acid and 2
Solution
(Monograph under this new title—to become official drops of crystal violet TS, and titrate with 0.1 N perchloric
June 1, 2005) acid VS to a blue endpoint. Perform a blank determination,
(Current monograph title is Meperidine Hydrochloride
Syrup) and make any necessary correction. Each mL of 0.1 N
perchloric acid is equivalent to 28.38 mg of meperidine
» Meperidine Hydrochloride Oral Solution con- hydrochloride (C15H21NO2 • HC\).AUSP26
tains not less than 95.0 percent and not more than (Official June 1,2005)
105.0 percent of the labeled amount of meperidine

hydrochloride (C15H21NO2 • HC1).
BRIEFING
Meperidine Hydrochloride Syrup, USP 25 page 1074. It is
containers. proposed to change the title of this monograph to Meperidine Hy-
USP Reference standards {11)—USP Meperidine Hydro- Hydrochloride Syrup.
chloride RS.
Identification—Transfer a volume of Oral Solution,
equivalent to about 100 mg of meperidine hydrochloride,
Meperidine Hydrochloride Syrup
to a 125-mL separator, add 40 mL of water and 3 mL of 1
N sodium hydroxide, and extract with three 25-mL portions Monograph title change—to become official June 1,
2005
of «-hexane. Wash the combined extracts with two 20-mL (see Official Title Changes on the first page of In-Pro-
cess Revision):
portions of water, discard the water, and then extract with See Meperidine Hydrochloride Oral Solution
three 25-mL portions of 0.1 N hydrochloric acid. Transfer
Pharmacopeial Forum
for 30 minutes. Rotate the plate 90°. At a point about
BRIEFING
four-fifths of the distance between the initial application
of the Oral Solution extract and the solvent front, apply
Metaproterenol Sulfate Oral Solution—See briefing under
Amantadine Hydrochloride Syrup. 10 jxL of a Standard solution of USP Metaproterenol
(NL: C. Bamstein; AER: K. Zaidi) RTS—35975-1 Sulfate RS in water containing about 2 mg per mL.
Proceed as directed in Identification test A under
Add the following: Metaproterenol Sulfate Inhalation Solution, beginning

A with "Allow the spots to dry:" the RF value of the
Metaproterenol Sulfate Oral Solution
principal spot obtained from the Oral Solution
June 1, 2005) corresponds to that obtained from the Standard solution.
(Current monograph title is Metaproterenol Sulfate Syr-
up) B: The retention time of the major peak for metaprolol
in the chromatogram of the Assay preparation corresponds
» Metaproterenol Sulfate Oral Solution contains to that in the chromatogram of the Standard preparation, as
not less than 90.0 percent and not more than obtained in the Assay.
110.0 percent of the labeled amount of metapro- pH (791): between 2.5 and 4.0, in a solution obtained by
terenol sulfate [(CHHI7NO3)2 • H2SOJ. mixing 1 volume of Oral Solution and 4 volumes of water.
Assay—
Mobile phase—Mix 10 mL of formic acid and water to
containers.
make 1000 mL of solution. Filter and degas this solution
USP Reference standards {11}—USP Metaproterenol
before use. Make adjustments if necessary (see System
Sulfate RS.
Identification—
A: Transfer a portion of Oral Solution, equivalent to
quantity of USP Metaproterenol Sulfate RS in water to
about 10 mg of metaproterenol sulfate, to a separator, and
extract with four 30-mL portions of ether, discarding the
0.2 mg per mL.
ether extracts. Apply 10 jiL of the extracted portion of
Oral Solution to the lower right corner of a suitable thin-
layer chromatographic plate (see Chromatography (621))
metaproterenol sulfate, to a 100-mL volumetric flask,
mixture, and allow to dry. Develop the chromatogram in a
solvent system consisting of the lower layer of a well-
shaken mixture of dioxane, methylene chloride, alcohol,
detector, a 4.6-mm x 5-cm guard column that contains
and ammonium hydroxide (4:4:1:1). Allow the solvent
packing L2, and a 3.9-mm x 30-cm analytical column
front to move about three-fourths of the length of the
that contains packing LI. [NOTE—After use, rinse the
plate. Remove the plate from the developing chamber,
analytical column with water and store with water in it.]
mark the solvent front, and dry in vacuum at 35° to 40°
Pharmacopeial Forum
The flow rate is about 2 mL per minute. Chromatograph the

BRIEFING
directed for Procedure: the tailing factor for the analyte
Methdilazine Hydrochloride Oral Solution—See briefing un-
peak is not more than 3.0; and the relative standard der Amantadine Hyrdrochloride Syrup.
deviation for replicate injections is not more than 2.0%. (NL: C. Barnstein; PA6: S. Dressrnan) RTS—35976-1
uX) of the Standard preparation and the Assay Add the following:
preparation into the chromatograph, record the A
Methdilazine Hydrochloride Oral
chromatograms, and measure the responses for the major Solution
peaks. Calculate the quantity, in mg, of metaproterenol (Monograph under this new title—to become official
June 1, 2005)
sulfate [(C n H 17 NO 3 ) 2 -H 2 SO 4 ] in each mL of the Oral (Current monograph title is Methdilazine Hydrochloride
Syrup)
» Methdilazine Hydrochloride Oral Solution con-

in which C is the concentration, in mg per mL, of USP Me- tains not less than 93.0 percent and not more than
taproterenol Sulfate RS in the Standard preparation; V\s the 107.0 percent of the labeled amount of methdila-
volume, in mL, of Oral Solution taken; and rv and rs are the
zine hydrochloride (C18H20N2S • HC1).
peak responses from the Assay preparation and the Stan-
dard preparation, respectively.AUSP26 Packaging and storage—Preserve in tight, light-resistant
(Official June 1,2005) containers.
USP Reference standards (11)—USP Methdilazine Hy-
drochloride RS. [NOTE—Throughout the following proce-
dures, protect test or assay specimens, the Reference
Standard, and solutions containing them, by conducting
the procedures without delay, under subdued light, or using
BRIEFING low-actinic glassware.]
Metaproterenol Sulfate Syrup, USP 25 page 1093. It is pro- Identification—Transfer a volume of Oral Solution,
posed to change the title of this monograph to Metaproterenol Sul-
fate Oral Solution. See also briefing under Amantadine equivalent to about 4 mg of methdilazine hydrochloride,
to a 60-mL separator, add 5 mL of 0.1 N hydrochloric
acid, and extract with 10 mL of ether, discarding the
extract. Add 10 mL of sodium bicarbonate solution (1 in
Metaproterenol Sulfate Syrup 10) to the separator, and extract with 3 mL of chloroform.
Monograph title change—to become official June 1, Filter the extract through a pledget of cotton. Evaporate the
2005
{see Official Title Changes on the first page of In-Pro- chloroform, carefully removing the last trace of solvent in a
cess Revision);
See Metaproterenol Sulfate Oral Solution small vacuum flask: the IR absorption spectrum of a
potassium bromide dispersion of the methdilazine so
Pharmacopeial Forum
obtained exhibits maxima only at the same wavelengths as in which C is the concentration, in ug per mL, of USP Meth-
that of a similar preparation of USP Methdilazine dilazine Hydrochloride RS in the Standard preparation; Fis
Hydrochloride RS that has been treated in the same manner. the volume, inmL, of Oral Solution taken; and Av and As are
pH (791): between 3.3 and 4.1. the absorbances of the solutions from the Assay prepara-
Alcohol content, Method7/(611): between 6.5% and 7.5% tion; and the Standard preparation, respectively.AWSW(5
ofC2H5OH.
Assay—
USP Methdilazine Hydrochloride RS, accurately weighed, BRIEFING
in chloroform, and quantitatively dilute with chloroform Methdilazine Hydrochloride Syrup, USP 25 page 1101. It is
proposed to change the title of this monograph to Methdilazine Hy-
to obtain a solution having a known concentration of drochloride Oral Solution. See also briefing under Amantadine
Hyrdrochloride Syrup.
about 400 ug per mL.
(NL: C. Barnstein; PA6: S. Dressman) RTS—35976-1
Assay preparation—Transfer a volume of Oral Solution,
equivalent to about 4 mg of methdilazine hydrochloride, to a
60-mL separator, add 10 mL of a saturated solution of Methdilazine Hydrochloride Syrup
sodium chloride, and extract with three 10-mL portions of (Current title—not to change until June 1, 2005)
chloroform, transferring the extracts to a 100-mL 2005
volumetric flask. cess Revision):
See Methdilazine Hydrochloride Oral Solution
Procedure—Transfer 10.0 mL of Standard preparation to
a 100-mL volumetric flask, and add 20 mL of chloroform.
To this flask and to the flask containing the Assay
preparation add 4.0 mL of buffered palladium chloride
T S , d i l u t e with a l c o h o l to v o l u m e , and m i x .
Concomitantly determine the absorbances of the solutions
BRIEFING
in 1-cm cells at the wavelength of maximum absorbance
Methenamine Elixir, USP 25 page 1103. It is proposed to
at about 460 nm, with a suitable spectrophotometer, using change the title of this monograph to Methenamine Oral Solution.
a mixture of 30 mL of chloroform, 4 mL of palladium
chloride TS, and 66 mL of alcohol as the blank. Calculate (NL: C. Barnstein; PA7: W. Wright) RTS—35977-1
the quantity, in mg, of methdilazine hydrochloride

(C18H20N2S -HC1 )in each mL of the Oral Solution taken Methenamine Elixir
by the formula: (Current title—not to change until June 1, 2005)
2005
{QmCIV){AvIAs), (see Official Title Changes on the first page of In-Pro-
cess Revision):
See Methenamine Oral Solution
Pharmacopeia! Forum
excessive heat generated during mixing causes a violet

color to appear in the solution, discard the solution, and
BRIEFING
prepare another, taking precautions to avoid excessive heat.]
Methenamine Oral Solution—See briefing under Amantadine
Hydrochloride Syrup. Standard preparation—Transfer about 50 mg of USP
(NL: C. Bamstein; PA7: W. Wright) RTS—35977-1 Methenamine RS, accurately weighed, to a 1000-mL
volumetric flask, dissolve in and dilute with water to
Add the following: volume, and mix. Proceed as directed for Assay
A preparation, beginning with "Transfer a 2.0-mL portion
Methenamine Oral Solution
of this stock solution to a 100-mL volumetric flask." The
June 1, 2005) concentration of USP Methenamine RS in the Standard
(Current monograph title is Methenamine Elixir)
preparation is about 1 ug per mL.
» Methenamine Oral Solution contains not less
volume of Oral Solution, equivalent to about 1.5 g of
methenamine, to a 500-mL volumetric flask, dissolve in
of the labeled amount of methenamine (C6H12N4).
and dilute with water to volume, and mix. Transfer 2.0
Packaging and storage—Preserve in tight containers. mL of this solution to a 100-mL volumetric flask, dilute
USP Reference standards (11)—USP Methenamine RS. with water to volume, and mix to obtain the stock
Identification—Heat a volume of Oral Solution, equivalent solution. Transfer a 2.0-mL portion of this stock solution
to about 1 g of methenamine, with 10 mL of 2 N sulfuric to a 100-mL v o l u m e t r i c flask, add 25 mL of
acid: formaldehyde is liberated, recognizable by its odor Chromotropic acid solution and 50 mL of dilute sulfuric
and by its darkening of paper moistened with silver acid (1 in 2), and mix. Transfer another 2.0-mL portion of
ammonium nitrate TS. On the subsequent addition of an the stock solution to a second 100-mL volumetric flask to
excess of 1 N sodium hydroxide to the solution, ammonia provide a blank, add 75 mL of dilute sulfuric acid (1 in
is evolved. 2), and mix. Place the two 100-mL flasks in a boiling
water bath for 30 minutes, accurately timed, then remove
them from the bath, cool immediately to room
110.0% of the labeled amount of C2H5OH.
temperature, add dilute sulfuric acid (1 in 2) to volume,
Assay—
and mix.
Chromotropic acid solution—Mix 100 mg of
Procedure—Concomitantly determine the absorbances of
chromotropic acid with 50 mL of water in a 100-mL
the solutions in 1-cm cells at the wavelength of maximum
volumetric flask. Cool in an ice bath and, while cooling,
a b s o r b a n c e at a b o u t 570 nm, with a s u i t a b l e
cautiously and slowly add 50 mL of sulfuric acid, and
spectrophotometer, using dilute sulfuric acid (1 in 2) to set
mix. Allow the solution to reach room temperature, and
the instrument. Calculate the quantity, in mg, of
add dilute sulfuric acid (1 in 2) to volume. [NOTE—If
methenamine (C6H12N4) in each mL of the Oral Solution
Pharmacopeial Forum
(1250C/V)[(Au-Bu)/(As-
in which C is the concentration, in (xg per mL, of USP Me- BRIEFING
thenarnine RS in the Standard preparation; Fis the volume, Morphine Sulfate, USP 25 page 1173.
in rnL, of Oral Solution taken; Av ®cAAs are the absorbances
of the Assay preparation and the Standard preparation, re-
spectively; and Bv and Bs are the absorbances of the blanks

Erratum:
from the Assay preparation and the Standard preparation, Assay, line 2 under Chromatographic system: Change "4.6-
mm" to 3.9-mm
respectively.^^
BRIEFING
BRIEFING Morphine Sulfate Suppositories, USP 25 page 1175 and page

3318 of PF 27(6) [Nov.-Dec. 2001 ]—See briefing under Cefazolin
Ophthalmic Solution.
Methenamine Tablets, USP 25 page 1103. Editorial revisions
are indicated to conform with the title change proposed for Methe-
namine Elixir. See also briefing under Amantadine Hydrochloride (CRX: C. Okeke) RTS—35463-7
Syrup
(NL: C. Bamstein) RTS—35978-1 Change to read:
» Morphine Sulfate Suppositories contain not less than

90.0 percent and not more than 110.0 percent of the
Change to read: labeled amount of morphine sulfate [(C 17^19
Assay— NO 3 ) 2 -H 2 SO 4 -5H 2 O].
Chromotropic acid solution and Standard preparation—Prepare
as directed in the Assay under Methenamine Elixir SUPPOSITORIES COMPOUNDED IN FATTY ACID BASE
A
Prepare Morphine Sulfate Suppositories in Fatty
Oral Solution. ±USP26 Acid Base as follows (see Pharmacy Compounding
Assay preparation—Weigh and finely powder not fewer than 20
Tablets. Transfer an accurately weighed portion of the powder, {)
equivalent to about 500 mg of methenamine, to a 250-mL
volumetric flask, dilute with water to volume, mix, and filter, ^Pharmaceutical Compounding—Nonsterile
discarding the first 20 mL of the filtrate. Transfer 25.0 mL of the
subsequent filtrate to a 1000-mL volumetric flask, dilute with water Preparations {195))\AUSP26
to volume, and mix. Proceed as directed for Assay preparation in
the Assay under Methenamine Elixir
A Morphine Sulfate 50 mg
Oral Solution AUSP26
, beginning with "Transfer a 2.0-mL portion of this stock solu- Silica Gel 25 mg
tion." Fatty Acid Base, a sufficient quantity to
Procedure—Proceed as directed for Procedure in the Assay make one suppository
under Methenamine Elixir
A
Oral Solution. AUSP2S Calibrate the actual molds with the Fatty Acid Base
Calculate the quantity, in mg, of methenamine (C6H12N4) in the that is used for preparing the Suppositories, and adjust
portion of Tablets taken by the formula: the formula accordingly. Mix thoroughly the Morphine
500C[(Au-Bu)f(As-Bs)], Sulfate and Silica Gel to obtain a uniform powder.
Heat the Fatty Acid Base slowly and evenly until
in which C is the concentration, in ug per mL, of USP Methena- melted. Slowly add the powder to the melted base,
mine RS in the Standard preparation;, and Av, As, Bv, and Bs are
as defined therein. with stirring. Mix thoroughly, and pour into molds.
Cool, trim, and wrap.
Pharmacopeia! Forum
Change to read: filter the extracts through a dry filter, collecting the filtrate
SUPPOSITORIES COMPOUNDED IN POLYETHYLENE GLYCOL BASE
Prepare Morphine Sulfate Suppositories in Polyethylene Glycol in a small flask. Evaporate the filtrate on a steam bath to
Base as follows (see Phaimaey Compounding (19$)
dryness, and dry the residue at 105° for one hour.AUSp26
A
Pharmaceutical Compounding—Nonsterile Preparations
(195)):AUSP26
Morphine Sulfate 50 mg
Silica Gel 25 mg
Polyethylene Glycol Base, a sufficient quantity
to make one suppository
Calibrate the actual molds with Polyethylene Glycol Base that is
used for preparing the Suppositories, and adjust the formula ac-
cordingly. Mix thoroughly the Morphine Sulfate and Silica Gel
to obtain a uniform powder. Heat the Polyethylene Glycol Base BRIEFING
slowly and evenly until melted. Slowly add the powder to the
melted base, with stirring. Mix thoroughly, and pour into molds.
Cool, trim, and wrap. Naltrexone Hydrochloride, USP 25 page 1187. Based on cor-
respondence received from industry, it is proposed to use Infrared
Absorption (197K) instead of (197S) in the test for Identification
in order to eliminate the interference of chloroform peaks on the
infrared spectra of naltrexone.
Change to read:
BRIEFING
Identification, Infrared Absorption (197S)—
Solution: 20 mg of residue por mL: Obtain the residue as
Naloxone Hydrochloride, USP 25 page 1185. Based on corre- follows: Dissolve about 150 mg in 25 mL of wator in a small
sondence received from industry, it is proposed to use Infrared Ab- separator; add a fow drops of 6 N ammonium hydroxide, oxtraot
sorption (197K) instead of (197S) in the test for Identification in with throe 5 mL portions of ohloroform, and filtor tho extracts
order to eliminate the interference of chloroform peaks on the in- through a dry filtor, oolleoting the filtrate in a small flask.
frared spectra of naloxone. Evaporate tho filtrate on a stoam bath to drynoss, and dry tho
residue at 105° for 1 hour.
(PA2: J. Kelly) RTS—35621-1 A
(197K)—
Test specimen—Dissolve about 150 mg in 25 mL of water
in a small separator, add a few drops of 6 N ammonium
Change to read:
Identification—Dissolve about150 mg in 25 mL of water in a hydroxide slowly until no more white precipitate is
small separator, add a few drop3 of 6 N ammonium hydroxide,
oxtraot with throe 5 mL portions of ohloroform, and filtor tho formed. Extract with three 5-mL portions of chloroform,
extracts through a dry filter, oollooting tho filtrate in a small
flaok. Evaporate tho filtrate on a steam bath to drynoao, and dry filter the extracts through a dry filter, collecting the filtrate
at 105° for1 hour: the infrared abaorption opootrum of a 1 in 50
solution in ohloroform of tho residue 30 obtained^ determined in in a small flask. Evaporate the filtrate on a steam bath to
a 0.5 mm cell, exhibits maxima only at the same wavelengths as
that of a similar solution of USP Naloxono RS. dryness, and dry the residue at 105° for one hour.AUSP26
Înfrared Absorption <197K). Medium: chloroform.
Cell size: 0.5-mm cell.
Test specimen—Dissolve about 150 mg in 25 mL of water
in a small separator, add a few drops of 6 N ammonium
hydroxide slowly until no more white precipitate is
formed. Extract with three 5-mL portions of chloroform,
Pharmacopeial Forum

BRIEFING
quantity of USP Nandrolone Decanoate RS with
Nandrolone Decanoate Injection, USP 25 page 1189. It is pro- tetrahydrofuran, and dilute quantitatively and stepwise if
posed to revise the Assay procedure by replacing it with a more
selective method. The Assay procedure is based upon analyses per- necessary, with tetrahydrofuran to obtain a solution having
formed using an Alltech Econosphere C18 brand of LI column;
and the retention time for the nandrolone decanoate peak is about a known concentration of about 0.2 mg per mL.
15 minutes.
volume of Injection, equivalent to about 400 mg of
nandrolone decanoate, to a 200-mL volumetric flask,
Change to read: dilute with tetrahydrofuran to volume, and mix. Transfer
Assay—
Isoniasid reagent—Dissolve 500 mg of isoniazid in about 250 10.0 mL of this solution to a 100-mL volumetric flask,
mL of mothanol; add 0.63 mL of hydroohlorio aoid; dilute with
mothonol to 500:0 mLj and mix. dilute with tetrahydrofuran to volume, and mix.
Nandrolono Deoanoato RS, aoouratoly woighod, to a 100 mL Chromatographic system (see Chromatography (621))—
volumotrio flask, dissolve in chloroform, dilute with chloroform
to volume, and mix: Transfer 5.0 mL of this aolution to a 50 mL The liquid chromatograph is equipped with a 254-nm
volumotrio flaok, dilute with ohloroform to volume, and mix.
Assay preparation—Transfer to a 200 mL volumotrio flaok an detector and a 4.6-mm x 15-cm column containing 5-um
aoouratoly moaourod volumo of Injootion, equivalent to about 50
mg of nandrolono dooanoato, add ohloroform to volume, and packing LI. The flow rate is about 1.5 mL per minute.
mix. Tranofor 10.0 mL of thio oolution to a 100 mL volumotrio
flask, dilute with ohloroform to volumo, and mix. The column t e m p e r a t u r e is maintained at 4 0 ° .
Procedure—Transfer 5.0 mL oaoh of tho Standard preparation;
tho Assay preparation, and ohloroform to providethe blank; to Chromatograph the Standard preparation, and record the
ooparato 10 mL volumotrio flasks, dilute oaoh with Isoniasid
rcagentto volumo, and mix: Allow tho flasks to stand for 1 hour peak responses as directed for Procedure', the capacity
with oooasional shaking. Conoomitantly determine tho
absorbanoos of tho solutions in 1 om oollo at tho wavelength of factor, kf, for nandrolone decanoate is not less than 5.3;
maximum absorbanoo at about 380 nm, with a suitable
spootrophotomotor, using tho blank to sot tho instrument. the tailing factor for the nandrolone decanoate peak is not
Calculate tho quantity, in mg, of C^H^Q^ in oaoh mL of the
Injootion talcon by tho formula: more than 1.4; and the relative standard deviation for
in whioh C io the oonoentration;in ^g per mL-of USP Nandrolono Procedure—Separately inject equal volumes (about 10
Dooanoato RS in tho Standardpreparation, Fis tho volumo, in mL^
of Injootion taken, and A# and A$ arc tho absorbanoos of tho solu uL) of the Standard preparation and the Assay
tions from tho Assay preparation and tho Standard preparation,
respootivoly. preparation into the chromatograph, record the
A
0.02 M Ammonium acetate solution—Transfer about 1.6 chromatograms, and measure the responses for the major
g of ammonium acetate to a 1000-mL volumetric flask. peaks. Calculate the quantity, in mg, of C28H44O3 in each
Dissolve in and dilute with water to volume. mL of the Injection taken by the formula:
2000(C7 V)(ru/rs),
alcohol and 0.02 M Ammonium acetate solution (66:34).
Make adjustments if necessary (see System Suitability
under Chromatography (621)).
Pharmacopeial Forum
in which C is the concentration, in mg per mL, of USP Nan- Packaging and storage—Preserve in well-closed
drolone Decanoate RS in the Standard preparation; V'\s the containers.
volume, in mL, of the Injection taken to prepare the Assay USP Reference standards (11)—USP Norgestimate RS.
preparation, and rv and rs are the peak responses obtained Identification—
from the Assay preparation and the Standard preparation, A: Infrared Absorption (197K)—
respectively.^™ Test specimen—Use a dispersion in potassium bromide
prepared by mixing the specimen with potassium bromide
in a 1 to 100 ratio.
BRIEFING obtained in the Assay.
Norgestimate, page 1413 of PF 26(5) [Sept.-Oct. 2000]. This Specific rotation (78IS): between +40° and +46°.
new monograph, which first appeared in Pharmacopeial Previews
is now moved to In-Process Revision with the following changes Test solution: 10 mg per mL, in chloroform. [NOTE—Use
based on comments received. In the test for Limit of residual sol-
vents, chloroform is added to the Standard solution to better reflect within 10 minutes of preparation.]
the approved method. Also several changes to the Chromato-
graphic system in the Assay are proposed to better describe the ac- Loss on drying (731)—Dry it at 105° for 3 hours: it loses
tual method.
(PA1:S. Salado) RTS—34378-1
Add the following:
A Limit of residual solvents—
Norgestimate
Internal standard solution—Prepare a solution of isobutyl
(Chemical structure to come) alcohol in dimethylformamide containing 2 uL of isobutyl
C23H31NO3 369.50 alcohol per 100 mL of solution.
18,19-Dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)- Standard solution—Prepare a solution in Internal
13-ethyl-, oxime, (17oc)-(+)-. standard solution containing 5 uL each of acetone,
(+)-13-Ethyl-17-hydroxy-18,19-dinor-17a-pregn-4-en-20- alcohol, chloroform, diisopropyl ether, and methanol per
yn-3-one oxime acetate (ester) [35189-28-7] 100 mL of solution.
System suitability solution—Dilute a portion of the
Standard solution with Internal standard solution to
» Norgestimate is a mixture of (E)- and (Z)-iso-
obtain a solution containing 0.05 jxL each of acetone,
mers having a ratio of (E)- to (Z)-isomer between
alcohol, diisopropyl ether, and methanol per 100 mL of
1.27 and 1.78, and it contains not less than 98.0 solution.
percent and not more than 102.0 percent of Test solution—Transfer about 40 mg of Norgestimate and
C23H31NO3, calculated on the dried basis. 2 mL of Internal standard solution to a 5-mL volumetric
flask or a suitable vial, and shake well to dissolve.
Pharmacopeial Forum
taken to prepare the Test solution; and Rv and Rs are the

peak response ratios of the appropriate analyte to the inter-
nal standard obtained from the Test solution and the Stan-
detector, a 0.53-mm x 30-m fased-silica capillary column
dard solution, respectively. Not more than 0.05% each of
bonded with a 1-um layer of phase G16, and a split injection
acetone and diisopropyl ether is found; not more than
system. The detector temperature is about 250°, and the
0.08% of alcohol is found; not more than 0.1% of chloro-
injection port temperature is about 180°. The column
form is found; and not more than 0.2% of methanol is found.
temperature is programmed as follows. It is maintained at
Chromatographic purity—
about 65° for 2.5 minutes, increased at a rate of 35° per
TEST 1—
minute to 100°, maintained for 2 minutes, then at a rate of
Diluent, Mobile phase, System suitability solution, and
30° per minute increased to 160°, and maintained for 2.5
Chromatographic system—Proceed as directed in the Assay.
minutes. The carrier gas is helium, flowing at a rate of
Standard solution—Use the Standard preparation,
about 6 mL per minute, and the split flow rate is about 16
prepared as directed in the Assay.
mL per minute. Chromatograph the Internal standard
Test solution—Use the Assay preparation, prepared as
solution, the Standard solution, and the System suitability
directed in the Assay.
Procedure: there are no interfering peaks due to Procedure—Separately inject equal volumes (about 25
dimethylformamide; the retention time of isobutyl alcohol uL) of the Standard solution and the Test solution into the
in the chromatogram of the Internal standard solution is chromatograph, record the chromatograms, and measure the
between 4 and 5 minutes; the signal-to-noise ratio for peak areas. Calculate the percentage of each impurity in the
alcohol obtained from the System suitability solution is portion of Norgestimate taken by the formula:
not less than 2.0; and the relative standard deviation for
replicate injections of the Standard solution, determined
from the peak response ratios of each solvent to the
gestimate RS in the Standard solution; P is the fraction of
internal standard, is not more than 3.0%.
(£)-norgestimate in USP Norgestimate RS; Wis the weight,
in mg, of Norgestimate taken to prepare the Test solution; rt
of the Standard solution and the Test solution into the
is the peak area for each impurity obtained from the Test so-
chromatograph, record the chromatograms, and measure
lution; F is the relative response factor and it is equal to 0.83
the responses for the major peaks. Calculate the
for any peak having a relative retention time of 0.50, 1.13
percentage of each solvent in the portion of Norgestimate
for any peak having a relative retention time of 0.56, 0.85
for any peak having a relative retention time of 0.72, and 1.0
2W(CD/W){RulRs), for any other peak; and rs is the peak area of (^-norgesti-
mate obtained from the Standard solution. Not more than
in which C is the concentration, in mL per mL, of each sol-
0.3% of total impurities having relative retention times of
vent in the Standard solution; D is the density, in mg per
mL, of each solvent; W'\s the weight, in mg, of Norgestimate
Pharmacopeial Forum
0.50 and 0.56 is found; not more than 0.3% of the impurity the relative standard deviation for replicate injections,
having a relative retention time of 0.72 is found; and not determined from the peak area fatie of (Z)-norgestimate to
more than 0.1% of any other impurity is found. (£)-norgestimate, is not more than 2.0%.
TEST 2— Procedure—Separately inject equal volumes (about 25
Mobile phase—Prepare a filtered and degassed mixture of uL) of the Standard solution and the Test solution into the
cyclohexane and alcohol (50:1). Make adjustments if chromatograph, record the chromatograms, and measure the
necessary (see System Suitability under Chromatography peak areas. Calculate the percentage of each impurity in the
(621)). portion of Norgestimate taken by the formula:
quantity of USP Norgestimate RS in Mobile phase, and
gestimate RS in the Standard solution; P is the fraction of
(£)-norgestimate in USP Norgestimate RS; Wis the weight,
in mg, of Norgestimate taken to prepare the Test solution; rt
System suitability solution—Dilute a portion of Standard
is the peak area for each impurity obtained from the Test so-
solution quantitatively, and stepwise if necessary, with
lution; F is the relative response factor and it is equal to 1.4
for any peak having a relative retention time of 0.74, 1.5 for
concentration of about 0.5 ug per mL.
any peak having a relative retention time of 0.78, and 1.2 for
Test solution—Transfer about 10 mg of Norgestimate,
any peak having a relative retention time of 0.91; and rs is
accurately weighed, to a 10-mL volumetric flask, dissolve
the peak area of (£)-norgestimate obtained from the Stan-
in and dilute with Mobile phase to volume, and mix.
dard solution. Not more than 0.2% of the impurity having
a relative retention time of 0.74 is found; and not more than
0.1% each of the impurities having relative retention times
detector and a 4.6-mm x 25-cm column that contains a
of 0.78 and 0.91 is found. Not more than 1.0% of total im-
5-um packing L20. The flow rate is about 1 mL per
purities is found, the results for Test 1 and Test 2 being
minute. Chromatograph the System suitability solution,
added.
and record the peak responses as directed for Procedure:
the signal-to-noise ratio for (E)-norgestimate is not less Organic volatile impurities, Method IV (467): meets the
than 3.0. Chromatograph the Standard solution, and requirements. , oxoopt that not moro than 1 mg per g of
record the peak areas as directed for Procedure: the chloroform ia found. Chloroform is tested in the Limit of
retention time is about 18.6 minutes for (£)-norgestimate; residual solvents test.
the relative retention times are about 1.0 for (E)- Solvent—Use dimethyl sulfoxide.
norgestimate and 1.1 for (Z)-norgestimate; the tailing Assay—
factor is not more than 1.5; the resolution, R, between (2)- Diluent—Prepare a mixture of water and methanol (4r
norgestimate and (£)-norgestimate is not less than 1.5; and (1:4).
Pharmacopeial Forum
Mobile phase—Prepare a filtered and degassed mixture of Procedure—Separately inject equal volumes (about 25
water, tetrahydrofiiran, and acetonitrile (30:11:9). Make uL) of the Standard preparation and the Assay
adjustments if necessary (see System Suitability under preparation into the chromatograph, record the
Chromatography (621)). chromatograms, and measure the areas for the major
Standard preparation—Dissolve an accurately weighed peaks. Calculate the quantity, in mg, of C23H31NO3 in the
quantity of USP Norgestimate RS in Diluent, and dilute portion of Norgestimate taken by the formula:
quantitatively, and stepwise if necessary, with Diluent to
0.5 mg per mL.
gestimate RS in the Standard preparation; and rv and rs are
System suitability solution—Dilute a portion of Standard
the sums of peak areas of (Z)-norgestimate and (^-norges-
preparation quantitatively, and stepwise if necessary, with
timate obtained from the Assay preparation and the Stan-
Diluent to obtain a solution having a known concentration
dard preparation, respectively. Calculate the percentages
of about 0.05 ug per mL.
of the (£)- and (£)-isomers, Uz and UE, respectively, in the
portion of Norgestimate taken by the formula:
Norgestimate, accurately weighed, to a 50-mL volumetric
flask, dissolve in and dilute with Diluent to volume, and
mix.
gestimate RS in the Standard preparation; P is the fraction
of (£)- or (Z)-norgestimate in USP Norgestimate RS; Wis
the weight, in mg, of Norgestimate taken to prepare the As-
um packing LI. The flow rate is about 4 mL 1.2 mL per
say preparation; and rv and rs are the peak responses of the
minute. The column temperature is maintained at about
appropriate norgestimate isomer obtained from the Assay
40°. Chromatograph the System suitability solution, and
preparation and the Standard preparation, respectively.
record the peak areas as directed for Procedure: the
Calculate the ratio of (£)-norgestimate to (Z)-norgestimate,
signal-to-noise ratio for (Z)-norgestimate is not less than
that is, the ratio of Uz to UE.AUSP26
3.0. Chromatograph the Standard preparation, and record
the peak areas as directed for Procedure: the relative
retention times are about 0.86 for (Z)-norgestimate and 1.0
for (is)-norgestimate; the resolution, R, between (Z)- BRIEFING
norgestimate and (£)-norgestimate is not less than 1.5; the Oxybutynin Chloride Oral Solution—See briefing under
tailing factor for (£)-norgestimate and for (Z)-norgestimate
is not more than 1.5; and the relative standard deviation for (NL: C. Barnstein; PA4: A. Medjedovic) RTS—35979-1
replicate injections, determined from the peak area ratio of

(iT)-norgestimate to (Z)-norgestimate, is not more than
2.0%.
Pharmacopeial Forum
Add the following: Standard preparation—Dissolve an accurately weighed

A quantity of USP Oxybutynin Chloride RS in 0.05 N
Oxybutynin Chloride Oral Solution
(Monograph under this new title—to become official sulfuric acid to obtain a solution having a known
June 1, 2005)
(Current monograph title is Oxybutynin Chloride Syrup) concentration of about 100 ug per mL.
» Oxybutynin Chloride Oral Solution contains not
oxybutynin chloride, to a 100-mL volumetric flask, dilute
with water to volume, and mix.
percent of the labeled amount of C22H31NO3 • HC1.
Procedure—Separately transfer 10.0 mL of the Standard
Packaging and storage—Preserve in tight, light-resistant preparation and the Assay preparation to separate 125-mL
containers. separators. Add 20 mL of pH 4 Phosphate buffer to each
USP Reference standards (11)—USP Oxybutynin Chlo- separator, and extract each solution with a 25-mL portion
ride RS. of chloroform. [NOTE—Allow at least 10 minutes for the
Identification—Place a volume of Oral Solution, layers to separate.] Collect the chloroform extracts in
equivalent to about 50 mg of oxybutynin chloride, in a respective 125-mL separators, each containing a mixture
separator, and extract with 10 mL of chloroform. The of 2 mL of pH 5.6 Phosphate buffer and 1 mL of
extract so obtained responds to the Thin-Layer Bromocresol green solution. Shake the separators, and
Chromatographic Identification Test (201), methanol filter the chloroform extracts through rayon pledgets,
being used as the developing solvent, and iodine vapor collecting the extracts in respective 100-mL volumetric
being used to visualize the spots. flasks. Repeat the double extractions with 25-mL portions
Assay— of chloroform. Wash the rayon pledgets with chloroform,

collecting the washings in the respective 100-mL
pH 4 Phosphate buffer—Place 38 mL of 0.2 M dibasic
volumetric flasks. Dilute both solutions with chloroform
sodium phosphate in a 100-mL volumetric flask. Dilute
to volume, and mix. Concomitantly determine the
with 0.1 M citric acid to volume, and mix. Adjust the pH,
absorbances of both solutions at the wavelength of
if necessary, with either the dibasic sodium phosphate
maximum absorbance at about 415 nm, with a suitable
solution or the citric acid solution.
spectrophotometer, against a blank prepared using 10 mL
pH 5.6 Phosphate buffer—Place 58 mL of 0.2 M dibasic
of 0.05 N sulfuric acid treated in the same manner as the
sodium phosphate in a 100-mL volumetric flask. Dilute with
Standard preparation and the Assay preparation.
0.1 M citric acid to volume, and mix. Adjust the pH, if
Calculate the quantity, in mg, of C22H3]NO3 • HC1 in each
necessary, with either the dibasic sodium phosphate
mL of Oral Solution taken by the formula:
solution or the citric acid solution.
Bromocresol green solution—Transfer 125 mg of
bromocresol green to a 25-mL volumetric flask, dissolve
in 3.5 mL of 0.05 N sodium hydroxide, dilute with water
to volume, and mix.
Pharmacopeial Forum
in which C is the concentration, in ug per mL, of USP Oxy- Add the following:
A
butynin Chloride RS in the Standard preparation^ is the PacIitaxel
volume, in mL, of Oral Solution taken; and Av and As are
the absorbances of the solutions from the Assay preparation
C47H51NO14853.91
and the Standard preparation, respectively.AUsrc<s
(Official June 1,2005) Benzenepropanoic acid, /?-(benzoylamino)-a-hydroxy-,
6,12b-bis(acetyloxy)-12-(benzoyloxy)-
2a,3,4,4a,5,6,9,10,11,12,12a, 12b-dodecahydro-4,11 -
dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11 -metha-
BRIEFING
no-l//-cyclodeca[3,4]benz[l ,2-b]oxet-9-ylester, [2ai?-
Oxybutynin Chloride Syrup, USP 25 page 1280. It is proposed [2aa,4/?,4a/3,6/?,9a(ai?*,£S*), 11 a, 12a, 12aa, 12ba]]-.
to change the title of this monograph to Oxybutynin Chloride Oral
Solution. See also briefing under Amantadine Hydrochloride Syr- (2 ai?, 4 S, 4 a S , 6R, 9 S, 11 S, 1 2S, 1 2 a/?, 1 2b S) -
up.
l,2a,3,4,4a,6,9,10,11,12,12a,12b-Dodecahydro-
(NL: C. Barnstein; PA4: A. Medjedovic) RTS—35979-1
4,6,9,11,12,12b-hexahydroxy-4a,8,13,13-tetramethyl-
7,ll-methano-5//-cyclodeca[3,4]-benz[l,2-Z)]oxet-5-
Oxybutynin Chloride Syrup one 6,12b-diaectate, 12-benzoate, 9-ester with (2R,3S)-
{Current title—not to change until June 1, 2005)
Monograph title change—to become official June 1, iV-benzoyl-3-phenylisoserine [33069-62-4].
2005
cess Revision):
See Oxybutynin Chloride Oral Solution » Paclitaxel contains not less than 97.0 percent
and not more than 102.0 percent of C47H51NO14,
calculated on the anhydrous, solvent-free basis.
Caution—Paclitaxel iscytotoxic. Great care
should be taken to prevent inhaling particles of
BRIEFING
Paclitaxel and exposing the skin to it.
Paclltaxel, page 2183 of PF 21(2) [Mar-Apr. 2001]. This new Packaging and storage—Preserve in tight, light-resistant
proposed monograph is being republished with changes to the tests
for Related compounds. Based on comments received, Table 1 has containers.
been modified to incorporate three additional related compounds
and limits and to increase the limits for Baccatin III and 7-Epipa- Labeling—The labeling indicates the type of process used
clitaxel. Table 2 has been modified to remove those related com-
pounds having a limit of 0.1 % and a relative response factor of 1.00 to produce the material and the Related compounds Test
because these limits are redundant with the general limit for indi-
vidual impurities. USP received comments that the nomenclature with which the product complies.
in Table 1 and Table 2 was unclear for certain related compounds.
In response, USP has added chemical names as footnotes for four
of the related compounds in Tables 1 and 2. USP Reference standards (U)—USP Endotoxin RS. USP
Paclitaxel RS. USP Paclitaxel Related Compound A RS.
(PA6: S. Dressman) RTS—34160-1; 34163-1; 34170-1;
34189-1; 34878-1 USP Paclitaxel Related Compound B RS.
Pharmacopeial Forum
Identification— 10 ug of each per mL. Transfer 5.0 mL of this solution to

A: Infrared Absorption (197K). a 50-mL volumetric flask, dilute with Diluent to volume,
B: The retention time of the major peak in the and mix.
chromatogram of Assay preparation corresponds to that in Standard solution—Dissolve, with the aid of sonication,
the chromatogram of the Standard preparation, as obtained an accurately weighed quantity of USP Paclitaxel RS in
in the Assay. Diluent, and dilute quantitatively, and stepwise if
Specific rotation (78IS): between -49.0° and -55.0° at necessary, with Diluent to obtain a solution having a
20°, calculated on the anhydrous, solvent-free basis. known concentration of about 5 ug per mL.
Test solution: 10 mg per mL, in methanol. Test solution—Use the Assay preparation.
Microbial limits (61)—The total aerobic microbial count Chromatographic system (see Chromatography (621))—
does not exceed 100 cfu per g. It meets the requirements of The liquid chromatograph is equipped with a 227-nm
the tests for the absence of Staphylococcus aureus, detector and a 4.6-mm x 25-cm column that contains 5-
um packing L43. The flow rate is about 2.6 mL per
Pseudomonas aeruginosa, Salmonella species, and
minute. The column temperature is maintained at 30°. The
Escherichea coli.
chromatograph is programmed as follows.
Bacterial endotoxins (85)—It contains not more than 0.4
USP Endotoxin Unit per mg of paclitaxel.
Water, Method Ic (921): not more than 4.0%.
Residue on ignition (281): not more thanO.2%.
35-60 35->80 65^20 linear gradient
Related compounds— 60-70 80->35 20->65 linear gradient
TEST 1 (for material labeled as isolated from natural 70-80 35 65 isocratic
sources)—If the product complies with this test, the
labeling indicates that it meets USP Related compounds
the peak responses as directed for Procedure: the relative
Test 1.
retention times are about 0.78 for paclitaxel related com-
Diluent—Prepare as directed in the Assay.
pound A and 0.86 for paclitaxel related compound B (rela-
Solution A—Prepare filtered and degassed acetonitrile.
tive to the retention time for paclitaxel obtained from the
Solution B—Prepare filtered and degassed water.
Test solution); and the resolution, R, between paclitaxel re-
lated compound A and paclitaxel related compound B is not
less than 1.0. Chromatograph the Standard solution, and re-
cord the peak responses as directed for Procedure: the rela-
tive standard deviation for replicate injections is not more
System suitability solution—Dissolve accurately weighed
than 2.0%.
quantities of USP Paclitaxel Related Compound A RS and
USP Paclitaxel Related Compound B RS in methanol to
obtain a solution having known concentrations of about
Pharmacopeial Forum

solution into the chromatograph, record the chro-
in which F is the relative response factor for each impurity
matogram, and measure the areas for the major peaks.
peak (see Table 1 for values); r, is the peak area for each
Calculate the percentage of each impurity in the portion of
individual impurity; and rv is the peak area for paclitaxel.
Paclitaxel taken by the formula:
Table 1
Relative Relative Response

Retention Factor (F) Limit
Time Name (%)
0.24 1.29 Baccatin III Or+0.2

0.53 1.00 10-Deacetylpaclitaxel 0.5
0.57 1.00 7-Xylosylpaclitaxel 0.2
0.78 1.26 Cephalomannine (paclitaxel related compound A)
0.78 1.26 2",3"-Dihydrocephalomannine
0.86 1.00 10-Deacetyl-7-epipaclitaxel (paclitaxel related compound B) 0.5
3 1
1.10 1.00 Benzyl analog
1.10 1.00 3",4"-Dehydropaclitaxel C b22
1.40 1.00 7-Epicephalomannine 0.3
1.85 1.00 7-Epipaclitaxel &4 0.5
1
Resolution may be incomplete for these peaks depending upon the relative amounts present; the sum of al and a2 is not
more than 0.5%.
2
Resolution may be incomplete for these peaks depending upon the relative amounts present; the sum of b, and b 2 is not
more than 0.5%.
3
The following chemical name is assigned to the related compound, benzyl analog: Baccatin III 13-ester with (2R,3S)-2-
hydroxy-3-phenyl-3-(2-phenylacetylamino)propanoic acid.
Pharmacopeial Forum
In addition to not exceeding the limits for paclitaxel re- um packing LI. The flow rate is about 1.2 mL per minute.
lated impurities in Table 1, not more than 0.1% of any single The column temperature is maintained at 35°. The
unknown other single impurity is found; and not more than chromatograph is programmed as follows.
2.0% of total impurities is found.

TEST 2 (for material labeled as produced by a semi- Time Solution A Solution B
synthetic process)—If the product complies with this test, (minutes) (%) (%) Elution
the labeling indicates that it meets USP Related 0-20 100 0 isocratic
compounds Test 2. 20-60 100 -»10 0->90 linear
Diluent—Use acetonitrile. 60-62 10^100 90-»0 linear gradient
Solution A—Use a filtered and degassed mixture of water 62-70 100 0 isocratic
and acetonitrile (3:2). Chromatograph the System suitability solution, and record
Solution B—Use filtered and degassed acetonitrile. the peak responses as directed for Procedure: the relative
Mobile phase—Use variable mixtures of Solution A and retention times are about 0.94 for paclitaxel related com-
Solution B as directed for Chromatographic system. Make pound B and 1.0 for paclitaxel; the resolution, R, between
adjustments if necessary (see System Suitability under paclitaxel related compound B and paclitaxel is not less than
Chromatography (621)). 1.2; and the relative standard deviation for replicate injec-
System suitability solution—Dissolve accurately weighed tions is not more than 2.0%.
quantities of USP Paclitaxel RS and USP Paclitaxel Related Procedure—Separately inject equal volumes (about 15
Compound B RS in Diluent, using shaking and sonication if uL) of the Diluent and the Test solution into the
necessary, to obtain a solution having known concentrations chromatograph, record the chromatograms, and measure
of about 0.96 mg and 0.008 mg per mL, respectively. the areas for all of the peaks. Disregard any peaks due to
Test solution—Transfer about 10 mg of Paclitaxel, the Diluent. Calculate the percentage of each impurity in
accurately weighed, to a 10-mL volumetric flask, dissolve the portion of Paclitaxel taken by the formula:
in and dilute with Diluent to volume, using shaking and
100(Fr,/r,),
sonication if necessary, and mix.
in which F is the relative response factor for each impurity
(see Table 1 for values); r, is the peak area for each impurity
obtained from the Test solution; and rs is the sum of the areas
detector and a 4.6-rnm x 15-cm column that contains 3-
of all the peaks obtained from the Test solution.
Pharmacopeial Forum
Table 2
Relative Retention Time Relative response factor (F) Name Limit (%)
0.11 1.24 10-Deacetylbaccatin III 0.1

0.20 1.29 Baccatin III 0.1
0.42 1.39 Unknown Photodegradant2 0.1
0.47 1.00 10-Deacetylpaclitaxel 0.5
0.80 1.00 2-Debenzoylpaclitaxel-2-pentenoate 0.7
1 2
0.92 1.00 Oxetane ring opened, acetyl and benzoyl Xj
0.921 1.00 10-Acetoacetylpaclitaxel x2
1
0.94 1.00 10-Deacetyl-7-epipaclitaxel (paclitaxel JC 3
related compound B)
1.37 1.00 7-Epipaclitaxel 0.4
1.45 1.00 10,13-Bissidechainpaclitaxel2 0.5
1.54 1.00 7-Acetylpaclitaxel 0.6
1 nn 2 Sidoohainpaolitaxol Ori-
i.VV
1 AA
TvvTT
2,4 Diphonyl o oxazolinyl baocatin III O?4-
1.80 1.75 13-Tes-baccatin III 0.1
2.14 1.00 7-Tes-paclitaxel 0.3
1 AA
2 Mop 7 tc-3 paolitaxol 0r4-
1
Resolution may be inadequate incomplete for these depending upon present; the sum of x\, x2,
and JC3 is not more than 0.4%.
2
The following chemical names are assigned to the related compounds Photodegradant, Oxetane ring opened, acetyl and
benzoyl, and 10,13-Bissidechainpaclitaxel:
Photodegradant
(IR,2RAS,5S,7R, 105,1IR, 12S, 13S, 155,16S)-2,10-diacetyloxy-5,13-dihydroxy-4,16,17,17-tetramethyl-8-oxa-3-oxo-
12-phenylcarbonyloxypentacyclo[l 1.3.1.0111.04-1' .07-10]heptadec-15-yl
(2i?,35)-2-hydroxy-3-phenyl-3-(phenylcarbonylamino)propanoate
Qxetane ring opened, acetyl and benzoyl migrated
(1 S,2S,3RAS,5S,7S,%S, 1 OR, 135)-5,10-diacetyloxy-1,2,4,7-tetrahydroxy-8,12,15,15-tetrarnethyl-9-oxo-4-(phenylcarbo-
nyloxymethyl)tricyclo[9.3.1.03>8]pentadec-l l-en-13-yl
(2i?,35)-2-hydroxy-3-phenyl-3-(phenylcarbonylamino)propanoate
10,13-bissidechainpaclitaxel
Baccatin III 13-ester with (2i?,35)-2-hydroxy-3-phenyl-3-(phenylcarbonylamino)propanoic acid, 10-ester with (25,3S)-
2-hydroxy-3-phenyl-3-(phenylcarbonylamino)propanoic acid
Pharmacopeial Forum
In addition to not exceeding the limits for paclitaxel re- chromatograms, and measure the areas for the major
lated impurities in Table 2, not more than 0.1% of any single peaks. Calculate the quantity, in mg, of C47H51NO14 in the
unknown other single impurity is found; and not more than portion of Paclitaxel taken by the formula:
2.0% of total impurities is found.
Organic volatile impurities, Method IV (467): meets the
in which C is the concentration, in mg per mL, of USP Pa-
requirements.
clitaxel RS in the Standard preparation; and rv and rs are
Assay—
the peak responses for paclitaxel obtained from the Assay
Diluent—Prepare a mixture of methanol and acetic acid
(200:1).
ly- A USP26
water and acetonitrile (11:9). Make adjustments if necessary
Standard preparation—Dissolve, using sonication if
necessary, an accurately weighed quantity of USP
Paclitaxel RS in Diluent, and dilute quantitatively, and BRIEFING
stepwise if necessary, with Diluent to obtain a solution
Paromomycin Oral Solution—See briefing under Lincomycin
having a known concentration of about 1 mg per mL. Hydrochloride Syrup.
Assay preparation—Transfer about 10 mg of Paclitaxel, (NL: C. Barnstein; PA7: W. Wright) RTS—35936-1

accurately weighed, to a 10-mL volumetric flask. Dissolve
in Diluent, using sonication if necessary, dilute with Diluent Add the following:
to volume, and mix. A
Paromomycin Oral Solution
Chromatographic system (see Chromatography (621))— {Monograph under this new title—to become official
The liquid chromatograph is equipped with a 227-nm June 1, 2005)
{Current monograph title is Paromomycin Sulfate Syr-
detector and a 4.6-mm x 25-cm column that contains 5- up)

minute. Chromatograph the Standard preparation, and » Paromomycin Oral Solution contains an amount
record the peak responses as directed for Procedure: the of Paromomycin Sulfate equivalent to not less
tailing factor is between 0.7 and 1.3; and the relative than 90.0 percent and not more than 130.0 percent
standard deviation for replicate injections is not more than of the labeled amount of paromomycin
1.5%.
(C23H45N5O14). It may contain one or more suit-
able buffers, colors, flavors, preservatives, and
solvents.
Pharmacopeial Forum
USP Reference standards (11)—USP Paromomycin Sul-

fate RS. BRIEFING
Uniformity of dosage units (905)— Pentobarbital Elixir, USP 25 page 1340. It is proposed to
change the title of this monograph to Pentobarbital Oral Solution.
F O R ORAL SOLUTION PACKAGED IN SINGLE-UNIT See also briefing under Amantadine Hydrochloride Syrup.
CONTAINERS: meets the requirements. (NL: C. Barnstein; PA3: S. Salado) RTS—35980-1

pH (791): between 7.5 and 8.5. Pentobarbital Elixir
Assay—Proceed with Oral Solution as directed under (Current title—not to change until June 1, 2005)
Antibiotics—Microbial Assays (81), diluting an accurately 2005
measured volume of Oral Solution with Buffer No. 3 to cess Revision):
See Pentobarbital Oral Solution
yield a stock solution of convenient concentration.
Quantitatively dilute this stock solution with the same
buffer to obtain a Test Dilution having a concentration
assumed to be equal to the median dose level of the BRIEFING
Standard. A.USP26
Pentobarbital Oral Solution—See briefing under Amantadine
(Official June 1,2005) Hydrochloride Syrup.
BRIEFING Add the following:

A
Paromomycin Sulfate Syrup, USP 25 page 1312. It is pro- Pentobarbital Oral Solution
posed to change the title of this mongraph to Paromomycin Oral
Solution. See also briefing under Lincomycin Hydrochloride Syrup. (Monograph under this new title—to become official
June 1, 2005)
(Current monograph title is Pentobarbital Elixir)
(NL: C. Barnstein; PA7: W. Wright) RTS—35936-1
» Pentobarbital Oral Solution contains not less

Paromomycin Sulfate Syrup
(Current title—not to change until June 1,2005) than 92.5 percent and not more than 107.5 percent
2005 of the labeled amount of pentobarbital
cess Revision): (CnH18N2O3)-
See Paromomycin Oral Solution
USP Reference standards (11)—USP Pentobarbital RS.
Identification—Dilute a volume of Oral Solution with
alcohol to obtain a concentration of about 1 mg of
pentobarbital per mL. Apply 50 uL of this solution and 50
HL of a Standard solution of USP Pentobarbital RS in
alcohol containing 1 mg per mL as streaks about 1 cm in
Pharmacopeial Forum
length along the spotting line to a suitable thin-layer chloroform to volume, and mix. Combine 4.0 mL of this
chromatographic plate (see Chromatography (621)) solution with 1.0 mL of Internal standard solution in a
coated with a 0.25-mm layer of chromatographic silica gel suitable container, and reduce the volume to about 1.5 mL
mixture. Allow the streaks to dry, and develop the by evaporation, with the aid of a stream of dry nitrogen, at
chromatogram in a solvent system consisting of a mixture room temperature.
of isopropyl alcohol, ammonium hydroxide, chloroform, Chromatographic system and System suitability—Proceed
and acetone (9:4:2:2) until the solvent front has moved as directed for Chromatographic System and System
about three-fourths of the length of the plate. Remove the Suitability under Barbiturate Assay (361), the resolution,
plate from the developing chamber, mark the solvent R, between pentobarbital and n-tricosane being not less
front, and allow the solvent to evaporate. Locate the spots than 2 . 3 . [NOTE—Relative retention times are,
by viewing the plate under short-wavelength light: the RF approximately, 0.5 for n-tricosane and 1.0 for
value of the principal spot obtained from the test solution pentobarbital.]
corresponds to that obtained from the Standard solution. Procedure—Proceed as directed for Procedure under
Alcohol content, Method I (611): between 16.0% and Barbiturate Assay (361). Calculate the quantity, in mg, of
20.0%ofC 2 H 5 OH. pentobarbital (C n H 1 8 N 2 O 3 ) in each mL of the Oral
Assay— Solution taken by the formula:

weighed quantity of n-tricosane in chloroform, and
the other terms are as defined therein. A[/iSp2«
having a known concentration of about 0.6 mg per mL. (Official June 1,2005)
quantities of USP Pentobarbital RS and n-tricosane in
chloroform, and quantitatively dilute with chloroform to
obtain a solution that contains, in each mL, known
amounts of about 1 mg of USP Pentobarbital RS and
about 0.4 mg of n-tricosane. BRIEFING
Assay preparation—Transfer an accurately measured Phenobarbital Elixir, USP 25 page 1353. It is proposed to
volume of Oral Solution, equivalent to about 20 mg of change the title of this monograph to Phenobarbital Oral Solution.
pentobarbital, to a separator, add 1 mL of dilute
hydrochloric acid (1 in 5), and extract with four 10-mL
portions of chloroform. Filter the extracts through about
15 g of anhydrous sodium sulfate that is supported on a Phenobarbital Elixir
funnel by a small pledget of glass wool. Collect the Monograph title change—to become official June 1,
2005
combined filtrate in a 50-mL volumetric flask, wash the (see Official Title Changes on the first page of In-Pro-
cess Revision):
sodium sulfate with 5 mL of chloroform, dilute with See Phenobarbital Oral Solution
Pharmacopeial Forum

BRIEFING chromatogram of the Assay preparation corresponds to
Phenobarbital Oral Solution—See briefing under Amantadine that in the chromatogram of the Standard preparation,
both relative to the internal standard, as obtained in the
Assay.
Alcohol content, Method II (611): between 12.0% and

Add the following:
15.0%ofC 2 H 5 OH.
A
Phenobarbital Oral Solution Assay—
Monograph under this new title to become official June
1, 2005 pH 4.5 buffer solution, Mobile phase, and
(Current monograph title is Phenobarbital Elixir)
Chromatographic system—Prepare as directed in the
Assay under Phenobarbital.
» Phenobarbital Oral Solution contains not less Diluent—Prepare a mixture of methanol and pH4.5 buffer
than 90.0 percent and not more than 110.0 percent solution (2:1).
of the labeled amount of phenobarbital Internal standard solution—Dissolve a sufficient quantity
(C12H12N2O3). of caffeine in Diluent to obtain a solution having a
containers.
Phenobarbital RS, accurately weighed, to a 25-mL
USP Reference standards {\\)—USPPhenobarbitalRS.
volumetric flask containing 2.0 mL of Internal standard
Identification—
solution. Dilute with Diluent to volume, and mix.
A: Place 10 mL of Oral Solution in a separator
Assay preparation—Transfer a quantity of Oral Solution,
containing 20 mL of water, add 5 mL of 1 N sodium
equivalent to about 33 mg of phenobarbital, to a 25-mL
volumetric flask containing 2.0 mL of Internal standard
chloroform, discarding the chloroform extracts. Add 5 mL
solution. Dilute with Diluent to volume, and mix.
of 3 N hydrochloric acid, and extract with two 25-mL
portions of chloroform, filtering the extracts through paper
Assay under Phenobarbital. Calculate the quantity, in mg,
into a beaker. Remove the chloroform by evaporation on a
of phenobarbital (C12H12N2O3) in the portion of the Oral
steam bath, and dry the residue at 105° for 2 hours: the
residue so obtained meets the requirements for
W(RJRS),
Identification test A under Phenobarbital.
in which the terms are as defined therein.±USP26
Pharmacopeial Forum
Identification—
BRIEFING
A: It meets the requirements of the flame test for
Potassium Gluconate Elixir, USP 25 page 1411. It is proposed Potassium (191).
to change the title of this monograph to Potassium Gluconate Oral
Solution. See also briefing under Amantadine Hydrochloride Syr- B: Evaporate 5 mL on a steam bath to dryness: a
up.
mineral oil dispersion of the residue exhibits an IR
(NL: C. Bamstein; DSN: G. Giancaspro) RTS—35982-1
absorption maximum in the spectral region between 6.2
and 6.25 um (carboxylic acid salt).
Potassium Gluconate Elixir Alcohol content, MethodII (611): between 4.5% and 5.5%
Monograph title change—to become official June 1, ofC2H5OH.
2005
(see Official Title Changes on the first page of In-Pro- Assay—
cess Revision):
See Potassium Gluconate Oral Solution Potassium stock solution and Standard preparations—
Prepare as directed in the Assay under Potassium
Gluconate.
volume of Oral Solution, equivalent to about 1.8 g of
potassium gluconate, to a 1000-mL volumetric flask,
BRIEFING dilute with water to volume, and mix. Transfer 10.0 mL

of the solution to a 100-mL volumetric flask, dilute with
Potassium Gluconate Oral Solution—See briefing under
Amantadine Hydrochloride Syrup. water to volume, and mix. Transfer 5.0 mL of the
(NL: C. Barnstein; DSN: G. Giancaspro) RTS—35982-1 resulting solution to a 100-mL volumetric flask, add 2.0
mL of sodium chloride solution (1 in 5) and 1.0 mL of
Add the following: hydrochloric acid, dilute with water to volume, and mix.
A Procedure—Proceed as directed for Procedure in the
Potassium Gluconate Oral Solution
(Monograph under this new title—to become official Assay under Potassium Gluconate. Calculate the quantity,
June 1, 2005)
(Current monograph title is Potassium Gluconate Elixir) in mg, of potassium gluconate (C 6 H n KO 7 ) in each mL of
the Oral Solution taken by the formula:
» Potassium Gluconate Oral Solution contains not (200C/F)(234.25/39.10),

less than 95.0 percent and not more than 105.0 in which Fis the volume of Oral Solution taken; 234.25 is
percent of the labeled amount of potassium gluco- the molecular weight of potassium gluconate; and 39.10 is
nate (C6H,,KO7). the atomic weight of potassium.AUS.w<s
containers.
Pharmacopeial Forum

BRIEFING containers.
Prazosin Hydrochloride Capsules, USP 25 page 1426. It is USP Reference standards (11)—USP Prednisolone RS.
proposed to change the Dissolution Medium in the Dissolution test
from 0.01 N hydrochloric acid to 0.1 N hydrochloric acid. A Dis- Identification—The retention time of the major peak in the
solution Medium with a lower pH is more desirable in order to
more readily dissolve the capsule and its contents. chromatogram of the Assay preparation corresponds to that
(BPC: M. Marques) RTS—31463-1 in the chromatogram of the Standard preparation, as
Change to read:
Dissolution (711) Alcohol content, Method II (611)( if present): not less than
Medium: &Q4
90.0% and not more than 115.0% of the labeled amount.
A.USP26
N hydrochloric acid containing 3% sodium lauryl sulfate; 900 mL. Assay—
Time: 60 minutes. Citrate buffer—Prepare a 0.0033 M solution of citric acid
Procedure—Determine the amount of C, 9 H 21 N 5 O 4 dissolved,
employing the procedure set forth in the Assay, using a filtered in water, adjust with 1 N sodium hydroxide to a pH of 6.2,
portion of the solution under test as the Assay preparation in
comparison with a Standard solution having a known and mix.
concentration of USP Prazosin Hydrochloride RS in the same
Medium.
Tolerances—Not less than 75% (Q) of the labeled amount of Diluting solution: a mixture of methanol and water (1:1).
C 19 H 2 jN 5 O 4 is dissolved in 60 minutes.
Citrate buffer and methanol (31:19). Make adjustments if
(621)).
System suitability solution—Dissolve suitable quantities
of prednisolone and hydrocortisone in a mixture of
BRIEFING
methanol and water (1:1) to obtain a solution containing
Prednisolone Oral Solution—See briefing under Amantadine
Hydrochloride Syrup. about 100 ug per mL and 90 jig per mL, respectively.
(NL: C. Barnstein; PA1: C. Anthony) RTS—35983-1
quantity of USP Prednisolone RS in Diluting solution, and
Add the following:
Diluting solution to obtain a solution having a known
A
Prednisolone Oral Solution concentration of about 0.1 mg per mL.
June 1, 2005) Assay preparation—Transfer an accurately measured
(Current monograph title is Prednisolone Syrup)
volume of Oral Solution, equivalent to about 5.0 mg of
prednisolone, to a 50-mL volumetric flask, dissolve in
» Prednisolone Oral Solution contains not less
Diluting solution, shake by mechanical means for 15
than 90.0 percent and not more than 110.0 percent minutes, dilute with Diluting solution to volume, and mix.
of the labeled amount of prednisolone (C21H28O5).
It may contain alcohol.
Pharmacopeial Forum
Chromatographic system (see Chromatography (621))— Prednisolone Syrup

The liquid chromatograph is equipped with a 254-nm (Current title—-not to change until June 1, 2005)
detector and a 4.6-mm x 15-cm column that contains 2005
packing L10. The flow rate is about 1 mL per minute. cess Revision):
See Prednisolone Oral Solution
retention times are about 0.8 for hydrocortisone and 1.0
for prednisolone; the resolution, R, between
hydrocortisone and prednisolone is not less than 2.5; and
the relative standard deviation for replicate injections is
BRIEFING
not more than 2.0%.
Procedure—Separately inject equal volumes (about 10 Probenecid Tablets, USP 25 page 1440. It is proposed to
change the rotation of the paddles in Apparatus 2, in the test for
uL) of the Standard preparation and the Assay Dissolution, from 50 rpm to 75 rpm to improve the dissolution per-
formance of the products commercially available.
peaks. Calculate the quantity, in mg, of prednisolone
(C21H28O5) in the volume of Oral Solution taken by the Change to read:
formula: Medium: simulated intestinal fluid TS, prepared without
pancreatin, pH 7.5 ± 0 . 1 ; 900 mL.
Apparatus 2: #Q
ID
AUSP26
in which C is the concentration, in mg per mL, of USP Pred- rpm.
Time: 30 minutes.
nisolone RS in the Standard preparation; and rv and rs are Procedure—Determine the amount of CjjHjpNC^S dissolved
by employing UV absorption at the wavelength of maximum
the peak responses obtained from the Assay preparation and absorbance at about 244 nm on filtered portions of the solution
under test, suitably diluted with 0.1 N sodium hydroxide, if
the Standard preparation, respectively. AVSP26 necessary, in comparison with a Standard solution having a
known concentration of USP Probenecid RS.
(Official June 1,2005) Tolerances—Not less than 80% (Q) of the labeled amount of
C13H|pNO4S is dissolved in 30 minutes.
BRIEFING
BRIEFING
Prednisolone Syrup, USP 25 page 1427. It is proposed to
change the title of this monograph to Prednisolone Oral Solution. Procainamide Hydrochloride Tablets, USP 25 page 1444. In
See also briefing under Amantadine Hydrochloride Syrup. accordance with the approved NDA, it is proposed to change the
concentration of the Medium in the test for Dissolution and the type
Pharmacopeia! Forum
of Apparatus used and its speed of rotation. The Tolerances are

also being modified to better reflect the performance of the com- Progesterone
mercial product. (micronized) 25 mg to 600 mg
Silica Gel 25 mg
(BPC: M. Marques) RTS—23781-1 Fatty Acid Base, a sufficient
quantity to make one supposi-
tory
Calibrate the actual molds with the Fatty Acid Base
Change to read: that is used for preparing the suppositories, and adjust
Dissolution (711)— the formula accordingly. Mix thoroughly the Proges-
Medium: 0.01 N terone and Silica Gel to obtain a uniform powder. Heat
A
0 1N the Fatty Acid Base slowly and evenly until melted.
hydrochloric acid; 900 mL. Slowly add the powder to the melted base, with stir-
Apparatus 1:100 rpm: ring. Mix thoroughly, and pour into molds. Cool in a
A
2: 5 0 rpm. A a y W ( j
refrigerator until solidified, trim, and wrap.
Time: 1$ Change to read:

SUPPOSITORIES COMPOUNDED IN POLYETHYLENE GLYCOL BASE
minutes. Prepare Progesterone Vaginal Suppositories in Polyethylene
Procedure—Determine the amount of Cj 3 H 2 jN 3 O -HC1 Glycol Base as follows (see Pharmacy Compounding f9&)
dissolved by employing UV absorption at the wavelength of A
Pharmaceutical Compounding—Nonsterile Preparations
maximum absorbance at about 275 nm on filtered portions of the
solution under test, suitably diluted with an amount of 0.01 N
sodium hydroxide that is not less than twice the volume of the
portion of test solution taken, in comparison with a Standard
solution having a known concentration of USP Procainamide Progesterone (micronized) 25 mg to 600 mg
Hydrochloride RS in the same media. Silica Gel 25 mg
Tolerances—Not less than 80% (Q) of the labeled amount of Polyethylene Glycol Base, a sufficient
C13H2jN3O • HC1 is dissolved in ?5 quantity to make one suppository
Calibrate the actual molds with Polyethylene Glycol Base that is
minutes. used for preparing the Suppositories, and adjust the formula ac-
cordingly. Mix thoroughly the Progesterone and Silica Gel to ob-
tain a uniform powder. Heat the Polyethylene Glycol Base slowly
and evenly until melted. Slowly add the powder to the melted base,
with stirring. Mix thoroughly, and pour into molds. Cool, trim, and
wrap.
BRIEFING
Progesterone Vaginal Suppositories, USP 25 page 1455—See

briefing under Cefazolin Ophthalmic Solution.
BRIEFING
Promethazine Hydrochloride Oral Solution—See briefing
Change to read: (NL: C. Barnstein; AER: K. Zaidi) RTS—35984-1
» Progesterone Vaginal Suppositories contain not less

than 90.0 percent and not more than 110.0 percent of
the labeled amount of progesterone (C21H30O2). Add the following:
SUPPOSITORIES COMPOUNDED IN FATTY ACID BASE A
Prepare Progesterone Vaginal Suppositories in Fatty Promethazine Hydrochloride Oral
Acid Base as follows (see Pharmacy Compounding Solution
() (Monograph under this new title—to become official
A
Pharmaceutical Compounding—Nonsterile June 1, 2005)
(Current monograph title is Promethazine Hydrochlor-
ide Syrup)
Preparations (795)):AUSP26
Pharmacopeia! Forum
» Promethazine Hydrochloride Oral Solution con- volumetric flask with the aid of additional acid. Cool, add
tains not less than 90.0 percent and not more than dilute sulfuric acid (1 in 100) to volume, mix, and filter,
rejecting the first half of the filtrate. Dissolve an
110.0 percent of the labeled amount of prometha-
accurately weighed quantity of USP Promethazine
zine hydrochloride (C17H20N2S • HC1).
Hydrochloride RS in dilute sulfuric acid (1 in 100), and
Packaging and storage—Preserve in tight, light-resistant dilute quantitatively and stepwise with the dilute acid to
containers. obtain a Standard solution having a known concentration
USP Reference standards (11)—USP Promethazine Hy- of about 50 jig per mL. Concomitantly determine the
drochloride RS. absorbances of both solutions in 1-cm cells at the
NOTE—Throughout the following procedures, protect test wavelength of maximum absorbance at about 298 nm,
or assay specimens, the Reference Standard, and solutions with a suitable spectrophotometer, using dilute sulfuric
containing them, by conducting the procedures without de- acid (1 in 100) as the blank. Calculate the quantity, in mg,
lay, under subdued light, or using low-actinic glassware. of promethazine hydrochloride (C17H20N2S • HC1) in each
Identification—Treat 25 mL of Oral Solution as directed in mL of the Oral Solution taken by the formula:
the Assay, ending with "using a current of air only."

Dissolve the residue in 2.5 mL of carbon disulfide, filter
in which C is the concentration, in mg per mL, of USP Pro-
through paper if necessary, and determine the IR
methazine Hydrochloride RS in the Standard solution; Fis
absorption spectrum as directed under Identification—
the volume, in mL, of Oral Solution taken; and-^ andAs are
Organic Nitrogenous Bases (181), obtaining the spectrum
the absorbances of the solution from the Oral Solution and
of USP Promethazine Hydrochloride RS as directed: the
the Standard solution, respectively.^^*
Oral Solution meets the requirements of the test.
Assay—[NOTE—Use low-actinic glassware in this assay.]
Transfer an accurately measured volume of Oral Solution,
equivalent to about 25 mg of promethazine hydrochloride,
BRIEFING
to a 250-mL separator. Add 10 mL of ammonium
hydroxide, and extract the promethazine base with six 40- Promethazine Hydrochloride Syrup, USP 25 page 1460. It is
proposed to change the title of this monograph to Promethazine
mL portions of chloroform. Wash the combined Hydrochloride Oral Solution. See also briefing under Amantadine
chloroform extracts with 25 mL of dilute hydrochloric
acid (1 in 9). Wash the acid solution with 25 mL of
chloroform, and add the washings to the main chloroform
extract. Evaporate the chloroform extract on a steam bath, Promethazine Hydrochloride Syrup
with the aid of a current of air, to a volume of 5 to 10 Monograph title change—to become official June 1,
2005
mL, and finally evaporate, using only a current of air, to (see Official Title Changes on the first page of In-Pro-
cess Revision):
dryness. Dissolve the residue, with slight warming, in See Promethazine Oral Solution
dilute sulfuric acid (1 in 100), and transfer to a 500-mL
Pharmacopeial Forum
Calculate tho peak heights of the oarbinol, aootoxy, and n trioo

sano peaks in oaoh ohromatogram. Tho ordor of olution is oarbinol,
aootoxy, propoxyphonov and n trioosano.
BRIEFING Caloulato tho poroentago of oarbinol hydroohlorido in the Pro
poxyphono Hydroohlorido taken by tho formula:
Propoxyphene Hydrochloride, USP 25 page 1466. It is pro-
posed to replace the different chromatographic methods in the test
for Related compounds and in the Assay with an HPLC method. in which C is tho concentration, in mg por mL; of tho oarbinol hy
The stability-indicating liquid chromatographic procedures in the droohlorido standard in Solution A, Wia tho weight, in mg, of tho
newly proposed methods are based on analyses performed with 3peoimon taken; and Ryand R^ are tho ratios of tho poalc heights of
the uBondapak brand of LI column. The typical retention times oarbinol hydroohloride to thoso of n trioosano of tho Test prcpara
reported are about 9 minutes for propoxyphene hydrochloride (ion and theStandard preparation, respectively: tho limit is 0.5%.
and 7 minutes for oc-rf-2-acetoxy-4-dimethylamino-l,2-diphenyl- Caloulato tho peroentago of aootoxy hydroohlorido in tho Pro
3-methylbutane. poxyphono Hydro chloride taken by tho formula:

in whioh C is tho concentration; in mg per mL; of the aootoxy ana
log standard in Solution A, Win tho weight, inmg;of tho spooimon
taken, 1.112 is tho ratio of tho molecular weight'of the aoetoxy hy
droohlorido to that of tho aootoxy free base;and~R# and Rg are the
Change to read: ratios of tho peak heights of tho-aootoxy froo baso to that of n tri
Related compounds— oosano of tho Test preparation and tho Standard preparation, re
Internal standard solution—Dissolve- a quantity of n triooaano in 3pootivoly: tho limit m 0.6%.
chloroform to obtain a solution containing 1 mg por mL.
Solution A—Weigh accurately 12.5 mg of tho acotoxy analog ^Mobile phase and Chromatographic system—Proceed as
standard, USP a d 2 Aootoxy4 dimothylamino 1,2 diphonyl 3
mothylbutano RS, and 12.5 mg of the carbinol hydroohlorido directed in the Assay.
(standard, USP a d A Dimethylamino 1,2 diphonyl 3 methyl 2
butanol Hydroohlorido RS, and transfer to tho oamo 50 mL Standard solution— Proceed as directed for the Standard
volumotrio flask. Add chloroform to volume^ and mix.
Standard preparation—Transfer about 200 mg of USP preparation in the Assay.
Propoxyphono Hydroohlorido RS; aoouratoly weighed, to a 125
mL separator, and add about 25 mL of water and 5.0 mL of Test solution—Use the Assay preparation.
sodium hydroxide solution (1 in 10). Add 3.0 mL of Solution A
and 30 mL of chloroform to tho contents of tho aoparator, ohako Related compounds standard solution—Dissolve about
for 1 minute; and allow the phases to separate. Drain tho
chloroform layer, through a small portion of anhydrous sodium 10 mg each of USP Propoxyphene Related Compound A
sulfato previously washed with ohloroform, into a 100 mL
volumotrio flask containing 2.0 mL of Internal standard solution. RS and USP a-£/-2-acetoxy-4-dimethylamino-l,2-
Extract tho aqueous phase in tho separator with two 25 mL
portions of ohloroform, draining oaoh through tho anhydrous diphenyl-3-methylbutane RS in 20 mL of methanol in a
sodium sulfato into tho volumotrio flask: Rinso tho sodium
sulfato with ohloroform; dilute with ohloroform to volume, and 50-mL volumetric flask, dilute with Mobile phase to
mix. Evaporate 10.0 mL of this chloroform solution under a
stream of nitrogen to about 2 mL. volume, and mix.
Test preparation—Proparo as dirootod for Standard preparation,
except to U3O 200 mg of Propoxyphono Hydroohlorido and to omit System suitability solution—Combine 1.0 mL of the
tho addition of the 3.0 mL of Solution A.
Procedure—Injoot separately a suitable volumo of tho Standard Related compounds standard solution containing about
preparation and an identical volume of tho Test preparation into a
suitable gas ohromatograph equipped with a flame ionization 0.2 mg per mL of each related compound with 10.0 mL
dotootor and in which tho 0.6 m x 3 mm column is packed with
3% phaoo G2 on packing S1AB. NOTD Froquont roailylation of of the Standard solution, and mix.
the column packing may bo necessary to prevent on column
decomposition of propoxyphono. Tho temperatures of tho Chromatographic system (see Chromatography (621))—
injootion port and oolumns aro maintained at 160°^ and tho
dotootor temperature is maintained at 190°. NOTE—Do not allow Proceed as directed in the Assay. Chromatograph the System
tho temperature to exceed 200°. Tho carrier ga3 is helium. In a
suitable ohromatogram, tho retention timo3 for tho oarbinol and suitability solution, and record the peak responses as
aootoxy compounds are about 0.3 and 0:4;roapootivoly, relative
to tho internal standard, tho resolution factor, R, between tho directed for Procedure: the relative retention times are
carbinol and tho acctoxy poaka is not Ic33 than L5; five roplioato
injootions of tho Standard preparation show a oooffioiont of about 0.63 for propoxyphene related compound A, 0.78
variation of not moro than 6:0% in tho ratios of tho peak heights
of tho aootoxy analog to that of n trioosano and of the oarbinol for a-£/-2-acetoxy-4-dimethyl-amino-l,2-diphenyl-3-
analog to that of n trioosano, and there is no evidence of
spurious poak3 ro3ulting from tho decomposition of methylbutane, and 1.0 for propoxyphene hydrochloride;
propoxyphono in tho system.
the resolution, R, between a-i/-2-acetoxy-4-dimeth-
Pharmacopeial Forum
A
ylamino-l,2-diphenyl-3-methylbutane and propoxy-phene 0.01M Monobasic ammonium phosphate buffer, pH
is not less than 1.4; and the relative standard deviation for 6.3—Dissolve 11.5 g of monobasic ammonium phosphate
replicate injections is not more than 2.0%. and 1.0 mL of triethylamine in 1000 mL of water, adjust
Procedure—Separately inject equal volumes (about 50 with 10% sodium hydroxide to a pH of 6.3 ± 0.05, and
uL ) of the Test solution into the chromatograph, record mix.
the chromatograms, and measure the peak responses. Mobile phase—Prepare a filtered and degassed mixture of
Calculate the percentage of propoxyphene related methanol and 0.01M Monobasic ammonium phosphate
compound A in the portion of Propoxyphene Hydro- buffer, pH 6.3 ( 67:33). Make adjustments if necessary
chloride taken by the formula: (see System suitability under Chromatography (621)).
100(r,/r,),
quantity of USP Propoxyphene Hydrochloride RS in
in which r, is the individual peak response of propoxyphene Mobile phase to obtain a solution having a known con-
related compound A in the Test solution; and rs is the sum of centration of about 5.0 mg per mL.
the responses for all of the peaks: not more than 0.5% of Assay preparation—Transfer about 250 mg of
propoxyphene related compound A as the hydrochloride is Propoxyphene Hydrochloride, accurately weighed, to a
found. Calculate the percentage of a-J-2-acetoxy-4-di- 50-mL volumetric flask, dissolve in and dilute with
methylamino-1,2-diphenyl-3-methylbutane hydrochloride Mobile phase to volume, and mix.
in the portion of Propoxyphene Hydrochloride taken by
the formula:
100(1.112)^/0, detector and a 3.9-mm x 30-cm column that contains
in which 1.112 is the ratio of the molecular weight of a-of-2-
Chromatograph the Standard preparation and record the
acetoxy-4-dimethylamino-1,2-diphenyl-3-methylbutane
peak responses as directed for Procedure: the retention
hydrochloride to that of a-c/-2-acetoxy-4-dimethylamino-
time of propoxyphene hydrochloride is about 9 minutes;
l,2-diphenyl-3-methylbutane free base; r, is the individual
the r e s o l u t i o n , R, b e t w e e n oc-d-2-acetoxy-4-
peak response of a-</-2-acetoxy-4-dimethylamino-l,2-di-
dimethylamino-1,2-diphenyl-3-methylbutane and
phenyl-3-methylbutane in the Test solution; and rs is the
propoxyphene is not less than 1.4; and the relative stan-
sum of the responses for all of the peaks: not more than
dard deviation for replicate injections is not more than 2.0%.
0.6% of a-fi?-2-acetoxy-4-dimethylamino-l,2-diphenyl-3-
methylbutane hydrochloride is found. AUSP26
^L) of the Standard preparation and the Assay
Change to read: preparation into the chromatograph, record the chro-
Assay—Diaaolvo about 600 mg of Propoxyphono Hydroohlorido,
aoouratoly woighod, in 10 mL of glaoial aootio aoid, and add 10 mL matograms, and measure the responses for the major
of morourio aootato TS. Add oryotal violet TS, and titrate with 0.1 N
porohlorio aoid VS to a dark greenish bluo Midpoint. Perform a peaks. Calculate the quantity, in mg, of C22H29NO2 • HC1
blank determination (ooo Titrimotry (§44-)), and mako any
neooooary oorrootion. Eaoh mL of 0.1 N porohlorio aoid io in the portion of Propoxyphene Hydrochloride taken by
equivalent to 37.59 mg of C g g t f ^ N Q G ^
the formula:
Pharmacopeial Forum
on oolumn dooompooition of propoxyphono. Tho tomporaturos of

tho oolumn and tho injector port aro maintained at about 160°, and
the temperature of tho dotoetor blook io maintained at about 190°;
in which C is the concentration, in mg per mL, of USP Pro- NOTE—Do not allow tho temperature to oxooed 200°. Dry holium
ia used as tho carrier ga3 at a flow rato of about 75 mL per minuto:
poxyphene Hydrochloride RS in the Standard preparation; System suitability—Chromatograph fivo injootions of the
Standard preparation, and rooord peak heights as directed under
and rv and rs are the peak responses obtainedfromthe Assay Procedure. The development timo for ono ohromatogram i#
about 10 minutoo, and retention times for tho oarbinol precursor
preparation and the Standard preparation, respective- and acotoxy analog aro, respectively, about 0.3 and 0.1 rolativo
to tho internal standard; the analytical syotom io suitable for
\/-AUSP26 conducting tho tost if tho resolution factor, R, between the
earbinol and tho aootoxy poako io not looo than 1.5, the
oooffioionts of variation for tho ratioo RA and R^ do not oxooed
6.0%, and thoro is no ovidenoo of opuriouo poako resulting from
tho decomposition of propoxyphono in tho system.
Procedure—Injoot ooparatoly a suitable volume of tho Standard
preparation and an identical volume of tho Test preparation into a
suitable gas ohromatograph, and rooord tho ohromatogramr
Calculate tho poak hoighto of tho oarbinol proouroor, tho aootoxy
analog, and tho n trioosano peaks in oaoh ohromatogram.
Galoulato the poroontago of oarbinol napsylato precursor in tho por
BRIEFING
tion of Propoxyphono Napoylato taken by tho formula: -
(509.67 / 319.88)(200CVffO(^/^
Propoxyphene Napsylate, USP 25 page 1470. It is proposed to
replace the different chromatographic methods in the test for Re- in which 509.67 and 319.88 aro tho molecular woighto of oarbinol
lated compounds and in the Assay with an HPLC method that is napaylato monohydrato proouroor and anhydrous oarbinol hydro
stability indicating. The liquid chromatographic procedures in ohlorido proouroor, respectively, C^ io tho oonoontration, in mg
the newly proposed methods are based on analyses performed with por mL, of USP a d <\ Dimothylamino1,2 diphonyl 3 mothyl 2
the uBondapak brand of LI column. The typical retention times butanol Ilydroohlorido RS in Solution A, Wia tho woight, in mg;
reported are about 9 minutes for propoxyphene napsylate and 7 of Propoxyphcno Napoylato taken, and -r^ and Rg aro tho ratioo of
minutes for a-J-2-acetoxy-4-dimethylamino-l,2-diphenyl-3- the peak heights of the oarbinol proouroor to those of n trioosano in
methylbutane. tho Test preparation and tho Standard preparation, rospootivoly:
tho limit io 0.5%.
Galoulato tho poroontago of acotoxy analog napsylato in tho Pro-
(PA2: J. Kelly) RTS—33608-1 poxyphono Napsylato tokon by tho formula:
(551.71 / 3 2 5 . 1 5 ) ( 2 0 0 Q - / 4 ^ ^ J ? ^
in which 551.71 and 325.15 aro tho molecular woighto of aootoxy
Change to read: analog napaylato monohydrato and anhydrous aootoxy analog; re
opootivoly, Q is tho concentration; in mg por mL, of USP a d <\
Related compounds— Dimothylamino 1,2 diphonyl 3 mothyl 2 butanol Hydroohlorido
Internal standard solution and Solution A—Prepare aa directed RS in Solution A, Ww the weight, in mg, of Propoxyphono Nap-
in tho toot forRelated compounds under Propoxyphene aylato takon, and r^ and Rj aro tho ratioo of tho poak hoighto of tho
Hydrochloridc. aeotoxy analog to those of n- trioosano in tho Test preparation and
Standard preparation—Transfer about 150 mg of USP tho Standard preparation, rospootivoly: tho limit is 0.6%.
Propoxyphono Napoylato RS, accurately weighed, to a 125 mL
separator, add 15 mL of water, and mix: Add 5.0 mL of oodium ^Mobile phase and Chromatographic system—Proceed
hydroxide solution (1 in 10), 2.0 mL of Solution 'A; and15 mL
of chloroform to tho oontonto of tho separator, ahako for 1 as directed in the Assay.
minuto, and allow tho phaoos to separata. Drain tho chloroform
extract" through a layer of about 2 g of anhydrou3 granular Standard solution—Proceed as directed for Standard
aodium sulfato, supported on glass wool and provioualy washed
with ohloroform, into a 50 mL volumetric flask containing 1.0 preparation in the Assay.
mL of Internal standa/d solution: Extract tho aquoouo phase in
tho separator with two additional 15 mL portions of ohloroform,
draining each ohloroform extract through the oamo oodium Test solution—Use the Assay preparation.
oulfato filter into tho oamo volumotrio flask: Rinoo tho oodium
oulfate filter with 1 to 2 mL of ohloroform; oolloot tho rinsing Related compounds standard solution—Dissolve about
with tho combined ohloroform extracts, dilute with ohloroform to
volume, and mix. Evaporate 10.0 mL of thio ohloroform solution 10 mg each of USP Propoxyphene Related Compound A
under a stroam of nitrogen to about 2 mL.
RS and USP a-J-2-Acetoxy-4-dimethylamino-l,2-
Test preparation—Proparo as direotod for Standard preparation,
except to uao 150 mg of Propoxyphono Napsylato and to omit tho diphenyl-3-methylbutane RS in 20 mL of methanol in a
addition of tho 2.0 mL of Solution A.
Chromatographic system (ooo Chmmatography (434-) j—Under 50-mL volumetric flask, dilute with Mobile phase to
typioal conditions; the instrument io equipped with a flame
ionization detector and contains a 0.6 m x 3 mm glaoo column volume, and mix.
packed with 3% phaoo G2 on packing S1AB. NOTE—Frequont
roailylation of tho column packing may bo nooossary toprevent
Pharmacopeial Forum
System suitability solution—Combine 1.0 mL of the in which 533.71 and 325.45 are the molecular weights of a-
Related compounds standard solution containing about fi?-2-acetoxy-4-dimethylamino-1,2-diphenyl-3 -methy lbu-
0.2 mg per mL of each related compound with 10.0 mL tane napsylate and a-J-2-acetoxy-4-dimethylamino-l,2-di-
of the Standard solution, and mix. phenyl-3-methylbutane, respectively; r, is the individual
Chromatographic system (see Chromatography (621))— peak response of a-d-2-acetoxy-4-dimethylamino-l,2-di-
Proceed as directed in the Assay. Chromatograph the System phenyl-3-methylbutane napsylate; and rs is sum of the re-
suitability solution, and record the peak responses as sponses for all the peaks: not more than 0.6% of a-d-2-
directed for Procedure: the relative retention times are acetoxy-4-dimethylamino-l,2-diphenyl-3-methylbutane
about 0.63 for propoxyphene related compound A, 0.78 napsylate is found.Aas7,2(5
for a-c/-2-acetoxy-4-dimethylamino-l,2-diphenyl-3-
Change to read:
methylbutane, and 1.0 for propoxyphene napsylate; the Assay—
Dicthylaminc phosphate buffer—Mix 5.0 mL of diothylamino
resolution, R, between a-d-2-acetoxy-4-dimethylamino- with 995 mL of water, and adjust with phosphorio aoid to a pH
l,2-diphenyl-3-methylbutane and propoxyphene is not less Diluent—Prepare a mixture of Dicthylaminc phosphate buffer
and aoetonitrilo (4:1).
than 1.4; and the relative standard deviation for replicate Mobile phase—Prepare a mixture of Dicthylaminc phosphate
buffet' and aeotonitrilo (3:2). Sonicate for 15 minutea, and pass
injections is not more than 2.0%. through a filter having a 0.5 [am or finer porooity. Make
adjustments if noooaaary (aoo System Suitability under
Procedure—Separately inject equal volumes (about 50 Chromatography (624-))?
uL) of the Test solution into the chromatograph, record of USP Propoxyphono Napaylato RS \n Diluent to obtain a solution
the chro-matograms, and measure the peak responses. Assay preparation—Transfer about 10 mg of Propoxyphono
Napsylato, aoouratoly woighod; to a 100 mL volumctrio flask.
Calculate the percentage of propoxyphene related Dissolve in and dilute with Diluent to volume, and mix.
Chromatographic system (soo Chromatography (6S4-))—tte
compound A as the napsylate salt in the portion of liquid chromatograph is equipped with a 217 nm detector and a
3.9 mm x 30 cm column containing packing LI. Tho flow rate
Propoxyphene Napsylate taken by the formula : is about 1 mL per minute Chromatograph the Standard
preparation, and record tho responses as dirootod for Proccduiv:
100(491.67/319.88)(r,/r,), tho tailing factor is not more than 1.5; and tho relative standard
deviation for replicate injections is not more than 2.0%.
Pivccdure—Soparatoly injoot equal volumes (about 20 uL) of
in which 491.67 and 319.88 are the molecular weights of tho Standard preparation and tho Assay preparation into tho
ohro matograph, rooord tho ohromatograms; and measure tho
propoxyphene related compound A napsylate and propoxy- areas for tho propoxyphono peaks. Caloulato the quantity, in mg,
of C g j H ^ N O y " Q m ^ a ^ S in the portion of Propoxyphono
phene related compound A, respectively; r, is the individual NapsyTato taken by the formula:
peak response of propoxyphene related compound A; and rs

in which C is tho concentration, in mg per mL, of USP Propoxy
is the sum of the responses for all the peaks: not more than phono Napsylate RS in the Standard prvparation; and f% and r^ are
tho peak ro3pon3O3 obtainod from tho Assay preparation and tho
0.5% of propoxyphene related compound A is found. Cal- Standard preparation, rospootivoly.
culate the percentage of a-<i-2-acetoxy-4-dimethylamino- A
0.01M Monobasic ammonium phosphate buffer, pH
l,2-diphenyl-3-methylbutane napsylate in the portion of 6.3—Dissolve 11.5 g of monobasic ammonium phosphate
Propoxyphene Napsylate taken by the formula: and 1.0 mL of triethylamine in 1000 mL of water, adjust
100(533.71/325.45)(r,./r,), with 10% sodium hydroxide to a pH of 6.3 ± 0.05, and

mix.
Pharmacopeial Forum
Mobile phase—Prepare a filtered and degassed mixture of in which C is the concentration, in mg per mL, of USP Pro-
methanol and 0.01M Monobasic ammonium phosphate poxyphene Napsylate RS in the Standard preparation; and
buffer, pH 6.3 (67:33). Make adjustments if necessary (see rv and rs are the peak responses obtained from the Assay
System suitability under Chromatography (621)). preparation and the Standard preparation, respective-
Standard preparation—Dissolve an accurately weighed >Y-AUSP26
quantity of USP Propoxyphene Napsylate RS in Mobile

phase to obtain a solution having a known concentration
propoxyphene napsylate, accurately weighed, to a 50-mL
volumetric flask, dissolve in and dilute with Mobile phase BRIEFING
to volume, and mix. Pseudoephedrine Hydrochloride Oral Solution—See briefing

packing LI. The flow rate is about 1.5 mL per minute. Add the following:
A
Chromatograph the Standard preparation, and record the Pseudoephedrine Hydrochloride Oral
peak responses as directed for Procedure: the retention Solution
time of propoxyphene napsylate is about 9 minutes; the June 1, 2005)
(Current monograph title is Pseudoephedrine Hydro-
resolution, R, between a-c?-2-acetoxy-4-dimethylamino- chloride Syrup)
l,2-diphenyl-3-methylbutane and propoxyphene napsylate
is not less than 1.4; and the relative standard deviation for
» Pseudoephedrine Hydrochloride Oral Solution
contains not less than 90.0 percent and not more
than 110.0 percent of the labeled amount of
pseudoephedrine hydrochloride (C 10 H 15
NOHC1).
peaks. Calculate the quantity, in mg, of C 2 2H 29 NO 2 Packaging and storage—Preserve in tight, light-resistant
•C 10 H 8 O 3 S in the portion of Propoxyphene Napsylate containers.
taken by the formula: USP Reference standards {11)—USP Pseudoephedrine
100C(ru/rs), Hydrochloride RS.
Identification—Extract a volume of Oral Solution,
equivalent to about 120 mg of pseudoephedrine
hydrochloride, with two 30-mL portions of ether, discard
the extracts, and add 4 mL of 1 N sodium hydroxide.
Pharmacopeial Forum
Extract with 30 mL of chloroform, and evaporate the Procedure—Separately inject equal volumes (about 10
chloroform on a steam bath, avoiding overheating: the uL) of the Standard preparation and the Assay
pseudoephedrine so obtained melts at about 118°, the preparation into the chromatograph, record the chro-
procedure for Class I being used (see Melting Range or matograms, and measure the responses for the major
Temperature (741)), and when 50 mg is dissolved in 10 peaks. Calculate the quantity, in mg, of pseudoephedrine
mL of 0.1 N hydrochloric acid, the resulting solution is hydrochloride (C10H15NO HC1) in each mL of the Oral
dextrorotatory. Solution taken by the formula:
Reaction—It is acid to litmus. 50{C/V)(rv/rs),
Assay— in which C is the concentration, in mg per mL, of USP

Mobile phase—Prepare a filtered and degassed mixture of Pseudoephedrine Hydrochloride RS in the Standard pre-
alcohol and 0.40% ammonium acetate solution (17:3). paration; V is the volume, in mL, of Oral Solution taken;
Make adjustments if necessary (see System Suitability and rv and rs are the peak responses obtained from the Assay
under Chromatography (621)). preparation and the Standard preparation, respectively.
Standard preparation—Dissolve an accurately weighed (Official June 1,
quantity of USP Pseudoephedrine Hydrochloride RS in
0.01 N hydrochloric acid to obtain a solution having a
pseudoephedrine hydrochloride, to a 50-mL volumetric BRIEFING
flask, dilute with 0.01 N hydrochloric acid to volume, Pseudoephedrine Hydrochloride Syrup, USP 25 page 1486. It
is poposed to change the title of this monograph to Pseudo-
mix, and filter. ephedrine Hydrochloride Oral Solution. See also briefing under
(NL: C. Bamstein; PA2: J. Kelly) RTS—35985-1
packing L3. The flow rate is about 1.5 mL per minute. Pseudoephedrine Hydrochloride Syrup
Chromatograph five replicate injections of the Standard (Current title—not to change until June 1, 2005)
preparation, and record the peak responses as directed for 2005
Procedure: the tailing factor is not more than 2.0; and the cess Revision):
See Pseudoephedrine Hydrochloride Oral Solution
more than 2.0%.
Pharmacopeial Forum
» Pyridostigmine Bromide Oral Solution contains,

BRIEFING
in each 100 mL, not less than 1.08 g and not more
Pseudoephedrine Hydrochloride Tablets, USP 25 page 1486.
Editorial revision is indicated to conform with the title change pro- than 1.32 g of pyridostigmine bromide (C9H13
posed for Pseudoephedrine Hydrochloride Syrup. See also briefing
BrN2O2).
containers.
Change to read: USP Reference standards (11)—USP Pyridostigmine
Assay—
Mobile phase, Standard preparation, and Chromatographic Bromide RS.
system—Proceed as directed in the Assay under Pseudo-
ephedrine Hydrochloride Syrup Identification—To 5 mL of Oral Solution in a separator add
A
Oral Solution. ±USP26
Assay preparation—Weigh and finely powder not fewer than 20 100 mL of 2.5 N hydrochloric acid, and mix. Extract with
Tablets. Transfer an accurately weighed portion of the powder,
equivalent to about 120 mg of pseudoephedrine hydrochloride, five 20-mL portions of chloroform, place 2 mL of the
to a 100-mL volumetric flask, add 0.01 N hydrochloric acid, and
sonicate to dissolve. Cool to room temperature. Dilute with 0.01 N aqueous solution in a 50-mL volumetric flask, and add
hydrochloric acid to volume, mix, and filter.
Procedure—Separately inject equal volumes (about 10 uL) of water to volume: the UV absorption spectrum of this
the Standard preparation and the Assay preparation into the
chromatograph, record the chromatograms, and measure the solution exhibits maxima and minima at the same
responses for the major peaks. Calculate the quantity, in mg, of
pseudoephedrine hydrochloride (C10H15NO-HC1) in the portion wavelengths as that of a similar solution of USP Pyrid-
of Tablets taken by the formula:
ostigmine Bromide RS, concomitantly measured.
in which C is the concentration, in mg per mL, of USP Pseudo- Assay—

ephedrine Hydrochloride RS in the Standard preparation; and rv
and rs are the peak responses obtained from the Assay preparation Phosphate solution—Dissolve 38 g of monobasic sodium
and the Standard preparation, respectively.
phosphate and 2 g of anhydrous dibasic sodium phosphate
in water to make 1000 mL. Adjust the pH, if necessary, by
slight variation of the ratio of the two ingredients, to 5.3 +
0.1.
Bromocresol green solution—Dissolve 250 mg of
bromocresol green sodium salt in 250 mL of Phosphate
solution.
BRIEFING
Pyridostigmine Bromide Oral Solution—See briefing under
Amantadine Hydrochloride Syrup. USP Pyridostigmine Bromide RS, accurately weighed, in
(NL: C. Barnstein; PA3: S. Salado) RTS—35987-1 water, to obtain a solution having a known concentration
Add the following: Assay preparation—Transfer an accurately measured

^Pyridostigmine Bromide Oral Solution
pyridostigmine bromide, to a 100-mL volumetric flask,
June 1,2005) add water to volume, and mix.
(Current monograph title is Pyridostigmine Bromide
Syrup)
Pharmacopeial Forum
Procedure—Transfer 10 mL each, accurately measured, Pyridostigmine Bromide Syrup

of the Assay preparation and the Standard preparation to (Current title—-not to change until June 1,2005)
separate 125-mL separators. Into each separator pipet 10 2005
mL of water, 20 mL of Phosphate solution, and 5 mL of cess Revision):
See Pyridostigmine Bromide Oral Solution
Bromocresol green solution. Extract each solution with six
15-mL portions of chloroform, collecting the chloroform
extracts in respective 100-mL volumetric flasks, then add
chloroform to volume in each flask, and mix.
Concomitantly determine the absorbances of both
solutions in 1-cm cells at the wavelength of maximum
BRIEFING
a b s o r b a n c e at a b o u t 415 nm, with a s u i t a b l e
spectrophotometer, using chloroform as the blank. Ramipril, page 3039 of PF 27(5) [Sept.-Oct. 2001]. Based on
comments received, it is proposed to use a preparation of a Refer-
Calculate the quantity, in mg, of pyridostigmine bromide ence Standard in the test for Related compounds rather than a dilu-
tion of the Test solution to quantitate the related compounds. It is
(C9H13BrN2O2) in the portion of Oral Solution taken by also proposed to use additional related compounds to provide a
more suitable means for identification of the specified impurities
the formula: than the relative retention times previously proposed. In addition,
the requirement for relative standard deviation of replicate injec-
tions is revised to a more appropriate limit of 5.0%.

in which C is the concentration, in mg per mL, of USP Pyr-
idostigmine Bromide RS in the Standard preparation; and
Add the following:
Ay and 4s are the absorbances of the solutions obtained from A
Ramipril
the Assay preparation and the Standard preparation, re-
spectively. AUSP26
(Official June 1,2005) C23H32N2O5 116.52 416.51
Cyclopenta[Z?]pyrrole-2-carboxylic acid, l-[2-[[l-(ethoxy-
carbonyl)-3-phenylpropyl]amino]-l-oxopropyl]octa-
hydro-, [2S-[l[#*(i?*)],2oc,3a/?,6a/?]]-.
(2S,3aS,6a5>l-[(S>A4(S)-l-Carboxy-3-phenylpropyl]ala-
nyl]octahydrocyclopenta[&]pyrrole-2-carboxylic acid,
BRIEFING
1-ethyl ester [87333-19-5]
Pyridostigmine Bromide Syrup, USP 25 page 1494. It is pro-
posed to change the title of this monograph to Pyridostigmine Bro-
mide Oral Solution. See also briefing under Amantadine
Hydrochloride Syrup. » Ramipril contains not less than 98.0 percent and
(NL: C. Barnstein; PA3: S. Salado) RTS—35987-1 not more than 101.0 percent of C23H32N2O5, cal-
culated on the dried basis.
Pharmacopeial Forum
USP Reference standards (11)—USP Ramipril RS. USP 247.6 nm, with a suitable atomic absorption spec-
Ramipril Related Compound A RS. USP Ramipril Related trophotometer (see Spectrophotometry and Light-
Compound B RS. USP Ramipril Related Compound C RS. Scattering (851)) equipped with a palladium hollow-
USP Ramipril Related Compound D RS. cathode lamp, using a 10-uL injection of Blank solution
Identification, Infrared Absorption (197K). as the blank. Plot the absorbances of the Standard
Melting range (741): between 105° and 112°. solutions versus concentration, in ug per mL, of
palladium, and draw the straight line best fitting the three
Specific rotation (781S): between +32.0° and +38.0°,
plotted points. From the graph so obtained, determine the
determined at 20°.
concentration, CP, in ug per mL, of palladium in the Test
Test solution: 10 mg per mL, in 0.1 M methanolic
solution. Calculate the percentage of palladium in the
hydrochloric acid.
portion of Ramipril taken by the formula:
Loss on drying (731)—Dry it in vacuum at a pressure not
exceeding 5 mm of mercury at 60° for 6 hours: it loses not 0ACp/CR,
more than &S% 0.2% of its weight. in which CR is the concentration, in mg per mL, of Ramipril
Residue on ignition (281): not more than 0.1%. taken to prepare the Test solution. The limit is 0.002%.
Heavy metals, Method II (33i):0.002%. Related compounds—
Limit of palladium— Solution A—Dissolve 2.0 g of sodium perchlorate in a
Diluent—Prepare a mixture of water and nitric acid mixture of 800 mL of water; aootonitriloj and 0.5 mL of
(997:3). triethylamine (160: 40:0.1), adjust with phosphoric acid to
Standard stock solution—Transfer about 50 mg of a pH of about 3r& 3.6 ± 0.1, add 200 mL of acetonitrile, and
palladium metal, accurately weighed, to a 100-mL mix.
volumetric flask, dissolve in 9 mL of hydrochloric acid, Solution B—Dissolve 2.0 g of sodium perchlorate in a
and dilute with water to volume. mixture of aoetonitrilo, 300 mL of water and 0.5 mL of
Standard solutions—Dilute the Standard stock solution triethylamine (140: 60:0.1), adjust with phosphoric acid to
quantitatively, and stepwise if necessary, with Diluent to a pH of about £r& 2.6 ± 0.1, add 700 mL of acetonitrile, and
obtain solutions containing 0.02, 0.03, and 0.05 ug of mix.
palladium per mL. Mobile phase—Use variable filtered and degassed
Test solution—Transfer about 200 mg of Ramipril, mixtures of Solution A and Solution B as directed for
accurately weighed, to a 100-mL volumetric flask, and Chromatographic system. Make adjustments if necessary
dissolve in and dilute with Diluent to volume. (see System Suitability under Chromatography (621)).
Blank solution—Transfer about 150 mg of magnesium Test solution—Transfer about 25 mg of Ramipril,
nitrate to a 100-mL volumetric flask, and dissolve in and accurately weighed, to a 25-mL volumetric flask, dissolve
dilute with Diluent to volume. in and dilute with Solution A to volume, and mix.
Procedure—Concomitantly determine the absorbances of [NOTE—Keep the Test solution cold until injected.]
equal volumes of the Standard solutions and the Test
solution (about 20 uL), at the palladium emission line at
Pharmacopeial Forum
Resolution solution—Tranofor 5.0 mg of USP Ramipril [NOTE—Make adjustments at the 75:25 ratio stage, if nec-
Rolatod Compound A RS, aoouratoly weighed, to a 10-mL essary, to achieve elution of ramipril between 16 and 19
volumotrio flask, add 5.0 mL of tho Teat solution, dilute with minutes after injection of the Rcfcivncc Standard solution.]
Solution A B to volume, and mix. Dissolve a quantity of Chromatograph the Resolution solution, and record the peak
USP Ramipril RS, USP Ramipril Related Compound A responses as directed for Procedure: the resolution, R, be-
RS, USP Ramipril Related Compound B RS, USP tween ramipril related compound A and ramipril is not less
Ramipril Related Compound C RS, and USP Ramipril than 3.0. Similarly chromatograph the Test solution, and re-
Related Compound D RS in Solution B to obtain a cord the peak responses as directed for Procedure: the reten-
solution with a concentration of about 0.5 mg of each per tion time for ramipril is between 16 and 19 minutes; and the
mL. tailing factor for the ramipril peak is between 0.8 and 2.0.
Reference Standard solution—Tranofor about 5.0 mL of Chromatograph the Reference Standard solution, and record
tho Test solution to a100 mL volumotrio flask, dilute with the peak responses as directed for Procedure: the relative
Solution A B to volume, and mix. Transfer 5.0 mL of thia standard deviation for replicate injections is not more than
solution to a 50 mL volumotrio flask; dilute with Solution 3rO% 5.0% . [NOTE—The relative retention times are QM
A B to volume, and mix. Dissolve an accurately weighed about 0.8 for ramipril related compound A, 1.0 for ramipril,
quantity of USP Ramipril RS in Solution B, and dilute ±r2& 1.3 for ramipril iaopropyl ostor, related compound
quantitatively, and stepwise if necessary, with Solution B B,L50 1.5 for hoxahydroramipril ramipril related com-
to obtain a solution having a known concentration of pound C, and 4-TST1 1.6 for ramipril dikotopiporazino related
about 0.005 mg per mL. compound D.]
Chromatographic system (see Chromatography (621))— Procedure—Separately inject equal volumes (about 10
The liquid chromatograph is equipped with a 210-nm uL) of the Test solution and the Reference Standard
detector and a 4.0-mm x 25-cm column that contains 3- solution into the chromatograph, record the
um packing LI, and is maintained at a temperature of 65°. chromatograms, and measure the peak response for
The flow rate is about 1 mL per minute. The chromatograph ramipril obtained from the Reference Standard solution
is programmed as follows. and the responses of all the peaks, other than the ramipril
peak, obtained from the Test solution. Calculate the
percentage of each related compound and unknown
impurity in the portion of Ramipril taken by the formula:
0-4 0-6 90 10 isocratic
M6-7 90->75 10-»25 linear gradient
S-24-7-20 75-^65 25->35 linear gradient
2A-Z± 20-30 65->25 35-^75 linear gradient
34-40 30-40 25 75 isocratic
40^5 25->90 75->10 linear gradient in which F is the relative response factor for the named re-
45-55 90 10 isocratic lated compound, which is 1.0 for ramipril rolatod oompound
A, 1.1 for ramipril isopropyl ootor^ 2.4 for hexahydrorami
Pharmacopeial Forum
j » i ramipril related compound C, 1 2 for ramipril dikctopi The test for Microbial limits is being revised to include names of
the microorganisms whose absence is required. The test for Anti-
porozkiOj and 1.0 for all other individual impurities; Cs is the microbial preservatives—effectiveness is being renamed to reflect a
recent change in the name of the chapter cross-referenced in this
concentration, in mg per mL, of USP Ramipril B RS in the test.
Standard solution; CTis the concentration, in mg per mL, of (PA4: A. Medjedovic; AMB: D. Porter) RTS—34795-2;
34843-1
ramipril in the Test solution; r, is the peak response for each
individual peak obtained from the Test solution; and rs is the
ramipril peak response obtained from the Reference Stan- Change to read:
USP Reference standards {11)—USP Ranitidine Hydrochloride
dard solution: not more than 0.5% of ramipril related com-
RS. USP Ranitidine Related Compound A RS.
A
pound A, ramipril related compound B, ramipril related AJJSP26
USP Ranitidine Related Compound C RS.
compound C, or ramipril related compound D is found;
Change to read:
not moro than 0:5% of ramipril iaopropyl oster ia found; Identification—
•M—The Rj. valuo of the principal opot oboorvod in the
not more than 0.5% of hcxahydroramipril io found; not more ohromatogram of tho Teat preparation obtained aa directed in tho
Chromatographic purity toot corresponds to that obtained from tho
than 0:5% of ramipril dikctopiporaBinc io found; not more Standard preparation.
than 0.1% of any other individual impurity is found; and
AUSP26
not more than 1.0% of total impurities is found. The retention time of the major peak in the chromatogram of the
Assay preparation corresponds to that in the chromatogram of the
Assay—Dissolve about 300 mg of Ramipril, accurately Standard preparation, as obtained in the Assay.
weighed, in 25 mL of methanol, add 25 mL of water, and Change to read:

Antimicrobial preservatives effectiveness
titrate with 0.1 N sodium hydroxide VS, determining the
Effectiveness testingAC/5K(S
e n d p o i n t p o t e n t i o m e t r i c a l l y . Perform a b l a n k (51): meets the requirements.
determination, and make any necessary correction (see Change to read:

Microbial limits (61)—Whento3todao directed for tho absence of
Titrimetry (541)). Each mL of 0.1 N sodium hydroxide is indicator organisms, tho total
A
equivalent to 41.65 mg of C23H32N2 It meets the requirements of the tests for absence of Salmo-
nella species and Escherichia coli; and the total

aerobicAUSp26
microbial count does not exceed 100 organisms per mL.
Change to read:
•Teat preparation—NOTE—Apply a quantity of extractives from
Oral Solution to tho ohromatographio plate so as to achieve a
nominal loading of 200 ug of ranitidino. Tranafor a woighod
BRIEFING quantity of Oral Solution, equivalent to 10 mg of ranitidino, t o a
suitable syringe. Attach tho tip of tho syringo tothe top of a
Ranitidine Oral Solution, USP 25 page 1511. It is proposed to oartridgo (11 mm H 12 mm) of volumo 0.5 mL containing 0.1 g
replace the thin-layer chromatographic procedure in the test for of an LI packing for high prosauro liquid ohromatography that has
Chromatographic purity and the liquid chromatographic procedure boon previously prepared by passage of 10 mL of methanol
in the Assay with a single liquid chromatographic method. This sta- followed by passage of 20 mL of 0.5 M ammonia solution. Add
bility-indicating liquid chromatographic procedure is based on 2.0 mL of 0.5 M ammonia solution to tho syringo and foroo tho
analyses performed with the Partisil 10 SCX brand of L9 column. mixture slowly through tho cartridge. Repeat with 2 further 3
The typical retention time for ranitidine is about 8 minutes. In ad- mL portions of 0i5 M ammonia solution. Discard all tho liquid
dition, the revision in the test for Chromatographic purity necessi- that has traversed tho oartridgo. Pa30 5 mL of a mixture of 0.1 M
tates the deletion of Identification test A and editorial changes in hydroohlorio aoid and methanol (3:1) through tho oartridgo, and
the USP Reference standards section. oolloot tho cluant in a oloan round bottom, 25 mL flaak. Ropoat
this with another 5 mL portion of tho samo oluting mixture and
oolloot tho oluant in tho same flask. Evaporato the oontonta of tho
flask to drynoss at a tomporaturo not oxoooding 30°. Rodissolvo tho
residue in 1.0 mL of a mixture of mothanol and water (50:50):
Pharmacopeial Forum
Standard preparation—Disoolve USP Ranitidino Hydroohlorido in which C is the concentration, in mg per rnL, of ranitidine
RS in a mixturo of mothanol and wator (50:50) to obtain a solution
having a known oonoontration of 448 ug (equivalent to 400 ug of in the Standard solution; r, is the peak response for each im-
ranitidino) per mL. Dilute portions of this Standard preparation
quantitatively with tho mixturo of mothanol and wator (50:50) to purity obtained from the Test solution; and rs is the raniti-
obtain solutions having oonoontrations of 224 ug por mL
{Diluted standard preparation A), 112 ug por mL {Diluted dine peak response obtained from the Standard solution:
standard preparation B), 56 ;xg por mL {Diluted standard
preparation Q , 22 ug por mL {Diluted standard preparation D), no single peak of more than 2.0% is found; not more than
and 11 ug por mL {Diluted standard preparation E), respectively.
Resolution preparation—Dissolve USP Ranitidino Related 1.0% of any other individual impurity is found; and not
Compound A RS, 5 [[(2 aminocthyl)thio]methyl] N,N dimethyl
2 furanmothanamino, homifumarato salt, in mothanol to obtain a more than 5.0% of total impurities is found.AUSP26
solution having a known oonoontration of 1.27 mg por mL.
Procedure—Apply soparatoly 10 uL of tho Standard
preparation, tho Diluted standard preparations {A, B, C, D, and Change to read:
E) and 20 uL (superposition of 2 x 10 [xL) of tho Test Assay—NOTE'—Whore peak responses are indicated, use peak
preparation to a suitable thin layer ohromatographio plato (300
Ch ro m atograp hy—(6£4-)) ooatod with a 0.25 mm layer of Mobile phase,Standard preparation^ Systom suitability solution^
ohromatographio ailioa gel mixturo. In addition, apply soparatoly and Chromatographio system—Prepare as directed in tho Assay
a further loading of 10 uL of tho Test preparation to tho same under Ranitidinc Hydrochloridc, tho ohromatographio column
plato, and on top of this application, apply 10 uL of the being fitted with a suitable pro column also containing packing LI.
Resolution preparation: Perform the ohromatography as Assay preparation—Diluto an aoourately measured quantity of
described in Chromatographic purity under Ranitidinc Oral Solution, quantitatively, and atopwiso if nooossary, with
Hydrochloridc. Examine tho plato and compare the intensities of Mobile phase to obtain a aolution having a oonoontration of 0.1
any scoondary spots observed in tho ohromatogram of tho Test mg of ranitidino por mL.
preparation with those of tho prinoipal spots in tho
ohromatogramg of tho Standard preparation and Diluted Procedure—Separately injoot an equal quantity (about 10 uL) of
standard preparations {A, B, C, D, and E): tho systom suitability tho Standard preparation and tho Assay preparation into tho
requirements are mot when thoro is complete resolution botwoon ohromatograph; rooord the ohromatograms, and measure tho
the primary spots of tho Test preparation and the Resolution responses for the major peaks. Calculate tho quantity', in mg, of
preparation and if a spot is observed in tho ohromatogram of €^HggN4Q^S in tho portion of Oral Solution taken by tho formula:
Diluted standard preparation E. Tho major secondary spot is not
groator in sizo or intensity than tho prinoipal spot produced by tho
Standard preparation (2.0%), and no other secondary spot is in whioh 31 <\AQ and 350.86 are the moleoular weights of ranitidino
groator in sizo or intensity than the prinoipal spot produced by and ranitidino hydroohlorido respectively, L is the labeled quantity
Diluted standard preparation A (1.0%). The sum of the of ranitidino in tho Oral Solution takon, D is tho oonoontration, in
intonaitioa of all oooondary spots obtained from tho Test mg por mL, of ranitidino in tho Assay preparation, on the basis of
preparation oorrosponda to not more than 5.0%. NOTE—Spots the labeled quantity and tho extent of dilution, C is tho oonocntra
established as arising from other oompononts in tho formulation tion, in mg por mL, of USP Ranitidino Hydroohlorido RS in tho
are to bo ignored. Standard preparation, and r^ and r^ are tho peak responses ob
tainod from tho Assay preparation and the Standard preparation,
^Diluent, Mobile phase, Standard stock preparation, respectively.
Resolution solution, and Chromatographic system— ^Diluent—Prepare a filtered and degassed mixture of
Proceed as directed in the Assay. methanol and water (7:3).
Standard solution—Prepare as directed for Standard Mobile phase—Dissolve 5.0 g of monobasic potassium
preparation. phosphate in 1000 mL of a mixture of water and methanol
Test solution—Prepare as directed for Assay preparation. (3:2). Make adjustments if necessary (see System Suitability
Procedure—Separately inject equal volumes (about 25 under Chromatography {621)).
JIL) of the Standard solution and the Test solution into the Standard stock preparation—Dissolve an accurately
chromatograph, record the chromatograms, and measure the weighed quantity of USP Ranitidine Hydrochloride RS in
responses for the major peaks. Calculate the percentage of Diluent to obtain a solution having a known concentration
each impurity in the portion of Oral Solution taken by the of about 1.2 mg of ranitidine per mL.
formula: Resolution solution—Dissolve an accurately weighed
quantity of USP Ranitidine Related Compound C RS in
Diluent to obtain a solution having a known concentration
Pharmacopeia! Forum
of about 0.1 mg per mL. Pipet 5.0 mL each of this solution in which C is the concentration, in mg per mL, of ranitidine
and the Standard stock preparation into a 50-mL volumetric in the Standard preparation; and rv and rs are the peak re-
flask, dilute with Diluent to volume, and mix. sponses obtained from the Assay preparation and the Stan-
Standard preparation—Quantitatively dilute a volume of dard preparation, respectively.AUSP26
the Standard stock preparation in Diluent to obtain a
solution having a concentration of about 0.12 mg of
ranitidine per mL.
ranitidine, to a 50-mL volumetric flask, dilute with
BRIEFING
Diluent to volume, and mix. Pipet 4.0 mL of this solution
Reserpine Elixir, USP 25 page 1518. It is proposed to change
into a second 50-mL volumetric flask, dilute with Diluent the title of this monograph to Reserpine Oral Solution. See also
to volume, and mix.
(NL: C. Barnstein; PA5: J. Esker) RTS—35988-1
detector and a 4.6-mm x 25-cm column that contains Reserpine Elixir
packing L9. The flow rate is about 1.5 mL per minute. {Current title—not to change until June 1, 2005)
Chromatograph the Resolution solution, and record the 2005
{see Official Title Changes on the first page of In-Pro-
peak responses as directed for Procedure: the relative cess Revision):
See Reserpine Oral Solution
retention times are about 1.0 for ranitidine and 1.3 for
ranitidine related compound C; and the resolution, R, is
not less than 2.0. Chromatograph the Standard
Procedure: the tailing factor is not more than 2.0; the
BRIEFING
and the relative standard deviation for replicate injections
Reserpine Oral Solution—See briefing under Amantadine Hy-
is not more than 2.0%. drochloride Syrup.
(NL: C. Barnstein; PA5: J. Esker) RTS—35988-1
preparation into the chromatograph, record the chro-
Add the following:
matograms, and measure the responses for the major A
Reserpine Oral Solution
peaks. Calculate the quantity, in mg, of ranitidine
(C13H22N4O3S) in the portion of Oral Solution taken by June 1, 2005)
{Current monograph title is Reserpine Elixir)
the formula:
©2002 The United States Pharmacopeial Convention, Inc. AH Rights Reserved.

Pharmacopeial Forum
» Reserpine Oral Solution contains not less than in which Fis the volume, in mL, of Oral Solution taken; and
90.0 percent and not more than 110.0 percent of the parenthetic expressions are the differences in absor-
bances of the nitrite-treated and blank solutions, respec-
the labeled amount of reserpine (C33H40N2O9).
tively, from the Assay preparation (U) and the Standard
Packaging and storage—Preserve in tight, light-resistant preparation (S).AUSP26
containers. (Official June 1,2005)
USP Reference standards (11)—USP Reserpine RS.

Identification—Evaporate about 2 mL of the chloroform-
methanol solution obtained from the Assay preparation as
directed for Procedure in the Assay, in a test tube to
dryness, add to the residue 0.5 mL of glacial acetic acid,
BRIEFING
swirl for 1 to 2 minutes, and add 1 mL of a 1 in 50
solution of vanillin in hydrochloric acid: a pink color is Rifampin Oral Suspension, USP 25 page 1533 and page 3327
of PF 27(6) [Nov.-Dec. 2001]—See briefing under Cefazolin
produced, and it becomes deep violet-red within a few Ophthalmic Solution.
minutes or as a result of warming the solution for 10 to (CRX: C. Okeke) RTS—35463-2

20 seconds.
Alcohol content (611): between 11.0% and 13.0% of Change to read:
C2H5OH. » Rifampin Oral Suspension contains not less than
Assay— 90.0 percent and not more than 110.0 percent of the
labeled amount of rifampin (C^tLJÔ^). Use Rifam-
Standard preparation—Prepare as directed in the Assay pin or the number of Rifampin Capsules that contain
the designated amount of Rifampin, and prepare Ri-
under Reserpine. fampin Oral Suspension as follows (see Pharmacy
Procedure—Transfer an accurately measured volume of Compounding ( 9 )
Oral Solution, equivalent to about 1 mg of reserpine, into ^Pharmaceutical Compounding—Nonsterile Pre-
a separator or a suitably stoppered, 50-mL centrifuge tube, parations (195)):AUSP26
add 5 mL of citric acid solution (1 in 50) and 10 mL of

chloroform, and shake for 2 minutes. Proceed as directed L2
Rifampin °g
in the second paragraph of the Procedure in the Assay Syrup, a sufficient quantity to make . . . 120 mL
under Reserpine, beginning with "Separate and withdraw
Transfer 1.20 g of Rifampin, or the contents of Ri-
the chloroform." Calculate the quantity, in mg, of fampin Capsules, into a mortar. [NOTE—If necessary,
gently crush the Capsule contents with a pestle to pro-
reserpine (C33H40N2O9) in each mL of the Oral Solution duce a fine powder.] Add about 2 mL of Syrup to the
mortar, and triturate until a smooth paste is formed.
Add about 10 mL of Syrup, and triturate to form a sus-
pension. Continue to add Syrup, until about 80 mL has
been added. Transfer this suspension to a 120-mL pre-
calibrated light-resistant glass or plastic prescription
bottle. Rinse the mortar and pestle with successive
Pharmacopeial Forum
small portions of Syrup, and add the rinses to the bot- » Secobarbital Oral Solution contains, in each 100
tle. Shake vigorously. If necessary, add Citric Acid or
Sodium Citrate to adjust to a pH of 5.0. Add a suitable mL, not less than 417 mg and not more than 461
flavor if desired. Add sufficient Syrup to make the pro-
duct measure 120 mL, and shake vigorously to pro- mg of secobarbital (C12H18N2O3), in a suitable, fla-
duce the Oral Suspension.
vored vehicle.

USP Reference standards (11)—USP Secobarbital RS.
Identification—Place 10 mL of Oral Solution in a separator
containing 20 mL of water, add 5 mL of 1 N sodium
BRIEFING
chloroform, discarding the chloroform extracts. Add 5 mL
Secobarbital Elixir, USP 25 page 1559. It is proposed to
change the title of this monograph to Secobarbital Oral Solution. of 3 N hydrochloric acid, and extract with two 25-mL
portions of chloroform, filtering the extracts through paper
into a beaker. Remove the chloroform by evaporation on a
steam bath, and dry the residue at 105° for 2 hours: the
Secobarbital Elixir residue so obtained meets the requirements of the
{Current title—not to change until June 1, 2005) Identification test under Secobarbital.
2005 Alcohol content (611): between 10.0% and 14.0% of
see Official Title Changes on the first page of In-Process
Revision): C2H5OH.
See Secobarbital Oral Solution
Assay—
Internal standard—Butabarbital.
weighed quantity of Butabarbital in chloroform, and
BRIEFING having a known concentration of about 0.7 mg per mL.
Secobarbital Oral Solution—See briefing under Amantadine Standard preparation—Dissolve accurately weighed
quantities of USP Secobarbital RS and Butabarbital in
(NL: C. Barnstein; PA3: S. Salado) RTS—35989-1 chloroform, and quantitatively dilute with chloroform to
obtain a solution that contains, in each mL, known
Add the following: amounts of about 1.2 mg of USP Secobarbital RS and
A
Secobarbital Oral Solution about 0.9 mg of Butabarbital.
(Monograph under this new title—to become official Assay preparation—Transfer an accurately measured
June 1, 2005)
(Current monograph title is Secobarbital Elixir) volume of Oral Solution, equivalent to about 22 mg of
secobarbital, to a separator, add 1 mL of dilute
hydrochloric acid (1 in 5), and extract with four 10-mL
Pharmacopeial Forum
portions of chloroform. Filter the extracts through about 15 Add the following:
g of anhydrous sodium sulfate that is supported on a funnel A
Senna Oral Solution
by a small pledget of glass wool. Collect the combined (Monograph under this new title—to become official
June 1, 2005)
filtrate in a 50-mL volumetric flask, wash the sodium (Current monograph title is Senna Syrup)
sulfate with 5 mL of chloroform, dilute with chloroform
to volume, and mix. Combine 4.0 mL of this solution
» Prepare Senna Oral Solution as follows:
with 2.0 mL of Internal standard solution in a suitable
container, and reduce the volume to about 1.5 mL by Senna Fluidextract 250 mL
Suitable essential oil(s)
evaporation, with the aid of a stream of dry nitrogen, at Sucrose 635 g
room temperature. Purified Water, a sufficient quantity,
to make 1000 mL
Chromatographic system and System suitability—Proceed
as directed for Chromatographic System and System Mix the oil(s) with the Senna Fluidextract, and
Suitability under Barbiturate Assay (361), the resolution, gradually add 330 mL of Purified Water. Allow
R, between secobarbital and butabarbital being not less the mixture to stand for 24 hours in a cool place,
than 3.0. [NOTE—Relative retention times are, with occasional agitation, then filter, and pass en-
approximately, 0.6 for butabarbital and 1.0 for secobarbital.]
ough Purified Water through the filter to obtain
Procedure—Proceed as directed for Procedure under
580 mL of filtrate. Dissolve the Sucrose in this li-
Barbiturate Assay (361). Calculate the quantity, in mg, of
quid, and add sufficient Purified Water to make
secobarbital (C 1 2 H 1 8 N 2 O 3 ) in each mL of the Oral
Solution taken by the the formula:
the product measure 1000 mL. Mix, and strain.

temperature not exceeding 25°.
the other terms are as defined therein. A.VSP26
(Official June 1,2005) 110.0% of the labeled amount of C2H5OH.AUSWtf
BRIEFING
BRIEFING
Senna Oral Solution—See briefing under Amantadine Hydro-
chloride Syrup, Senna Syrup, USP 25 page 1566. It is proposed to change the
title of this monograph to Senna Oral Solution. See also briefing
(NL: C. Barnstein) RTS—35990-1 under Amantadine Hydrochloride Syrup.
Pharmacopeial Forum
Senna Syrup Change to read:

Monograph title change—to become official June 1, » Sodium Hypochlorite Topical Solution contains not
2005 less than 0.20 g and not more than 0.32 g of Sodium
(see Official Title Changes on the first page of In-Pro- Hypochlorite (NaCIO) in 1000 mL of Topical Solu-
cess Revision):
See Senna Oral Solution tion. Prepare Sodium Hypochlorite Topical Solution
as follows (see Pharmacy Compounding ( )
^Pharmaceutical Compounding—Nonsterile
Preparations (795)): AUSP26
Sodium Hypochlorite Solution 5.0 mL

Monobasic Sodium Phosphate mono- 1.02 g
BRIEFING hydrate
Dibasic Sodium Phosphate anhydrous. 17.61 g
Simethicone, USP 25 page 1569. A statement is being added to Purified Water, a sufficient 1000 mL
clearly indicate that the Standard preparation, which contains USP
Polydimethylsiloxane RS, is used in the test fox Identification. This quantity to make
statement clarifies that the use of USP Polydimethylsiloxane RS—
not USP Simethicone RS—is intended. Dissolve the Dibasic Sodium Phosphate anhydrous
and the Monobasic Sodium Phosphate monohydrate in
(PA4: A. Medjedovic) RTS—35159-1 about 500 mL of Purified Water. Add the Sodium Hy-
pochlorite Solution and sufficient Purified Water to
make the product measure 1000 mL, and mix to pro-
duce the Topical Solution.
Change to read: [NOTE—The source of the Sodium Hypochlorite
Identification, Infrared Absorption {197S)— Solution may be commercial unscented laundry bleach
Solution: prepared ao dirootod in tho Assay.
(nominally 5.25% w/v) provided that the commercial
^Test solution—Prepare as directed for Assay preparation laundry bleach was recently acquired.]
in the Assay.
Standard solution—Prepare as directed for Standard
preparation in the Assay. AUSP2S
Cell size: 0.5 mm.
BRIEFING
Sodium Sulfide Topical Gel, USP 25 page 1594. The lead per-
chlorate titrant under Assay is modified to conform with the addi-
tion of 0.01 M lead perchlorate VS, appearing elsewhere in this PF.
(PA7: B. Gilbert) RTS—35840-1

BRIEFING
Sodium Hypochlorite Topical Solution, USP 25 page 1585

and page 3329 of PF 27(6) [Nov.-Dec. 2001]—See briefing under
Cefazolin Ophthalmic Solution. Change to read:
Assay—
(CRX: C. Okeke) RTS—35643-4 Diluent—Transfer 500.0 mL of a 4.0 M sodium hydroxide
solution to a 1000-mL volumetric flask, and add about 67.0 g of
edetate disodium and 36.0 g of ascorbic acid, each accurately
weighed. Dilute with water to volume, and mix.
Pharmacopeial Forum
Assay preparation—Transfer an accurately weighed portion of Change to read:

the Topical Gel, equivalent to about 30 mg of sodium sulfide, to a
100-mL volumetric flask, add 50 mL of Diluent, and shake by
mechanical means until the Topical Gel is dispersed. Dilute with » Sucralfate is the hydrous basic aluminum salt of su-
Diluent to volume, and mix. crose octasulfate. It contains
Procedure—Transfer 30.0 mL of the Assay preparation to a A
suitable beaker, and titrate with 0.01 M lead perchlorate aolution the equivalent ofAKSWtf
v
not less than tho equivalent of
ÂUSP26
A
, determining the endpoint potentiometncally. Perform a blank de- A.USP26
termination, and make any necessary correction. Each mL of 0.01 30.0 percent and not more than tho equivalent of
M lead perchlorate is equivalent to 2.4018 mg of sodium sulfide
•
(Na2S • 9H2O). AUSP26
38.0 percent of sucrose octasulfate (C12H14O35S8).
Change to read:
Identification—
A: The ohromatogram of tho Assay preparation oxhibita a
poak for auoroao ootaaulfato, tho retention time of whioh
oorroopondo to that oxhibitod by tho Standard preparation ao
obtained in tho Assay:
A
BRIEFING
The retention time of the sucrose octasulfate peak in the
chromatogram of the Assay preparation corresponds to that
Stanozolol Tablets, USP 25 page 1600, and page 3331 of PF
27(6) [Nov.-Dec. 2001]. in the chromatogram of the Standard preparation, as ob-
(BPC: M. Marques) RTS—36187-1 tained in the Assay.. VSP26
B: Add 0.1 N hydrochloric acid to a few g of Sucralfate, boil,
and neutralize with 0.1 N sodium hydroxide. Add alkaline cupric
tartrate TS. Boil a small amount of this solution: a red precipitate of
Errata: cuprous oxide is produced.
Definition, line 3: After "labeled amount of" Add: stanozolol C: A solution in 3 N hydrochloric acid meets the requirements
Dissolution test, Medium: Change 0.01 N to 0.1 N of the tests for Aluminum (191).
Change to read:
Acid-neutralization equivalent
A
Acid-neutralizing capacityAC/iyW(5
—Transfer about 250 mg, accurately weighed, to a 250-mL screw-
capped bottle, add 100.0 mL of 0.1 N hydrochloric acid, previously
heated to 37°, cap the bottle, and rotate it at 30 rpm
A
place itAl/SP26
in a 37 water bath,
A
BRIEFING and stir the contents continuouslyAas.P2(j
for 1 hour. Cool to room temperature, and transfer 20.0 mL to a
Sucralfate, USP 25 page 1605; Sucralfate Tablets, USP 25 100-mL beaker. Add 30 mL of water, and titrate with with 0.1 N
page 1607. The procedure in the test for Acid neutralization sodium hydroxide VS to a pH of 3.5. Perform a blank titration on a
equivalent, which employs equipment that provides rotation at mixtue of water and 0.1 N hydrochloric acid (30:20.0). Calculate
30 rpm, is being revised, because it is not critical to stir the sample the mEq of acid consumed per g of Sucralfate taken by the formula:
at a particular rotation speed. It is sufficient to continuously stir the 5N(VB - VT)/W,
sample, by any appropriate means, while the water bath is main-
tained at 37° for 1 hour. If the contents are not stirred continuously, where Nis the exact normality of the sodium hydroxide VS; VB and
a gum-like substance might form on the bottom of the bottle con- Fj-are the volumes, in mL, of sodium hydroxide VS consumed by
taining the sample, which would result in lower values being ob- the blank and the test solution, respectively; and W\s the weight, in
served. This revision also affects the test for Acid neutralization g, of Sucralfate taken: not less than 12 mEq of acid is consumed.
equivalent under Sucralfate Tablets, which cross-references the
test for Acid neutralization equivalent under Sucralfate. Change to read:
The molecular weights in the Assay are being changed to reflect Chloride (221)—Transfer 500 mg to a 100-mL volumetric flask,
the current atomic weight values published in USP 25. Other add 30 mL of 2 N nitric acid, dilute with water to volume, and mix.
changes are intended to conform the text to the current USP style. Transfer 10.0 mL of this solution to a 50-mL color comparison
tube, add 3 mL of 2 N nitric acid and 2 mL of silver nitrate TS,
(PA4: A. Medjedovic) RTS—35127-1 dilute with water to 50 mL, and mix. Allow to stand, protected
Pharmacopeial Forum
from direct sunlight, for 5 minutes. The sample shows no more tur- Change to read:
bidity than that produced in a solution containing 0.35 mL of 0.020 Related compounds
N hydrochloric acid: (0.50%).
A
A Limit of sucrose heptasulfate.^p^—
not more than 0.50% of chloride is found.Af/5/>2($ Mobile phase—Dissolve 99.1 g oiammonium sulfate in 900 mL
of water, dilute with water to 1000 mL, and mix. Adjust with
phosphoric acid to a pH of 3.5 ± 0 . 1 , filter, and degas. Make
Change to read: adjustments if necessary (see System Suitability under
Limit of pyridine and 2-methylpyridine— Chromatography (621).
Internal standard solution—Transfer 1.0 mL of 3- Standard solution—Prepare as directed for the Standard
methylpyridine to a 50-mL volumetric flask, dilute with preparation in the Assay.
chloroform to volume, and mix. Transfer 1.0 mL of this solution Chromatographic system—Prepare as directed in the Assay.
to a 50-mL volumetric flask, dilute with chloroform to volume, and Test solution—Prepare as directed for Assay preparation in the
mix. Assay.
Standard stock solution—Transfer about 0.5 g each of 2- Procedure—Inject about 50 uL of the Test solution into the
methylpyridine and pyridine to a 50-mL volumetric flask, chromatograph, record the chromatograms, and measure the
dissolve in chloroform, dilute with chloroform to volume, and responses for the major peaks. The relative retention times are
mix. Quantitatively dilute 5.0 mL of this solution with about 0.6 for sucrose heptasulfate and 1.0 for sucrose
chloroform to 50.0 mL. Transfer 5.0 mL of this solution to a octasulfate. The ratio of the peak response of the sucrose
50.0 mL volumetric flask, dilute with chloroform to volume, and heptasulfate peak to that of the sucrose octasulfate peak is not
mix. more than 0.1.
Standard solution—Transfer 5.0 mL of Standard stock solution
to a 20-mL volumetric flask, add 1.0 mL of the Internal standard Change to read:
solution, dilute with chloroform to volume, and mix. Assay—
Test solution—Sonicate about 1 g of Sucralfate, accurately Mobile phase—Dissolve 132 g of ammonium sulfate in 900 mL
weighed, in 10.0 mL of 1 M sodium hydroxide until a uniformly of water, dilute with water to 1000 mL, and mix. Adjust with
cloudy mixture is obtained. Extract this solution with three 5-mL phosphoric acid to a pH of 3.5 + 0.1, filter, and degas. Make
portions of chloroform, and collect the chloroform extracts in a 20- adjustments if necessary (see System Suitability under
mL volumetric flask. Add 1.0 mL of the Internal standard solution, Chromatography (621)).
dilute with chloroform to volume, and mix. Standard preparation—Dissolve an accurately weighed quantity
Chromatographic system (see Chromatography (621))—The of USP Potassium Sucrose Octasulfate RS in Mobile phase, and
gas chromatograph is equipped with a flame-ionization detector, dilute quantitatively, and stepwise if necessary, with Mobile
a split injection system, and a 0.53-mm x 10-m capillary phase to obtain a solution having a known concentration of
column coated with a 2.65-um layer of phase G27. Helium is about 10 mg of anhydrous potassium sucrose octasulfate (as
used as the carrier gas, at a pressure of 36-mm of mercury. The determined from the concentration of USP Potassium Sucrose
column temperature is maintained at 50°. The injection port Octasulfate RS corrected for water content by a titrimetric water
temperature and the detector temperature are maintained at 150° determination) per mL.
and 200°, respectively. Chromatograph the Standard solution, Assay preparation—Transfer about 450 mg of Sucralfate,
and record the peak responses as directed for Procedure: accurately weighed, to a 35-mL centrifuge tube, and shake at a
A
the relative retention times of pyridine, 2-methylpyridine, moderate rate on a vortex mixer. While shaking add 10.0 mL of
a mixture of 4.0 N sulfuric acid and 2.2 N sodium hydroxide
(1:1). Sonicate with swirling for 5 minutes, keeping the
and 3-methylpyridine are about 0.42, 0.72, and 1.0, respec- temperature of the mixture below 30°. Without delay transfer the
tube to a vortex mixer and while shaking at moderate rate, add an
tively;^*™ accurately measured volume, V, in mL, of 0.1 N sodium hydroxide
the resolution, R, between pyridine and 2-methylpyridine is not to bring the pH of the solution to approximately 2, and dilute the
less than 3.5; the resolution, R, between 2-methylpyridine and 3- solution with (15.0 - V) mL of water. Shake for 1 minute, and
methylpyridine is not less than 2.5; and the relative standard devia- centrifuge for 5 minutes. Separate the clear supernatant layer,
tion for replicate injections is not more than 2.0%. and allow it to stand at room temperature until the pH stabilizes.
Procedure—Separately inject equal volumes (about 1 uL) of the If the pH is not between 2.3 and 3.5, repeat the test using a different
Standard solution and the Test solution into the chromatograph, volume of 0.1 N sodium hydroxide. Use the clear supernatant
record the chromatograms, and measure the peak responses. ¥ke layer.
relative rotontion timog of pyridinc, 2 mothylpyridino, and 3 Chromatographic system (see Chromatography (621))—The
mothylpyridine aro about 0.12, 0.72, and 1.0, roapootivoly. liquid chromatograph is equipped with a refractive index
• detector and a 3.9-mm x 30-cm column that contains packing
1USP26 L8. The detector and column temperatures are maintained at 30°.
Separately calculate the quantities, in ug, of pyridine and 2-methyl- The flow rate is about 1 mL per minute. Chromatograph the
pyridine, if present, in the portion of Sucralfate taken by the for- Standard preparation, and record the peak responses as directed
mula: for Procedure: the column efficiency determined from the
20C(Ru/Rs), sucrose octasulfate peak is not less than 400 theoretical plates;
in which C is the concentration, in ug per mL, of pyridine or 2- the tailing factor for the sucrose octasulfate peak is not more
methylpyridine in the Standard solution; and Rv and Rs are the than 4.0; and the relative standard deviation for replicate
peak response ratios of the analyte to the internal standard obtained injections is not more than 2.0%.
from the Test solution and the Standard solution, respectively: not
more than 0.05% each of pyridine and 2-methylpyridine is found.
Pharmacopeial Forum

the Standard preparation and the Assay preparation into the AUSP ; 6
chromatograph, record the chromatograms, and measure the than 20 Tablets. Transfer an accurately weighed portion of the
responses for the major peaks. Calculate the quantity, in mg, of powder, equivalent to about 250 mg of sucralfate, to a 250-mL
sucrose octasulfate (C 12 H 14 O 35 S 8 ) in the portion of Sucralfate screw-capped bottle, and proceed as directed in the test for Acid
taken by the formula: neutralization equivalent under Sucralfate, beginning with "add
100.0 mL of 0.1 N hydrochloric acid": not less than 12 mEq of
(971.73 / 1287.55 acid is consumed.
Change to read:
Assay—
A Mobile phase, Standard preparation, and Chromatographic
(974.75/1287.53)(25Q(>y system—Prepare as directed in the Assay under Sucralfate.
Assay preparation—Weigh and finely powder not less
in which 071.73 A
fewerAUSP26
A
974.75, than 20 Tablets. Transfer an accurately weighed portion of the
and powder, equivalent to about 450 mg of sucralfate, to a 35-mL cen-
trifuge tube, and shake at a moderate rate on a vortex mixer. Pro-
1287.53. USP26 ceed as directed for Assay preparation in the Assay under
are the molecular weights of sucrose octasulfate and anhydrous po- Sucralfate beginning with "While shaking, add 10.0 mL".
tassium sucrose octasulfate, respectively; C is the concentration, in Procedure—Proceed as directed for Procedure in the Assay
mg per mL, of anhydrous potassium sucrose octasulfate in the under Sucralfate. Calculate the quantity, in mg, of sucrose
Standard preparation; and rv and rs are the peak responses of su- octasulfate (Cj 2 Hj 4 0 35 Sg) in the portion of Tablets taken by the
crose octasulfate obtained from the Assay preparation and the formula:
Standard preparation, respectively.
(971.73 / 1287.55)(2
A
(974.75/1287.53)(25Q(r [/ /r 5 ), AOT , 2(5
in which the terms are as defined therein.
BRIEFING
Sucralfate Tablets, USP 25 page 1607. The formula in the As-

say is being corrected to correspond with that specified under Su-
cralfate. See also briefing under Sucralfate.

BRIEFING
Terazosin Hydrochloride, page 2202 of PF 27(2) [Mar.-Apr.

2001]. Because USP Reference Standards for terazosin related
Change to read: compounds B, C, and D, which were initially under consideration,
Identification— are no longer planned for development, it is proposed to rename
A: Tho ohromatogram of the Assay preparation exhibits a terazosin related compound E and terazosin related compound F
poak for auoro3o ootaaulfato, tho retention timo of whioh to terazosin related compound B and terazosin related compound
oorroapond9 to that exhibited by tho Standard preparation aa C, respectively. Accordingly, the name changes are being made
obtained in tho Assay. throughout this monograph and in the general tests chapter USP
A
Reference Standards (11), which appears elsewhere in this PF.
The retention time of the sucrose octasulfate peak in the
chromatogram of the Assay preparation corresponds to that (PA5: J. Esker) RTS—35643-1
in the chromatogram of the Standard preparation, as ob-

tained in the Assay. AUSP26
Add the following:
B: Shake a portion of finely powdered Tablets, equivalent to A
about 1 g of sucralfate, with 3 N hydrochloric acid, andfilter:the
Terazosin Hydrochloride
solution so obtained meets the requirements of Identification test C
under Sucralfate. (Chemical structure to come)
Change to read:
Acid neutralization equivalent C 19 H 2 5N 5 O4HC1-2H 2 O 159.93 459.92
A
Acid-neutralizing capacity. VSP26
—Weigh and finely powder not less
Pharmacopeial Forum
Piperazine, 1 -(4-amino-6,7-dimethoxy-2-quinazolinyl)-4- Residue on ignition (281): not more than 0.2%, determined
[(tetrahydro-2-fliranyl)carbonyl]-, monohydrochloride on a 1.0-g specimen.
dihydrate. Heavy metals, Method II (231): 0.002%.
l-(4-Ammo-6,7-dimethoxy-2-quinazolinyl)-4-(tetrahydro- Limit of tetrahydro-2-furancarboxylic acid—
2-furoyl)piperazine monohydrochloride dihydrate Blank solution—Transfer 2.0 mL of glacial acetic acid to a
[70024-40-7]. 100-mL volumetric flask, dilute with acetone to volume,
Anhydrous 423.89 [63074-08-8]. and mix. Mix 5.0 mL of this solution and 5.0 mL of
acetone, pass through a nylon membrane filter having a
» Terazosin Hydrochloride contains not less than 0.45-um or finer porosity, previously washed with
acetone, and discard the first 1 mL of the filtrate.
Internal standard solution—Transfer about 100 mg of
C19H25N5O4 • HC1, calculated on the dried basis.
capric acid, accurately weighed, to a 100-mL volumetric
Packaging and storage—Preserve in well-closed flask, dissolve in and dilute with acetone to volume, and
containers. mix. Transfer 10.0 mL of this solution and 2.0 mL of
USP Reference standards (11)—USP Terazosin Hydro- glacial acetic acid to a 100-mL volumetric flask, dilute
chloride RS. USP Terazosin Related Compound A RS. with acetone to volume, and mix.
USP Terazosin Related Compound B B RS. USP Terazosin Standard stock solution—Dissolve an accurately weighed
Related Compound ¥ C RS. amount of tetrahydro-2-furancarboxylic acid in acetone to
Color and clarity of solution—Dissolve a quantity of obtain a solution having a known concentration of about
Terazosin Hydrochloride in methanol solution (90 in 100) 1.0 mg per mL. Dilute with acetone quantitatively, and
to obtain a 1 in 100 solution: this solution is clear and stepwise if necessary, to obtain a solution having a known
colorless to pale yellow, when compared to methanol concentration of about 100 ug per mL.
solution (90 in 100). Standard solution—Transfer 5.0 mL of the Standard stock
Identification— solution and 5.0 mL of Internal standard solution to a 50-
A: Infrared Absorption (197K). mL centrifuge tube, and mix. Pass through a nylon
B: The retention time of the major peak in the membrane filter having a 0.45-um or finer porosity,
chromatogram of the Assay preparation corresponds to previously washed with acetone, and discard the first 1
that in the chromatogram of the Standard preparation, as mL of the filtrate.
obtained in the Assay. Test solution—Transfer about 100 mg of Terazosin
C: It meets the requirements of the tests for Chloride Hydrochloride, accurately weighed, to a 50-mL centrifuge
(191), a solution prepared by dissolving 100 mg in 10 mL tube, add 5.0 mL of acetone and 5.0 mL of Internal
standard solution, and shake for about 30 minutes.
of methanol solution (90 in 100) being examined.
Centrifuge for about 10 minutes, pass through a nylon
Loss on drying (731)—Dry it in vacuum at 105° for 3
hours: it loses not more than 9.0% of its weight.
Pharmacopeial Forum
membrane filter having a 0.45-um or finer porosity, the Test solution; and Rv and Rs are the peak response ratios
previously washed with acetone, and discard the first 1 obtained from the Test solution and the Standard solution,
mL of the filtrate. respectively: not more than 0.2% 0.1% is found.
Chromatographic system (see Chromatography (621))— Limit of l-[(tetrahydro-2-furanyl)carbonyl]piper-
The gas chromatograph is equipped with a flame-ionization azine—
detector and a 0.53-mm x 10-m fused-silica capillary Derivatization solution—Dissolve about 2.0 g of 3,5-
column coated with a 1.2-um film of liquid phase G25. dinitrobenzoyl chloride in 250 mL of acetonitrile.
The column temperature is maintained at about 170°. The Phosphate buffer solution—Transfer about 96.3 g of
injector is configured for splitless injection, and its dibasic potassium phosphate and 3.85 g of monobasic
temperature is maintained at about 230°. The detector potassium phosphate, each accurately weighed, to a 500-
temperature is maintained at about 240°. The carrier gas is mL volumetric flask. Dissolve in and dilute with water to
helium, flowing at a rate of about 9 mL per minute. volume. Adjust with phosphoric acid solution (10 in 100)
Chromatograph the Blank solution, and measure the peak or sodium hydroxide solution (10 in 100) to a pH of 8.0
responses as directed for Procedure: ensure that there are + 0.1. Transfer 25.0 mL of this solution to a 100-mL
no extraneous peaks. Chromatograph the Standard volumetric flask, and dilute with water to volume. Adjust
solution, and measure the peak responses as directed for with phosphoric acid solution (10 in 100) or sodium
Procedure: the relative retention times are 1.0 for hydroxide solution (10 in 100) to a pH of 8.0 ± 0.1.
tetrahydro-2-furancarboxylic acid and 1.2 for capric acid; Solution A—Use filtered and degassed water.
the resolution, R, between tetrahydro-2-furancarboxylic Solution B—Use filtered and degassed acetonitrile.
acid and capric acid is not less than 2.3; and the relative Mobile phase—Use variable mixtures of Solution A and
standard deviation, determined from the peak response Solution B as directed for Chromatographic system. Make
ratios of tetrahydro-2-furancarboxylic acid to capric acid adjustments if necessary (see System Suitability under
for replicate injections is not more than 6.5%. Chromatography (621)).
Procedure—Separately inject equal volumes (about 0.2 Blank solution—Use acetonitrile.
uL) of the Standard solution and the Test solution into the Standard solution—Dissolve an accurately weighed
chromatograph, record the chromatograms, and measure the quantity of l-[(tetrahydro-2-furanyl)carbonyl]piperazine in
peak responses. Calculate the percentage of tetrahydro-2- acetonitrile to obtain a solution having a known
furancarboxylic acid in the portion of Terazosin concentration of about 1.0 mg per mL. Dilute
Hydrochloride taken by the formula: quantitatively, and stepwise if necessary, with acetonitrile,
to obtain a solution having a known concentration of
about 5 ug per mL.
in which C is the concentration, in ug per mL, of tetrahydro-
Test solution—Transfer about 125 mg of Terazosin
2-furancarboxylic acid in the Standard solution; W is the
Hydrochloride, accurately weighed, to a 25-mL
weight, in mg, of Terazosin Hydrochloride taken to prepare
volumetric flask, dissolve in and dilute with a mixture of
acetonitrile and water (1:1) to volume, and mix.
Pharmacopeial Forum
Derivatization procedure—Transfer 5-mL portions of the Procedure—Separately inject equal volumes (about 50
Blank solution, the Standard solution, and the Test solution, uL) of the derivatized Standard solution and the
each to a separate 100-mL volumetric flask, and proceed derivatized Test solution into the chromatograph, record
with each as follows. Add 5.0 mL of Phosphate buffer the chromatograms, and measure the peak areas. Calculate
solution, and mix. Add 10.0 mL of Derivatization the percentage of l-[(tetrahydro-2-furanyl)carbonyl]-
solution while swirling, allow to stand at room piperazine in the portion of Terazosin Hydrochloride taken
temperature for about 20 minutes, and mix. Dilute with a by the formula:
mixture of acetonitrile and water (1:1) to volume, and mix.
in which C is the concentration, in mg per mL, of l-[(tetra-
hydro-2-furanyl)carbonyl]piperazine in the Standard solu-
detector and a 4.6-mm x 25-cm analytical column that
tion; W is the weight, in mg, of Terazosin Hydrochloride
contains packing L7. The flow rate is 1.5 mL per minute,
taken to prepare the Test solution; and rv and rs are the peak
except it is changed to 2.0 mL per minute during the
areas for l-[(tetrahydro-2-furanyl)carbonyljpiperazine deri-
period between 40 and 80 minutes. The chromatograph is
vative obtained from the derivatized Test solution and the
programmed as follows.
derivatized Standard solution, respectively: not more than
Time Solution A Solution B 0.1% is found.
(minutes) (%) (%) Elution Related compounds—
0-35 82 18 isocratic pH 3.2 Citrate buffer, Mobile phase, and Standard stock
35-40 82->10 18->90 linear gradient preparation—Proceed as directed in the Assay.
40-75 10 90 isocratic Diluent 1—Dissolve 6.0 g of sodium citrate and 4.0 g of
75-80 10-»82 90-* 18 linear gradient anhydrous citric acid in water, dilute with water to 1.0 liter,
80-100 82 18 isocratic and mix.
Separately inject equal volumes (about 50 uL) of the de- Diluent 2—Prepare a mixture of water, acetonitrile, and
rivatized Blank solution and the derivatized Standard solu- methanol (60:30:10).
tion, and measure the peak responses as directed for Standard stock solution 1—Dissolve an accurately
Procedure, ensuring that the peaks in the chromatogram weighed quantity of USP Terazosin Related Compound A
of the derivatized Standard solution that correspond to those RS in Diluent 1, and dilute with Diluent 1 to obtain a
obtained from the derivatized Blank solution do not interfere solution having a known concentration of about 0.5 mg
with the determination: the retention time for l-[(tetrahydro- per mL.
2-furanyl)carbonyl]piperazine is more than 22 minutes; the Standard stock solution 2—Dissolve an accurately
column efficiency is not less than 3500 theoretical plates; weighed quantity of USP Terazosin Related Compound £
and the relative standard deviation for replicate injections B RS in methanol, and dilute with methanol to obtain a
is not more than 3.0%. solution having a known concentration of about 0.5 mg
per mL.
Pharmacopeial Forum
Standard stock solution 3—Dissolve an accurately Procedure—Separately inject equal volumes (about 20
weighed quantity of USP Terazosin Related Compound F uL) of the Standard solution and the Test solution into the
C RS in Diluent 2, a mixture of acetonitrile and methanol chromatograph, record the chromatograms for about 60
(1:1), and dilute with Diluent 2 a mixture of acetonitrile minutes, and measure the peak responses. Separately
and methanol (1:1) to obtain a solution having a known calculate the quantities, in mg, of terazosin related
concentration of about 0.1 mg per mL. compound A and terazosin related compound F C in the
Standard solution—Transfer 5.0 mL of Standard stock portion of Terazosin Hydrochloride taken by the formula:
preparation, 4.0 mL of Standard stock solution 1, 4.0 mL
of Standard stock solution 2, and 20 mL of Standard
in which C is the concentration, in mg per mL, of the appro-
stock solution 3 to a 100-mL volumetric flask containing
priate USP Reference Standard in the Standard solution;
about 60 mL of Diluent 2. Dilute with Diluent 2 to
and rv and rs are the peak responses for the corresponding
volume, and mix. Transfer 10.0 mL of this solution to a
related compound obtained from the Test solution and the
100-mL volumetric flask, dilute with Mobile phase to
Standard solution, respectively: not more than 0.3% of ter-
volume, and mix.
azosin related compound A is found; and not more than
Test solution—Use the Assay stock preparation.
0.4% of terazosin related compound F C is found. Calculate
Chromatographic system—Prepare as directed in the
the quantity, in mg, of each impurity in the portion of Ter-
Assay. Chromatograph the Mobile phase, and record the
azosin Hydrochloride taken by the formula:
peak responses as directed for Procedure: ensure that
there are no significant interfering peaks. Chromatograph 200C(r,/r r ),
the Standard solution, and record the peak responses as
in which C is the concentration, in mg per mL, of USP Ter-
azosin Hydrochloride RS in the Standard solution; rt is the
about 0.2 for terazosin related compound A, 1.0 for
peak response for each impurity, other than terazosin related
terazosin, 4T94 1.48 for terazosin related compound E B,
compound A and terazosin related compound F C, obtained
and 2.57 for terazosin related compound F C ; the
from the Test solution; and rT is the terazosin peak response
resolution, R, between terazosin and terazosin related
obtained from the Standard solution: not more than 0.3% of
compound £ B is not less than 9.0; the column efficiency
any impurity eluting prior to the terazosin peak is found; not
determined from the terazosin peak is not less than 12,000
more than 0.5% 0.1% of any other impurity is found; and
theoretical plates; the tailing factor for the terazosin related
not more than 1.5% 0.6% of total impurities is found.
compound F C peak is not more than 3.0; and the relative
Assay—
standard deviation for replicate injections determined from
pH 3.2 Citrate buffer—Dissolve 12.0 g of sodium citrate
the terazosin peak is not more than 2.0%, and not more than
dihydrate and 28.5 g of anhydrous citric acid in 1.95 liters of
5.0% determined from the terazosin related compound F C
water. Adjust with anhydrous citric acid or sodium citrate to
peak.
a pH of 3.2 + 0.1. Dilute with water to 2.0 liters, and mix.
Pharmacopeial Forum
Mobile phase—Prepare a filtered and degassed mixture of than 12,000 theoretical plates; the tailing factor is not less
pH 3.2 Citrate buffer and acetonitrile (1685:315). Make than 0.9 and not more than 1.3; and the relative standard
adjustments if necessary (see System Suitability under deviation for replicate injections is not more than 0.9%.
Chromatography (621)). Procedure—Separately inject equal volumes (about 20
Standard stock preparation—Dissolve an accurately jiL) of the Standard preparation and the Assay
weighed quantity of USP Terazosin Hydrochloride RS in preparation into the chromatograph, record the
Mobile phase, and dilute with Mobile phase to obtain a chromatograms for about 45 minutes, and measure the
solution having a known concentration of about 0.5 mg peak responses. Calculate the quantity, in mg, of
per mL. C19H25N5O4-HC1 in the portion of Terazosin Hydro-
Standard preparation—Transfer 10.0 mL of Standard chloride taken by the formula:
stock preparation to a 50-mL volumetric flask, and dilute
with Mobile phase to volume. Transfer 10.0 mL of this
in which C is the concentration, in mg per mL, of USP Ter-
solution to a 100-mL volumetric flask, dilute with Mobile
phase to volume, and mix. azosin Hydrochloride RS in the Standard preparation; and
Assay stock preparation—Transfer about 100 mg of rv and rs are the peak responses obtained from the Assay
Terazosin Hydrochloride, accurately weighed, to a 200- preparation and the Standard preparation, respective-
mL volumetric flask, dissolve in and dilute with Mobile ly- A USP26

Assay preparation—Transfer 10.0 mL of Assay stock
preparation to a 50-mL volumetric flask, dilute with
Mobile phase to volume, and mix. Transfer 10.0 mL of
this solution to a 100-mL volumetric flask, dilute with
BRIEFING
Mobile phase to volume, and mix.
Terpin Hydrate Elixir, USP 25 page 1661. It is proposed to
Chromatographic system (see Chromatography (621))— change the title of this monograph to Terpin Hydrate Oral Solu-
detector and a 4.6-mm x 25-cm column that contains (NL: C. Barnstein; PA2: J. Kelly) RTS—35991-1
packing L7. The column temperature is maintained at

about 30°. The flow rate is about 1.0 m L per minute. Terpin Hydrate Elixir
Chromatograph the Mobile phase, and record the peak (Current title—not to change until June 1, 2005)
responses as directed for Procedure: ensure that there are 2005
no significant interfering peaks. Chromatograph the cess Revision):
See Terpin Hydrate Oral Solution
Pharmacopeia! Forum
Procedure—Inject about 1 |iL of the Standard prep-

BRIEFING aration into a suitable gas chromatograph, and record the
Terpin Hydrate Oral Solution—See briefing under Amanta- chromatogram. Similarly, inject about 1 uL of the Assay
preparation, and record the chromatogram. Calculate the
(NL: C. Barnstein; PA2: J. Kelly) RTS—35991-1 quantity, in mg, of terpin hydrate (C 10 H 20 O 2 -H 2 O) in
each mL of the Oral Solution taken by the formula:
Add the following:
0.1(190.28/172.27)0^//^),
A
Terpin Hydrate Oral Solution
June 1, 2005) terpin hydrate (C 10 H 20 O 2 -H 2 O) and anhydrous terpin
(Current monograph title is Terpin Hydrate Elixir)
(C10H20O2), respectively; Ws is the weight, in mg, of USP
Terpin Hydrate RS, calculated on the anhydrous basis;
» Terpin Hydrate Oral Solution contains, in each
and Ry and Rs are the area-ratios of terpin to biphenyl ob-
100 mL, not less than 1.53 g and not more than
tained from the chromatograms for the Assay preparation
1.87 g of terpin hydrate (C10H20O2 • H2O). and the Standard preparation, respectively. AUSP26
USP Reference standards {11)—USP Terpin Hydrate RS.
Assay—
Internal standard solution, Standard preparation, BRIEFING
Chromatographic system, and System suitability—Proceed
Terpin Hydrate and Codeine Elixir, USP 25 page 1661. It is
as directed in the Assay under Terpin Hydrate. proposed to change the title of this monograph to Terpin Hydrate
and Codeine Oral Solution. See also briefing under Amantadine
Assay preparation—Pipet 10 mL of Oral Solution into a Hydrochloride Syrup.
separator, add 20 mL of water and 10 mL of 5 N sodium (NL: C. Barnstein) RTS—35992-1

hydroxide, and extract with three 25-rnL portions of
chloroform, filtering each, successively, through cotton.
Terpin Hydrate and Codeine Elixir
Rinse the cotton with chloroform. To the combined rinse (Current title—not to change until June 1,2005)
and extracts add 5.00 mL of Internal standard solution, Monograph title change—to become official June 1,
2005
and mix. (see Official Title Changes on the first page of In-Pro-
cess Revision):
See Terpin Hydrate and Codeine Oral Solution
Pharmacopeial Forum
Test solution—Transfer 10 mL of Oral Solution to a

BRIEFING suitable separator containing 10 mL of water, and add 1
Terpin Hydrate and Codeine Oral Solution—See briefing un- mL of 1 N sodium hydroxide. Add 10 mL of methylene
chloride, shake for 1 minute, and allow the layers to
(NL: C. Barnstein) RTS—35992-1 separate. Use the clear lower organic layer as the Test
solution.
Add the following: Procedure—Apply separately 5 uL of Standard solution
A
Terpin Hydrate and Codeine Oral A, Standard solution B, and the Test solution to a suitable
Solution thin-layer chromatographic plate (see Chromatography
{Monograph under this new title—to become official (621)) coated with a 0.25-mm layer of chromatographic
June 1, 2005)
(Current monograph title is Terpin Hydrate and Codeine silica gel mixture. Develop the chromatogram in a
Elixir)
chromatographic chamber containing the Developing
solvent until the solvent front has moved three-fourths of
» Terpin Hydrate and Codeine Oral Solution con-
the length of the plate. Remove the plate from the
tains, in each 100 mL, not less than 1.53 g and not
chromatographic chamber, mark the solvent front, and
more than 1.87 g of terpin hydrate (C10H20
allow the plate to dry. Examine the plate under short-
O2 • H2O), and not less than 180 mg and not more
wavelength UV light, and mark the location of the
than 220 mg of codeine (C18H21NO3 • H2O). codeine spots. Spray the plate with phosphomolybdic acid
Packaging and storage—Preserve in tight containers. TS, and heat at 105° for 5 minutes. The terpin hydrate
USP Reference standards (11 )—USP Terpin Hydrate RS. spots appear blue on a yellow background. The RF values
of the spots due to terpin hydrate and codeine obtained
USP Codeine Phosphate RS.
from the Test solution correspond to those obtained from
Identification—
Standard solutions A and B, respectively.
Developing solvent—Prepare a mixture of methylene
chloride and methanol (9:1).
Standard solution A—Dissolve a suitable quantity of USP
Assay for terpin hydrate—
Terpin Hydrate RS in methylene chloride to obtain a
solution having a concentration of about 3 mg per mL. Internal standard solution—Prepare a chloroform
[NOTE—A small volume of methanol may be used to aid solution containing 20 mg of biphenyl and 2.6 mg of N-
dissolution of the terpin hydrate.] phenylcarbazole in each mL.
Standard solution B—Transfer 20 mg of USP Codeine Standard preparation—Transfer about 26 mg of USP
Phosphate RS to a suitable separator containing 10 mL of Codeine Phosphate RS and about 170 mg of USP Terpin
water, add 1 mL of 1 N sodium hydroxide, and mix. Add Hydrate RS, both accurately weighed, to a separator, add
10 mL of methylene chloride, and shake for 1 minute. 5 mL of alcohol, shake to dissolve the terpin hydrate, add
Allow the layers to separate, and drain the lower organic 25 mL of water to dissolve the codeine phosphate, add 10
layer into a suitable flask. Discard the aqueous layer. mL of 5 N sodium hydroxide, and extract with three 25-mL
portions of chloroform, filtering each, successively, through
Pharmacopeia! Forum
cotton. Rinse the cotton with chloroform. To the combined Assay for codeine—
rinse and extracts add 5.00 mL of Internal standard Internal standard solution—Prepare as directed under
solution, and mix. Assay for terpin hydrate.
Assay preparation—Pipet 10 mL of Oral Solution into a Standard preparation—Evaporate the remaining
separator, add 20 mL of water and 10 mL of 5 N sodium Standard preparation for Oral Solution from the Assay for
hydroxide, and extract with three 25-mL portions of terpin hydrate nearly to dryness, and dissolve the residue in
chloroform, filtering each, successively, through cotton. about 20 mL of chloroform.
Rinse the cotton with chloroform. To the combined rinse Assay preparation—Evaporate the remaining Assay
and extracts add 5.00 mL of Internal standard solution, preparation for Oral Solution from the Assay for terpin
and mix. hydrate nearly to dryness, and dissolve the residue in
Chromatographic system and System suitability— about 20 mL of chloroform.
Proceed as directed in the Assay under Terpin Hydrate. Chromatographic system and System suitability—
[NOTE—Heat the column to 230° to remove the N- Proceed as directed in the Assay under Terpin Hydrate,
phenylcarbazole and codeine from prior injections.] except to maintain the temperature of the column at 230°
Procedure—Inject about 1 uL of the Standard instead of 120°.
preparation into a suitable gas chromatograph, and record Procedure—Proceed as directed under Assay for terpin
the chromatogram. Similarly, inject about 1 |iL of the hydrate, except to maintain the temperature of the column
Assay preparation, and record the chromatogram. at 230° instead of 120°. The retention times for N-
Calculate the quantity, in mg, of terpin hydrate phenylcarbazole and codeine are about 7 minutes and 10
(C 10 H 20 O 2 -H 2 O) in each mL of the Oral Solution taken minutes, respectively. Calculate the quantity, in mg, of
by the formula: codeine (C 1 8 H 2 1 NO 3 H 2 O)in each mL of the Oral
0.1(190.28/172.27) W^RJRS),
0.1(317.39 /397.37)W^RU/RS),
terpin hydrate (C 10 H 20 O 2 -H 2 O) and anhydrous terpin in which 317.39 and 397.37 are the molecular weights of
(C10H20O2), respectively; Ws is the weight, in mg, of USP codeine (C 1 8 H 2 1 NO 3 -H 2 O) and codeine phosphate
Terpin Hydrate RS, calculated on the anhydrous basis; (C 18 H 21 NO 3 -H 3 PO 4 ), respectively; Ws is the weight, in
and Rv and Rs are the area-ratios of terpin to biphenyl ob- mg, of USP Codeine Phosphate RS; and Rv and Rs are the
tained from the chromatograms for the Assay preparation area-ratios of codeine to iV-phenylcarbazole obtained from
and the Standard preparation, respectively. the chromatograms for the Assay preparation and the Stan-
dard preparation, respectively.AVSP26
Pharmacopeia! Forum
378 IN-PROCESS REVISION Vol. 28(2) [Man-Apr. 2002]
Dissolve the Sodium Hydroxide in 5 mL of Purified

BRIEFING Water, and while mixing, slowly add this solution to
the prepared mixture. Complete the suspension by
Tetracycline Hydrochloride Oral Suspension, USP 25 page adding a sufficient quantity of the Suspension Struc-
1678 and page 3333 of PF 27(6) [Nov.-Dec. 2001]—See briefing
under Cefazolin Ophthalmic Solution. tured Vehicle or Sugar-Free Suspension Vehicle to
make a final volume of 100 mL, and pass this final dis-
(CRX: C. Okeke) RTS—35643-8 persion through a hand homogenizer prior to transfer-
ring it to the dispensing container.
Change to read:
» Tetracycline Hydrochloride Oral Suspension con-

tains not less than 2.25 g and not more than 2.75 g
of Tetracycline Hydrochloride in 100 mL of Oral Sus-
pension.
Prepare Tetracycline Hydrochloride Oral Suspen-
sion as follows (see Pharmacy Compounding BRIEFING
Practices (4464-)
A Theophylline Sodium Glycinate Elixir, USP 25 page 1691. It
Pharmaceutical Compounding—Nonsterile Pre- is proposed to change the title of this monograph to Theophylline
Sodium Glycinate Oral Solution. See also briefing under Arnanta-
parations {795)):AUSP26 dine Hydrochloride Syrup.

Tetracycline Hydrochloride 2.50 g
Cetylpyridinium Chloride 10 mg
Xanthan Gum 0.15 g Theophylline Sodium Glycinate Elixir
Disbasic Sodium Phosphate 60 mg
Monobasic Sodium Phosphate 0.65 g (Current title—-not to change until June 1, 2005)
Sodium Hydroxide 0.30 g 2005
35 m L (see Official Title Changes on the first page of In-Pro-
Purified Water
Suspension Structured Vehicle or cess Revision):
See Theophyline Sodium Glycinate Oral Solution
Sugar-Free Suspension Structured
Vehicle, a sufficient quantity, to make. 100 mL
Dissolve the Dibasic Sodium Phosphate and the

Monobasic Sodium Phosphate in 25 mL of Purified
Water. Separately dissolve an accurately weighed BRIEFING
quantity of Cetylpyridinium Chloride in Purified Water
and dilute quantitatively, and stepwise if necessary, Theophylline Sodium Glycinate Oral Solution—See briefing
with Purified Water to obtain 5 mL of a solution con- under Amantadine Hydrochloride Syrup.
taining 10 mg of Cetylpyridinium Chloride. Mix this
solution with 5 mL of the aqueous phosphate solution (NL: C. Barnstein; AER: K. Zaidi) RTS—35993-1
and add the resulting solution, in divided portions,
with mixing, to the Tetracycline Hydrochloride in a
glass mortar to completely wet the powder, and make Add the following:
a smooth paste.
A
Transfer the remaining 20 mL of the aqueous phos- Theophylline Sodium Glycinate Oral
phate solution to a beaker. Using moderate heat, stir to Solution
form a vortex, and slowly sprinkle the Xanthan Gum
into the vortex to produce a uniform dispersion. Add (Monograph under this new title—to become official
this dispersion to the paste in the glass mortar, and June 1, 2005)
(Current monograph title is Theophylline Sodium Glyci-
mix until smooth; then add 20 mL of the Suspension nate Elixir)
Structured Vehicle or Sugar-Free Suspension Vehicle
to the mixture.
Pharmacopeial Forum
» Theophylline Sodium Glycinate Oral Solution mL of this solution to a 100-mL volumetric flask, add
contains an amount of theophylline sodium glyci- 20.0 mL of Internal standard solution, dilute with Mobile
nate equivalent to not less than 93.0 percent and
Assay under Theophylline. Calculate the quantity, in mg,
of anhydrous theophylline (C7H8N4O2).
of anhydrous theophylline (C7H8N4O2) in each mL of the
Packaging and storage—Preserve in tight containers. Oral Solution taken by the formula:
USP Reference standards (11)—USP Theophylline RS.
Labeling—Label Oral Solution to state both the content of
in which Fis the volume, in mL, of Oral Solution taken, and
theophylline sodium glycinate and the content of anhydrous
the other terms are as defined therein. AUSp26
theophylline.
Identification—Mix a volume of Oral Solution, equivalent
to about 500 mg of theophylline, with 10 mL of 6 N
ammonium hydroxide, and evaporate on a steam bath to a
volume of about 20 mL. Neutralize with 6 N acetic acid to
litmus, and cool, with stirring, to about 15°. Collect the
precipitate on a filter, wash with cold water, and dry at BRIEFING
105° for 4 hours: the theophylline so obtained melts Thiamine Hydrochloride Elixir, USP 25 page 1695. It is pro-
posed to change the title of this monograph to Thiamine Hydro-
between 270° and 274°, the procedure for Class I being chloride Oral Solution. See also briefing under Amantadine
used (see Melting Range or Temperature (741)), and
meets the requirements for Identification test B under (NL: C. Barnstein) RTS—35994-1
Theophylline Sodium Glycinate.

pH (791): between 8.3 and 9.1. Thiamine Hydrochloride Elixir
Alcohol content, Method II (611): between 17.0% and (Current title—not to change until June 1, 2005)
23.0%ofC 2 H 5 OH. 2005
Assay— cess Revision):
See Thiamine Hydrochloride Oral Solution
Buffer solution, Mobile phase, Internal standard solution,
Standard preparation, and Chromatographic system—
Prepare as directed in the Assay under Theophylline.
theophylline sodium glycinate, to a 100-mL volumetric
flask, dilute with water to volume, and mix. Transfer 10.0
Pharmacopeial Forum
Add the following:

BRIEFING
A
Thiamine Hydrochloride Oral
Thiamine Hydrochloride Injection, USP 25 page 1695. Edi- Solution
torial revisions are indicated to conform with the title change pro-
posed for Thiamine Hydrochloride Elixir. See also briefing under (Monograph under this new title—to become official
Amantadine Hydrochloride Syrup. June 1, 2005)
(Current monograph title is Thiamine Hydrochloride
(NL: C. Bamstein;; DSN: G. Giancaspro) RTS—35995-1 Elixir)
» Thiamine Hydrochloride Oral Solution contains

Change to read:
Assay— not less than 95.0 percent and not more than 135.0
Mobile phase, Internal standard solution, Standard preparation,
and Chromatographic system—Prepare as directed in the Assay percent of the labeled amount of thiamine hydro-
under Thiamine Hydrochloride Elixir
A
Orat Solution. AUSP26
chloride (C12H17C1N4OS • HC1).
Assay preparation—Quantitatively dilute an accurately
measured volume of Injection with Mobile phase to obtain a
solution containing about 500 ug of thiamine hydrochloride per Packaging and storage—Preserve in tight, light-resistant
mL. Pipet 10 mL of the resulting solution and 10 mL of Internal
standard solution into a 100-mL volumetric flask, dilute with containers.
Procedure—Proceed as directed for Procedure in the Assay USP Reference standards (11)—USP Thiamine Hydro-
under Thiamine Hydrochloride Elixir
A chloride RS.
Oral Solution. AUSP26
Calculate the quantity, in mg, of thiamine hydrochloride
(C12H,7C1N4OS -HC1) in each mL of the Injection taken by the Identification—It meets the requirements for Identification
formula:
test B under Thiamine Hydrochloride Injection.
C(LID){RJRS),
in which C is the concentration, in mg per mL, of USP Thiamine
Hydrochloride RS in the Standard preparation; L is the labeled 110.0% of the labeled amount of C2H5OH, acetone being
quantity, in mg per mL, of thiamine hydrochloride in the Injection;
D is the concentration, in mg per mL, of thiamine hydrochloride in
the Assay preparation on the basis of the labeled quantity and the used as the internal standard.
extent of dilution; and Rv and Rs are the ratios of the peak re-
sponses of thiamine to methylparaben obtained from the Assay pre- Assay—
paration and the Standard preparation, respectively.
0.04 M aqueous monobasic potassium phosphate and
methanol (55:45). Make adjustments if necessary (see
Internal standard solution—Prepare a solution of
methylparaben in Mobile phase having a concentration of
BRIEFING
Standard preparation—Prepare a solution of USP
Thiamine Hydrochloride Oral Solution—See briefing under
Amantadine Hydrochloride Syrup. Thiamine Hydrochloride RS in Mobile phase having an
(NL: C. Barnstein) RTS—35994-1 accurately known concentration of about 500 ug per mL.
Pipet 10 mL of this solution and 10 mL of Internal
standard solution into a 100-mL volumetric flask, dilute
Pharmacopeial Forum
with Mobile phase to volume, and mix to obtain a Standard and Ry and Rs are the ratios of the peak responses of thia-
preparation having a known concentration of about 50 ug mine to methylparaben obtained from the Assay preparation
per mL. and the Standard preparation, respectively. AUSP26
Assay preparation—Quantitatively dilute an accurately (Official June 1,2005)
measured volume of Oral Solution with Mobile phase to

obtain a solution containing about 500 jig of thiamine
hydrochloride per mL. Pipet 10 mL of the resulting
solution and 10 mL of Internal standard solution into a
100-mL volumetric flask, dilute with Mobile phase to
BRIEFING
volume, and mix.
Chromatographic system (see Chromatography (621))— Thiamine Mononitrate Elixir, USP 25 page 1696. It is pro-
posed to change the title of this monograph to Thiamine Mononi-
The liquid chromatograph is equipped with a 254-nm trate Oral Solution. See also briefing under Amantadine
(NL: C. Barnstein; DSN: G. Giancaspro) RTS—35996-1
peak responses as directed for Procedure: the resolution, Thiamine Mononitrate Elixir
{Current title—not to change until June 1,2005)
R, between the thiamine and methylparaben peaks is not Monograph title change—to become official June 1,
2005
less than 6.0; and the relative standard deviation for (see Official Title Changes on the first page of In-Pro-
cess Revision):
replicate injections is not more than 2.0%. See Thiamine Mononitrate Oral Solution
peaks. The relative retention times are about 0.35 for
thiamine and 1.0 for methylparaben. Calculate the
BRIEFING
q u a n t i t y , in mg, of t h i a m i n e hydrochloride
Thiamine Mononitrate Oral Solution—See briefing under
(C12H17C1N4OS HC1) in each mL of the Oral Solution Amantadine Hydrochloride Syrup.
taken by the formula: (NL: C. Bamstein; DSN: G. Giancaspro) RTS—35996-1
Add the following:

in which C is the concentration, in mg per mL, of USP Thia-
A
mine Hydrochloride RS in the Standard preparation; L is Thiamine Mononitrate Oral Solution
the labeled quantity, in mg per mL, of thiamine hydrochlor- June 1, 2005)
(Current monograph title is Thiamine Mononitrate Elixir)
ide in the Oral Solution; D is the concentration, in mg per
mL, of thiamine hydrochloride in the Assay preparation on
the basis of the labeled quantity and the extent of dilution;
Pharmacopeial Forum
» Thiamine Mononitrate Oral Solution contains Q2131im.21)C{LID){RuIRs),

not less than 95.0 percent and not more than in which 327.37 and 337.27 are the molecular weights of
115.0 percent of the labeled amount of thiamine thiamine mononitrate and thiamine hydrochloride, respec-
mononitrate (C12H17N5O4S). tively; C is the concentration, in mg per mL, of USP Thia-
mine Hydrochloride RS in the Standard preparation; L is
the labeled quantity, in mg per mL, of thiamine mononitrate
containers.
in the Oral Solution; D is the concentration, in mg per mL,
USP Reference standards (11)—USP Thiamine Hydro-
of thiamine mononitrate in the Assay preparation on the ba-
chloride RS.
sis of the labeled quantity and the extent of dilution; and Rv
Identification— and Rs are the ratios of the peak responses of thiamine to
A: It meets the requirements for Identification test B methylparaben obtained from the Assay preparation and
under Thiamine Hydrochloride Injection. the Standard preparation, respectively. AUSP26
B: To 5 mL of Oral Solution add 2 mL of sulfuric acid, (Official June 1, 2005)
cool, and superimpose 2 mL of ferrous sulfate TS: a brown
ring is produced at the junction of the two liquids.
110.0% of the labeled amount of C2H5OH, acetone being
used as the internal standard.
Assay— BRIEFING
Mobile phase, Internal standard solution, Standard Torsemide, USP 25 page 1736. From correspondence received,
it is proposed to remove the indication of the polymoric form from
preparation, and Chromatographic system—Prepare as the title of the official USP reference standard, since there are no
compendial requirements for this specific polymorph. Based upon
directed in the Assay under Thiamine Hydrochloride Oral supporting stability data, it is also proposed to increase the water
content limit to not more than 0.8%.
Solution.
(PA5: J. Esker) RTS—36077-1; 36082-1; 36188-1
Assay preparation—Quantitatively dilute an accurately
measured volume of Oral Solution with Mobile phase to
obtain a solution containing about 500 ug of thiamine Change to read:
USP Reference standards (11)—USP Torsemide (Foiin I)
mononitrate per mL. Pipet 10 mL of the resulting solution •
AUSP26
and 10 mL of Internal standard solution into a 100-mL RS. USP Torsemide Related Compound A RS. USP Torsemide Re-
lated Compound B RS. USP Torsemide Related Compound C RS.
volumetric flask, dilute with Mobile phase to volume, and
Change to read:
mix. Water, Method I (921): not more than &

Assay under Thiamine Hydrochloride Oral Solution. Change to read:
Calculate the quantity, in mg, of thiamine mononitrate Related compounds—
0.02 M Potassium phosphate buffer and Mobile phase—Prepare
(C12H!7N5O4S) in each mL of the Oral Solution taken by as directed in the Assay.
the formula:
Pharmacopeial Forum
Resolution solution—Transfer about 3 mg each of USP RS, accurately weighed, to a 50-mL volumetric flask, add 15 mL
Torsemide (Form I) of methanol, mix, and sonicate for not less than 8 minutes. Add
• 22.5 mL of 0.02 MPotassium phosphate buffer, cool to room tem-
AUSP26 perature, dilute with Mobile phase to volume, and mix.
RS and USP Torsemide Related Compound A RS to a 10-mL vol- Assay preparation—Transfer about 38 mg of Torsemide,
umetric flask, add 3 mL of methanol, mix, and sonicate for not less accurately weighed, to a 100-mL volumetric flask, add 30 mL of
than 8 minutes. Add 4.5 mL of 0.02 MPotassium phosphate buffer, methanol, mix, and sonicate for not less than 8 minutes. Add 45
cool to room temperature, dilute with Mobile phase to volume, and mL of 0.02 M Potassium phosphate buffer, cool to room
mix. temperature, dilute with Mobile phase to volume, and mix.
Standard solution—Transfer about 8 mg each of USP Torsemide Chromatographic system (see Chromatography (621))—The
Related Compound A RS, USP Torsemide Related Compound B liquid chromatograph is equipped with a 288-nm detector and a
RS, and USP Torsemide Related Compound C RS, accurately 4.6-mm x 15-cm column that contains 7-um packing LI. The
weighed, to a 100-mL volumetric flask, add 30 mL of methanol, flow rate is about 1.5 mL per minute. Chromatograph the
mix, and sonicate for not less than 8 minutes. Add 45 mL of Standard preparation, and record the peak responses as directed
0.02 M Potassium phosphate buffer, cool to room temperature, for Procedure: the tailing factor is not more than 2.0; and the
dilute with Mobile phase to volume, and mix. Quantitatively relative standard deviation for replicate injections is not more
dilute a portion of this solution with Mobile phase to obtain a than 2.0%.
solution having a known concentration of about 0.0019 mg per Procedure—Separately inject equal volumes (about 20 uL) of
mL. the Standard preparation and the Assay preparation into the
Test solution—Use the Assay preparation. chromatograph, record the chromatograms, and measure the
Chromatographic system—Prepare as directed in the Assay. responses for the major peaks. Calculate the amount, in mg, of
Chromatograph the Resolution solution and the Standard C16H20N4O3S in the portion of Torsemide taken by the formula:
solution, and record the peak responses over a period three times
the retention time of torsemide as directed for Procedure: the
resolution, R, between torsemide and torsemide related
compound A is not less than 1.0; the tailing factors are not more in which C is the concentration, in mg per mL, of USP Torsemide
than 2.0; and the relative standard deviation for replicate injections
is not more than 10.0%.
AUSP26
the Standard solution and the Test solution into the RS in
i tthe Standard preparation; and rv and rs are the peak re-
chromatograph, record the chromatograms, and measure the peak sponses obtained from the Assay preparation and the Standard
areas for torsemide related compound A, torsemide related preparation, respectively.
compound B, and torsemide related compound C. Calculate the
percentage of each related compound, if present, in the portion
of Torsemide taken by the formula:
in which Cs is the concentration, in mg per mL, of the relevant USP

Reference Standard in the Standard solution; Cv is the concentra-
tion of Torsemide, in mg per mL, in the Test solution; and rv and rs
are the peak areas for the relevant torsemide related compound ob-
tained from the Test solution and the Standard solution, respec-
tively: not more than 0.2% of torsemide related compound C, BRIEFING
not more than 0.3% of torsemide related compound B, and not
more than 0.5% of torsemide related compound A are found. Cal- Triamcinolone Diacetate Oral Solution—See briefing under
culate the percentage of any other impurity in the portion of Tor- Amantadine Hydrochloride Syrup.
semide taken by the formula:
lOOfo/r,), (NL: C. Barnstein; PA1: C. Anthony) RTS—35997-1
in which r(- is the peak response for each other impurity obtained
from the Test solution; and rs is the sum of the responses of all the
peaks obtained from the Test solution: not more than 0.1% of any Add the following:
other impurity is found; not more than 0.2% of total other impuri-
ties is found; and not more than 1.0% of total impurities (including A
torsemide related compounds A, B, and C) is found. Triamcmolone Diacetate Oral Solution
(Current monograph under this new title—to become of-
Change to read: ficial June 1, 2005)
Assay— (Current monograph title is Triamcinolone Diacetate
0.02 M Potassium phosphate buffer—Dissolve 2.7 g of Syrup)
monobasic potassium phosphate in about 900 mL of water.
Adjust with phosphoric acid to a pH of 3.5, dilute with water to
1000 mL, and mix.
Mobile phase—Prepare a filtered and degassed mixture of 0.02
M Potassium phosphate buffer and methanol (3:2). Make
Standard preparation—Transfer about 19 mg of USP Torsemide
7 *
A.USP26
Pharmacopeial Forum
» Triamcinolone Diacetate Oral Solution contains Assay—

not less than 90.0 percent and not more than 110.0 0.005 M Monobasic sodium phosphate solution, Mobile
percent of the labeled amount of triamcinolone phase, Standard preparation, System suitability
diacetate (C25H31FO8). It contains a suitable pre- preparation, and Chromatographic system—Proceed as

directed in the Assay under Triamcinolone Diacetate.
servative.
Assay preparation—Quantitatively transfer an accurately
Packaging and storage—Preserve in tight, light-resistant measured portion of Oral Solution, equivalent to about 50
containers. mg of triamcinolone diacetate to a 100-mL volumetric
USP Reference standards {11)—USP Triamcinolone Dia- flask. Dilute with Mobile phase to volume, and mix. Pipet
cetate RS. 4 mL of this solution into a 50-mL volumetric flask, dilute
Identification—Transfer a quantity of Oral Solution, with Mobile phase to volume, and mix. Transfer about 25
equivalent to about 10 mg of triamcinolone diacetate, to a mL of this solution to a 50-mL, glass-stoppered centrifuge
separator, and extract with three 10-mL portions of tube, and centrifuge at high speed for 10 minutes.
chloroform. Evaporate the combined chloroform extracts Procedure—Proceed as directed for Procedure in the
on a steam bath to dryness, and dissolve the residue in 5.0 Assay under Triamcinolone Diacetate. Calculate the
mL of chloroform. Apply 10 uL each of this solution and a quantity, in mg, of triamcinolone diacetate (C25H31FO8) in
solution of USP Triamcinolone Diacetate RS in chloroform the portion of Oral Solution taken by the formula:
containing 2 mg per mL to a suitable thin-layer \25C{rulrs),
chromatographic plate (see Chromatography (621))
coated with a 0.25-mm layer of chromatographic silica
Triamcinolone Diacetate RS in the Standard preparation;
gel. Allow the spots to dry, and develop the
and rv and rs are the peak responses obtainedfromthe Assay
chromatogram in a solvent system consisting of a mixture
of ethyl acetate and chloroform (9:1) until the solvent
ly- • USP26
front has moved about three-fourths of the length of the
plate. Remove the plate from the developing chamber,
mark the solvent front, and allow the solvent to evaporate.
Locate the spots on the plate by lightly spraying with dilute
sulfuric acid (1 in 2) and heating on a hot plate or under a
lamp until spots appear: the RF value of the principal spot
obtained from the test solution corresponds to that BRIEFING
obtained from the Standard solution.
Triamcinolone Diacetate Syrup, USP 25 page 1746. It is pro-
posed to change the title of this monograph to Triamcinolone Dia-
cetate Oral Solution. See also briefing under Amantadine
Pharmacopeial Forum
Triamcinolone Diacetate Syrup C: To 2 mL of a dilution of Oral Solution (1 in 20) add 5 mL of

sodium cobaltinitrite TS: a yellow precipitate is formed
(Current title—not to change until June 1, 2005) immediately (presence of potassium).
Monograph title change—to become official June 1, D: It responds to the tests for Citrate (191), 3 to 5 drops of
2005 Oral Solution and 20 mL of the mixture of pyridine and acetic
(see Official Title Changes on the first page of In-Pro- anhydride being used.
cess Revision):
See Triamcinolone Diacetate Oral Solution
BRIEFING
Trifluoperazine Hydrochloride Syrup, USP 25 page 1759. It

BRIEFING
is proposed to change the title of this monograph to Trifluoperazine
Oral Solution. See also briefing under Lincomycin Hydrochloride
Triazolam, USP 25 page 1751. Syrup.
(PA3: S. Salado) RTS—350876-1 (NL: C. Barnstein; PA3: S. Salado) RTS—35937-1
Erratum:
Assay, line 4 under Procedure: Change "C 17 H 13 C1N 4 " to:
Trifluoperazine Hydrochloride Syrup
C17H12C12N4 (Current title—not to change until June 1, 2005)
2005
cess Revision):
See Trifluoperazine Oral Solution
BRIEFING
Tricitrates Oral Solution, USP 25 page 1754. It is proposed to

replace cobalt-uranyl acetate TS in Identification test B with potas-
sium pyroantimonate TS, because cobalt-uranyl acetate TS is ra-
dioactive and difficult to obtain. BRIEFING
(PA4: A. Medjedovic) RTS—35476-1 Trifluoperazine Oral Solution—See briefing under Lincomy-

cin Hydrochloride Syrup.

Change to read:
Identification—
A: It responds to the flame test for Sodium (191).
B: To a mixture of 1 mL of Oral Solution with 1 mL of Add the following:
hydroohlorio aoid add 10 mL of cobalt uranylaootato TS, and otir A
well with a glaaa rod: a pale yellow, fino oryatallino prooipitato ia Trifluoperazine Oral Solution
formed within several minutes
A (Monograph under this new title—to become official
Add 2 mL of a solution of anhydrous potassium carbonate June 1, 2005)
(Current monograph title is Trifluoperazine Hydrochlor-
(15 in 100) to 2 mL of Oral Solution, boil, and cool. Add 4 ide Syrup)
mL of potassium pyroantimonate TS: a dense precipitate is
(presence of sodium).
Pharmacopeial Forum
» Trifluoperazine Oral Solution contains an hydrochloric acid to volume, and mix. Concomitantly
amount of trifluoperazine hydrochloride determine the absorbances of this solution and of a

Standard solution of USP Trifluoperazine Hydrochloride
(C21H24F3N3S • 2HC1) equivalent to not less than
RS in the same medium having a known concentration of
about 12 ug per mL in 1-cm cells at 278 nm and at the
the labeled amount of trifluoperazine
wavelength of maximum absorbance at about 255 nm,
(C2,H24F3N3S).
with a suitable spectrophotometer, using 0.1 N hydro-
Packaging and storage—Preserve in tight, light-resistant chloric acid as the blank. Calculate the quantity, in mg, of
containers. trifluoperazine (C 21 H 24 F 3 N 3 S) in each mL of the Oral
USP Reference standards {11)—USP Trifluoperazine Hy- Solution taken by the formula:
drochloride RS. [NOTE—Throughout the following proce- (407.51/480.43)(5CA%4255- AÛ/{A^ A

in)s,
dures, protect test or assay specimens, the Reference
Standard, and solutions containing them, by conducting
trifluoperazine and trifluoperazine hydrochloride, respec-
the procedures without delay, under subdued light, or using
tively; C is the concentration, in ug per mL, of USP Trifluo-
low-actinic glassware.]
perazine Hydrochloride RS in the Standard solution; Kis the
Identification—
volume, in mL, of Oral Solution taken; and the parenthetic
A: Ultraviolet absorption (197U)—
expressions are the differences in the absorbances of the two
Solution: Prepared as directed in the Assay.
solutions at the wavelengths indicated by the subscripts, for
B: Mix 1 mL of Oral Solution with 5 mL of methanol: a
the assay solution (U) and the Standard solution (S), respec-
5-uL portion of this solution meets the requirements of
tively.AKSPM
Identification test D under Trifluoperazine Hydrochloride. (Official June 1,2005)
Assay—[NOTE—Use low-actinic glassware.] Transfer an
accurately measured volume of Oral Solution, equivalent
BRIEFING
to about 50 mg of trifluoperazine, to a 250-mL separator
Trihexyphenidyl Hydrochloride Elixir, USP 25 page 1764. It
with the aid of about 100 mL of water. Add 10 mL of is proposed to change the title of this monograph to Trihexypheni-
dyl Hydrochloride Oral Solution. See also briefing under Amanta-
sodium hydroxide solution (1 in 10), and extract with dine Hydrochloride Syrup.
three 50-mL portions of cyclohexane. Wash the combined (NL: C. Barnstein; PA3: S. Salado) RTS—35998-1
cyclohexane extracts with about 20 mL of water, and
discard the water washing. Extract the combined
Trihexyphenidyl Hydrochloride Elixir
cyclohexane extracts with four 50-mL portions of 0.1 N
{Current title—-not to change until June 1,2005)
hydrochloric acid, collecting the aqueous extracts in a Monograph title change—to become official June 1,
2005
500-mL volumetric flask. Dilute with 0.1 N hydrochloric (see Official Title Changes on the first page of In-Pro-
cess Revision):
acid to volume, and mix. Transfer 10.0 mL of this See Trihexyphenidyl Hydrochloride Oral Solution
solution to a 100-mL volumetric flask, dilute with 0.1 N
Pharmacopeia! Forum
B: The retention time exhibited by trihexyphenidyl

hydrochloride in the chromatogram of the Assay
BRIEFING
preparation corresponds to that of the Standard
Trihexyphenidyl Hydrochloride Oral Solution—See briefing
under Amantadine Hydrochloride Syrup. preparation, both relative to the internal standard, as
(NL: C. Bamstein; PA3: S. Salado) RTS—35998-1 obtained in the Assay.
Add the following: Alcohol content (611): between 90.0% and 110.0% of the
A labeled amount of C2H5OH.
Trihexyphenidyl Hydrochloride Oral
Solution Assay—
(Monograph under this new title—to become official Mobile phase and Chromatographic system—Prepare as
June 1, 2005)
(Current monograph title is Trihexyphenidyl Hydro- directed in the Assay under Trihexyphenidyl Hydrochloride.
chloride Elixir)
quantity of USP Trihexyphenidyl Hydrochloride RS in
» Trihexyphenidyl Hydrochloride Oral Solution
methanol, and dilute quantitatively, and stepwise if
contains not less than 90.0 percent and not more
necessary, with methanol to obtain a solution having a
than 110.0 percent of trihexyphenidyl hydrochlor-
ide (C20H31NO • HC1). Assay preparation—Transfer an accurately measured
Packaging and storage—Preserve in tight containers. volume of Oral Solution, equivalent to about 2 mg of
USP Reference standards (11)—USP Trihexyphenidyl trihexyphenidyl hydrochloride, to a 25-mL volumetric
Hydrochloride RS. flask, dilute with methanol to volume, and mix.

Identification—
Assay under Trihexyphenidyl Hydrochloride. Calculate the
A: To 50 mL of Oral Solution add 50 mL of water and
quantity, in mg, of trihexyphenidyl hydrochloride
50 mL of 1 N sodium hydroxide, and stir. Cool the mixture
at 4° to 5° for 30 minutes: a white precipitate or cloudiness (C 20 H 31 NOHC1) in each mL of the Oral Solution taken
is observed. Add 100 mL of water to the cooled mixture, by the formula:
stir, and filter by means of vacuum through a 47-mm {25CIV)(rvlrs\

membrane filter of 1-um pore size. Wash the crystals with
in which Fis the volume, in mL, of Oral Solution taken to
about 100 mL of water, and allow to air-dry: the IR
prepare the Assay preparation, and the other terms are as
absorption spectrum of a potassium bromide dispersion of
defined therein. AUSP26
the crystals so obtained exhibits maxima only at the same (Official June 1,2005)
wavelengths as that of the crystalline base obtained from
about 20 mg of USP Trihexyphenidyl Hydrochloride RS,
similarly prepared and measured.
Pharmacopeial Forum
the ether by warming, and dissolve the residue in 5 mL of

BRIEFING methanol: 5 uL of this solution meets the requirements of
Trimeprazine Oral Solution—See briefing under Lincomycin Identification test C under Trimeprazine Tartrate.
(NL: C. Bamstein; PA6: S. Dressman) RTS—35938-1
C2H5OH.
Limit of trimeprazine sulfoxide—
Add the following:
A
Trimeprazine Oral Solution directed in the Assay.
(Monograph under this new title—to become official Standard solution—Transfer about 60.6 mg of USP
June 1, 2005)
(Current monograph title is Trimeprazine Tartrate Syrup) Trimeprazine Tartrate RS, accurately weighed, to a 50-mL
volumetric flask. Add 5 mL of dilute hydrochloric acid (1 in

» Trimeprazine Oral Solution contains an amount 100) followed by 2 mL of 30 percent hydrogen peroxide,
of trimeprazine tartrate [(C18H22N2S)2 • C4H6O6] and heat at 60° for 10 minutes. Cool, dilute with 1 M
equivalent to not less than 90.0 percent and not sodium bisulfite to volume, and mix. Transfer 10.0 mL to
more than 110.0 percent of the labeled amount a 60-mL separator, add 2 mL of sodium hydroxide
solution (1 in 2), and mix. Extract with three 30-mL
of trimeprazine (C,8H22N2S).
portions of ether. Filter the extracts through ether-wetted
Packaging and storage—Preserve in tight, light-resistant anhydrous sodium sulfate into a 250-mL conical flask.
containers. Cautiously evaporate the flask to dryness. Dissolve the
USP Reference standards (11)—USP Trimeprazine Tar- residue in 10.0 mL of methanol, and filter if necessary.
trate RS. Each mL of this solution contains about 1 mg of
NOTE—Throughout the following procedures, protect test trimeprazine sulfoxide. Transfer 1.0 mL of this solution to
or assay specimens, the Reference Standard, and solutions a 500-mL volumetric flask, dilute with Mobile phase to
containing them, by conducting the procedures without de- volume, and mix to obtain a solution containing about
lay, under subdued light, or using low-actinic glassware. 0.0024 mg per mL of trimeprazine sulfoxide, expressed as
Identification— trimeprazine tartrate.
A: The retention time of the major peak in the Test solution—Use the Assay preparation as directed in
chromatogram of the Assay preparation corresponds to the Assay.
that in the chromatogram of the Standard preparation, as Procedure—Separately inject equal volumes (about 25
obtained in the Assay. uL) of the Standard solution and the Test solution into the
B: Mix 10 mL of Oral Solution with about 30 mL of chromatograph, record the chromatograms, and measure the
water in a separator, render the solution alkaline with 1 N responses for the peaks. The Test solution may exhibit a
sodium hydroxide, and extract with two 30-mL portions minor peak whose retention time corresponds to the peak
of ether. Transfer the ether extracts to a beaker, evaporate exhibited by the Standard solution and whose retention
Pharmacopeia! Forum
time is about 0.6 relative to the main peak. Calculate the tartrate, respectively; and ru and rs are the peak responses
concentration, in mg per mL, of trimeprazine sulfoxide, in obtained from the Assay preparation and the Standard pre-
the portion of Oral Solution taken by the formula: paration, respectively.AUS.P2(j
100(C/F)(596.89/746.98)(rc//r5),
in which C is the concentration, in mg per mL, of trimepra-

zine tartrate in the Standard solution; Fis the volume, in
mL, of Oral Solution taken; 596.89 and 746.98 are the mo-
lecular weights of trimeprazine and trimeprazine tartrate, re-
spectively; and rv and rs are the peak responses obtained BRIEFING
from the Test solution and the Standard solution, respec- Trimeprazine Tartrate Syrup, USP 25 page 1766. It is pro-
posed to change the title of this monograph to Trimeprazine Oral
tively. Not more than 0.036 mg per mL is found. Solution. See also briefing under Lincomycin Hydrochloride Syrup.
Assay—
(NL: C. Bamstein; PA6: S. Dressman) RTS—35938-1
Mobile phase, Standard preparation, and Chro-
matographic system— Proceed as directed in the Assay
Trimeprazine Tartrate Syrup
under Trimeprazine Tartrate.
Assay preparation—Using a "to contain" pipet, transfer Monograph title change—to become official June 1,
2005
an accurately measured volume of Oral Solution, equivalent (see Official Title Changes on the first page of In-Pro-
cess Revision):
to about 2.5 mg of trimeprazine, to a 100-mL volumetric See Trimeprazine Oral Solution
flask containing 50 mL of Mobile phase. Rinse the pipet
with Mobile phase, collecting the rinses in the volumetric
flask. Dilute with Mobile phase to volume, and mix.
uL) of the Standard preparation and the Assay prep-
aration into the chromatograph, record the chromato- BRIEFING
grams, and measure the responses for the major peaks. Trimethoprim, USP 25 page 1768. A revision is proposed for
the test for Chromatographic purity in order to establish a more
Calculate the quantity, in mg, of trimeprazine (C18H22N2S) meaningful resolution requirement. The current resolution require-
ment is not meaningful when the chromatogram for the Test solu-
in each mL of Oral Solution taken by the formula: tion contains no measurable impurity peaks. Also, a change to the
column dimensions is proposed because the current column dimen-
100(C/F)(596.89/746.98)(rc//r5), sions are not readily available in the United States. The flow rate is
being changed to decrease the total run time of the method. The
relative retention time for diaveridine is 0.9 (trimethoprim = 1.0),
in which C is the concentration, in mg per mL, of USP Tri- when obtained on a Hypersil C18 BDS brand of LI column.
meprazine Tartrate RS in the Standard preparation; Fis the (PA6: S. Dressman) RTS—34961-1
volume, in mL, of Oral Solution taken; 596.89 and 746.98
are the molecular weights of trimeprazine and trimeprazine
Change to read:
Buffer solution—Prepare a 10 mM sodium perchlorate solution
in water, adjust with phosphoric acid to a pH of 3.6, and mix.
Pharmacopeial Forum
Mobile phase—Prepare afilteredand degassed mixture of Buffer

solution and methanol (7:3). Make adjustments if necessary (see BRIEFING
Triprolidine Hydrochloride Oral Solution—See briefing un-
^Resolution solution—Dissolve accurately weighed der Amantadine Hydrochloride Syrup.
quantities of USP Trimethoprim RS and diaveridine, and
(NL: C. Bamstein; AER: K. Zaidi) RTS—35999-1
Mobile phase to obtain a solution having known
Add the following:
concentrations of about 10 jig per mL and 5 ug per mL, A
respectively.AasPM
Triprolidine Hydrochloride Oral
Solution
Test solution—Transfer about 25.0 mg of Trimethoprim,
accurately weighed, to a 25-mL volumetric flask, dissolve in and (Monograph under this new title—to become official
dilute with Mobile phase to volume, and mix. June 1, 2005)
Chromatographic system (see Chromatography (621))—The (Current monograph title is Triprolidine Hydrochloride
liquid chromatograph is equipped with a 280-nm detector and a Syrup)
*r?rr"" 1 riiiT
x 25-cm column that contains base-deactivated packing LI. The » Triprolidine Hydrochloride Oral Solution con-
flow rate is about 1
1
-->AUSP26
tains not less than 90.0 percent and not more than
mL per minute. Chromatograph the Test solution
110.0 percent of the labeled amount of triprolidine
^Resolution solution,AUSP26
and record the peak responses as directed for Procedure: the reso- hydrochloride (C19H22N2 • HC1 • H2O).
lution, R, between the trirnothoprim poak and any other peak
A
peaks for trimethoprim and diaveridineAVSP26
is not less than 2.5; and the relative standard deviation for replicate Packaging and storage—Preserve in tight, light-resistant
Procedure—Inject a volume (about 20 uL) of the Test solution containers.
into the chromatograph, record the chromatogram for not less than
11 times the retention time of the trimethoprim peak, and measure USP Reference standards {11)—USP Triprolidine Hydro-
all of the peak responses. Calculate the percentage of each impurity
in the portion of Trimethoprim taken by the formula: chloride RS.
100{Fr,./[E(Fr,) + Fr r ]}, Identification—
in which F is a relative response factor, and is equal to 0.5 for any
peak having a relative retention time of 0.9,2.3,2.7, or 10.3, and is A: Transfer a volume of Oral Solution, equivalent to
equal to 1.0 for all other peaks; r, is the peak response for each
impurity; and rT is the peak response for trimethoprim obtained about 12 mg of triprolidine hydrochloride, to a 125-mL
from the Test solution: not more than 0.1% of any individual im-
purity is found; and not more than 0.2% of total impurities is found. separator, add 25 mL of water, then add 4 mL of sodium
hydroxide solution (1 in 2), and mix. Add 10 mL of
cyclohexane, shake, allow the phases to separate
completely, and discard the aqueous layer. Transfer 8 mL
of the cyclohexane solution to a glass-stoppered, 25-mL
conical flask, evaporate on a steam bath with the aid of a
current of air to dryness, and continue to heat the flask for
about 1 minute after the solvent has completely evaporated.
Cool, add 2 mL of cyclohexane, and mix: the IR absorption
spectrum of the cyclohexane solution so obtained exhibits
maxima only at the same wavelengths as that of a similar
preparation of USP Triprolidine Hydrochloride RS.
Pharmacopeial Forum
peaks. Calculate the quantity, in mg, of triprolidine

hydrochloride (C, 9 H 22 N 2 -HC1-H 2 O) in the portion of
obtained in the Assay. (332.88/314.86X50CXV rs),
pH (791): between 5.6 and 6.6. in which 332.88 and 314.86 are the molecular weights of
Alcohol content, MethodII (611): between 3.0% and 5.0% triprolidine hydrochloride monohydrate and anhydrous tri-
ofC2H5OH. prolidine hydrochloride, respectively; C is the concentra-
Assay— tion, in mg per mL, calculated on the anhydrous basis, of
Mobile phase—Prepare a suitable degassed and filtered USP Triprolidine Hydrochloride RS in the Standard pre-
mixture of alcohol and ammonium acetate solution (1 in paration; and rv and rs are the peak responses obtained from
250) (17:3). the Assay preparation and the Standard preparation, re-
Standard preparation—Dissolve an accurately weighed spectively. AUSP26

quantity of USP Triprolidine Hydrochloride RS in 0.01 N
hydrochloric acid, and dilute quantitatively and stepwise
with 0.01 N hydrochloric acid to obtain a solution having
a known concentration of about 0.05 mg of anhydrous
USP Triprolidine Hydrochloride RS per mL.
BRIEFING
volume of Oral Solution, equivalent to about 2.5 mg of
Triprolidine Hydrochloride Syrup, USP 25 page 1773. It is
triprolidine hydrochloride, to a 50-mL volumetric flask, proposed to change the title of this monograph to Triprolidine Hy-
dilute with 0.01 N hydrochloric acid to volume, and mix. Hydrochloride Syrup.
(NL: C. Barnstein;; AER: K. Zaidi) RTS—35999-1
packing L3. The flow rate is about 1.5 mL per minute.
Triprolidine Hydrochloride Syrup
Chromatograph five replicate injections of the Standard Monograph title change—to become official June 1,
2005
preparation, and record the peak responses as directed for (see Official Title Changes on the first page of In-Pro-
cess Revision):
Procedure: the relative standard deviation is not more See Triprolidine Hydrochloride Oral Solution
than 2.0%; and the tailing factor is not more than 1.5.
\xL) of the Standard preparation and the Assay
Pharmacopeial Forum
» Triprolidine and Pseudoephedrine Hydrochlor-

BRIEFING
ides Oral Solution contains not less than 90.0 per-
Triprolidine Hydrochloride Tablets, USP 25 page 1773. Edi-
torial revisions are indicated to conform with the title change pro- cent and not more than 110.0 percent of the
posed for Triprolidine Hydrochloride Syrup. See also briefing
labeled amounts of triprolidine hydrochloride
(NL: C. Barnstein; AER: K. Zaidi) RTS—36000-1 (C19H22N2 • HC1 • H2O) and pseudoephedrine hy-
drochloride (C10H15NO • HC1).
Change to read: Packaging and storage—Preserve in tight, light-resistant
Assay—
Mobile phase and Standard preparation—Prepare as directed in containers.
the Assay under Triprolidine Hydrochloride Symp
A
Oral Solution. ±USP26 USP Reference standards {11)—USP Triprolidine Hydro-
Assay preparation—Weigh and finely powder not fewer than 20
Tablets. Transfer an accurately weighed portion of the powder, chloride RS. USP Pseudoephedrine Hydrochloride RS.
equivalent to about 5.0 mg of triprolidine hydrochloride, to a
100-mL volumetric flask. Add about 10 mL of 0.01 N Identification—
hydrochloric acid, and sonicate for 10 minutes. Cool to room
temperature. Dilute with 0.01 N hydrochloric acid to volume, A: The retention times of the major peaks in the
mix, and filter.
Chromatographic system and Procedure—Proceed as directed chromatogram of the Assay preparation correspond to
in the Assay under Triprolidine Hydrochloride Syrup
A those in the chromatogram of the Standard preparation,
Oral Solution,AUSP26
except to calculate the quantity, in mg, of triprolidine hydrochlor- as obtained in the Assay.
ide (C, 9 H 22 N 2 • HC1 • H2O) in the portion of Tablets taken by the
formula: B: Transfer 10 mL of Oral Solution to a suitable glass-
(332.88/314.86)(100q(r c//r5),
stoppered tube, add 10 mL of ether and 2 mL of 1 N sodium
in which 332.88 and 314.86 are the molecular weights of triproli-
dine hydrochloride monohydrate and anhydrous triprolidine hy- hydroxide, shake for 5 minutes, and allow the layers to
drochloride, respectively; C is the concentration, in mg per mL,
calculated on the anhydrous basis, of USP Triprolidine Hydro- separate. The ether layer is the test solution. Prepare a
chloride RS in the Standard preparation; and rv and rs are the peak
responses obtained from the Assay preparation and the Standard Standard solution in water of USP Pseudoephedrine
preparation, respectively.
Hydrochloride RS and USP Triprolidine Hydrochloride
RS having known concentrations of 6 mg per mL and 250
ug per mL, respectively. Separately apply 10-uL portions of
BRIEFING the test solution and the Standard solution to a suitable thin-
Triprolidine and Pseudoephedrine Hydrochlorides Oral So- layer chromatographic plate (see Chromatography (621))
lution—See briefing under Amantadine Hydrochloride Syrup.
mixture. Allow the spots to dry, and develop the
chromatogram in a solvent system consisting of a mixture
Add the following:
of butyl alcohol, glacial acetic acid, and water (8:2:2)
A
Triprolidine and Pseudoephedrine until the solvent front has moved about three-fourths of
Hydrochlorides Oral Solution the length of the plate. Remove the plate, mark the
June 1, 2005) solvent front, allow the solvent to evaporate, and examine
(Current monograph title is Triprolidine and Pseudo-
ephedrine Hydrochlorides Syrup) the plate under short-wavelength and long-wavelength UV
Pharmacopeial Forum
light: the RF values of the principal spots obtained from the Procedure—Separately inject equal volumes (about 10
test solution correspond to those obtained from the Standard uL) of the Standard preparation and the Assay
solution. preparation into the chromatograph, record the
Assay— chromatograms, and measure the responses for the major
Mobile phase—Prepare a filtered and degassed mixture of peaks. The relative retention times are about 0.68 for
alcohol and 0.40% ammonium acetate solution (17:3). pseudoephedrine hydrochloride and 1.0 for triprolidine
Make adjustments if necessary (see System Suitability hydrochloride. Calculate the quantity, in mg, of
under Chromatography (621)). pseudoephedrine hydrochloride (C10H15NO-HC1) in the
Standard preparation—Dissolve accurately weighed portion of Oral Solution taken by the formula:
quantities of USP Pseudoephedrine Hydrochloride RS and

USP Triprolidine Hydrochloride RS in 0.01 N hydrochloric
acid, and dilute quantitatively and stepwise with 0.01 N
Pseudoephedrine Hydrochloride RS in the Standard pre-
hydrochloric acid to obtain a solution having known
paration; and rv and rs are the peak responses for pseudo-
concentrations of about 1.2 mg of USP Pseudoephedrine
ephedrine hydrochloride obtained from the Assay
Hydrochloride RS per mL and about 0.05 mg of
preparation and the Standard preparation, respectively.
anhydrous USP Triprolidine Hydrochloride RS per mL,
Calculate the quantity, in mg, of triprolidine hydrochloride
and filter.
(C19H22N2 • HC1 • H2O) in the portion of Oral Solution taken
by the formula:
pseudoephedrine hydrochloride, to a 50-mL volumetric (332.88 / 314.86)(50C)(r(;/ rs),
flask, dilute with 0.01 N hydrochloric acid to volume, and in which 332.88 and 314.86 are the molecular weights of
mix. triprolidine hydrochloride monohydrate and anhydrous tri-
Chromatographic system (see Chromatography (621))— prolidine hydrochloride, respectively; C is the concentra-
The liquid chromatograph is equipped with a 254-nm tion, in mg per mL, calculated on the anhydrous basis, of
detector and a 4.6-mm x 25-cm column that contains USP Triprolidine Hydrochloride RS in the Standard pre-
packing L3. The flow rate is about 1.5 mL per minute. paration; and rv and rs are the peak responses for triproli-
Chromatograph replicate injections of the Standard dine hydrochloride obtained from the Assay preparation
preparation, and record the peak responses as directed for and the Standard preparation, respectively.^^**
Procedure: the relative standard deviation is not more (Official June 1,2005)
than 2.0%; and the resolution factor between triprolidine
and pseudoephedrine is not less than 2.0. The tailing
factor for the triprolidine peak is not more than 2.0, and
the tailing factor for pseudoephedrine peak is not more
than 2.0.
Pharmacopeial Forum
Procedure—Inject an accurately measured volume (about 200

uL) of a filtered portion of the solution under test into the
BRIEFING chromatograph by means of a microsyringe or a sampling valve,
record the chromatogram, and measure the responses for the
Triprolidine and Pseudoephedrine Hydrochlorides Syrup, major peaks. Calculate the quantities of pseudoephedrine
USP 25 page 1774. It is proposed to change the title of this monohydrochloride ( C , Q H , ^ N O - H C 1 ) and triprolidine hydrochloride
graph to Triprolidine and Pseudoephedrine Hydrochlorides Oral (C, 9 H 22 N 2 -HC1 H2O) dissolved in comparison with a Standard
Solution. See also briefing under Amantadine Hydrochloride Syr- solution having known concentrations of" USP Pseudoephedrine
up. Hydrochloride RS and USP Triprolidine Hydrochloride RS in
the same medium and similarly chromatographed.
(NL: C. Barnstein; AER: K. Zaidi) RTS—36001-1 Tolerances—Not less than 75% (Q) of the labeled amounts of
C l 0 H 1 5 NO-HCl and C 19 H 22 N 2 -HC1-H 2 O is dissolved in 45
minutes.
Change to read:
Triprolidine and Pseudoephedrine
Hydrochlorides Syrup Assay—
Mobile phase and Standard preparation—Prepare as directed in
(Current title—not to change until June 1, 2005) the Assay under Triprolidine and Pseudoephedrine Hydrochlorides
2005 A
(see Official Title Changes on the first page of In-Pro- Oral Solution AUSP26
cess Revision): Assay preparation—Weigh and finely powder not fewer than 20
See Triprolidine and Pseudoephedrine Hydrochlorides Tablets. Transfer an accurately weighed portion of the powder,
Oral Solution equivalent to about 120 mg of pseudoephedrine hydrochloride,
to a 100-mL volumetric flask. Add about 10 mL of 0.01 N
hydrochloric acid, and sonicate for 10 minutes. Cool to room
temperature. Dilute with 0.01 N hydrochloric acid to volume,
mix, and filter.
Chromatographic system (see Chromatography (621)) and
Procedure—Proceed as directed in the Assay under Triprolidine
and Pseudoephedrine Hydrochlorides Syntp
A
Oral Solution, AUSP26
except to calculate the quantity, in mg, of pseudoephedrine hydro-
chloride (C10H15NO • HC1) in the portion of Tablets taken by the
formula:
BRIEFING
l00Ci.ru/rs),
Triprolidine and Pseudoephedrine Hydrochlorides Tablets, in which C is the concentration, in mg per mL, of USP Pseudo-
USP 25 page 1774. Editorial revisions are indicated to conform ephedrine Hydrochloride RS in the Standard preparation; and rv
with the title change proposed for Triprolidine and Pseudo- and rs are the peak responses for pseudoephedrine hydrochloride
ephedrine Hydrochlorides Syrup. See also briefing under Amanta- obtained from the Assay preparation and the Standard prepara-
dine Hydrochloride Syrup. tion, respectively. Calculate the quantity, in mg, of triprolidine hy-
drochloride (C19H22N2 • HC1 • H2O) in the portion of Tablets taken
(NL: C. Bamstein; AER: K. Zaidi) RTS—36002-1 by the formula:
(332.88/314.86)(100Q(r £/ /r 5 ),
in which 332.88 and 314.86 are the molecular weights of triproli-
dine hydrochloride monohydrate and anhydrous triprolidine hy-
Change to read: drochloride, respectively; C is the concentration, in mg per mL,
calculated on the anhydrous basis, of USP Triprolidine Hydro-
Dissolution, Procedure for a Pooled Sample (711)— chloride RS in the Standard preparation; and rv and rs are the peak
Medium: water; 900 mL. responses for triprolidine hydrochloride obtained from the Assay
Apparatus 2: 50 rpm. preparation and the Standard preparation, respectively.
lime: 45 minutes.
Determine the amounts of pseudoephedrine hydrochloride and (Official June 1, 2005)
triprolidine hydrochloride dissolved using the following method.
directed in the Assay under Triprolidine and Pseudoephedrine
Hydrochlorides Syntp.
A
Oral Solution. AUSP26
Pharmacopeial Forum
Assay—
BRIEFING
Valproic Acid Oral Solution—See briefing under Amantadine Chromatographic system—Prepare as directed in the
Assay under Valproic Acid Capsules.
Add the following:
valproic acid, to a separator. Add 40 mL of water and 2
A
Valproic Acid Oral Solution mL of hydrochloric acid, mix, and extract gently with 80
(Monograph under this new title—to become official mL of n -heptane until the aqueous layer is clear (about 3
June 1, 2005)
(Current monograph title is Valproic Acid Syrup) minutes). Filter the n -heptane layer through glass wool,
collecting the filtrate in a 100-mL volumetric flask. Rinse
» Valproic Acid Oral Solution contains not less the separator and the glass wool with small portions of n -
than 90.0 percent and not more than 110.0 percent heptane, add the rinsings to the flask, dilute with n -heptane
of the labeled amount of valproic acid (C8H16O2). to volume, and mix. Transfer 5.0 mL to a container
It is prepared with the aid of Sodium Hydroxide. equipped with a closure. Add 2.0 mL of Internal standard
solution, close the container, and mix.
USP Reference standards (11 )—USP Valproic Acid RS. of the Standard preparation and the Assay preparation into
Identification— the chromatograph, record the chromatograms, and measure
A: The retention time ratios of the valproic acid peak to the peak responses for valproic acid and biphenyl. Calculate
the internal standard peak obtained from the Standard the quantity, in mg, of valproic acid (C8H16O2) in each mL
preparation and the Assay preparation as directed in the of the Oral Solution taken by the formula:
Assay do not differ by more than 2.0%.
B: Place a volume of Oral Solution, equivalent to about
250 mg of valproic acid, in a separator. Add 40 mL of water in which C is the concentration, in mg per mL, of USP Val-
and 2 mL of hydrochloric acid, mix, and extract with 40 mL proic Acid RS in the Standard preparation; Fis the volume,
of n-heptane. Filter the n-heptane layer through glass wool in mL, of Oral Solution taken; and Rv and Rs are the peak
into a beaker, and evaporate the solvent completely on a response ratios obtained from the Assay preparation and the
steam bath with the aid of a current of air. Transfer 2 Standard preparation, respectively.AUSP26
drops of the residue to a test tube containing 0.5 mL each
of potassium iodide solution (1 in 50) and potassium
iodate solution (1 in 25), and mix: a yellow color is
produced.
Pharmacopeia! Forum
» Valsartan contains not less than 98.0 percent and

BRIEFING
not more than 102.0 percent of C24H29N5O3, cal-
Valproic Acid Syrup, USP 25 page 1791. It is proposed to
change the title of this monograph to Valproic Acid Oral Solution. culated on the anhydrous basis.
(NL: C. Barnstein;; PA3: S. Salado) RTS—36003-1 Packaging and storage—Preserve in well-closed

containers.
Valproic Acid Syrup USP Reference standards (11)—USP Valsartan RS. USP
(Current title—not to change until June 1,2005) Valsartan Related Compound A RS. USP Valsartan Related
2005 Compound B RS. USP Valsartan Related Compound C RS.
cess Revision): Identification—
See Valproic Acid Oral Solution
A: Infrared Absorption (197M).
Absorbance: not more than 0.070, determined at 420 nm, in

BRIEFING
a 4-cm cell, on a solution prepared by dissolving 1 g in 20
Valsartan, page 8076 of PF 25(3) [May-June 1999]. This new
monograph, which previously appeared in Pharmacopeial Pre- mL of methanol.
views, is now forwarded to In-Process Revision with minor proce-
dural and editorial changes: the calculations for the tests for Specific rotation (78IS): between -64° and -69° at 20°.
Related compounds have been clarified, including a change in Test
2 of the analysis wavelength and the requirement for the relative Test solution: 10 mg per mL, in methanol.
standard deviation; also the analysis wavelength in the Assay has
been revised. Water, Method I (921): not more than 2.0%.
(PA5:J. Esker) RTS—30743-1 Residue on ignition (281): not more than 0.1%.
Add the following: Related compounds—
A
Valsartan TEST 1 (LIMIT OF VALSARTAN RELATED COMPOUND A)—
(Graphic formula to come) 0.07 MPhosphate buffer solution—Dissolve 10.99 g of

dibasic sodium phosphate and 3.81 g of monobasic
435.52
potassium phosphate in water, dilute with water to 1000
L-Valine, N-(l-oxopentyl)-iV-[[2'-(l//--tetrazol-5-yl)[l, 1 '-bi-
mL, and mix.
phenyl]-4-yl]methyl]-;
JV-[p-(o-l//-Tetrazol-5-yl-phenyl)benzyl]-iV-valeryl-L-va-
0.07 M Phosphate buffer solution and isopropyl alcohol
line [137862-53-4].
(98:2). Make adjustments if necessary (see System
Pharmacopeia! Forum
System suitability solution—Transfer about 30 mg of USP and record the peak responses as directed for Procedure:
Valsartan Related Compound A, accurately weighed, to a the relative retention times are 0.60 for valsartan related
100 mL volumotrio flask; and dissolve in and dilute with compound A and 1.0 for valsartan; the ratio of the height
Mobile phase to volume. Pipot 5:0 mL of this solution between the baseline and the lowest point between the
into a 50 mL volumetric flask, and dilute with Mobile valsartan and valsartan related compound A peaks to the
phase to volume (Solution 1). Transfer about 15 mg of height of the valsartan related compound A peak is not
USP Valoartan RS, aoouratoly weighed, to a 100 mL more than 0.4. aad Chromatograph the Standard solution,
volumotrio flaskjand dissolve in Mobile phase. Add, by and record the peak responses as directed for Procedure:
pipetting, 10.0 mL of Solution 1 to the same flask, dilute the relative standard deviation, determined from the
with Mobile phase to volume, and mix. Dissolve valsartan related compound A peaks, for replicate
accurately weighed quantities of USP Valsartan RS and injections is not more than 15.0%.
USP Valsartan Related Compound A RS in Mobile phase, Procedure—Separately inject equal volumes (about 10
serially diluting, if necessary, to obtain a solution having a uL) of the Standard solution and the Test solution into the
known concentration of about 0.15 mg of valsartan per mL chromatograph, record the chromatograms, and measure the
and about 0.003 mg of valsartan related compound A per heights for the major peaks. Calculate the percentage of
mL. valsartan related compound A in the portion of Valsartan
Standard solution—Pipot 5.0 mL of System suitability taken by the formula:
solution into a 50 mL volumetric flask, dilute with Mobile
phase to volume, and mix. Dissolve an accurately weighed
in whioh r^ and ^ aro tho peak rooponsoo obtained from tho
quantity of USP Valsartan Related Compound A RS in
Test solution and the Standard solution; respectively: not
Mobile phase, and dilute quantitatively, and stepwise if
more than 1.5% is found.
necessary, to obtain a solution having a known
concentration of about 0.003 mg of valsartan related
compound A per mL.
in which Cs is the concentration, in mg per mL, of USP Val-
Test solution—Transfer about 100 mg of Valsartan,
sartan Related Compound A RS in the Standard solution;
accurately weighed, to a 100-mL volumetric flask,
Cv is the concentration, in mg per mL, of valsartan in the
dissolve in and dilute with Mobile phase to volume, and
Test solution; and rv and rs are the peak responses for val-
mix. Pipet 5.0 mL of this solution into a 25-mL
sartan related compound A obtained from the Test solution
volumetric flask, dilute with Mobile phase to volume, and
and Standard solution, respectively: not more than 1.5% is
mix.
found.
TEST 2 (LIMIT OF VALSARTAN RELATED COMPOUND B,
VALSARTAN RELATED COMPOUND C,AND OTHER RELATED
COMPOUNDS)—
Diluent and • Mobile phase—Proceed as directed in the
minute. Chromatograph the System suitability solution,
Assay.
Pharmacopeial Forum
Standard stock solution -A—Dissolve an aoouratoly weighed Test solution—Transfer about 50 mg of Valsartan,
quantity of USP Valsartan RS in Mobile phase to obtain a solution accurately weighed, to a 100-mL volumetric flask,
having a known concentration of about 5 mg pormL: dissolve in and dilute with Mobile phase to volume, and
Standard stock solution B—Dissolve an aoouratoly weighed mix.
quantity of USP Valsartan Related Compound B RS in Mobile Chromatographic system (see Chromatography {621))—
phase, and diluto quantitatively, and stepwiso if necessary; to Prepare as directed in the Assay, except to use a 225-nm
obtain a solution having a known concentration of about 0:05 detector. Chromatograph the Resolution solution, and
mgper mlr record the peak responses as directed for Procedure: the
Standard stock solution C—Dissolve an aoouratoly woighed relative retention times are 0.73 for valsartan related
quantity of USP Valsartan Related Compound C RS in Mobile compound B, 1.0 for valsartan, and 3.8 for valsartan
phase; and diluto quantitatively, and stopwiso if necessary, to related compound C; the resolution, R, between valsartan
obtain a solution having a known concentration of about 0;025 related compound B and valsartan is not less than 1.8; and
mg por mix the relative standard deviation, determined from the
Resolution solution—Pipot 10.0 mL of Standard stock valsartan related compound B peaks, for replicate
solution A, 5.0 mL of Standard stock solution B, and 2.0 injections is not more than 5.0% 10.0%.
mL of Standard stock solution C into a 100 mL Procedure—Separately inject equal volumes (about 10
volumotrio flaok, diluto with Mobile phase to volumo, and uL) of the Resolution solution, the Standard solution, and
mix. Dissolve accurately weighed quantities of USP the Test solution into the chromatograph, record the
Valsartan RS, USP Valsartan Related Compound B RS, chromatograms, and measure the areas for the major
and USP Valsartan Related Compound C RS in Mobile peaks. Calculate the percentage of each impurity valsartan
phase, serially diluting if necessary, to obtain a solution related compound B and valsartan related compound C in
having known concentrations of about 0.5 mg of valsartan the portion of Valsartan taken by the formula:
per mL, 0.0025 mg of valsartan related compound B per
mL, and 0.0005 mg of valsartan related compound C per
in whioh D is the faotor duo to the oxtont of dilution and is
mL.
equal to 2.5 for valsartan related oompound B; 0.5 for val
Standard solution—Diluto an accurately measured
sartan related oompound Q and 0.05 for all other impurities;
volumo of Standai'd stock solution A quantitatively, and
r4 is the peak response for each impurity obtained from the
stopwisoif nooosoary^ with Mobile phase to obtain a
Test solution; and r9is the peak response for valaartan re-
solution having a known concentration of about 0.0005
lated oompound B or valsartan related oompound C ob-
mg por mL. Dissolve an accurately weighed quantity of
tained from the Resolution solution or the valsartan peak
USP Valsartan RS in Mobile phase, and dilute
response obtained from tho Standard solution, as appropri
quantitatively, and stepwise if necessary, to obtain a
titU.'
solution having a known concentration of about 0.0005
mg of valsartan per mL.
Pharmacopeia! Forum
in which Cs is the concentration, in mg per mL, of the ap- mix. Pipet 10.0 mL of this solution into a 100-mL
propriate USP Valsartan Related Compound RS in the Re- volumetric flask, dilute with Mobile phase to volume, and
solution solution; Cv is the concentration, in mg per mL, of mix.
valsartan in the Test solution; r, is the peak response for the Chromatographic system—The liquid chromatograph is
impurity obtained from the Test solution; and rs is the peak equipped with a 230 nm 248-nm detector and a 3.0-mm
response for the appropriate valsartan related compound ob- x 12.5-cm column that contains 5-um packing LI. The
tained from the Resolution solution. Calculate the percen- flow rate is about 0.4 mL per minute. Chromatograph the
tage of each other impurity in the portion of Valsartan Standard preparation, and record the peak responses as
taken by the formula: directed for Procedure: the tailing factor is between 0.8
and 1.5; and the relative standard deviation for replicate
sartan RS in the Standard solution; rs is the peak response
for valsartan obtained from the Standard solution; and the
other terms are as defined above: not more than 0.5% of val-
sartan related compound B is found; not more than 0.1% of
peaks. Calculate the quantity, in mg, of C24H29N5O3 in the
valsartan related compound C is found; not more than 0.1% portion of Valsartan taken by the formula:
of any other individual impurity, oxoluding the valsartan ro
latod compound A, is found; and not more than 0.5% of total
impurities is found. in which C is the concentration, in mg per mL, of USP Val-
Assay— sartan RS in the Standard preparation; and rv and rs are the
Diluent—Proparo a mixturo of aootonitrilo and water peak responses obtained from the Assay preparation and the
Standard preparation, respectively.AUSP26
water, acetonitrile, and glacial acetic acid (500:500:1).
Make adjustments if necessary (see System Suitability
under Chromatography (621)).
BRIEFING
quantity of USP Valsartan RS in Mobile phase, and dilute
quantitatively, and stepwise if necessary, with Mobile Valsartan Capsules, page 3050 of PF 27(5) [Sept.-Oct. 2001].
Based upon comments received, minor procedural and editorial
phase to obtain a solution having a known concentration changes are proposed. The capsule shells in both the Test solution
in the test for Uniformity of dosage units (905) and those in the
of about 0.05 mg per mL. Assay stock preparation should be included in the preparation of
the solutions. The procedure for reporting impurities in the Related
Assay preparation—Transfer about 50 mg of Valsartan,
accurately weighed, to a 100-mL volumetric flask,
dissolve in and dilute with Mobile phase to volume, and
Pharmacopeia! Forum
compounds test is clarified. In the Assay, the relative standard de- Procedure—Determine the amount of C24H29N5O3
viation, the column size, and the injection volume have been re-
vised. dissolved by employing UV absorption at a wavelength of
(PA5: J. Esker) RTS—30743-2 maximum absorbance at about 250 nm on filtered portions

of the solution under test, suitably diluted with Dissolution
Add the following: Medium, in comparison with a Standard solution having a

A
Valsartan Capsules known concentration of USP Valsartan RS in the same
Medium.
Tolerances—Not less than 1S% 80% (Q) of the labeled
» Valsartan Capsules contain not less than 90.0
amount of C24H29N5O3 is dissolved in 30 minutes.
percent and not more than 110.0 percent of the la-
beled amount of valsartan (C24H29N5O3).
PROCEDURE FOR CONTENT UNIFORMITY—
Packaging and storage—Preserve in well-closed Diluent and Mobile phase—Prepare as directed in the
containers. Assay.
USP Reference standards (11)—USP Valsartan RS. USP Standard solution—Prepare as directed for Standard
Valsartan Related Compound B RS. preparation in the Assay.
Identification— Resolution solution—Dissolve accurately weighed
A: Thin-Layer Chromatographic Identification Test quantities of USP Valsartan Related Compound B RS and
(201)- USP Valsartan RS in Diluent, and dilute quantitatively,
Test solution—Remove the contents of 10 Capsules. Mix and stepwise if necessary, with Diluent to obtain a
the combined contents of the Capsules, transfer an solution having known concentrations of about 5 ug per
accurately weighed portion, equivalent to about 40 mg of mL and 50 ug per mL, respectively.
valsartan, to a centrifuge tube, add 20.0 mL of methanol, Test solution—Romovo tho contents of 10 Capsules;
and shake for 10 minutes. Centrifuge, and use the clear transfer tho oontonto of oaoh to separate suitable
supernatant. volumotrio flaoka, and prooood with oaoh aa folio wo. Add
Application volume: 20 uL. about 100 mL of Diluent, and shako vigorously for 30
Developing solvent system: a mixture of chloroform, minutos: Sonioato for 10 minutes, and shako by hand for 3
methanol, ammonia, and water (6:3:0.5:0.3). minutes. Diluto with Diluent to volume to obtain a solution
B: The retention time of the major peak in the having a concentration of about 0.4 mg of valsartan per mL:
chromatogram of the Assay preparation corresponds to Carefully open 10 Capsules, quantitatively transfer the
that in the chromatogram of the Standard preparation, as contents and the Capsule shells of each Capsule to a
obtained in the Assay. volumetric flask of at least 50-mL capacity, and proceed
Dissolution (711)— with each as follows. Add Diluent to about half of the
Medium: pH 6.8 phosphate buffer; 1000 mL. flask volume, and shake vigorously for 30 minutes.
Apparatus 1: 100 rpm. Sonicate for 10 minutes, shake briefly, and sonicate for an
Time: 30 minutes. additional 3 minutes. Dilute with Diluent to volume, and
Pharmacopeial Forum
mix. Centrifuge a portion of this solution at about 3000 rpm. solution having a known concentration of about 0.4 mg of
Quantitatively dilute a volume of the clear supernatant with valsartan per mL and about 0.004 mg of valsartan related
Diluent to obtain a solution containing about 0.05 mg of compound B per mL.
valsartan per mL. Standard solution—Dissolve an accurately weighed
Chromatographic system (see Chromatography (621))— quantity of USP Valsartan RS in Diluent, and dilute
Prepare as directed in the Assay. Chromatograph the quantitatively, and stepwise if necessary, with Diluent to
Resolution solution, and record the peak responses as obtain a solution having a known concentration of about
directed for Procedure: the relative retention times are 0.004 mg per mL.
0.81 for valsartan related compound B and 1.0 for Test solution—Use the portion of the Assay stock
valsartan; and the resolution, R, between valsartan related preparation retained from the Assay.
compound B and valsartan is not less than 1.5. Chro- Procedure—Separately inject equal volumes (about 50
matograph the Standard solution, and record the peak uL) of the Standard solution and the Test solution into the
responses as directed for Procedure: the tailing factor is chromatograph, record the chromatograms, and measure the
between 0.8 and 1.5; and the relative standard deviation areas for the major peaks. Calculate the percentage of each
for replicate injections is not more than 2.0%. impurity in the portion of Capsules taken by the formula:
uL) of the Standard solution and the Test solution into the
areas for the major peaks. Calculate the quantity, in mg, of
valsartan (C24H29N5O3) in each Capsule taken by the
formula:
sartan RS in the Standard solution; CT is the concentration,
CD{rulrs), in mg per mL, of valsartan in the Test solution based on the
labeled capsule content and the extent of dilution; r, is the
in which C is the concentration, in mg per mL, of USP Val-
peak response for each impurity obtained from the Test so-
sartan RS in the Standard solution; D is the dilution factor
lution; and rs is the valsartan peak response obtained from
based on the volume of the flask used and the extent of dilu-
the Standard solution: not moro than 0.5% of valaartan ro
tion used to prepare the Test solution; and rv and rs are the
lated oompound B ia found, not more than 0.2% of any other
impurity is found, excluding valsartan related compound D,
and not more than 0.7% of total impurities is found, exclud-
ing valsartan related compound D.
Diluent, Mobile phase, Resolution solutions, and
Assay—
Diluent—Prepare a mixture of acetonitrile and water
Resolution solution—Dissolve accurately weighed
(1:1).
quantities of USP Valsartan RS and USP Valsartan
Related Compound B RS in Mobile phase, and dilute
quantitatively and stepwise if necessary to obtain a
Pharmacopeial Forum
Mobile phase—Prepare a filtered and degassed mixture of Chromatographic system (see Chromatography (621))—
water, acetonitrile, and glacial acetic acid (500:500:1). The liquid chromatograph is equipped with a 230-nm
Make adjustments if necessary (see System Suitability detector and a 3.0 mm >< 12.5 om 25-mm x 4.6-cm
under Chromatography (621)). column that contains 10-urn packing LI. The flow rate is
Resolution solution—Prepare a solution in Diluent about 1.0 mL per minute. The column temperature is
containing about 4-j*g 5 jig of USP Valsartan Related maintained at 30°. Chromatograph the Resolution
Compound B RS per mL and 10 ug 50 |xg of USP solution, and record the peak responses as directed for
Valsartan RS per mL. Procedure: the relative retention times are 0.81 for
Standard preparation—Dissolve an accurately weighed valsartan related compound B and 1.0 for valsartan; and
quantity of USP Valsartan RS in Diluent, and dilute the resolution, R, between valsartan related compound B
quantitatively, and stepwise if necessary, with Diluent to and valsartan is not less than 1.5. Chromatograph the
obtain a solution having a known concentration of about Standard preparation, and record the peak responses as
0.05 mg per mL. directed for Procedure: the relative standard deviation for
Assay stock preparation—Transfer the contents of 10 replicate injections is not more than 5.0% 2.0% .
Capsules and their shells to a suitable volumetric flask, Procedure—Separately inject equal volumes (about -tO
add about 100 mL of Diluent, and shake vigorously for 30 ph 20 uL) of the Standard preparation and the Assay
minutes. Sonicate for 10 minutes, aa4 shake by hand briefly, preparation into the chromatograph, record the
and sonicate for an additional 3 minutes. Dilute with Diluent chromatograms, and measure the areas for the major
to volume to obtain a solution having a concentration of peaks. Calculate the quantity, in mg, of valsartan
about 3.2 mg of valsartan per mL. Centrifuge a portion of (C24H29N5O3) in the portion of Capsules taken by the
this solution at about 3000 rpm. Quantitatively dilute a formula:
volume of the clear supernatant with Diluent to obtain a
CD{rulrs),
solution containing about 0.4 mg of valsartan per mL.
[NOTE—Retain a portion of the Assay stock preparation in which C is the concentration, in mg per mL, of USP Val-
to use as the Test solution in the test for Related sartan RS in the Standard preparation; D is the dilution fac-
compounds.] tor based on the volume of the flask used and the extent of
Assay preparation— Quantitatively dilute an accurately dilution used to prepare the Assay preparation; and rv and rs
measured portion of the Assay stock preparation with are the peak responses obtained from the Assay preparation
Diluent to obtain a solution having a concentration of and the Standard preparation, respectively.AUSP26
about 0.05 mg of valsartan per mL.
Pharmacopeial Forum
Labeling—Label it to indicate its nominal dextrose

MONOGRAPHS (NF) equivalent. Label it also to indicate the presence of sulfur
dioxide if the residual concentration is greater than 10 mg
per kg.
USP Reference standards (11)—USP Dextrose RS.
Identification—Add a few drops of a solution of Syrup (1
in 20) to 5 mL of hot, alkaline cupric tartrate TS: a copious,
BRIEFING red precipitate of cuprous oxide is formed.
Corn Syrup, page 1436 of PF 26(5) [Sept.-Oct. 2000]. This Microbial limits (61)—The total aerobic microbial count
new monograph, which previously appeared in Pharmacopeial
Previews, is now forwarded to In-Process Revision. To better de- does not exceed 1000 per g, and the total combined molds
scribe the process of discriminating various corn syrup products,
the assay title is changed to Assay for reducing sugars (dextrose and yeast count does not exceed 100 per g.
equivalent).
(EMC: C. Sheehan) RTS—35646-2
Heavy metals, Method II (231): not more than 5 ug per g,
an ignition temperature of 500° being used.
Add the following:
A Starch—Dissolve 1 g in 10 mL of water, and add 1 drop of
Corn Syrup
iodine TS: a yellow color indicates the absence of soluble
starch.
» Corn Syrup is an aqueous solution of sacchar-
Total solids—Determine the refractive index of Corn Syrup
ides obtained by partial hydrolysis of edible corn
at 20° or 45° (see Refractive Index (831)). Convert the
starch by food grade acids or enzymes. It contains refractive index value to the percent solids value using the
not less than 20.0 percent reducing sugar content accompanying table. The total solids value is not less than
(dextrose equivalent) expressed as D-glucose, cal- 70%.
culated on the dried basis.
Pharmacopeial Forum
Refractive Index Refractive Index 0

Baume at 140° F
Dextrose Equivalent (DE) % Dry Substance (DS) at 20° at 45° (60° C) + 1
28 DE Corn syrup—0.3% ash 76.0 1.4888 1.4837 40.98

77.0 1.4915 1.4864 41.49
78.0 1.4943 1.4892 42.00
79.0 1.4971 1.4919 42.51
80.0 1.4999 1.4947 43.01
34 DE High-maltose corn 78.6 1.4933 1.4882 41.99

syrup—0.3% ash 79.6 1.4960 1.4909 42.49
80.6 1.4988 1.4936 42.99
81.6 1.5015 1.4964 43.49
82.6 1.5043 1.4992 43.99
36 DE Corn syrup—0.3% ash 78.4 1.4938 1.4887 42.01

79.4 1.4965 1.4914 42.52
80.4 1.4993 1.4941 43.02
81.4 1.5021 1.4969 43.52
82.4 1.5049 1.4997 44.02
43 DE High-maltose corn 78.9 1.4934 1.4883 42.00

syrup—0.3% ash 79.9 1.4961 1.4910 42.51
80.9 1.4988 1.4937 43.01
81.9 1.5016 1.4964 43.51
82.9 1.5044 1.4992 44.01
43 DE Corn syrup—0.3% ash 78.7 1.4933 1.4882 42.01

79.7 1.4960 1.4909 42.51
80.7 1.4988 1.4936 43.02
81.7 1.5015 1.4964 43.52
82.7 1.5043 1.4992 44.01
43 DE (Ion-exchanged) Corn 78.8 1.4935 1.4884 41.99

syrup—0.03% ash 79.8 1.4962 1.4911 42.50
80.8 1.4990 1.4938 43.00
81.8 1.5018 1.4966 43.50
82.8 1.5045 1.4994 43.99
Pharmacopeial Forum
Refractive Index Refractive Index 0

Baume at 140° F
Dextrose Equivalent (DE) % Dry Substance (DS) at 20° at 45° (60° C) + 1
53 DE Corn syrup—0.3% ash 80.5 1.4962 1.4911 42.64

81.5 1.4989 1.4938 43.14
82.5 1.5016 1.4965 43.64
83.5 1.5044 1.4992 44.13
84.5 1.5072 1.5020 44.63
63 DE Corn syrup—0.3% ash 81.0 1.4955 1.4904 42.53

82.0 1.4982 1.4931 43.02
83.0 1.5009 1.4958 43.52
84.0 1.5037 1.4985 44.01
85.0 1.5064 1.5012 44.50

syrup—0.03% ash 82.3 1.4990 1.4939 43.10
83.3 1.5017 1.4965 43.59
84.3 1.5044 1.4993 44.09
85.3 1.5072 1.5020 44.58
66 DE Corn syrup—0.3% ash 81.0 1.4949 1.4898 42.36

82.0 1.4975 1.4924 42.86
83.0 1.5002 1.4951 43.36
84.0 1.5029 1.4978 43.85
85.0 1.5056 1.5005 44.35
95 DE Corn syrup—0.3% ash 69.0 1.4598 1.4550 35.46

70.0 1.4621 1.4573 35.96
71.0 1.4644 1.4596 36.46
72.0 1.4668 1.4619 36.96
73.0 1.4692 1.4643 37.45

syrup—0.03% 70.0 1.4620 1.4572 35.89
71.0 1.4644 1.4595 36.39
72.0 1.4667 1.4619 36.89
73.0 1.4691 1.4642 37.38
Pharmacopeial Forum
Limit of sulfur dioxide—Transfer about 100 g of Syrup, Standard solutions—Transfer 10.0 mL of Lead Nitrate
accurately weighed, to a 250-mL conical flask, add 100 Stock Solution, prepared as directed under Heavy Metals
mL of water, and mix. Cool to between 5° and 10°. While (231), to a 100-mL volumetric flask, add 40 mL of water
stirring with a magnetic stirrer, add 10 mL of cold 1.5 N and 5 mL of nitric acid, dilute with water to volume, and
sodium hydroxide (between 5° and 10°). Stir for an mix. Transfer 1.0 mL of this solution to a second 100-mL
additional 20 seconds, and add 10 mL of starch indicator volumetric flask, dilute with 5% nitric acid to volume, and
solution, prepared as follows. Mix 10 g of soluble starch mix. This solution contains 0.1 ug of lead per mL. Transfer
with 50 mL of cold water, transfer to 1000 mL of boiling portions of this solution to four suitable containers, and
water, stir until completely dissolved, cool, and add 1 g of dilute quantitatively, and stepwise if necessary, with 5%
salicylic acid preservative. [NOTE—Discard this solution nitric acid to obtain Standard solutions having lead
after 1 month.] Add 10 mL of cold 2.0 N sulfuric acid concentrations of 100, 50, 25, and 10 ng per mL.
(between 5° and 10°), and titrate immediately with 0.005 Test solution—[NOTE—Perform this procedure in a fume
N iodine VS until a light blue color persists for 1 minute hood.] Transfer about 1.5 g of Syrup, accurately weighed, to
(see Titrimetry (541)). Perform a blank determination, two digestion tubes labeled Test solution and Temperature
using 200 mL of water treated similarly to the solution monitor solution, and add 0.75 mL of nitric acid to each
under test, and make any necessary correction. Each mL tube. Warm both solutions slowly to between 90° and 95°
of 0.005 N iodine is equivalent to 0.16 mg of SO2: not to avoid spattering. Heat until all brown vapors have
more than 40 ug per g is found. dissipated and any rust-colored tint is gone from the tube
Limit of lead—[NOTE—For the preparation of all aqueous labeled Test solution (20 to 30 minutes). Cool, add 0.5
solutions and for the rinsing of glassware before use, mL of 50% hydrogen peroxide dropwise to both
employ water that has been passed through a strong-acid, solutions, heat to between 90° and 95° for 5 minutes, and
strong-base, mixed-bed ion-exchange resin before use. For cool. Add a second 0.5-mL portion of 50% hydrogen
digestion, use acid-cleaned, high-density polyethylene, peroxide dropwise to each solution, and heat between 90°
polypropylene, polytef, or quartz tubes. Select all reagents and 100° until clear (5 to 10 minutes). Cool and transfer
to have as low a content of lead as practicable, and store the solution labeled Test solution to a 10-mL volumetric
all reagent solutions in borosilicate glass containers. flask. Rinse the Test solution digestion tube with 5% nitric
Cleanse glassware before use by soaking in warm 8 N acid, add the rinse to the volumetric flask, dilute with 5%
nitric acid for 30 minutes and rinsing with deionized nitric acid to volume, and mix.
water. Store final diluted solutions in acid-cleaned plastic Standard blank—Use 5% nitric acid.
or polytef tubes or bottles.] Test blank—Transfer 1.5 g of water to a digestion tube,
Modifier solution—Prepare a solution of magnesium and proceed as directed for the Test solution, beginning
nitrate in water containing about 200 mg per mL. Just with "add 0.75 mL of nitric acid".
before use, transfer 1.0 mL of this solution to a 10-mL Procedure—[NOTE—Use peak area measurements for all
volumetric flask, dilute with 5% nitric acid to volume, and quantitations.] Add 5 uL of the Modifier solution to 20 uL
mix. each of the Standard solutions, the Test solution, the
Pharmacopeial Forum
Standard blank, and the Test blank, and mix. Separately Assay for reducing sugars (dextrose equivalent)—
inject equal volumes (about 20 uL) of the Standard Apparatus—Mount a ring support on a ring stand 1 to 2
solutions, the Test solution, the Standard blank, and the inches above a gas burner, and mount a second ring 6 to 7
Test blank into a suitable graphite furnace atomic inches above the first. Place 6-inch open-wire gauze on the
absorption spectrophotometer equipped with pyrolytically lower ring to support a 250-mL conical flask, and place a 4-
coated graphite tubes and adequate means of background inch watch glass with a center hole on the upper ring to
correction. The temperature is programmed as follows. deflect heat. Attach a 25-mL buret to the ring stand so
Maintain the drying temperature of the furnace at 200° for that the tip just passes through the watch glass centered
30 seconds after a 20-second ramp time using an argon gas above the flask. Place an indirectly lighted white surface
flow of about 300 mL per minute; maintain the ashing behind the assembly for observing the endpoint.
temperature at 750° for 40 seconds after a 40-second ramp Standard preparation—Dissolve an accurately weighed
time using an airflow of about 300 mL per minute; cool quantity of USP Dextrose RS in water, and dilute
down and purge the air from the furnace for 60 seconds quantitatively with water to obtain a solution having a
using a 20° set temperature and an argon gas flow of known concentration of about 6 mg per mL.
about 300 mL per minute; and maintain the atomization Assay preparation—Transfer about 5 g of Syrup,
temperature at 1800° for 10 seconds after a 0-second ramp accurately weighed, to a 500-mL volumetric flask, add
time with the argon gas flow stopped. [NOTE—The water to volume, and mix.
temperature program may be modified to obtain optimum Procedure—Transfer 25.0 mL portions of alkaline cupric
furnace temperatures.] Using the Standard blank to set the tartrate TS to each of two flasks, and boil. Immediately place
instrument to zero, determine the integrated absorbances of one flask on the wire gauze of the Apparatus, and adjust the
the Standard solutions at the lead emission line at 283.3 nm. burner so that the boiling point will be reached in about 2
Plot the integrated absorbances of the Standard solutions minutes. Titrate with the Standard preparation to within
versus their contents of lead, in ng per mL, and draw the 0.5 mL of the anticipated endpoint. Heat the flask, with
line best fitting the four points to determine the calibration swirling, boil moderately for 2 minutes, and add 2 drops
curve. Similarly determine the integrated absorbances of the of methylene blue solution (1 in 100). Immediately add
Test solution and the Test blank at the lead emission line at about 2 drops of the Standard preparation from the buret,
283.3 nm. Correct the absorbance value of the Test solution and bring to a boil. Allow the cuprous oxide to settle
by subtracting from it the absorbance value obtained from slightly, and observe the color of the supernatant.
the Test blank. Calculate the concentration, in ug per g, of Complete the titration within 1 minute by adding the
lead in the portion of Syrup taken by the formula: Standard preparation dropwise, and boiling after each
addition to the disappearance of the blue color, as
0.0l(C/W),
determined by viewing against a white background in
in which C is the concentration, in ng per mL, of lead in the
daylight or under equivalent illumination. If more than 0.5
Test solution, as determined from the calibration curve; and
mL of the titrant is required after the addition of the
Wis the weight, in g, of Syrup taken to prepare the Test so-
indicator, repeat the titration, adding the necessary volume
lution: the limit is 0.1 jig per g.
Pharmacopeial Forum
of titrant before adding the indicator. Bring the contents of tent. High Fructose Corn Syrup 42% contains not
:
the second flask to a boil, and similarly titrate with the fest less than 97.0 percent of total saccharides, ex-
Assay preparation.CalculatQ the percentage of reducing
pressed as a percentage of total solids, of which
sugars as D-glucose, calculated on the dried basis, in the
not less than 92.0 percent consists of monosac-
portion of Syrup taken by the formula:
charides (fructose and dextrose), including not
less than 41.5 percent and not more than 44.8 per-
in which A is the percentage of dry solids in the Syrup mea- cent of fructose, and not more than 8.0 percent
sured by the refractive index; Cv is the concentration, in mg consists of other saccharides. High Fructose Corn
per mL, of Syrup in the Assay preparation; Cs is the concen- Syrup 55% contains not less than 95.0 percent of
tration, in mg per mL, of USP Dextrose RS in the Standard
total saccharides, expressed as a percentage of to-
preparation; and Vs and Vv are the titrated volumes, in mL,
tal solids, of which not less than 95.0 percent con-
of the Standard preparation and the Assay preparation, re-
sists of monosaccharides (fructose and dextrose),
spectively.^.
including not less than 54.5 percent and not more
than 56.5 percent of fructose, and not more than
5.0 percent consists of other saccharides.

Labeling—Label it to state, as part of the official title, the
BRIEFING
nominal percentage of fructose, based on the specified
High Fructose Corn Syrup, page 1441 of PF26(5) [Sept-Oct.
2000]. This new monograph, which first appeared in Pharmaco- minimum percentage concentration of total saccharides.
peial Previews, is now forwarded to In-Process Revision.
Label it to indicate the presence of sulfur dioxide if the
residual sulfur dioxide concentration is greater than 10 mg
per kg.
Add the following:
A USP Reference standards (11)—USP Dextrose RS. USP
High Fructose Corn Syrup
Fructose RS. USP Maltose RS.
Identification—Add a few drops of a solution (1 in 10) of
» High Fructose Corn Syrup is a sweet, nutritive
Syrup to 5 mL of hot, alkaline cupric tartrate TS: a copious,
saccharide mixture prepared as a clear, aqueous red precipitate of cuprous oxide is formed (distinction from
solution from high-dextrose-equivalent corn sucrose).
starch hydrolysate by the partial enzymatic con- Microbial limits (61)—The total aerobic microbial count
version of dextrose to fructose, using an insoluble does not exceed 1000 per g, and the total combined molds
glucose isomerase enzyme preparation that com- and yeast count does not exceed 100 per g.
plies with 21 CFR 184.1372. It is available in Residue on ignition (281): not more than 0.05%.
two types, 42% and 55%, based on fructose con-
Pharmacopeial Forum
Heavy metals, Method II (231): not more than 5 jig per g, Total solids—Determine the refractive index of Syrup at
an ignition temperature of 500° being used. 20° or 45° (see Refractive Index (831)). Use the table
below for calculating the percentage of dry substance
(percentage of total solids).
Fructose Content % Dry Substance Refractive Index at 20c Refractive Index at 45c
42% 70.5 1.4632 1.4577

71.0 1.4643 1.4589
72.0 1.4667 1.4612
73.0 1.4691 1.4635
55% 76.5 1.4774 1.4716

77.0 1.4786 1.4728
78.0 1.4811 1.4752
79.0 1.4835 1.4776
Limit of sulfur dioxide—Transfer about 100 g of Syrup, between 5° and 10°." Each mL of 0.005 N iodine is
accurately weighed, to a 250-mL conical flask, add 100 equivalent to 0.16 mg of SO2: not more than 30 ug per g
mL of water, and mix. Cool to botwoon 5° and 10°. Whilo is found.
stirringwith a magnetiostirror, add 10 mL of oold 1.5 N Limit of lead—[NOTE—For the preparation of all aqueous
sodium hydroxide (at a tomporaturo botwoon 5° and 10°): solutions and for the rinsing of glassware before use,
Stir for an additional 20 sooondsând add 10 mL of staroh employ water that has been passed through a strong-acid,
indicator solution prepared as follows: Mix 10 g of solublo strong-base, mixed-bed ion-exchange resin before use. For
staroh with 50 mL of oold water, transfer to 1000 mL of digestion, use acid-cleaned, high-density polyethylene,
boiling water, otir until oomplotoly dissolved, oool, and polypropylene, polytef, or quartz tubes. Select all reagents
add l"g of salicylic acid preservative. NOTE—Discard the to have as low a content of lead as practicable, and store
solution after 1 month: Add10 mL of 2:0 N sulfurioacid all reagent solutions in borosilicate glass containers.
(at a temperature botwoon 5° and 10°), and titrate Cleanse glassware before use by soaking in warm 8 N
immediately with 0.005 N iodine VS until a light blue nitric acid for 30 minutes and rinsing with deionized
oolor persists for1minute (300 Titrimotry (544-)). Perform water. Store final diluted solutions in acid-cleaned plastic
a blank determination, using 200 mL of water treated or polytef tubes or bottles.]
similarly to the solution under tost, and make any Modifier solution, Standard solutions, Standard blank,
necessary correction. Proceed as directed for Limit of and Test blank—Proceed as directed for Limit of lead
sulfur dioxide under Corn Syrup beginning with "Cool to under Corn Syrup.
Pharmacopeial Forum
Test solution—[NOTE—Perform this procedure in a fume percentage concentrations are in the same ratio as those in
hood.] Transfer about 1.5 g of Syrup, accurately weighed, te the Assay preparation, based on the labeled nominal
two digoation tuboa, labolod "Tost solution" and fructose percentage for the Syrup under test. Calculate the
"Temperature- monitor solution", and add 0.75 mL of percentage of USP Maltose RS by the formula:
nitric- aoid to oaoh tube. Warm both solutions slowly to
100 -(F + D),
between 90 ? and 95° to avoid spattering. Hoat until all
brown vaporo have dissipated and any rust colored tint is in which F is the labeled nominal fructose percentage for the
gone from tho tube labolod "Tost solution" (20 to 30 Syrup under test; and D is the difference between the speci-
minutes). Cool, add 0.5 mL of 50% hydrogen peroxide fied minimum percentage concentration of total monosac-
dropwiso toboth solutions; hoat to between 90° and 95° charides for the Syrup and F.
for 5 minutes; and cool. Add a second 0:5 mL portion of Assay preparation—Dilute a known volume of Syrup,
50% hydrogen peroxide dropwiso to oaoh solution, and determined from the results of the test for Total solids and
hoat to between 90° and 100° for 5 to 10 minutoo until tho on the nominal total saccharides content, with water to
tube labolod "Tost solution" is dear. Cool, and transfer tho obtain a total saccharides concentration of about 10% (w/
Test solution to a 10 mL volumotrio flask. Rinse the tube v), and mix.
labeled "Tost solution" with 5% nitric aoid, add tho Chromatographic system (see Chromatography (621))—
rinsing to tho volumetrio flaok^ dilute with 5% nitrio aoid The liquid chromatograph is equipped with a refractive
to volume, and mix. and proceed as directed for Limit of index detector maintained at 45° and a 7.8-mm x 30-cm
lead under Corn Syrup beginning with "to two digestion column that contains packing L I 9 . The column is
tubes,..." maintained at a constant temperature of about 85°. The

flow rate is about 0.6 mL per minute. Chromatograph the
Procedure—Proceed as directed for Limit of lead under
Standard preparation, and record the peak areas as
Corn Syrup. Calculate the concentration, in ug per g, of
lead in the portion of Syrup taken by the formula:
about 0.83, 1.0, and 1.32 for maltose, dextrose, and
0.0l(C/W),
fructose, respectively; and the resolution, R, between the
in which C is the concentration, in ng per mL, of lead in the maltose and dextrose peaks is not less than 1.2.
Test solution, as determined from the calibration curve; and Procedure—Separately inject equal volumes (about 10
Wis the weight, in g, of Syrup taken to prepare the Test pre- uL) of the Standard preparation and the Assay
paration solution: and tho other terms are as defined therein: preparation into the chromatograph, record the
the limit is 0.1 ug per g. chromatograms, and measure the areas for the major
Assay— peaks. Calculate the percentage of fructose and of
Mobile phase—Use filtered and degassed water. dextrose in the portion of Syrup taken by the formula:
Standard preparation—Prepare a solution in water
containing a total of about 10% saccharide solids of USP
Dextrose RS, USP Fructose RS, and USP Maltose RS, in
which the USP Dextrose RS and USP Fructose RS
Pharmacopeial Forum
in which C is the concentration, in mg per mL, of USP Fruc- ANF21

2 mL of nitric acid and 1 mL of silver nitrate TS: any turbidity
tose RS or USP Dextrose RS in the Standard preparation; produced is not greater than that of a control containing 2.8 mL
of 0.020 N hydrochloric acid (0.2%).
VA is the volume, in mL, of the Assay preparation; Vs is the
volume, in mL, of Syrup taken to prepare the Assay pre-
paration; Si is the percentage of total saccharides in the
Standard preparation (corresponding to 97 for High Fruc-
tose Corn Syrup 42% and to 95 for High Fructose Corn Syr-
up 55%); S2 is the percentage of total solids in the Syrup as
BRIEFING
determined in the Total solids test; and rv and rs are the peak
Magnesium Aluminometasilicate, page 2590 of PF 27(3)
areas of fructose or dextrose obtained from the Assay pre- [May-June 2000]. Because USP has received no adverse commen-
tary, it is proposed to implement this new monograph for official
paration and the Standard preparation, respectively. Calcu- publication in NF 21.
late the percentage of other saccharides, expressed in terms
of maltose, in the portion of Syrup taken by the formula:
Add the following:

A
in which C is the concentration, in mg per mL, of USP Mal-
Magnesium Aluminometasilicate
tose RS in the Standard preparation; ru is the sum of all
peak areas obtained from the Assay preparation, except » Magnesium Aluminometasilicate is a synthetic
those of fructose and dextrose; and rs is the peak area of material that exists in two forms, Type I-A and
maltose obtained from the Standard preparation. ANF2] Type I-B, having different pH requirements. The
required contents for both forms is are the same:
not less than 29.1 percent and not more than 35.5
percent of aluminum oxide (AI2O3), not less than
BRIEFING
magnesium oxide (MgO), and not less than 29.2
Dextrin, NF 20 page 2539. It is proposed to change the concen-

percent and not more than 35.6 percent of silicon
tration of the test solution in the test for Chloride to be in accor-
dance with the control solution. dioxide (SiO2), calculated on the dried basis.
(ESC: E. Gonikberg) RTS—35838-1 Packaging and storage—Preserve in tight containers.

Labeling—Label it to indicate whether it is Type I-A or
Change to read: Type I-B.

Chloride (221)—Dissolve 4rO-g Identification—
A
3.0 gANF21
in 75 mL of boiling water, cool, dilute with water to 100 mL A: Transfer 0.5 g of Magnesium Aluminometasilicate
75 xriL,ANF2} to a suitable container, add 5 mL of a sulfuric acid
and filter if necessary. To 1:0 mL
A
25 m L A ^ 7 solution (1 in 3), and heat until white fiimes are observed.
of this solution add 24 mL of water,-
Pharmacopeial Forum
Cool, add 20 mL of water, and filter. Neutralize the filtrate Soluble salts—Transfer 10.0 g of Magnesium
with ammonia TS, and retain for use in Identification test B. Aluminometasilicate to a suitable container, add 150 mL
Collect the precipitate, and dissolve in 3 N hydrochloric of water, and boil gently for 15 minutes, with shaking.
acid: the solution meets the requirements of the tests for After cooling, dilute with water to 150 mL, and
Aluminum (191). centrifuge. Dilute 75 mL of the clear filtrate with water to
B: The filtrate retained from Identification test A meets 100 mL, and retain the diluted filtrate for use in
the requirements of the tests for Magnesium (191). subsequent tosts. the tests for Alkalinity, Chloride, and
C: Prepare a bead by fusing a few crystals of sodium Sulfate. Evaporate 25 mL of the diluted filtrate on a water
ammonium phosphate on a platinum loop in the flame of bath, and heat at 700° for 2 hours. The residue weighs not
a Bunsen burner. Place the hot, transparent bead in contact more than O^S 0.020 g: not more than 1.6% is found.
with Magnesium Aluminometasilicate, and again fuse: Alkalinity—Add 2 drops of phenolphthalein TS to 20 mL
silica floats about in the bead producing, upon cooling, an of the diluted filtrate retained from the test for Soluble salts,
opaque bead with a web-like structure. containing 1 g of Magnesium Aluminometasilicate: if a pink
Acid-consuming capacity—Transfer about 0.2 g of color is produced, not more than 0.50 mL of 0.1 N
Magnesium Aluminometasilicate, accurately weighed, to a hydrochloric acid is required to discharge it.
glass-stoppered flask, and add 100.0 mL of 0.1 N Chloride (221)—A 20-mL portion of the diluted filtrate
hydrochloric acid VS. Insert the stopper in the flask
retained from the test for Soluble salts shows no more
tightly, shake at 37 ± 2° for 1 hour, and filter. Transfer
chloride than corresponds to 0.75 mL of 0.020 N
50.0 mL of the filtrate to a beaker, and while stirring,
hydrochloric acid: not more than 0.053% is found.
titrate the excess hydrochloric acid with 0.1 N sodium
Sulfate (221)—A 2-mL portion of the diluted filtrate
hydroxide VS to attain a pH of 3.5. Perform a blank
retained from the test for Soluble salts shows no more
determination, and make any necessary correction. Not
sulfate than corresponds to 0.5 mL of 0.020 N sulfuric
less than 210 mL of 0.1 N hydrochloric acid is consumed
acid: not more than 0.480% is found.
per g of Magnesium Aluminometasilicate, calculated on
Arsenic, Method I (211): 3 ug per g.
the dried basis.
Iron (241)—
pH (791)—Transfer 2 g of Magnesium Alumino-
Test Preparation—To 0.11 g of Magnesium Alumino-
metasilicate to a suitable container, and add 50 mL of
metasilicate add 8 mL of 2 N nitric acid, boil for 1
water. While stirring, immerse the pH electrodes in the
minute, and cool. Dilute with water to 100 mL, and
suspension, and after 2 minutes, record the pH: between
centrifuge. Dilute 30 mL of the supernatant with water to
6.5 and 8.5 for Type I-A, and between 8.5 and 10.5 for
45 mL: the limit is 0.03%.
Type I-B.
Heavy metals, Method I (231)—
Test Preparation—Transfer 2.67 g of Magnesium
Aluminometasilicate to a suitable container, add 20 mL of
water and 8 mL of hydrochloric acid, and evaporate to
dryness on a water bath. To the residue add 5 mL of 1 N
Pharmacopeial Forum
acetic acid and 20 mL of water, boil for 2 minutes, add 0.4 g pink. Perform a blank determination, and make any
of hydroxylamine hydrochloride, and heat to boiling. Cool, necessary correction. Each mL of 0.05 M Edetate
dilute with water to 100 mL, and filter. Use 25 mL of the disodium titrant is equivalent to 2.5490 mg of A12O3.
filtrate as the Test Preparation. Assay for magnesium oxide—Transfer 50.0 mL of the
Monitor Preparation—Transfer another 25 mL of the Assay preparation retained from the Assay for aluminum
diluted filtrate from the teat for Soluble salts to a suitable oxide to a suitable container, add 50 mL of water and 25
container, and add 2.0 mL of Standard Lead Solution. mL of a trolamine solution (1 in 2), and shake well. Add
Standard Preparation—Transfer 2 mL of hydrochloric 25 mL of ammonia-ammonium chloride buffer TS and
acid to a suitable container, and evaporate to dryness on a 0.04 g of eriochrome black TS trituration as the indicator.
water bath. To the residue add 2.0 mL of Standard Lead Titrate with 0.05 M edetate disodium VS until the red-
Solution and 0.1 g of hydroxylamine hydrochloride. purple color changes to blue and persists for 30 seconds.
Dilute with water to 25 mL: the limit is 30 ug per g. Each mL of 0.05 M edetate disodium VS is equivalent to
Assay for aluminum oxide— 2.0152 mg of MgO.
Edetate disodium titrant—Prepare and standardize as Assay for silicon dioxide—Transfer about 1 g of
directed in the Assay under Ammonium Alum. Magnesium Aluminometasilicate, accurately weighed, to a
Assay preparation—Transfer about 1.25 g of Magnesium suitable container, add 30 mL of 3 N hydrochloric acid, and
Aluminometasilicate, accurately weighed, to a conical flask, evaporate on a water bath to dryness. Moisten the residue
add 10 mL of 3 N hydrochloric acid and 50 mL of water, and with hydrochloric acid, and again evaporate on a water
heat on a water bath for 15 minutes. To this solution add 8 bath to dryness. To the residue add 8 mL of hydrochloric
mL of hydrochloric acid, and heat on a water bath for 10 acid and 25 mL of hot water, and stir. Allow to stand, and
minutes. After cooling, transfer the solution to a 250-mL then decant the supernatant through an ashless filter paper.
volumetric flask, rinse the conical flask with water, and To the residue in the container add 10 mL of hot water, stir,
add the washings to the volumetric flask. Dilute with and decant the supernatant through the filter paper. Wash the
water to volume, and mix. Centrifuge, and use the residue in the container with three additional 10-mL
supernatant as the Assay preparation. Retain a portion of portions of hot water, stir, and decant as described above.
the Assay preparation for use in the Assay for magnesium Treat the residue in the container with 50 mL of water,
oxide. and heat on a water bath for 15 minutes. Filter, and rinse
Procedure—Transfer 20.0 mL of'the Assay preparation to the residue on the filter paper with hot water until no
a beaker, and add 20.0 mL of Edetate disodium titrant. To precipitate is obtained when 1 mL of silver nitrate TS is
this solution add 15 mL of acetic acid-ammonium acetate added to 5 mL of the washing. Transfer the filter paper
buffer TS and 20 mL of water, and boil for 5 minutes. and its contents to a tared platinum crucible, heat to
After cooling, add 50 mL of alcohol and 2 mL of dryness, incinerate, and continue to heat at 800 + 25° for
dithizone TS, and titrate with 0.05 M zinc sulfate VS until 1 hour. Cool, and weigh. Moisten the residue with 6 mL of
the color of the solution changes from green-violet to rose-
Pharmacopeia! Forum
hydrofluoric acid, evaporate to dryness, and ignite for 5 less than 250 mL of 0.1 N hydrochloric acid is consumed
minutes. Cool, and weigh. The loss in weight represents per g of Magnesium Aluminosilicate, calculated on the
the weight of silicon dioxide dried basis.
pH (791)—Transfer 2 g of Magnesium Aluminosilicate to
a suitable container, and add 50 mL of water. While stirring,
immerse the pH electrodes in the suspension, and after 2
BRIEFING
minutes record the pH: between 8.5 and 10.5.
Magnesium Aluminosilicate, page 2593 of PF 27(3) [May-
June 2001]. Because USP has received no adverse commentary, Other requirements—It meets the requirements for
it is proposed to implement this new monograph for official pub-
lication in NF 21. Identification, Loss on drying, Soluble salts, Alkalinity,
(EMC: C. Sheehan) RTS—36052-1 Chloride, Sulfate, Arsenic, Iron, and Heavy metals under
Magnesium Aluminometasilicate.
Add the following: Assay for aluminum oxide, magnesium oxide, and silicon
A
Magnesium Aluminosilicate dioxide—Proceed as directed in the Assay for aluminum
oxide, the Assay for magnesium oxide, and the Assay for
» Magnesium Aluminosilicate is a synthesized silicon dioxide under Magnesium Aluminometasilicate.
material that contains not less than 20.5 percent

and not more than 27.7 percent of magnesium
oxide (MgO), not less than 27.0 percent and not
more than 34.3 percent of aluminum oxide
(AI2O3), and not less than 14.4 percent and not BRIEFING
more than 21.7 percent of silicon dioxide (SiC>2), Milk Thistle, NF 20 page 2582; Powdered Milk Thistle, NF
20 page 2583. In the current proposal, the Latin binomial has been
calculated on the dried basis. changed to reflect the scientific name in Herbs of Commerce. The
content of silymarin was introduced in the Definition in accordance
with the new USP style for botanicals. It is also proposed to add a
Packaging and storage—Preserve in tight containers. new Identification test based on the retention times in the new li-
quid chromatographic method in the test for Content of silymarin.
Acid-consuming capacity—Transfer about 0.2 g of The spectrophotometric method for the test for Content of silymar-
in is substituted by a new chromatographic method. Validation data
Magnesium Aluminosilicate, accurately weighed, to a were obtained with the 5-um YMC-Pack ODS-A C18 brand of LI
column. Typical retention times are about 6.7 minutes for taxifolin,
glass-stoppered flask, and add 100.0 mL of 0.1 N 16.3 minutes for silychristin, 17.5 minutes for silydianin, 24.0 min-
utes for silybin A, 25.2 minutes for silybin B, 27.6 minutes for iso-
hydrochloric acid VS. Insert the stopper in the flask silybin A, and 28.5 minutes for isosilybin B. In addition, editorial
changes have been made.
tightly, shake at 37 + 2° for 1 hour, and filter. Transfer
50.0 mL of the filtrate to a beaker, and, while stirring,
titrate the excess hydrochloric acid with 0.1 N sodium
Change to read:
hydroxide VS to attain a pH of 3.5. Perform a blank
determination, and make any necessary correction: not » Milk Thistle consists of the dried ripe fruit of Sily-
bum marianum (Linnc) Gacrtnor (L.) Gaertn. (Fam.
Asteraceae), the pappus having been removed.
Pharmacopeial Forum
A Change to read:
It contains not less than 2.0% of silymarin, calcu-
Content of silymarin—
lated as silybin (C25H22O10), on the dried basis.AW-2/ Reagent solution D i s s o l v e about 1.0 g of 2,1
dinitrophonylhydraaine, dried for 8 hours in a doaiooator under
vnouum and aoouratoly woighod, in 2 mL of sulfurio aoid. Diluto
with mothanol to 100.0 mLv-Proparo thio solution frosh.
Change to read: Standard preparation—Dissolve an aoouratoly woighod
Labeling—The label states the Latin binomial name quantity of USP Silybin RS in mothanol to obtain a solution
having a known concentration of about 2.0 mg por mL.
•
A.NF21
Teat preparation—Transfer about 5.0 g of finely powdorod Milk
and, following the official name, the part of the plant contained in Thistle, aoouratoly woighod, to an oxtraotion thimblo, and oovor
the article. with a omall ootton ball. Tranofor the thimblo to a continuous •
oxtraotion apparatuo fittodwith a 250 mL round bottom flask
Change to read: containing 150 mL of aolvont hoxano, and heat the flaolc on a
USP Reference standards (11)— heating mantle for 1 hours: Following the 4 hour oxtraotion,
A
separate the round bottom flask containing aolvont hoxano
USP Powdered Milk Thistle Extract RS.ANF21 extract from the oxtraotion-apparatus, and discard tho solvent
USP Silybin RS. USP Silydianin RS. hoxano solution: Remove tho adherent solvent hoxano from the
oxtraotion thimblo by dryings and transfer the thimblo to an
Change to read: oxtraotion apparatus suitable for hot oxtraotion and fitted with a
Identification— 250 mL round' bottom flask containing 100 mL of ethyl aootato.
A: Thin-Layer Chromatographic Identification Test (201)— Hoat tho flask on a heating mantle to allow tho aolvont to reflux
Test solution—Use the Test solution, prepared as directed in the gently. After 8 hours of oxtraotion, ovaporato tho othyl aootato
test for Content of silymarin. solution in tho round bottom flask at about 40° undor roduood
Standard solution: 1.0 mg of USP Silydianin RS per mL, in pressure on a rotary evaporator. Dissolve tho rosiduo in about 25
methanol. mL of mothanol, filtor tho solution quantitatively into a 50 mL
Developing solvent system: freshly prepared mixture of volumetric flask; diluto with mothanol to volume; and mix.
chloroform, acetone, and anhydrous formic acid (75:16.5:8.5). Procedure—Transfer 1.0 mL oaoh of tho StandaM preparation
Procedure—Proceed as directed in the chapter, except to dry the and tho Test preparation to two separate amber 10 mL volumotrio
plate for 30 minutes in a current of cold air. Spray the plate with a flasks, labeled appropriately for identification, add 2.0 mL of
solution of 2-aminoethyl diphenylborinate in methanol (1 in 100), Reagent aolution to oaoh flask, and mix. Inaort tho stoppor into
allow to dry briefly, and then spray with a solution of polyethylene each flask tightly; and maintain tho flasks at a thermostatically
glycol 4000 in alcohol (5 in 100). An hour later, examine the plate controlled temperature of 50 + 1°, with gentle agitation, for 50
under long-wavelength UV light: the chromatogram of the Test minutes. Remove tho flasks from tho hoat, cool, dilute tho
solution exhibits an intense green-blue fluorescent zone at an RF contents of oaoh flask with mothanol to volume, and mix.
value of about 0.5 {presence of silybin); and a gray-blue spot at Transfer 2:0 mL of the solution from each of the volumotrio
an RF value of about 0.4, corresponding to a spot observed in the flasks containing the Standard preparation and the Teat
chromatogram of the Standard solution. The chromatogram of the preparation to two soparato 100 mL volumotrio flasks, labeled
Test solution may exhibit other colored zones: an intense green- appropriately for identification; and add to oaoh flask 3.0 mL of
blue zone at an RF value of about 0.25 (presence of silychristin) totramethylammonium hydroxido solution in methanol (25%).
and a red-orange zone at an RF value of about 0.3 (presence of NOTE—Uao a froohly prepared, clear, and colorless solution of
taxifolin). totramothylammonium hydroxido in mothanol. Diluto tho
contents of oaoh flask with mothanol to volume, mix, and allow
A tho flasks to stand for 30 minutos. Gonoomitantly determine tho
B: The retention times of the peaks for silydianin, aboorbanooo of tho solutions obtainod from tho Standard
silychristin, silybin A, silybin B, isosilybin A, and preparation and tho Teat preparation in 1 om colls at tho
wavelength of maximum absorbanoo at about 190 nm, with a
isosilybin B in the chromatogram of the Test solution suitable apootrophotomotor; using mothanol as tho blank.
Caloulato tho poroontago of oilymarin, as ailybin, in tho portion
correspond to those in the chromatogram of the Milk of Milk Thistlo taken by tho formute;-
thistle standard solution, as obtained in the test for

in whioh C is tho oonoontration, in mg por mL, of USP Silybin RS
Content of silymarin. ANF21 in the Standard prcparationt Win tho woight, in mg, on tho dried
basis of tho Milk Thistle taken for tho Teat prcpamtion; andA^/es^
A$ are the absorbanoos of tho solutions from tho -Test preparation
Change to read: and tho Standard pivparation, respectively; not loss than 2% of si
Microbial limits (64-) lymarin, calculated as ailybin, is found.
()ANF2l ^Solution A—Use a filtered and degassed mixture of
The total bacterial count does not exceed 10,000 per g, the total
combined molds and yeasts count does not exceed 100 per g, and it water, methanol, and phosphoric acid (80:20:0.5).
meets the requirements of the tests for the absence of Salmonella
species and Escherichia coli and for absence of Staphylococcus Solution B—Use a filtered and degassed mixture of
aureus.
methanol, water, and phosphoric acid (80:20:0.5).
Pharmacopeial Forum
Mobile phase—Use a variable mixture of Solution A and into a 100-mL volumetric flask, dilute with methanol to
Solution B as directed in the Chromatographic system. volume, and mix. Transfer 1.0 mL of this solution to a
Make adjustments if necessary (see System Suitability 25-mL volumetric flask, and dilute with methanol to
under Chromatography (621)). volume.
Milk thistle standard solution—Dissolve an accurately Chromatographic system (see Chromatography (621))—
weighed quantity of USP Powdered Milk Thistle Extract The liquid chromatograph is equipped with a 288-nm
RS in methanol, sonicate for 20 minutes, and dilute with detector and a 4.6-mm x 15-cm column that contains 5-
methanol to obtain a solution having a known um packing LI and is maintained at a temperature of 40°.
concentration of about 0.7 mg of extract per mL. Transfer The flow rate is about 1.0 mL per minute. The
1 mL of this solution to a 5-mL volumetric flask, and chromatograph is programmed as follows:
dilute with methanol to volume. Pass through a membrane
filter having a 0.45-um or finer porosity. Time Solution A Solution B
Silybin standard solutions—Dissolve an accurately (minutes) (%) (%) Elution
weighed quantity of USP Silybin RS in methanol, and 0-5 85 15 isocratic
dilute with methanol to obtain solutions having known 5-20 85->55 15->45 linear gradient
concentrations of about 0.20 mg per mL, 0.02 mg per mL, 20-40 55 45 isocratic
and 0.004 mg per mL. Pass through a membrane filter 40^1 55->85 45->15 linear gradient
having a 0.45-uxn or finer porosity. 41-55 85 15 equilibration
Test solution—Transfer about 10 g of finely powdered Chromatograph the Milk thistle standard solution, and re-
Milk Thistle, accurately weighed, to an extraction thimble, cord the peak responses as directed for Procedure: the chro-
and cover with a small cotton ball. Transfer the thimble to a matogram obtained is similar to the Reference
continuous-extraction apparatus fitted with a 250-mL Chromatogram provided with the USP Powdered Milk
round-bottom flask containing 150 mL of solvent hexane, Thistle Extract RS; the relative retention times are about
and heat the flask on a heating mantle for 4 hours. 0.68 for silychristin, 0.73 for silydianin, 1.00 for silybin
Following the extraction, separate the round-bottom flask A, 1.05 for silybin B, 1.09 for dehydrosilybin, 1.15 for iso-
containing solvent hexane extract from the extraction silybin A, and 1.19 for isosilybin B; the resolution factor, R,
apparatus, and discard the solvent hexane solution. between silybin A and silybin B is not less than 1.0; the tail-
Remove the adherent solvent hexane from the extraction ing factor is not less than 0.8 and not more than 2.0; and the
thimble by drying, and transfer the thimble to an relative standard deviation for the sum of peak responses
extraction apparatus suitable for hot extraction and fitted due to silybin A and silybin B is not more than 2.0%.
with a 250-mL round-bottom flask containing 100 mL of Procedure—Separately inject equal volumes (about 10
ethyl acetate. [NOTE—Adjust the volume of ethyl acetate, uL) of the Milk thistle standard solution, each of the
if necessary, to sustain a continuous extraction.] Heat the Silybin standard solutions, and the Test solution into the
flask on a heating mantle to allow the solvent to reflux chromatograph, and record the chromatograms. Identify
gently. After 8 hours, transfer the extract quantitatively the peaks due to silychristin, silydianin, silybin A, silybin
Pharmacopeial Forum
B, isosilybin A, and isosilybin B by comparison with the Change to read:

Labeling—The label states the Latin binomial namo
chromatogram of the Milk thistle standard solution, and •
ANF21
measure the peak areas of the relevant peaks. Plot the and, following the official name, the part of the plant source from
areas of the sum of silybin A and silybin B peaks versus
Change to read:
the concentration of USP Silybin RS in the Silybin USP Reference standards (11)—
A
USP Powdered Milk Thistle Extract RS.ANF21
standard solutions, and obtain a regression line for USP Silybin RS. USP Silydianin RS.
calibration. Separately calculate the percentage of each Change to read:
relevant component of silymarin as silybin (C25H22O10) in Heavy metals (231): 0.002%.
A
20 ug per g.ANF21
the portion of Milk Thistle taken by the formula:
250C/W, Change to read:

Other requirements—It responds to tho Identification t03t and
•
in which C is the concentration, in mg per mL, of the rele- ANF2I
meets the requirements
vant component in the Test solution as interpolated in the A
in the tests ANF21
calibration graph; and W is the weight, in g, of the portion for
A
Identification,ANF2]
of Milk Thistle taken. Calculate the content of silymarin, in Foreign organic matter, Total ash, Pesticide residues, Loss on dry-
ing, Microbial limits, and Content of silymarin under Milk Thistle.
percentage, in the portion of Milk Thistle taken by adding
the individual percentages.Aivra
BRIEFING
Powdered Milk Thistle Extract, page 2259 of PF 27(2) [Mar.-

Apr. 2001], A change in the Definition is proposed to recognize the
BRIEFING
fact that various manufacturers use different concentrations of ex-
tract mixed with carrier excipients and that excipients may be
Powdered Milk Thistle, NF 20 page 2583—See briefing under added in varying amounts. This results in a variability of the ratio
Milk Thistle. of starting plant material to final extract, rendering this parameter
of little value. Therefore, it is proposed to delete the ratio of starting
(DSB: G. Giancaspro) RTS—33114-2 plant material to final extract and change the limits in the test for
Content for silymarin to a range in percentage of the labeled
amount. It is proposed to revise the Microbial limits according to
the current recommendations of the USP Expert Committee on
Change to read: Analytical Microbiology for botanical articles. See briefing under
Milk Thistle for changes in the chromatographic system of the test
for Content of silymarin. In addition, editorial changes have been
» Powdered Milk Thistle is Milk Thistle reduced to a made.
fine or very fine powder.
A (DSB: G. Giancaspro) RTS—33114-3
It contains not less than 2.0% of silymarin, calcu-
lated as silybin (C25H22O10), on the dried basis.ANF21
Pharmacopeia! Forum
Add the following:

Test solution—Dissolve 100 mg of Powdered Extract in
^Powdered Milk Thistle Extract 10 mL of methanol, and allow to stand for 15 minutes
before use.
» Powdered Milk Thistle Extract is prepared from B: Tho retention timea for tho silydianin, oilyoristin,
Milk Thistle fruits or seeds by fat removal and silybin A; silybin B, isoailybin A, and isosilybin B poaka
subsequent extraction with suitable solvents. The retention times of the peaks for silydianin,
Tho ratio of the? starting crude plant material to silychristin, silybin A, silybin B, isosilybin A, and
Powdered Extract is between 25:1 and 60:1. It isosilybin B in the chromatogram of the Test solution
correspond to those in the chromatogram of Standard
contains not less than 40.0 percent of 90.0 percent
solution 1, Milk thistle standard solution, as obtained in
and not more than 110.0 percent of the labeled
the test for Content of silymarin.
amount of silymarin calculated as silybin
Microbial limits (2021)—The total bacterial count does
(C25H22O10), on the dried basis, consisting of not
not exceed 10,000 104 per g, the total combined molds
less than 20.0 percent and not more than 45.0 per- and yeasts count does not exceed 1000 103 per g, tke
cent for the sum of silydianin and silychristin, not ooliform count dooo not oxoood 1000 per g, and the
less than 40.0 percent and not more than 65.0 per- enterobacterial count does not exceed 1000 103 per g. It
cent for the sum of silybin A and silybin B, and meets the requirements of the tests for absence of
not less than 10.0 percent and not more than Salmonella species, and Escherichia coli. and
20.0 percent for the sum of isosilybin A and iso- Staphylococcus aurcus.
silybin B. Loss on drying (731)—Dry it at 105° for 2 hours: it loses

Heavy metals, MethodII (231): 0.002%. 20 ug per g.
containers, in a cool place.
Labeling—The label states the Latin binomial namo and,
requirements.
which the article was prepared. It meets the requirements
Solution A—Uoo a filtered and degassed mixture of 0:05
for Labeling under Botanical Extracts (565).
M phosphoric aoid, mothanol, and totrahydrofuran
USP Reference standards (11)—USP Powdered Milk
(75:18:7).
Thistle Extract RS. USP Silybin RS. USP Silydianin RS.
Solution B—Use filtered and degassed mothanol.
Identification—
Solution B as directed for Chromatographic system. Mako
(201)-
Standard solution, Developing solvent system, and
Chromatography
Procedure—Proceed as directed for tho Identification tost
Identification test A under Milk Thistle.
Pharmacopeial Forum
Standard solution 1—Dissolve an aoouratoly weighed 2.0; and the relative standard deviation for tho sum of tho
quantity of USP Powdorod Milk Thiotlo Extract RS in peak responses duo to silybin A and oilybin B^ determined
mothanol; sonicate for 30 minutes, and dilute with from the peak for oilybin A and oilybin B, is not more than
mothanol to obtain a solution having a known
concentration of about1:0 mg per mL. Filter through a Procedure—Separately injoot equal volumes (about 10
membrane having a 0.45 urn or finer porosity. uL) of Standai«d solution I, Standard solution 2, and tho
Standard solution 2—Dioaolvo an aoouratoly weighed Test solution into tho ohromatograph; rooord tho
quantity of USP Silybin RS in mothanol, and dilute with ohromatograms; identify tho peaks duo to oilyoriotin,
mothanol to obtain a solution having a known silydianin; silybin A, silybin B, isosilybin A; and
concentration of about 0:35 mg per mL. Filter through a ioosilybin B tho peak for oilydianin, tho peak for
membrane having a 0.15 urn or finer porosity. silyohristin, tho peak for silybin A and ailybin B, and the
Test solution—Transfer about 100 mg of Powdered peak for isosilybin A and isosilybin B by comparison with
Extract, aoouratoly weighed, to a 100 mL volumotrio tho ohromatogram of Standaivl solution If and measure tho
flask; add 90 mL of mothanol, and oonioato for 20 aroas of tho relevant peaks. Separately oaloulato tho
minutOQ. Cool to 20°, and dilute with mothanol to volume. poroontago of oaoh relevantoomponont of silymarin as
Filter through a membrane having a 0.45 urn or finer silybin (C^HsaQ^.) in the portion of Powdorod Extraot
Chromatographic system (see Chmmatography (€H))—
The liquid ohromatograph ia equipped with a 288 nm
in which C ia the oonoontration, in mg per mL, of USP Si
detector and a 4.0 mm x 10 om column that contains 5
lybin RS in Standard solution 2; Wis the weight; in mg; of
urn paoking LI. The oolumn tomporature is maintained at
Powdorod Extraot takon; r# is tho poak area for tho relevant
40°. The flow rate is about 1 mL per minute. The
component obtained from tho Test solution; and r# is tho
ohromatograph is programmed as follows.
poak area for silybin A and silybin B obtained from Stan-
Solution A Solution B
X7Tf!tTTv7TT
dard solution 2. Calculate the poroontago of silymarin in
©-44 100 »60 0 )10 linear gradient tho portion of Powdered Extraot takon by adding the indivi
1 c 1 n en An
60 > 100 10 »0 linear gradient dual percentages.
£00 0. equilibration
Solution A, Solution B, Mobile phase, Silybin standard
Chromatograph Standard solution 1, and record tho peak
solutions, and Chromatographic system—Proceed as
responses as directed forProccdurc: the ohromatogram ob
directed in the test for Content of silymarin under Milk
tainod is similar to the Roforonoo Chromatogram provided
Thistle.
with USP Powdorod Milk Thistle Extraot RS. Chromato
Milk thistle standard solution—Dissolve an accurately
graph Standard solution 2, and record the peak responses
weighed quantity of USP Powdered Milk Thistle Extract
as directed forProccdurc: tho resolution, R, between oilybin
RS in methanol, sonicate for 20 minutes, and dilute with
diastoroomors and isosilybin diastorcomors is not less than
methanol to obtain a solution having a known
1.0; tho tailing factor is not loss than 0.8 and not more than
concentration of about 0.7 mg of extract per mL
Pharmacopeial Forum
Test solution—Transfer an accurately weighed amount of

BRIEFING
Powdered Extract, equivalent to about 40 mg of silymarin,
to a 100-mL volumetric flask. Add 70 mL of methanol, and Milk Thistle Capsules, page 2261 of PF 27(2) [Mar.-Apr.
2001 ]. In the test for Disintegration and dissolution, it is proposed
sonicate for 20 minutes. Cool at 20°, and dilute with to revise the Dissolution Medium by adding a surfactant that is ap-
propriate for silymarin. It is proposd to change the analytical meth-
methanol to volume. Pass through a membrane filter od for the determination of silymarin dissolved in the test for
Dissolution to that used in the test for Content of silymarin, to mea-
having a 0.45-um or finer porosity. sure all the peaks pertaining to the silymarin group instead of only
silybin. Revision of Microbial limits is proposed in accordance
Procedure—Separately inject equal volumes (about 10 with the current recommendations of the USP Expert Committee
on Analytical Microbiology for botanical articles. In addition, edi-
uL) of the Milk thistle standard solution, each of the torial changes have been made.
Silybin standard solutions, and the Test solution into the (BNA: G. Giancaspro) RTS—30689-2
chromatograph, and record the chromatograms. Identify
the peaks due to silychristin, silydianin, silybin A, silybin Add the following:
B, isosilybin A, and isolybin B by comparison with the A
Milk Thistle Capsules
chromatogram of the Milk thistle standard solution, and
measure the peak areas of the relevant peaks. Plot the
» Milk Thistle Capsules are prepared from Pow-
areas of the sum of silybin A and silybin B peaks versus
dered Milk Thistle Extract. They contain not less
the concentration of USP Silybin RS in the Silybin
standard solutions, and obtain a regression line for
calibration. Separately calculate the percentage of each
of the labeled amount of silymarin as silybin
relevant component of silymarin as silybin (C25H22O10) in (C25H22O10), calculated as the sum of silydianin,
the portion of Powdered Extract taken by the formula: silychristin, silybin A, silybin B, isosilybin A,
and isosilybin B.
10,000(C/FF),
in which C is the concentration, in mg per mL, of the rele- Packaging and storage—Preserve in tight, light-resistant
vant component in the Test solution as interpolated from the containers.
calibration graph; and W is the weight, in mg, of the portion Labeling—The label states the Latin binomial and,
of Powdered Extract taken. Calculate the content of silymar- following the official name, the article from which the
in, in percentage, in the portion of Powdered Extract taken Capsules were prepared. The label also indicates the
by adding the individual percentages. content of silymarin, in mg per Capsule.
Other requirements—It meets the requirements in the tests USP Reference standards (11)—USP Powdered Milk
for Residual Solvents and Pesticide Residues under Thistle Extract RS. USP Silybin RS. USP Silydianin RS.
Botanical Extracts (565).ANF2J Identification—
(201)-
Standard solution, Developing solvent system, and
Procedure—Proceed as directed for the Identification test
under Milk Thistle.
Pharmacopeial Forum
Test solution—Weigh aoouratoly and finely powder the Determine the amount of silymarin as silybin (C2s H2oOi0)
contents of not fewer than 20 Capsules. Transfer a» dissolved by employing the following method.
aoouratoly weighed portion a portion of the powder, Solution A,Solution B, Mobile phase± Standard solution
equivalent to about 50 mg of silymarin, to a suitable 1, Standai«d solution 2, and Chromato graphic system—
container, add 10 mL of methanol, shake for 1 minute, Proceed ao directed in the toot for Content of silymarin
and sonicate for 10 minutes. Allow to stand for 15 under Powdcivd Milk Thistle Extract.
minutes before use. Standard solution—Transfer 1.0 mL of Standard solution
B: Tho retention times of tho poako for silyoristin^ 2 to a 25 mL volumotrio flask, add 15 mL of Medium, and
oilybin A, oilybin B, The retention times of the peek peaks dilute with mothanol to volume to obtain a solution having a
for silydianin, the peak for silychristin, tho peak for silybin known concentration of about 0.014 mg of USP Silybin RS
A, ft»4 silybin B, and tho poak for isosilybin A, and
isosilybin B in the chromatogram of the Test solution Test solution—Transfer an aliquot of tho suspension under
correspond to those in the chromatogram of Standard tost to a suitable vial, and allow to settle for 5 minutes.
solution 7, Milk thistle standard solution, as obtained in Centrifuge or pass through a filter to olarify tho solution.
the test for Content of silymarin. Pmccdurc—Separately injoot equal volumes (about 250
Microbial limits (2021)—The total bacterial count does uL) of tho Standai«d solution and tho Test solution into tho
not exceed 10;000 104 per g, the total combined molds ohromatograph; rooord the ohromatograms; identify tho
3 peak duo to s i l y b i n A and s i l y b i n B in each
and yeasts count does not exceed 1000 10 per g, tke
ooliform oount dooo not oxoood 100 por g, and the ohromatogram; and measure tho areas of tho relevant
enterobacterial count does not exceed -tOQ 102 per g. It peaks: Calculate the amount^ in mg, of both silybin A and
meets the requirements of the tests for absence of oilybin B dissolved in tho portion of Capsules taken by tho
Salmonella species and Escherichia coli. «*4 formula:
Staphylococcus aurcus.
in which Fio tho volume, in mL, of Medium in oaoh diooo
requirements for Dissolution.
lution vessel; C is tho concentration, in mg por mL, of USP
pH 7.5 Phosphate buffer—Dissolve 27.2 g of monobasic
SilybinRS in the Standardsolution; v# is the sum of re-
potassium phosphate and 6.08 g of sodium hydroxide in
sponses of peak rooponso for oilybin A and oilybin B ob
water, and dilute with water to 4000 mL.
tainod from tho Test solution; and r$ is tho 3um of tho
Medium: pH 7.5 Phosphate buffer; 2000 mL for Capsules
peak responses of peak response for silybin A and oilybin
containing 70 mg of ailymarin or lcao; 1000 mL for
B obtained from tho Standard solution: Calculate tho
Capsules containing loss than 70 mg of oilymarin.
amount of silymarin dissolved as oilybin in tho portion of
containing 2% lauryl sulfate; 900 mL.
Capsules takon by tho formula:
Time: 45 minutes.
Pharmacopeial Forum
in whioh S io tho amount of 3ilybin A and silybin B dis Procedure—Proceed as directed in the test for Content of
oolvod as oaloulatod above; iS1^ is tho oontont of oilymarin silymarin under Powdcwd Milk Thistle, Extract, except to
in oaeh Capaulo, aa dotorminod in tho toot for Content ofsi- separately calculate the amount, in mg, of each relevant
tymarin; and iS^ ia tho oontont of silybin A and ailybin B in component of silymarin as silybin (C25H22O10) in the
each Capaulo, aa dotorminod in tho toot for Content of sily portion of Capsules taken by the formula:
marine method in the test for Content of silymarin, making
any necessary modifications.
100c,
silymarin as silybin (C25H22O10) is dissolved in 45 minutes.
in which the torma arc term, C, is as defined therein. Calcu-
late the content of silymarin, in mg, in the portion of Cap-
sules taken by adding the individual amounts. Am;
Solution A, Solution B, Mobile phase; Standard solution
1, Standard solution -2; and Chromatographic system—
Prooood as dirootod in tho toat for Content of silymarin
under Powdered Milk Tliistle Extract.
Solution A, Solution B, Mobile phase, Silybin standard
solutions, and Chromatographic system—Proceed as
BRIEFING
directed in the test for Content of silymarin under Milk
Milk Thistle Tablets, page 2263 of PF 27(2) [Mar.-Apr.
Thistle. 2001]—See briefing under Milk Thistle Capsules.
Milk thistle standard solution—Dissolve an accurately (BNA: G. Giancaspro) RTS—30689-3
weighed quantity of USP Powdered Milk Thistle Extract
RS in methanol, sonicate for 20 minutes, and dilute with Add the following:
methanol to obtain a solution having a known A
Milk Thistle Tablets
concentration of about 0.7 mg of extract per mL.
Test solution—Weigh and finely powder the contents of
» Milk Thistle Tablets are prepared from Pow-
not fewer than 20 Capsules. Transfer an accurately
dered Milk Thistle Extract. They contain not less
weighed amount of the powder, equivalent to about 100
mg of silymarin, to a 100-mL volumetric flask, add 90
mL of methanol, and sonicate for 20 minutes with
of the labeled amount of silymarin as silybin
occasional shaking. Cool to 20°, and dilute with methanol (C25H22O10), calculated as the sum of silydianin,
to volume. Filter through a membrane having a 0.45-um silychristin, silybin A, silybin B, isosilybin A,
or finer porosity. and isosilybin B.

containers.
Pharmacopeial Forum
Labeling—The label states the Latin binomial namo, and, Disintegration and dissolution (2040): meet the
following the official name, the article from which the requirements for Dissolution.
Tablets were prepared. The label also indicates the content Pwccdure—
of silymarin, in mg per Tablet. pH 7.5 Phosphate buffet' Disoolvo 27.2 g of monobaoio
USP Reference standards (11)—USP Powdered Milk potassium phosphate and 6.08 g of sodium hydroxide in
Thistle Extract RS. USP Silybin RS. USP Silydianin RS. water, and dilute with water to 1000 mL.
Identification— Medium: pH 7.5 Phosphate buffer; 2000 mL for Tabloto
A: Thin-Layer Chromatographic Identification Test oontaining 70 mg of ailymarin or loos; 1000 mL for Tablets
(201)- oontaining loss than 70 mg of oilymarin;
Standard solution, Developing solvent system, and Apparatus 2: 100 rpm.
Procedure—Proceed as directed for the Identification test Time: 15 minutoa.
under Milk Thistle. Determine tho amount of silymarin as silybin (C^-H^Q^)
Test solution—Weigh and finely powder not fewer than 20 dissolved by employing the following method.
Tablets. Transfer an aoouratoly weighed portion a portion of Solution A, Solution B, Mobile phase, Standard solution
the powder, equivalent to about 50 mg of silymarin, to a test I, Standard solution 2, and Chromatographic system—
tube, add 10 mL of methanol, shake for 1 minute, and Prooood as dirootod in tho tost for Content of silymarin
sonicate for 10 minutes. Allow to stand for 15 minutes under Powdered Milk Thistle Extract.
before use. Standard solution—Transfor 1.0 mL of Standard solution
B: Tho retention timos of tho peaks for silydianin, 2 to a 25 mL volumotrio flask, add 5 mL of Medium, and
silyoristinv silybin A, silybin B, iaosilybin A, and dilute with mothanol to volume to obtain a solution
isosilybin B The retention times of the peak peaks for having a known concentration of about 0.014 mg of USP
silydianin, tho peak for silychristin, tho peak for silybin A, Silybin RS por mL.
ead silybin B, and tho poalc for isosilybin A, and isosilybin Test solution—Transfor an aliquot of tho suspension undor
B in the chromatogram of the Test solution correspond to tost to a ouitablo vial, and allow to sottlo for 5 minutoa.
those in the chromatogram of Standard solution 1, Milk Contrifugo or pass through a filter to olarify tho solution.
thistle standard solution, as obtained in the test for Procedure—Separately inject equal volumes (about 250
Content of silymarin. uL) of the Standard solution and tho Test solution into tho
ohromatograph; rooord tho ehromatograms; identify tho
poak duo to s i l y b i n A and s i l y b i n B in oaoh
ohromatogram; and measure tho aroa3 of tho relevant
and yeasts count does not exceed 1000 103 per g, tke
poako. Caloulato tho amount dissolvod, in mg, of both
ooliform count doos not cxoood 100 por g, and the
silybin A and silybin B in tho portion of Tablets taken by
enterobacterial count does not exceed 4-00 102 per g. It
tho formula:
meets the requirements of the tests for absence of
Salmonella species and Escherichia coli. , and
Staphylococcus aweus.
Pharmacopeial Forum
ia which V'm tho volumes,in mL, of Medium in each disso Test solution—Weigh and finely powder not fewer than 20
lution vessel; Cisthe oonoentmtion, in mg por mL, of USP Tablets. Transfer an accurately weighed quantity of the
Silybin RS in tho Standard solution; rîa tho poak rooponso powder, equivalent to about 100 mg of silymarin, to a
for silybin A and silybin B obtainod from tho Test solution; 100-mL volumetric flask, add 90 mL of methanol, and
and ^ istho sum of responses of poak response for silybin A sonicate for 20 minutes with occasional shaking. Cool to
and silybin B obtainod from the Standard solution: Galou 20°, and dilute with methanol to volume. Filter through a
lato tho amount of silymarin dissolved as 3ilybin membrane having a 0.45-um or finer porosity.
in the portion of Capsules taken by tho formulae Procedure—Proceed as directed in the test for Content of
silymarin under Powdered Milk Thistle Extraet, except to
separately calculate the amount, in mg, of each relevant
in which S is tho amount of silybin A and silybin B dis component of silymarin as silybin (C25H22O10) in the
solved as oaloulatcd abovo; S$ is tho content of 3ilymarin portion of Tablets taken by the formula:
in oaoh Tablet as determined in the tost for Content ofsily
marin; and-S§ is tho content of silybin A and silybin B in
each Tablet, a3 determined in tho tost for Content of silymar
100C,
Tolerances—Not loss than 75% (Q) of tho labeled amount in which the terms are term, C, is as defined therein. Calcu-
of ailymarin a3 3ilybin (C^gHÔ^) is dissolved in 45 late the amount of silymarin, in mg, in the portion of Tablets
minutes: Proceed as directed in the test for Dissolution taken by adding the individual amounts obtained.
under Milk Thistle Capsules.
Solution A, Solution B, Mobile phase, Standard solution
4-r Silybin standard solutions £, and Chromatographic
BRIEFING
system—Proceed as directed in the test for Content of
silymarin under Powdered Milk Thistle Extraet. Myristyl Alcohol, page 2589 of PF 27(3) [May-June 2001].
Milk thistle standard solution—Prepare as directed for (EMC: C. Sheehan) RTS—36052-1
Milk thistle standard solution in the test for Content of
silymarin under Powdered Milk Thistle Extract.
Erratum:
Assay, line 1 under Procedure: Change "2 mL" to: 2 uL
Pharmacopeia! Forum
USP Reference standards (11)—USP Hexacosanol RS.

BRIEFING USP Methyl Caprate RS. USP Methyl Caproate RS. USP
Saw Palmetto Extract, page 1567 of PF 26(6) [Nov.-Dec. Methyl Caprylate RS. USP Methyl Laurate RS. USP Methyl
2000]. It is proposed to change the limits of fatty acid ratios in
the test for Identification to reflect the quality of the material ob- LinoleateRS. USP Methyl Linolenate RS. USP Methyl Myr-
tained by different extraction methods. In addition, editorial
changes have been made. istateRS. USP Methyl OleateRS. USP Methyl PalmitateRS.
USP Methyl Palmitoleate RS. USP Methyl StearateRS. USP
(3-Sitosterol RS.
Add the following: Identification—The retention times of the 11 major peaks

A in the chromatogram of the Test solution correspond to those
Saw Palmetto Extract
in the chromatogram of the Standard solution, as obtained
in the test for Content of fatty acids.
» Saw Palmetto Extract is obtained from commin-
The ratios of the concentration of lauric acid to the con-
uted Saw Palmetto by extraction with hydroalco-
centration of the respective fatty acid are in the following
holic mixtures or solvent hexane, or by
ranges.
supercritical extraction with carbon dioxide. The
ratio of starting crude plant material to Extract is Fatty Acid Minimum Ratio Maximum Ratio
between 8.0:1 and 14.3:1. The Extract contains 9r5-9.0 16
Capric
not less than 70.0 percent and not more than 8.5 SS 24
Caproic
408.5 17.5
95.0 percent of fatty acids and not less than 0.2 Caprylic
&6 5.0 12.5 16
percent and not more than 0.5 percent of sterols, Linoleic
31.5 4$ 55
calculated on the anhydrous basis. The lipophilic Linolenic
2.2 2.8
Extract contains not less than 0.15 percent and not Myristic
Q.6§' 0.60 1.15
Oleic
more than 0.35 percent of long-chain alcohols. 2.8 3r63.9
Palmitic
The hydroalcoholic Extract contains not less than 44 14 26
Stearic
long-chain alcohols. It contains no added sub- Iodine value (401): between 40 and 50.
stances. Saponification value (401): between 210 and 250.
Unsaponifiable matter (401): between 1.8% and 3.5%.
Labeling—The label states the Latin binomial and,
Water, Method I (921): not more than 3% is found in the
which the article was prepared. The label also indicates hydroalcoholic Extract.
the content of fatty acids and sterols and the ratio of the Heavy metals, Method II (231): 0.004%.
starting crude plant material to Extract. It meets the Organic volatile impurities, Method IV (467): meets the
requirements for Labeling under Botanical Extracts (565). requirements.
Solvent: benzyl alcohol.
Pharmacopeial Forum
Content of fatty acids— Dissolve the residue in 1.0 mL of Derivatizing reagent,

Internal standard solution, Standard solution, and and allow to stand for not less than 15 minutes at room
Chromatographic system—Prepare as directed for Content temperature.
of fatty acids under Saw Palmetto. System suitability solution—Prepare a solution containing
Test solution—Transfer about 100 mg of Extract, about 1 mg per mL each of tetracosanol, octacosanol, USP
accurately weighed, to a pressure-proof, screw-capped Hexacosanol RS, and triacontanol. Continue as directed for
vial, and add 3.0 mL of a solution of sulfuric acid in Standard solution, beginning with "Transfer 1.0 mL of this
methanol (5 in 100). Heat at 100° in an oil bath for 2 solution to a screw-capped vial".
hours, shaking from time to time. Allow to cool, and add Test solution—Transfer about 5 g of Extract, accurately
1.0 mL of Internal standard solution, 10.0 mL of water, 1 weighed, to a 250-mL round-bottom flask. Add 2.0 mL of
g of sodium chloride, and 5 mL of hexanes. Shake well, Internal standard solution 1 and 2.0 mL of Internal
allow the layers to separate completely, and use the standard solution 2. Evaporate in vacuum at a temperature
hexanes layer. [NOTE—Store in a refrigerator until ready not exceeding 50°. Add 50 mL of a solution prepared by
to use.] dissolving 130 g of potassium hydroxide in 200 mL of
Procedure—Proceed as directed for Content of fatty acids water and diluting with methanol to 1000 mL. Attach a
under Saw Palmetto. Calculate the percentage of each fatty condenser, and reflux on a water bath until a clear
acid in the portion of Extract taken by the formula: solution is obtained. Reflux for an additional 10 minutes,
and cool by adding 50 mL of water through the
500(CV W)(Ru/Rs)(MA /ME),
condenser. Quantitatively transfer to a separation funnel,
in which W'\s the weight, in mg, of Extract taken to prepare
rinsing the flask with a total of 50 mL of water divided
the Test solution; and the other terms are as defined therein. into small portions. Extract with three 80-mL portions of
Content of long-chain alcohols— ether, shaking for 30 seconds each time. [NOTE—If an
Derivatizing reagent—Prepare a mixture of pyridine and emulsion forms, eliminate it by adding small quantities of
iV-(trimethylsilyl)imidazole (4:1). methanol.] Transfer the combined ether layers into a
Internal standard solution I—Prepare a solution separation funnel, and wash with successive 50-mL
containing 1.0 mg of eicosanol per mL of chloroform. portions of water until a neutral washing is obtained.
Internal standard solution 2—Prepare a solution [NOTE—If an emulsion forms, eliminate it by adding
containing 1.0 mg of /?-cholestanol per mL of chloroform. small quantities of methanol.] Pass the ether extract
Standard solution—Transfer an accurately weighed through filter paper containing anhydrous sodium sulfate,
quantity of USP Hexacosanol RS to a volumetric flask, wash the filter with 30 mL of ether, evaporate to dryness
and dissolve in and dilute with chloroform to volume to in vacuum, and dissolve the residue in 2.0 mL of
obtain a solution having a known concentration of about 1 chloroform. Separately apply 200 uL of this solution, 20
mg per mL. Transfer 1.0 mL of this solution to a screw- (iL of a solution of eicosanol in chloroform (1 in 100),
capped vial, add 1.0 mL of Internal standard solution 1, and 20 uL of a solution of /?-cholestanol in chloroform (1
and evaporate to dryness using a stream of nitrogen. in 100) to a thin-layer chromatographic plate coated with
Pharmacopeia! Forum
a 0.25-mm layer of chromatographic silica gel mixture, column temperature is programmed as follows. Initially it is
previously dipped in 3 cm of a solution prepared by increased from 150° to 300° at a rate of 5° per minute, then
dissolving 13 g of potassium hydroxide in 20 mL of water maintained at 300° for 10 minutes. The injection port and
and diluting with methanol to 1000 mL. [NOTE—The plate the detector are maintained at a temperature of 350°.
is placed vertically in the potassium hydroxide solution so Chromatograph the Standard solution System suitability
that only the application zone is treated. Allow the plate to solution, and record the peak responses as directed for
dry, and heat to 100° for 1 hour before use. It can be stored Procedure: the relative retention times are 1.00, 1.35,
in a desiccator containing calcium chloride.] Develop with a 1.50, 1.65, and 1.82 for eicosanol, tetracosanol,
solvent consisting of a mixture of hexanes and ether (7:3) hexacosanol, octacosanol, and triacontanol, respectively;
until the solvent front has moved 17 to 19 cm. Keep the the column efficiency is not less than 200,000 theoretical
chamber temperature between 15° and 20°. Dry the plate plates determined from the eicosanol peak; and the tailing
with a current of warm air, then spray with an alkaline factor is not more than 2.0.
solution of 2,7-dichlorofluorescein in alcohol (0.2 in 100). Procedure—Separately inject equal volumes (about 1 uL)
Examine the plate under 366-nm UV light, and identify of the Standard solution and the Test solution into the
the bands corresponding to long-chain alcohols and to chromatograph, record the chromatograms, and measure
sterols using the spots of eicosanol and /3-cholestanol, the responses for the major peaks. Separately calculate the
respectively. Scrape off the zones of silica gel percentages of tetracosanol, hexacosanol, octacosanol, and
corresponding to long-chain alcohols, and transfer to a test triacontanol in the portion of Extract taken by the formula:
tube. [NOTE—Retain the plate for preparing the Test
200(C/W)(Ru/Rs),
solution in the test for Content of sterols.] Add 10 mL of
warm chloroform, and shake for two minutes with several in which C is the concentration, in mg per mL, of USP Hex-
glass beads. Filter, and wash the filter with chloroform. acosanol RS in the Standard solution; W is the weight, in
Evaporate the combined filtrate and washings to dryness mg, of Extract taken to prepare the Test solution; Rv is the
in vacuum. Dissolve the residue by adding a few drops of response ratio of the appropriate long-chain alcohol peak to
acetone, and evaporate in vacuum. Dry the residue in an the internal standard peak in the chromatogram of the Test
oven at 105° for 15 minutes. Dissolve the residue in 0.2 solution; and Rs is the response ratio of the hexacosanol
mL of Derivatizing reagent, and allow to stand for not peak to the internal standard peak in the chromatogram of
less than 15 minutes at room temperature. the Standard solution. Calculate the content of long-chain
alcohols by adding the individual percentages.
Content of sterols—
detector, a split injection system with a 50:1 split ratio, and a Derivatizing reagent, Internal standard solution 1, and
0.32-mm x 20-m capillary column coated with a 0.2- to Internal standard solution 2—Prepare as directed in the
0.25-um film of phase G27. The carrier gas is helium, test for Content of long-chain alcohols.
flowing at a rate of about 1.5 mL per minute, and the Standard solution—Transfer an accurately weighed
makeup gas is flowing at a rate of 30 mL per minute. The amount of USP /3-Sitosterol RS to a volumetric flask, and
dissolve in and dilute with chloroform to volume to obtain
Pharmacopeial Forum
a solution having a known concentration of about 1 mg per in which C is the concentration, in mg per mL, of USP (3-
mL. Transfer 1.0 mL of this solution to a screw-capped vial, Sitosterol RS in the Standard solution; W is the weight, in
add 1.0 mL of Internal standard solution 2, and evaporate to mg, of the Extract taken to prepare the Test solution; Rv is
dryness using a stream of nitrogen. Dissolve the residue in the response ratio of the appropriate sterol peak to the inter-
1.0 mL of Derivatizing reagent, and allow to stand for not nal standard peak in the chromatogram of the Test solution;
less than 15 minutes at room temperature. and Rs is the response ratio of the /3-sitosterol peak to the
System suitability solution—Prepare a solution containing internal standard peak in the chromatogram of the Standard
about 1 mg per mL each of campesterol, stigmasterol, and solution. Calculate the content of sterols by adding the indi-
USP /?-Sitosterol RS. Continue as directed for Standard vidual percentages.
solution, beginning with "Transfer 1.0 mL of this solution Alcohol content, Method II (611) (if present): not more
to a screw-capped vial". than 1% is found.
Test solution—Use the plate retained from the Test Other requirements—It meets the requirements of the tests
solution in the Content of long-chain alcohols test, and for Packaging and Storage, Microbial Limits [To come],
scrape off the zone of silica gel corresponding to sterols. and Pesticide Residues under Botanical Extracts
Proceed as directed for Test solution in the test for
Content of long-chained alcohols beginning with "Add 10
mL of warm chloroform".
Chromatographic system—Prepare as directed in the test
for Content of long-chain alcohols. Chromatograph the
Standai*d solution System suitability solution, and record
the peak responses as directed for Procedure: the relative BRIEFING
retention times are 1.00, 1.05, 1.06, and 1.09 for (3- Sugar-Free Suspension Structured Vehicle, NF 20 page 2632
and page 3346 of PF 27(6) [Nov.-Dec. 2001]—See briefing under
cholestanol, campesterol, stigmasterol, and /5-sitosterol, Cefazolin Ophthalmic Solution.
respectively; the column efficiency is not less than
200,000 theoretical plates determined from the (3-
cholestanol peak; and the tailing factor is not more than 2.0.
Change to read:
of the Standard solution and the Test solution into the » Prepare Sugar-Free Suspension Structured Vehicle as
follows (see Pharmacy Compounding ( )
chromatograph, record the chromatograms, and measure
*Pharmaceutical Compounding—Nonsterile
the responses for the major peaks. Separately calculate the
Preparations (795)):,•ANF21
percentages of campesterol, stigmasterol, and /?-sitosterol in
the portion of Extract taken by the formula:
Xanthan Gum 0.20 g
Saccharin Sodium 0.20 g
Potassium Sorbate 0.15 g
Citric Acid 0.10 g
Sorbitol 2.0 g
Mannitol 2.0 g
Pharmacopeial Forum
Glycerin 2.0 mL
Purified Water, a sufficient quantity BRIEFING
to make 100 mL
Xanthan Gum Solution, NF20 page 2644 and page 3347 of PF
27(6) [Nov.-Dec. 2001]—See briefing under Cefazolin Ophthal-
Transfer 30 mL of Purified Water to a beaker, pla- mic Solution.
cing it on an electric hot plate and stirrer. Using mod-
erate heat, stir to form a vortex, and slowly sprinkle the (CRX:C. Okeke) RTS—35643-11
Xanthan Gum into the vortex. In a separate beaker, dis-
solve the Saccharin Sodium, Potassium Sorbate, and
Citric Acid in 50 mL of Purified Water. Using moder- Change to read:
ate heat, incorporate the Sorbitol, Mannitol, and Gly-
cerin into this mixture. Add to this mixture the
previously prepared Xanthan Gum dispersion. Add a » Prepare Xanthan Gum Solution of the designated
sufficient quantity of Purified Water to obtain a final percentage strength as follows (see Pharmacy
volume of 100 mL, and mix. Compounding { )
A
Pharmaceutical Compounding—Nonsterile
Preparations {195)):ANF2J
BRIEFING
Xanthan Gum
for 0.1% Solution 100 mg
Suspension Structured Vehicle, NF 20 page 2632 and page for 1.0% Solution 1.0 g
3346 of PF 27 (6) [Nov.-Dec. 2001]—See briefing under Cefazolin Methylparaben 100 mg
Ophthalmic Solution. Propylparaben 20 mg
Purified Water, a sufficient quantity
(CRX: C. Okeke) RTS—35643-12 to make 100 mL
Dissolve an accurately weighed quantity of Propyl-

Change to read: paraben in Purified Water with heating to about 50°
and stirring. Cool, and dilute quantitatively, and step-
» Prepare Suspension Structured Vehicle as follows wise if necessary, with Purified Water to obtain 90 mL
(see Pharmacy Compounding { ) of solution containing 20 mg of Propylparaben. Heat to
A
Pharmaceutical Compounding—Nonsterile about 50°, and add the Methylparaben, with stirring, to
dissolve. Cool, stir with a blender, slowly sift the
Preparations {195)):ANF21 Xanthan Gum into the vortex, and continue to blend
for 2 minutes after the Xanthan Gum has been added.
Add 10 mL of Purified Water, and blend for 5 minutes.
Allow to stand for 1 hour for excess foam to subside,
Potassium Sorbate . 0.15 g and remove most of the remaining foam by passing the
Xanthan Gum 0.15 g solution through a strainer. Add Purified Water, if nec-
Citric Acid, Anhydrous 0.15 g essary, to make the final volume 100 mL, and stir.
Sucrose 20 g [NOTE—Depending on the volume needed and the
Purified Water, a sufficient quantity equipment available, adjust the formula proportio-
to make 100 mL nately.]
Transfer the Potassium Sorbate to a suitable beaker, Change to read:

and dissolve in 50 mL of Purified Water. Place the bea- Packaging and storage—Preserve in tight, light-resistant
ker on an electric hot plate and stirrer, and add into the containers, and store at
vortex, slowly stirring, the Xanthan Gum. Apply mini- •controlledB1
mal heat, and incorporate the Citric Acid and the Su- room temperature.
crose. Add a sufficient quantity of Purified Water to
obtain a final volume of 100 mL, and mix.
Pharmacopeial Forum
Where the individual monograph permits varying concentra-

tions of active ingredients in the large-volume parenteral, the con-
GENERAL CHAPTERS centration of each ingredient named in the official title is stated as if
part of the official title, e.g., Dextrose Injection 5%, or Dextrose
(5%) and Sodium Chloride (0.2%) Injection.
The labeling includes the following information if the complete
formula is not specified in the individual monograph: (1) In the
case of a liquid preparation, the percentage content of each ingre-
dient or the amount of each ingredient in a specified volume, ex-
General Tests and Assays cept that ingredients added to adjust to a given pH or to make the
solution isotonic may be declared by name and a statement of their
effect; and (2) in the case of a dry preparation or other preparation
to which a diluent is intended to be added before use, the amount of
each ingredient, the composition of recommended diluent(s) [the
name(s) alone, if the formula is specified in the individual mono-
General Requirements for graph], the amount to be used to attain a specific concentration of
active ingredient and the final volume of solution so obtained, a
Tests and Assays brief description of the physical appearance of the constituted so-
lution, directions for proper storage of the constituted solution, and
an expiration date limiting the period during which the constituted
solution may be expected to have the required or labeled potency if
it has been stored as directed.
Containers for Injections that are intended for use as dialysis,
BRIEFING hemofiltration, or irrigation solutions and that contain a volume
of more than 1 liter are labeled to indicate that the contents are
not intended for use by intravenous infusion.
(1) Injections, USP 25 page 1833 and page 3068 of PF 27(5) Injections intended for veterinary use are labeled to that effect.
[Sept.-Oct. 2001]. It is proposed to require special warning label- The container is so labeled that a sufficient area of the container
ing and packaging for neuromuscular blocking agents (paralyzing remains uncovered for its full length or circumference to permit
agents), to minimize the potential for serious, life-threatening med- inspection of the contents.
ication errors in their application. The proposal is the result of the
collaboration of the Expert Committees on Parenteral Products—
Industrial, Safe Medication Use, and Nomenclature and Labeling. A
It is intended that the proposed change will be adopted via the Sec- For neuromuscular blocking and paralyzing agents, re-
ond Supplement to USP 26, with an official date of Aug. 1,2003, to
provide sufficient time for manufacturers to take appropriate ac- fer to Containers for Injections in the section Packaging for
tion. It is also proposed to add a reference to Containers (661)
in the Packaging section. In the section Labels and Labeling, it appropriate warning labeling.
is proposed to make revisions in accordance with the FDA regula-
tion relating to aluminum in total parenteral nutrition solutions.
The final rule was issued in the Federal Register (65 FR 4103-
4111; Jan. 26, 2000) and was to become effective on Jan. 26, Aluminum in Large and Small Volume Parenterals Used
2001, but was postponed until Jan. 26, 2003 (see 66 FR 7864-
7865; Jan. 26, 2001). The intention of the Expert Committees is in Total Parenteral Nutrition
to have the USP revision and the FDA regulation become effective
on the same date. (a) The aluminum content of large volume parenteral
(LVP) drug products used in total parenteral nutrition

(PPI: F. Barletta) RTS—35542; 35900-1; 36027-1
(TPN) therapy must not exceed 25 micrograrns per liter
Change to read:
(b) The package insert of LVPs used in TPN therapy must
state that the drug product contains no more than 25 ug/

LABELS AND LABELING
L of aluminum. This information must be contained in
Labeling—[NOTE—See definitions of "label" and "labeling" un- the "Precautions" section of the labeling of all large
der Labeling in the section Preservation, Packaging, Storage, and
Labeling of the General Notices and Requirements.] volume parenterals used in TPN therapy.
The label states the name of the preparation; in the case of a li-
quid preparation, the percentage content of drug or amount of drug (c) The maximum level of aluminum present at expiry
in a specified volume; in the case of a dry preparation, the amount
of active ingredient; the route of administration; a statement of sto- must be stated on the immediate container label of all
rage conditions and an expiration date; the name of the manufac-
turer and distributor; and an identifying lot number. The lot number small volume parenteral (SVP) drug products and phar-
is capable of yielding the complete manufacturing history of the
specific package, including all manufacturing, filling, sterilizing, macy bulk packages (PBPs) used in the preparation of
and labeling operations.
Pharmacopeial Forum
TPN solutions. The aluminum content must be stated as Change to read:
follows: "Contains no more than ug/L of alumi-

num." The immediate container label of all SVPs and PACKAGING
PBPs that are lyophilized powders used in the prepara-
Containers for Injections
tion of TPN solutions must contain the following state-
Containers, including the closures, for preparations for injec-
ment: "When reconstituted in accordance with the tions do not interact physically or chemically with the preparations
in any manner to alter the strength, quality, or purity beyond the
package insert instructions, the concentration of alumi- official requirements under the ordinary or customary conditions
of handling, shipment, storage, sale, and use. The container is
num will be no more than ug/L." This maximum made of material that permits inspection of the contents. The type
of glass preferable for each parenteral preparation is usually stated
level of aluminum must be stated as the highest of the in the individual monograph. Unless otherwise specified in the in-
dividual monograph, plastic containers may be used for packaging
following: injections
A
(1) The highest level for the batches produced during (see Containers (66\).±VSP26
For definitions of single-dose and multiple-dose containers, see
the last 3 years; Containers under General Notices and Requirements. Containers
meet the requirements under Containers (661).
Containers are oloaod by fusion, or by applioation of Buitablo
(2) The highest level for the latest five batches, or oloauroa, in auoh manner aa to prevent contamination or loss of
contents. Closures for multiple dose oontainora permit the withdra
(3) The maximum historical level, but only until com- wal of the oontonts without removal or dootruotion of the closure.
ThO'Olosuro pormito penetration by a neodlo, and, upon withdrawal
pletion of production of the first five batches after of the noodle, at onoo rooloaoa the oontainor againat contamination:
January 26, 2001. Containers are closed or sealed in such a manner as to pre-
(d) The package insert for all LVPs, all SVPs, and PBPs vent contamination or loss of contents. Validation of con-
used in TPN must contain a warning statement. This tainer integrity must demonstrate no penetration of
warning must be contained in the "Warnings" section microbial contamination or chemical or physical impurities.
of the labeling. The warning must state the following: In addition, the solutes and the vehicle must maintain their
WARNING: This product contains aluminum that may specified total and relative quantities or concentrations when
be toxic. Aluminum may reach toxic levels with pro- exposed to anticipated extreme conditions of manufacturing
longed parenteral administration if kidney function is and processing, and storage, shipment, and distribution.
impaired. Premature neonates are particularly at risk Closures for multiple-dose containers permit the withdrawal
because their kidneys are immature, and they require of the contents without removal or destruction of the clo-
large amounts of calcium and phosphate solutions that sure. The closure permits penetration by a needle and, upon
contain aluminum. withdrawal of the needle, closes at once, protecting the con-
Research indicates that patients with impaired kid- tainer against contamination. Validation of the multiple-
ney function, including premature neonates, who re- dose container integrity must include verification that such
ceive parenteral levels of aluminum at greater than 4 a package prevents microbial contamination or loss of pro-
to 5 ug/kg/day accumulate aluminum at levels asso- duct contents under anticipated conditions of multiple entry
ciated with central nervous system and bone toxicity. and use.AUSra5
Tissue loading may occur at even lower rates of
administration. A.USP26
Pharmacopeia! Forum
A
Potassium Chloride for Injection Volume in Container
Concentrate,"A.USP26 Each container of an Injection is filled with sufficient excess of
the labeled "size" or that volume which is to be withdrawn. See
Injections under Pharmaceutical Dosage Forms (1151).
The use of a black closure system on a vial (e.g., a black flip-off
button and a black ferrule to hold the elastomeric closure), or the
use of a black band or series of bands above the constriction on an
ampul, is prohibited except for Potassium Chloride for Injection DETERMINATION OF VOLUME OF INJECTION IN
Concentrate. CONTAINERS
Select 1 or more containers if the volume is 10 mL or more, 3 or
more if the volume is more than 3 mL and less than 10 mL, or 5 or
A
Neuromuscular Blocking and Paralyzing more if the volume is 3 mL or less. Take up individually the con-
tents of each container selected into a dry hypodermic syringe of a
rated capacity not exceeding three times the volume to be mea-
AgentsAUSP36 sured, and fitted with a 21-gauge needle not less than 2.5 cm (1
inch) in length. Expel any air bubbles from the syringe and needle,
A and then discharge the contents of the syringe, without emptying
A11 injectable preparations of neuromuscular blocking
the needle, into a standardized, dry cylinder (graduated to contain
agents and paralyzing agents must be packaged in vials with rather than to deliver the designated volumes) of such size that the
volume to be measured occupies at least 40% of its rated volume.
a closure system that is entirely anesthesia red (ASTM Pan- Alternatively, the contents of the syringe may be discharged into a
dry, tared beaker, the volume, in mL, being calculated as the
tone Red 811). Both the container cap ferrule and the cap weight, in g, of Injection taken divided by its density. The contents
of two, three, or four 1 or 2-mL containers may be pooled for the
overseal must bear in white print the words: "Warning: Pa- measurement, provided that a separate, dry syringe assembly is
used for each container. The content of containers holding 10
ralyzing Agent" or "Paralyzing Agent" (depending on the mL or more may be determined by means of opening them and
emptying the contents directly into the graduated cylinder or tared
size of the closure system). Alternatively, the overseal may beaker.
The volume is not less than the labeled volume in the case of
be transparent and without words, allowing for visualization containers examined individually or, in the case of 1-mL and 2-
mL containers, is not less than the sum of the labeled volumes
of the warning labeling on the red closure ferrule. When of the containers taken collectively.
For Injections in multiple-dose containers labeled to yield a spe-
packaged in ampuls, the band or bands above the constric- cific number of doses of a stated volume, proceed as directed in the
foregoing, using the same number of separate syringes as the num-
tion must also be anesthesia red in color.A[/iSra5 ber of doses specified. The volume is such that each syringe deli-
vers not less man the stated dose.
For Injections containing oil, warm the containers, if necessary,
and thoroughly shake them immediately before removing the con-
tents. Cool to 25° before measuring the volume.
Containers for Sterile Solids For Injections in cartridges or prefilled syringes, assemble the
container with any required accessories, such as needle or plunger.
Containers, including the closures, for dry solids intended for Following the same procedure as above, and without emptying the
parenteral use do not interact physically or chemically with the pre- needle, transfer the entire contents of each container to a dry, tared
paration in any manner to alter the strength, quality, or purity be- beaker by slowly and constantly depressing the plunger. Weigh,
yond the official requirements under the ordinary or customary and calculate the volume as described above. The volume of each
conditions of handling, shipment, storage, sale, and use. container is not less than the labeled volume.
A container for a sterile solid permits the addition of a suitable For large-volume intravenous solutions, select 1 container, and
solvent and withdrawal of portions of the resulting solution or sus- transfer the contents into a dry measuring cylinder of such size that
pension in such manner that the sterility of the product is main- the volume to be measured occupies at least 40% of its rated vol-
tained. ume. The volume is not less than the labeled volume.
Where the Assay in a monograph provides a procedure for Assay
preparation in which the total withdrawable contents are to be
withdrawn from a single-dose container with a hypodermic needle
and syringe, the contents are to be withdrawn as completely as pos- Packaging and Storage
sible into a dry hypodermic syringe of a rated capacity not exceed-
ing three times the volume to be withdrawn and fitted with a 21- The volume of Injection in single-dose containers provides the
gauge needle not less than 2.5 cm (1 inch) in length, care being amount specified for parenteral administration at one time and in
taken to expel any air bubbles, and discharged into a container no case is more than sufficient to permit the withdrawal and admin-
for dilution and assay. istration of 1 liter.
Preparations intended for intraspinal, intracisternal, or peridural
administration are packaged only in single-dose containers.
Pharmacopeia! Forum
Unless otherwise specified in the individual monograph, a multi- 2000], page 1369 of PF 26(5) [Sept.-Oct. 2000], page 1606 of
ple-dose container contains a volume of Injection sufficient to per- PF 26(6) [Nov.-Dec. 2000], page 1832 of PF 27(1) [Jan.-Feb.
mit the withdrawal of not more than 30 mL. 2001], page 2268 of PF 27(2) [Mar.-Apr. 2001], page 2594 of
Injections packaged for use as irrigation solutions or for hemo- PF 27(3) [May-June 2001], page 2806 of PF 27(4) [July-Aug.
filtration or dialysis or for parenteral nutrition are exempt from the 2001], page 3071 of PF 27(5) [Sept.-Oct. 2001], page 3348 of
1-liter restriction of the foregoing requirements relating to packa- PF27(6) [Nov.-Dec. 2001], and page 111 of P F 28(1).
ging. Containers for Injections packaged for use as hemofiltration
or irrigation solutions may be designed to empty rapidly and may (HDQ) RTS—35617-1; 35776-2; 30473-1; 36043; 36081-1;
contain a volume of more than 1 liter. 36082-1; 36090-1; 36191-1
Injections labeled for veterinary use are exempt from packaging
and storage requirements concerning the limitation to single-dose
containers and the limitation on the volume of multiple-dose con-
tainers.
Change to read:
Change to read:
USP Clorsulon RS—Dry portion in vacuum at 100° for 4 hours
before using. Keep container tightly closed.
FOREIGN MATTER AND PARTICLES ^Protect from light.Aas.p2(5
Foreign Matter Add the following:

Every care should be exercised in the preparation of all products A
USP Doxazosin Mesylate RS—Do not dry.At/iSM(j
intended for injection, to prevent contamination with microorgan-
isms and foreign material. Good pharmaceutical practice requires Add the following:
also that each final container of Injection be subjected individually
to a physical inspection, whenever the nature of the container per- A
USP Ganciclovir RS—Dry portion in vacuum at 80° for
mits, and that every container whose contents shows evidence of
contamination with visible foreign material be rejected. 3 hours before using. Keep container tightly closed and pro-
tected from light.AWSK(j
Particulate Matter Add the following:
All large-volume Injections for single-dose infusion, and those A
small-volume Injections for which the monographs specify such USP Ganciclovir Related Compound A RS [Chomioal
requirements, are subject to the particulate matter limits set forth
under Particulate Matter in Injections (788). An article packaged name to come-:] [(RS)-2-Amino-9-(2,3-dihydroxy-propoxy-
as both a large-volume and a small-volume Injection meets the re-
quirements set forth for small-volume Injections where the con- methyl)-l,9-dihydro-purin-6-one]—Dry portion in vacuum
tainer is labeled as containing 100 mL or less if the individual
monograph includes a test for Particulate Matter; it meets the re- at 80° for 3 hours before using. Keep container tightly
quirements set forth for large-volume Injections for single-dose in-
fusion where the container is labeled as containing more than 100 closed and protected from light.AasP2(j
mL. Injections packaged and labeled for use as irrigating solutions
Add the following:
A
and radiopharmaceuticalsA(/iyp2fi
A
are exempt from requirements for Particulate Matter. USP Maltose RS—Do not dry; determine the water
content titrimetrically at the time of use for quantitative ana-
lyses. Keep container tightly closed. AUSP26
Add the following:
BRIEFING
A
USP Mangafodipir Trisodium [manganese(II) dipyri-
(11) Reference Standards, USP 25 page 1836, page 8060 of
PF 20(5) [Sept-Oct. 1994], page 3212 of PF 22(6) [Nov.-Dec. doxal diphosphate; Mn(II)DPDP]—[To come.]AUSP26
PF 23(5) [Sept.-Oct. 1997], page 5180 of P F 23(6) [Nov.-Dec. Add the following:
1997], page 5965 of PF 24(2) [Mar.-Apr. 1998], page 6925 of
PF 24(5) [Aug.-Sept. 1998], page 7511 of PF 25(1) [Jan.-Feb. A
1999], page 7876 of PF 25(2) [Mar.-Apr. 1999], page 8222 of USP Mangafodipir Related Compound A RS [manga-
PF 25(3) [May-June 1999], page 8561 of PF 25(4) [July-Aug.
1999], page 8893 of PF 25(5) [Sept.-Oct. 1999], page 9222 of nese(II) dipyridoxal monophosphate; Mn(II)DPMP]—[To
PF 25(6) [Nov.-Dec. 1999], page 218 of PF 26(1) [Jan.-Feb.
2000], page 471 of PF 26(2) [Mar.-Apr. 2000], page 793 of PF
26(3) [May-June 2000], page 1101 of PF 26(4) [July-Aug.
Pharmacopeial Forum
Add the following: Add the following:

A A
USP Mangafodipir Related Compound B RS [manga- USP Ramipril Related Compound C RS [(25,3 aS,
nese(II) dipyridoxal diphosphate mono overalkylated; 6a5)-1 -[(iS)2-[[(5) 1 -ethoxycarbonyl-3-cyclohexyl propyl]a-
Mn(II)DPDP-MOA)]—[To come.]AasPM mino]-1 -oxopropyl]-octahydrocyclopenta[Z?]pyrrole-2-car-
Add the following: boxylic acid] (C23H38N2O5 <> 422.56)—Do not dry. Keep
A
USP Mangafodipir Related Compound C RS [man- container tightly closed.AUSp26
ganese(II) dipyridoxal diphosphate; Mn(III)DPDP- Add the following:

A
MOA)]—[To come.]AWSP2<f USP Ramipril Related Compound D RS [ethyl (25)2-
Add the following: [(35f,5a5f;8a5',9a5)-3-methyl-l,4-dioxodecahydro-l//-cyclo-
A
USP Norgestimate RS—Dry a portion at 105° for 3 penta[e]pyrrolo[l,2-a]pyrazin-2-yl]-4-phenyl-butanoate]
hours. Keep containers tightly closed.AUs/>2({ (C 23 H 30 N 2 O 4 <> 398.50)—Do not dry. Keep container
Change to read: tightly closed.AMSPM
USP Potassium Sucrose Octasulfate RS [NOTE—Sucrosofate

Add the following:
Potassium is USAN.] [a-D-glucopyranoside, l,3,4,6-tetra-(3-sul- A
fo-/3-D-fructofuranosyl, tetrakis (hydrogen sulfate), octapotassium USP Terazosin Hydrochloride RS—[To oomo.] Use
salt, heptahydrate] (C 12 H 14 K 8 O 35 S 8 • 7H2O <> 1113.65
A
without drying; correct for moisture, determined by drying
1413.64 A U s r o ,
O CAS-76578-81-9). (anhydrous C 12 H 14 K 8 O 35 S 8 <0> 1287.55 a separate portion in vacuum at 105° for 3 hours. Keep con-
1287.534asw<5 tainer tightly closed and protected from light.AWSP2(f
<> CAS-73264-44-5)—Do not dry; determine the water content ti-
trimetrically when used for quantitative analyses. Keep container Add the following:
tightly closed and store in a freezer. Allow to equilibrate to ambient
temperature before opening. A
USP Terazosin Related Compound A RS [l-(4-amino-
Add the following: 6,7-dimethoxy-2-quinazolinyl)piperazine, dihydrochloride]
A
USP Ramipril Related Compound A RS [1 [2 [[1 (C14H19N5O2 • 2HC1 <> 289.34 362.25) [To oomo.] Do
(2£3aS;6aS>l-[(S)2-[[(S)l-(methoxycarbonyl)-3-phenyl- not dry. Correct for water, determined titrimetrically before
propyl]amino]-l-oxopropyl]-octahydrocyclopenta[6]pyr- use. Store with desiccant in a cold place. Keep container
role-2-carboxylic acid] (C 22 H 30 N 2 O 5 <> 402.48)—Do not tightly closed and protected from light.At/5P2(j
dry. Keep container tightly closed.A[/5W5
Add the following:
A
USP Ramipril Related Compound B RS [(2S,3aS,
6a5>1 -[(5)2-[[(5) 1 -(methylethoxy)carbonyl-3-phenylpro-
pyl]amino]-1 -oxopropyl]-octahydrocyclopenta[6]pyrrole-
2-carboxylic acid] (C 24 H 34 N 2 O 5 <C> 430.54)—Do not dry.
Keep container tightly closed.
Pharmacopeia! Forum
Add the following: Biological Tests and Assays

A
USP Terazosin Related Compound £ B RS [l-(4-hy-
droxy-6,7-dimethoxy-2-quinazolinyl))-4-[(tetrahydro-2-for-
anyl)carbonyl]piperazine] (C 1 9 H 2 4 N 4 O 5 <> 388.43
388.42)—[To oomo.] Do not dry. Keep container tightly
BRIEFING
closed and protected from light.AM7>25
(85) Bacterial Endotoxins Test, USP 25 page 1889.
Add the following:
A
(AMB: D. Porter) RTS—35397-1
USP Terazosin Related Compound ¥ C RS [l,4-bis(4-
amino-6,7-dimethoxy-2-quinazolinyl)piperazine, dihy-
Erratum:
drochloride] (C24H28N8O4 • 2HC1 <> 192.54 565.45)—ffe Footnote 4, lines 7-8: change "the formula is K/M x 180 m2,
come.] Do not dry. Keep container tightly closed and pro- where K = 5 EU/kg, and M is the maximum dose/kg/hour" to: the
formula is K/M, where K = 5 EU/kg, and M is the (maximum dose/
tected from lightAUSP26 mVhour x 180m2)/70kg.
Change to read:
USP Torscmidc (Form I) RS Other Tests and Assays
A
USP Torsemide RS—(Form I)AUSP26
Do not dry before using. Keep container tightly closed.
Add the following:
A BRIEFING
USP Valsartan RS—Do not dv/.AUSP26
Add the following: (563) Biological and Chemical Identification of Articles of
Botanical Origin, page 2391 of PF 27(2) [Mar.-Apr. 2001].
A
USP Valsartan Related Compound A RS [(R) N ([2' The title of the chapter is changed to reflect the actual intended pur-
pose that is the description of any current pharmacopeial methods
(IH totrazolo 5 yl)biphonyl A yl]mothyl)valino][(i?)-A^-va- applicable to identification of Botanicals. The term biological iden-
tification is changed all over the chapter to botanical identification
leryl-A^-([2'-(li^-tetrazole-5-yl)biphen-4-yl]methyl)valine] to be consistent with the current pharmacopeial requirements. The
expression "Complete herbarium samples" is changed to "Herbar-
(C24H29N5O3 <> 41&3Z- 435.52)—Do not fcy.AVSP26 ium samples" with a recommendation to keep the complete speci-
men if appropriate. A paragraph on spectroscopic and
chromatographicfingerprintis added to the section on Chemical
Add the following: Identification. More clear differentiation between Active Principles
A and Marker Compounds is introduced. Other changes are editorial.
USP Valsartan Related Compound B RS [(S)-iV-bu-
tyryl-A^([2'-(l//-tetrazole-5-yl)biphenyl-4-yl]methyl)-va- (DSB: G. Giancaspro) RTS—34717-1
line] (C23H27N5O>3 O 121.50 421.49)—Do not dry.AUSP26

A
USP Valsartan Related Compound C RS [(5)-iV-valer- *(563) BIOLOGICAL AND
yl-iV-([2'-(l/f-tetrazole-5-yl)biphenyl-4-yl]methyl)valine CHEMICAL IDENTIFICATION OF
benzyl ester] (C 3 jH 35 N 5 O 3 <> 526.65 525.64)—Do not ARTICLES OF BOTANICAL
ORIGIN
Identification of raw plant material intended for use in the
manufacture of pharmaceuticals, excipients, or dietary sup-
plements is carried out by examining the morphological and
Pharmacopeial Forum
histological features of the article under test and by perform- ven on the label. Active principles and marker compounds
ing diagnostic chemical tests on the article. The botanical typically degrade with time; therefore, expiration dates are
and chemical characteristics of the test article are then com- assigned to USP Authenticated Reference Materials for their
pared to the known botanical and chemical characteristics of use in chemical identification. USP Authenticated Reference
the plant species. Reference articles may be specified to as- Materials are not intended for use in the manufacture of
sist in the proper botanical and chemical identification of the Pharmaceuticals, excipients, or dietary supplements.
plant and plant part. A reference article may be either a USP
BIOLOGICAL BOTANICAL IDENTIFICATION
Authenticated Reference Material, which may be used for
The biological botanical identification of raw plant mate-
both botanical and chemical identification, or a USP Refer-
rials used in the manufacture of pharmaceuticals, excipients,
ence Standard, which is used for chemical identification
or dietary supplements consists of ascertaining the macro-
only.
scopic characteristics of the plant part, such as root, stem,
USP AUTHENTICATED REFERENCE MATERIALS leaf, flower, fruit, or seed, used in the manufacture of the
USP Authenticated Reference Materials are plant organs article, as well as ascertaining its histological (microscopic)
or tissues certified to have come from a plant that has been features. It may also include the inspection of organoleptic
properly identified as belonging to the species listed on the features of the botanical tissue, such as the presence or ab-
label. The oortification authentication is performed by bota- sence of a characteristic odor. Individual compendial mono-
nical taxonomists, plant anatomists, phytochemists, or other graphs may include botanical information on possible
plant scientists contracted by the USP. A USP Authenticated adulterant species to help ensure their absence in the raw
Reference Material is typically a dried, pulverized plant or- material. For a proper identification of the plant, plant organ,
gan or tissue, and it may be obtained from USP. Complete? or plant tissue, it is necessary to have a basic knowledge of
Herbarium samples that may include roots, stems, leaves, plant anatomy.
flowers, fruits, and seeds of the certified authenticated plants
are archived and made available for examination upon Diagnostic Plant Morphology and Anatomy
request. Standard herbarium samples usually consist of This section exclusively addresses the diagnostic mor-
the entire mature plant. USP Authenticated Reference Mate- phological and anatomical features of vascular plants and
rials undergo the same botanical and chemical diagnostic the various plant parts, such as roots, stems, leaves, flowers,
tests as those applied to the test raw materials. A test article fruits, and seeds, from which pharmaceuticals, excipients, or
must have all botanical and chemical characteristics speci- dietary supplements are derived. Vascular plants include
fied and found in the USP Authenticated Reference Materi- pteridophytes (ferns and fern allies; for example, genera As-
al. To serve its intended purpose, each USP Authenticated pidium, Equisetum, and Lycopodium), gymnosperms (seed
Reference Material is properly stored, handled, and used. plants, in which the seed is not enclosed within a fruit; for
Generally, USP Authenticated Reference Materials are example, genera Ephedra, Ginkgo, and Pinus), and angios-
stored in their original containers under cool and dry condi- perms (seed plants, in which the seed is enclosed within a
tions and protected from light and insect infestation. Where fruit; for example, genera Allium, Digitalis, Ginseng Panax,
special storage conditions are necessary, directions are gi- Matricaria, and Rauwolfia). Anatomical diagnostic features
Pharmacopeial Forum
that are specified in an individual monograph (see Botanic characterize these types of roots. The presence, type, and ar-
characteristics in individual monographs) may include, but rangement of fibers, sclereids, and other tissues, and the pre-
are not limited to, the presence of a particular tissue within sence and location of ergastic material may also be
an organ; the arrangement and type of cells within a tissue; diagnostic features. Morphologically, roots may be distin-
the presence and type of secretory canal, oil, or resin duct or guished from rhizomes (the underground stems) primarily
laticifers within an organ; the number of epithelial cells sur- by the absence of nodes and internodes, which are present
rounding a secretory canal; and the presence and type of er- in rhizomes. HiQtologically; rhizomoa havo tho internal anat
gastic substances such as starch, inulin, fat globules, omy of tho abovoground atoms.
essential oils, calcium oxalate crystals, cystoliths, polyphe-
nols, fluids, or other materials occurring in the cytoplasm, STEMS
organelles, vacuoles, cavities, or cell wall. Several external macroscopic features of stems that may
be diagnostic of the species include the attributes of the
nodes, internodes, leaf scars, vascular bundle scars, lenti-
ROOTS
cles, and buds; the growth pattern of the buds; position
The tissues present in young roots, starting with the most
and arrangement of the leaves along the stem; and the pre-
external tissue, include an epidermis with root hairs, cortex,
sence of tendrils, spines, thorns, or prickles. Starting with
endodermis, pericycle, phloem, xylem, and, in some spe-
the outermost tissue, the internal arrangement of tissues in
cies, pith. In some species, the outermost layer or layers
the young stems of most species is epidermis, cortex, a con-
of cortex are distinct from the inner layers, in which case
centric ring of vascular bundles separated from each other
they are referred to as a hypodermis. In species that undergo
by parenchymatous medullary rays, and pith. Depending
secondary growth in the roots, it is typical for all tissues ex-
on the species, stomata or trichomes or both structures
ternal to the pericycle to be sloughed off. Roots that exhibit
may be present in the epidermis. The cortex of some species
secondary growth have a periderm or bark, composed of a
may include a hypodermis or an endodermis or both. In
phellum (cork), phellogen (cork cambium), and phelloderm
most monocotyledons, the vascular bundles are not ar-
as the outermost tissue. Underneath the periderm, remnants
ranged concentrically; instead they are scattered throughout
of primary phloem, secondary phloem, vascular cambium,
a mass of parenchyma tissue internal to the epidermis. Be-
primary xylem, and secondary xylem can be found. Second-
cause of this arrangement, neither cortex, medullary rays,
ary vascular tissues have medullary rays separating clusters
nor pith can be discerned. In woody plant stems that under-
of the principal conducting cells of phloem (sieve elements
go secondary growth, it is typical for the epidermis to be
or sieve cells) and the principal conducting cells of xylem
sloughed off and replaced by a periderm composed of a
(vessels and tracheids). Most species of plants that undergo
phellum, phellogen, and phelloderm. Some species are char-
secondary growth lack pith in the root. The type and ar-
acterized by having multiple periderms (rhytidome). Lenti-
rangement of the principal conducting cells of the vascular
cles may be present in the periderm and their attributes may
tissues may be diagnostic of the species. Roots of many spe-
serve as diagnostic features. Underneath the periderm are
cies develop into food storage organs. Abundant parenchy-
the remnants of the cortex, primary phloem, secondary
ma and large amounts of starch or other polysaccharides
phloem, vascular cambium, and secondary xylem, and the
Pharmacopeial Forum
remnants of primary xylem and pith. Medullary rays are also FLOWERS
present. As in the root, the type and arrangement of the prin- Flowers are the best diagnostic morphological features of
cipal conducting cells of the vascular tissues; the presence, any flowering plant and the floral structure is the principal
type, and arrangement of fibers, sclereids, and other tissues; criterion used in modern plant taxonomy. The diagnostic
and the presence and location of ergastic material may also features of flowers include type of inflorescence; presence,
be diagnostic features. Rhizomes may have some morpho- number, and appearance of the primary floral parts (sepals,
logical characteristics similar to those of roots and therefore petals, stamens, and carpels); type of symmetry displayed
they may be mistaken for roots. However, rhizomes can be by the floral parts; relative position of the ovaries in regards
correctly identified as stems because they have distinct to the other parts of the flower; the number of ovules per
nodes and internodes. and the samo basic internal anatomy ovary; type of placentation of the ovary; physical appear-
as abovoground stems. ance of the pollen grains; presence of nectaries; presence
of covering or glandular trichomes; and physical features
of accessory structures, such as the receptacle and bracts.
LEAVES
The histological features and the presence of ergastic mate-
Several macroscopic features of leaves that may be diag-
rials in the tissues of floral parts are also diagnostic of the
nostic of the species include the attributes of the leaf blade,
species.
petiole, and stipules and the phyllotaxy. The outermost tis-
sue of a leaf blade is the epidermis, followed by mesophyll
and vascular tissues. Microscopic diagnostic features of FRUITS
epidermal cells include the cuticle thickness and markings, The identification of the species of plant from which a
the shape and arrangement of stomata and guard cells, the fruit was derived may be determined by observing several
arrangement and size of subsidiary cells, stomatal number macroscopic criteria. These criteria include the number of
(number of stomata per unit area), and stomatal index (num- pistils found in the fruit, the number of carpels within each
ber of stomata per unit number of epidermal cells). Addi- pistil, the number of seeds within each carpel, the placenta-
tional features useful in the identification of leaf material tion of the fruit, and the determination whether the fruit is
include types and arrangement of trichomes (plant hairs) dehiscent, indehiscent, or fleshy. Additional diagnostic fea-
present; type and arrangement of mesophyll and vascular tures include the number of sutures in a dehiscent fruit, the
tissues; palisade mesophyll ratio; presence and appearance determination whether the seeds are fused to or free from the
of accessory tissues such as parenchymatous or sclerenchy- pericarp wall, physical features of the three layers of the
matous bundle sheaths, paraveinal mesophyll, endodermis, pericarp of fleshy fruits (epicarp, mesocarp, and endocarp),
and transfusion tissue; type and arrangement of the principal and presence and physical appearance of accessory tissues
conducting cells of the vascular tissues; presence, type, and such as the receptacle and bracts. Histological features of
arrangement of fibers, sclereids, and other tissues; and pre- fruit tissues may aid in identification. The characteristics
sence, location, and physical appearance of ergastic materi- of the seeds within the fruit are also diagnostic features of
al. the species.
Pharmacopeial Forum
SEEDS PROCEDURE FOR TEMPORARY MOUNTS AND POWDERED
The macroscopic features of seeds used in identification MATERIAL
include the shape and size of the seed; appearance of the

seed-coat surface; placement of the hilum and micropyle;
General Procedure—Plant samples are observed under
and presence of accessory structures of the seed coat such
the microscope by employing different mounting media,
as arils, caruncle, or oil bodies. Physical features of the em-
stains, or other solutions to assist in the correct identification
bryo such as its size, shape, position, and the number and
of the test article. If a USP Authenticated Reference Material
appearance of the cotyledons, as well as the presence and
is available, prepare it with the same mounting media or re-
appearance of accessory nutritive tissues such as the rem-
agent solutions used for the test article. Place one or two
nants of a megagametophyte (in gymnosperms), perisperm
drops of water, Glycerin-Alcohol Solution, Chloral Hydrate
(nucellus), or endosperm are also diagnostic of the species.
Solution, or another reagent solution (see Preparation and
Histological features of the seed coat and other structures
Use of Reagent Solutions, Optical Devices, and Mountants)
and tissues of the seed may also be used for species identi-
in the center of a clean slide. Transfer a small plant tissue
fication.
section or a portion of plant powder into the mountant or
reagent solution, and cover with a clean coverslip. (For spe-
Microtechnique cific preparation techniques, see Preparation of Temporary
Histological analysis of botanical specimens can be per- Mounts and Hand Sections, Maceration, or Preparation of
formed on whole plant material or plant powder. The use of Powdered Material, as appropriate.) To prevent the forma-
cytological stain or other reagents may be necessary to vi- tion of air bubbles, the coverslip may be carefully placed at
sualize certain histological features. Crossed polarizers can an appropriate angle with its edge making the first contact
be used to detect structures that rotate plane-polarized light. with the slide and then pressed until it covers the specimen.
These structures include starch grains, calcium oxalate crys- Using a piece of filter paper, remove excess fluid from the
tals, some fibers, and grains of sand (present as a contami- margin of the coverslip. Air bubbles can be removed by pla-
nant) that can be observed as bright objects against a dark cing the slide in a vacuum desiccator. When using chloral
background. One polarizer is commonly placed in the con- hydrate, air bubbles can be removed by gently boiling the
denser or the light source, and the second polarizer is placed sample over a small flame such as that from an alcohol
in the ocular. Light entering the slide from below is plane lamp. To replace the mountant or reagent solution, place
polarized, permitting only some light waves in a specific drops of the new mountant or reagent solution on one edge
plane to pass through. When the two polarizers are aligned, of the coverslip. Place a strip of filter paper at the opposite
the field becomes bright; and when the two polarizers are edge of the coverslip to remove the old mountant or reagent
crossed, the field becomes dark. solution and to cause the new mountant or reagent solution
to be drawn over the powdered material or tissue. Plant oils
can be also washed away from the tissue in this manner,
Pharmacopeial Forum
when solvent hexane or acetone is washed through the slide

followed by water and, if necessary, Chloral Hydrate Solu- Reagent Solutions and Optical
tion. Do not use Chloral Hydrate Solution immediately after Detection Devices
treating the plant tissue with flammable solvents without
Essential oils Osmium Tetroxide Solution
thoroughly washing the tissue with water. This is to avoid
Sudan III Solution
setting fire to residual solvent when the microscope slide
Inulin Naphthol—Sulfuric Acid Solution
is later placed over a small flame to boil the tissue. Care
Lignin Carmine Alum-Methyl Green
must be taken when using reagent solutions that are volatile
Solution
or corrosive to the microscope. To prevent drying of aque-
Phloroglucinol-Hydrochloric
ous or chloral hydrate solutions during observation, add a
Acid Solution
small drop of glycerin to the slide. Observe the mounted
Universal Reagent
sample under an optical microscope (see Optical Micro-
Lipids (cutin, waxes, and Carmine Alum—Methyl Green
scopy (776)), and examine for histological features.
suberin included) Solution
Preparation and Use of Reagent Solutions, Optical De- Osmium Tetroxide Solution
vices, and Mountants—The following reagents, optical de- Sudan III Solution
vices, and mounting media are used to assist in the Universal Reagent
identification of cells, tissues, structural features, and ergas- Pectin and mucilage Ruthenium Red Solution
tic substances in the tissue or powdered material (see Tables Thionine Solution
/ and 2). Toluidine Blue Solution

Phytoglycogen Ruthenium Red Solution
Protein bodies Alcoholic Picric Acid Solution
Table 1. The Use of Reagent Solutions
Osmium Tetroxide Solution
and Optical Devices
Saponin Blood-Gelatin Mixture
Reagent Solutions and Optical Iodine—Glycerin Solution
Detection Devices (confirm by testing
Calcium carbonate Diluted Acetic Acid with Blood-Gelatin Mixture)
concretion Starch Crossed Polarizers
Calcium oxalate crystals Crossed Polarizers Iodine Solution
Cellulose Carmine Universal Reagent
Alum-Methyl Green Solution Tannins and other Ferric Chloride Solution
Hydriodic Acid polvphenols Osmium Tetroxide Solution
Zinc Chloride-Iodine Solution

Cytoplasm Alcoholic Picric Acid Solution
1,8-Dihydroxyan- 1 M Potassium Hydroxide
thraquinones Solution
Pharmacopeia! Forum
Table 2. Bleaching and Clarifying Agents saponins, place small clusters of the powdered plant mate-
and Mountants rial on the blood-gelatin layer, spacing them a few milli-
meters apart from each other, transfer to a humidifier for a
Use Mountants and Agents
few hours, and observe: saponin-containing particles will
Bleaching Agents Sodium Hypochlorite Solution cause light-transparent zones to appear in the blood-gelatin.
Clarifying Agents Chloral Hydrate Solution
Carmine Alum-Methyl Green Solution—Boil 1.5 g of car-
Lactochloral Solution
mine for 30 minutes in a 15% solution of aluminum potas-
Lactophenol Solution
sium sulfate. Cool, filter, and add 10 mL of a 0.75% methyl
Mountants Glycerin
green solution while stirring. Add 1 to 2 drops to plant ma-
Glycerin—Alcohol Solution
terial: lignin and suberin turn green and cellulose turns red-
Glycerin-Gelatin Mixture
violet.
Water
Chloral Hydrate Solution—Use chloral hydrate TS.
When using the solution as a clarifying agent, add a few
Alcoholic Picric Acid Solution—Prepare a 1% solution of
drops to the plant material, and boil briefly over a small
picric acid in alcohol. Picric acid is useful to stain cells hav-
flame. Chloral hydrate dissolves cellular contents and inter-
ing dense cytoplasm, such as aleurone cells in seeds. Place a
cellular substances and allows cell walls and shapes to be
small amount of powdered plant material in a test tube, and
easily observed. It can be used to assist in the identification
shake with about 1 mL of solvent hexane to remove plant
of cork, fibers, vessels, calcium oxalate crystals (with the aid
oils, which would interfere with the reaction. Centrifuge,
of crossed polarizers), trichomes, stomata, and pollen.
and discard solvent hexane. Soak the plant powder in Alco-
• Crossed Polarizers—This optical device is used to detect
holic Picric Acid Solution for about 30 minutes. Transfer a
calcium oxalate crystals and starch grains (amyloplasts). In
portion of the powder to a microscope slide, and observe
polarized light, calcium oxalate crystals andstarch grains ap-
under a microscope: cytoplasm and protein bodies turn
pear as bright, birefringent objects on a dark background.
bright yellow. [Caution—Picric acid is explosive when
Starch grains observed under polarized light will also have
dry. Handle appropriately]
a Maltese-cross effect with the arms of the cross intersecting
Blood-Gelatin Mixture—Add 4.5 g of gelatin powder to
at the hilum. Calcium oxalate crystals are usually best
100 mL of a 0.9% sodium chloride solution, and allow to
viewed after the sample has been clarified with Chloral Hy-
swell for 30 minutes. Heat the gel, while stirring, to about
drate Solution or another clarifying agent.
80° in a water bath. Cool to 40°, and add 6 mL of defibri-
Diluted Acetic Acid—Add 1 to 2 drops to the plant mate-
nated bovine blood. Heat to 45° to 50°, and pour onto a mi-
rial, and immediately observe under a microscope: calcium
croscope slide in a thin layer of about 1 mm while the slide
carbonate deposits dissolve with effervescence.
is in a horizontal position. To prevent loss of Blood-gelatin
mixture from the sides, seal the microscope slide edge with a
1-cm wide adhesive tape to form a tray. After cooling and
solidification, it is ready for use. [NOTE—Store in a humid
chamber for not more than 1 to 2 days at 3° to 4°.] To test for
Pharmacopeial Forum
Ferric Chloride Solution—Dilute 1 mL of ferric chloride Lactochloral Solution—Dissolve 50.0 g of chloral hy-
TS with 9 mL of water. For the detection of phenol hydroxyl drate in 50 mL of lactic acid with gentle heating. Add a
groups, such as tannins and flavonoids, from the side of the few drops to the plant material. Place the microscope slide
coverslip add the solution to the aqueous sample: tannins in a small vacuum desiccator if it is necessary to eliminate
and other polyphenols become blue-black to green. air bubbles. Chloral Hydrate Solution and Lactochloral So-
Glycerin—Use as a mountant to prevent the drying of lution are used for the same type of identification, except
aqueous and chloral hydrate solutions. that Lactochloral Solution is a stronger clarifying agent
and it is used for plant material that is more difficult to clar-
Glycerin-Alcohol Solution—-Mix equal volumes of gly-
ify.
cerin and alcohol. Use as a mounting medium.
Glycerin-Gelatin Mixture—Add 10.0 g of powdered ge- Lactophenol Solution—Mix 20 g of lactic acid, 40 g of
glycerin, and 20 mL of water. Add 20 g of phenol, and
latin to 60 mL of water. Allow to stand for 2 hours, and add
mix. This is a strong clarifying agent suitable for the exam-
70 mL of glycerin containing 1.5 g of dissolved phenol.
ination of pollen grains.
Heat in a water bath, and filter through a preheated funnel
containing glass wool. The filtered mixture is liquefied be- Naphthol-Sulfuric Acid Solution—Prepare a 20% solu-
fore use, and it serves as a mounting medium. Add a few tion of 1-naphthol in alcohol. To plant material add 1 drop
drops to the cut or powdered plant material, and cover with of 1-napthol solution and 1 drop of sulfuric acid: inulin crys-
a heated coverslip. This preparation is used for long-term tals turn brownish red and then dissolve.
storage of specimen mounts. The margins of the coverslip Osmium Tetroxide Solution—Dissolve 0.1 g of osmium
may be sealed with Canada balsam after a few months of tetroxide in 5 mL of distilled water. Add 1 to 2 drops of
drying. the solution so obtained to plant material: essential oils, fatty
Hydriodic Acid—Add 1 to 2 drops to plant material: cel- oils and other lipids, tannins, and protein bodies become
lulosic cell walls become blue to blue-violet. brown to black.
Iodine Solution—Add 1 to 2 drops of 0.1 N iodine VS to Phloroglucinol-Hydrochloric Acid Solution—This solu-
the plant material: starch particles become dark-blue to blue- tion is used for the identification of lignin and other hydro-
violet; this reaction is reversible on heating. [NOTE—Pro- xyphenylpropane derivatives, lignified tissues such as
teins, lipids, and cellulose turn yellow to brown; and guaiac sclereids, vessels, fibers, and stone cells, and lignified par-
powder particles become green to blue, but this reagent is enchyma. Moisten the powder or the cut sample with phlor-
not used for diagnostic identification of these features.] oglucinol TS, and allow to dry for 2 to 3 minutes before
placing the coverslip. Add a few drops of a 25% hydrochlor-
Iodine-Glycerin Solution—Dissolve 0.3 g of iodine and
ic acid solution, and cover with the coverslip. Lignified cell
1.0 g of potassium iodide in a small quantity of water, and
walls turn carmine red. [NOTE—This stain is not stable.]
add 10 mL of a mixture of glycerin and water (1:1). Add 1 to
Cells with hydroxyphenylpropane derivatives, such as va-
2 drops to the powdered plant material: samples containing
saponins form yellow lumps or aggregates. If a sample tests nillin and ferulic acid, also turn red. Alternatively, hydroxy-
positive for saponin, the result has to be confirmed by test- phenylpropane derivatives can be extracted from the plant
ing the sample with Blood-Gelatin Mixture as well. material and the plant material then examined. To extract
Pharmacopeia! Forum
hydroxyphenylpropane derivatives repeatedly immerse the Universal Reagent—

untreated material in alcohol, mix on a vortex mixer, centri- SOLUTION A—Dilute 20 mL of a lactic acid-saturated so-
fuge, and discard the alcohol between washings. Then treat lution of Sudan III with 30 mL of lactic acid.
the plant material as specified above, beginning with the ad- SOLUTION B—Dissolve 0.55 g of aniline sulfate in 35 mL
dition of phloroglucinol TS. of water.
/ M Potassium Hydroxide Solution—Add 1 drop to plant SOLUTION C—Dissolve 0.55 g of potassium iodide and
material: cells containing 1,8-dihydroxyanthraquinones will 0.05 g of iodine in 5 mL of water, and add 5 mL of alcohol.
stain red. PROCEDURE—Combine Solution A, Solution B, and So-
Ruthenium Red Solution—Add a few drops of ammonium lution C, and add 2.5 mL of hydrochloric acid while stirring.
hydroxide to ruthenium red TS. [NOTE—Store the solution [NOTE—The solution is used without filtering.] For identi-
protected from light.] Add 1 to 2 drops to plant material: fication, add 2 to 3 drops to the sample, and gently boil over
pectin-containing cell membranes, acidic mucilage, and a small flame. If necessary, small amounts of Universal Re-
phytoglycogen turn red. agent may be added during boiling. Cover with the cover-
Sodium Hypochlorite Solution—This solution is used to slip: lignified elements turn yellow; suberin turns red-
bleach deeply colored sections. Immerse the plant material brown; lipids turn red; and starch turns blue-violet.
in the solution for a few minutes until sufficiently bleached. Water—Use as a mounting medium. [NOTE—All grades
Wash the tissue with water, and mount with a suitable of water are acceptable for this purpose.]
mounting agent. [NOTE—Sodium hypochlorite will extract Zinc Chloride—Iodine Solution—Dissolve 20.0 g of zinc
lignin; plant tissue so treated will test negative for lignin.] chloride and 6.5 g of potassium iodide in 10.5 mL of water.
Sudan HI Solution—Dissolve 0.5 g of Sudan III in 50 mL Add 0.5 g of 0.1 N iodine VS, and shake for 15 minutes.
of alcohol or isopropyl alcohol with reflux boiling. Cool, fil- Filter if necessary. Store in low-actinic glassware. Add 1
ter, and add 50 mL of glycerin. Add 1 to 2 drops of this so- to 2 drops to plant material, and allow to stand for a few
lution to plant powder: essential oils, waxes, cutin, suberin, minutes: cellulosic cell walls are stained blue to blue-violet.
and fatty oils and other lipids combine with this lipophilic Preparation of Temporary Mounts and Hand Sec-
colorant and become orange-red to red after a short time. tions—When using the dry plant tissue, soak or gently boil
Thionine Solution—Prepare a 0.2% thionine acetate solu- in water until soft. Do not soften too much. Material can
tion in 25 percent alcohol. Immerse the dry sample in this then be treated like fresh plant material. When appropriate,
solution. After about 15 minutes, wash out the excess of use the mountants or reagent solutions listed for use with
stain with 25 percent alcohol: mucilage will have swollen plant powder to help visualize features of the tissue (see Pre-
into spherical globules and turned red-violet, while cellu- paration and Use of Reagent Solutions, Optical Devices,
lose, pectin, and lignified septa will turn blue or blue-violet. and Mountants).
Toluidine Blue Solution—Using toluidine blue, proceed To make an epidermal peel of the leaf, petal, sepal, bract,
as directed for Thionine Solution. and other leaf-like appendages, roll the tissue into a cylin-
der, and nick with a sharp, polytef-coated razor blade that
has been wetted with water. Grasp nicked piece of tissue
Pharmacopeia! Forum
with forceps, and strip back removing a clear section of the in which S is the number of stomata for a given area; and E
epidermis. Mount in water on a microscope slide, place a is the number of epidermal cells of the same area. Determine
coverslip over the tissue, and examine under a microscope. the stomatal index on at least 10 different sites of the speci-
If it is difficult to obtain an epidermal peel using the above men, and calculate a mean value. Again, keep track of which
procedure, proceed as follows. Soak the tissue in a 40% to leaf surface is being observed, abaxial or adaxial, as the sto-
60% nitric acid solution at 60° for 3 to 4 minutes or until the matal indices for different surfaces is frequently signifi-
epidermis can be easily peeled. The peel is then washed cantly different.
three to five times in water to remove the excess of nitric To make a cross section of a leaf or thin roots, stems, or
acid. Neutralize the tissue in a 1% potassium hydroxide so- other thin appendages, lay the appendage to be sectioned on
lution or a 1% sodium hydroxide solution. Wash the tissue a microscope slide. Place another microscope slide over the
again with water, mount in water on a microscope slide, appendage with a portion of the tissue exposed. Using a
place a coverslip over the tissue, and examine under a mi- sharp, polytef-coated razor blade that has been wetted, cut
croscope. straight down along the edge of upper slide. Without mov-
An alternative method of preparing leaf tissue for the ex- ing the upper slide, cut down again with the razor blade at an
amination of the epidermis is to heat a leaf fragment (about 5 angle. Some practice may be necessary for one to be able to
mm x 5 mm) for 15 minutes in Chloral Hydrate Solution get sections thin enough so that when they are mounted and
on a water bath. Transfer the tissue to a microscope slide, covered with a coverslip, these sections can be used to de-
add a drop of water, and cover with a coverslip. These pro- termine tissue arrangements (for instance, the number of pa-
cedures can be used to determine the stomatal type, distribu- lisade layers in leaf, thickness of cuticle, types of trichomes,
tion, number, and index. types of vascular bundles, and the like). Because razor
Stomatal number is determined by counting the number blades dull quickly, they have to be replaced frequently.
of stomata per unit area of a microscopic field. Determine Use the cross section of leaf tissue so obtained to deter-
the stomatal number on at least 10 different sites of the spe- mine the palisade mesophyll ratio. Alternatively, boil leaf
cimen, and calculate a mean value. Keep track of which leaf . fragments of about 2 mm2 in Chloral Hydrate Solution,
surface is being observed, abaxial or adaxial, as the stomatal mount, cover with a coverslip, and observe under a micro-
number for different surfaces is frequently significantly dif- scope. Identify groups of four adaxial epidermal cells, and
ferent. count the palisade mesophyll cells that are lying below and
To calculate the stomatal index, the specimen is observed are at least 50% covered by the epidermal cells. This value
under a microscope at a low magnification. The size of the divided by 4 is the palisade mesophyll ratio. Determine the
surface is determined with a calibrated micrometer ocular, palisade mesophyll ratio of at least 10 groups of epidermal
and the number of stomata and the number of epidermal cells, and calculate a mean value. Palisade mesophyll ratio
cells for that area are determined. Thestomatal index is cal- can also be determined on powdered leaf material.
culated by the formula: To make a cross section of thick stems, roots, or other
plant parts, including woody tissues, hold the tissue in one
\00S/(E + S),
hand and using a sharp, polytef-coated razor blade that has
Pharmacopeial Forum
been wetted with water, shave a cross section from the ap- edly with water, and transfer to a microscope slide. Add 1 to
pendage. Mount in water, another medium, or reagent solu- 2 drops of mountant. Place a coverslip over the tissue, press
tion, place a coverslip over the material, and examine under down, squashing the tissue, and examine under a micro-
a microscope. Sections thin enough to determine vascular scope. The macerated tissue will test negative for lignin.
tissue arrangement, ray type, parenchyma distribution, pre- Preparation of Powdered Materials—Place one or two
sence of crystals, and the like can usually be made with a drops of water, another mountant, or a reagent solution in
little practice. the center of a clean slide. Moisten the tip of a dissecting
Maceration—It is sometimes necessary, for the proper needle with water, and dip into the powder under test. Trans-
identification of a plant material, to macerate the tissue into fer a small amount of material that adheres to the needle into
its individual cells before microscopic examination. This the fluid on the slide, and stir thoroughly and carefully. Cov-
can be an especially useful technique for woody or other er with a clean coverslip. Because the arrangement of the
hard tissues. The material is cut into small pieces of about tissue structures within the plant tissue has been destroyed,
2-mm thickness and 5-mm length or sliced into pieces of the important features for observation of the powdered plant
about 1-mm thickness. Depending on the nature of the cell material are the chemical and physical features of tissues
wall, one of the following methods is used. For hard or and cell types, as well as the presence and chemical and
highly lignified tissues, use Method I. For tissues that are physical features of ergastic substances. The specific tissues,
not extensively lignified, use Method II. cells, and ergastic substances to be examined are specified in
Method I— the individual monograph.
SOLUTION A—Use 4 N nitric acid solution.

SOLUTION B—Prepare a mixture of 1.2 M chromium tri-
PROCEDURE FOR THIN, PERMANENT MOUNTS
oxide solution and sulfuric acid (7:4).
When it is necessary to reveal detailed histological fea-
PROCEDURE—Place the plant material in a test tube con-
tures of a plant specimen, thin tissue sections have to be ob-
taining about 5 mL of a mixture of Solution A and Solution
tained. The sections need to be thin enough to transmit light
5(1:1). Heat in a water bath for 20 minutes. Wash the tissue
and they have to be cut in such a plane that the desired fea-
repeatedly with water, and transfer to a microscope slide.
tures are exposed. The plant material is properly killed,
Tease tissue apart with dissecting needle, add 1 to 2 drops
fixed, dehydrated, and embedded in paraffin or other em-
of mountant, cover with a coverslip, and examine under a
bedding media. The embedding medium is used as a so-
microscope. If necessary, cells can be further separated from
lid-support matrix during tissue sectioning. After
each other by pressing down on the coverslip with a gentle,
sectioning and mounting, staining of the specimen is fre-
sliding motion. The macerated tissue will test negative for quently performed to aid in the differentiation of certain
lignin. structures. [NOTE—The process of fixing, dehydration, em-
Method II— bedding, and staining can be significantly expedited by uti-
PROCEDURE—Place the plant material in a test tube con- lizing a microwave oven specifically designed for
taining about 5 mL of 2 M potassium hydroxide solution. histological work.]
Heat in ajwater bath for 30 minutes. Wash the tissue repeat-
Pharmacopeial Forum
Killing and Fixation—As a first step in preparing plant drated alcohol. Begin by washing the fixed tissue once or
material for sectioning, living cells are killed, and the tissue twice with fresh 50 percent alcohol to remove traces of
is preserved. This is most frequently done by employing a FAA. Remove this solution, and subsequently remove any
chemical fixative. A good general purpose fixative for plant other dehydration solution, by decanting the solution or re-
material is a mixture of formaldehyde, acetic acid, and alco- moving it with the aid of a glass pipet. Add the first dehy-
hol (FAA). dration solution (70 percent alcohol) to the vial, completely
FAA Solution—Mix 50 mL of alcohol, 5 mL of glacial immersing the tissue. The graded alcohol-water series and
acetic acid, 10 mL of formaldehyde solution, and 35 mL the suggested times for tissue immersion are as follows.
of water. [NOTE—Periodically prepare fresh solution, as it

loses effectiveness with storage.] Dehydration Solution Time (hours)
1-2
Procedure—Completely immerse the plant material in 50 percent alcohol
FAA Solution. Allow the material to remain immersed for 70 percent alcohol 1-2
18 to 24 hours at room temperature. Plant material can be 90 percent alcohol 1-2
kept indefinitely in FAA Solution, as long as it remains com- 95 percent alcohol 1-2
pletely immersed and is not allowed to dry out. Certain plant Dehydrated alcohol containing 0.1% of
tissues may require vacuum infiltration to facilitate the pe- safranin O 2-4
netration of the fixative. Vacuum infiltration is required if Dehydrated alcohol 1
the tissue has abundant air spaces or epidermal hairs or if Safranin O is added to the penultimate dehydration solu-
it floats on top of the fixative solution. Place the tissue in tion in the series to visualize the tissue when it is has be-
a small vial containing the fixative. Place the uncapped vial come embedded in paraffin. If the tissue to be sectioned is
into a bell jar or desiccator that is connected to a vacuum hard or woody, the time for each step in the series may need
source, preferably an oil-sealed vacuum pump. The vacuum to be increased to up to 24 hours. If necessary, the tissue can
is vented into a fume hood to prevent fixative vapors from be stored for several days in 70 percent alcohol or in solu-
filling the room. Slowly turn on the vacuum. Do not use a tions of even higher alcohol concentrations.
strong vacuum because the fixative may start to boil and da- Embedding—
mage the tissue. As residual air is pulled from the tissue, it
Preparation for Embedding—
will rise to the surface. Turn the vacuum on and off through
ALCOHOL REMOVAL—Paraffin is the most common em-
several cycles until the tissue stays at the bottom of the con-
bedding medium, although other embedding media are
tainer during an "on" cycle.
available. After dehydration, alcohol is removed from the
Tissue Dehydration—Paraffin and other embedding tissue by using a graded series of dehydrated alcohol-xy-
media are hydrophobic; thus, water must be removed from lene solutions, because paraffin is not soluble in alcohol.
the plant tissue after fixation. This is accomplished by im- The graded dehydrated alcohol-xylene series and the sug-
mersing the fixed tissue in dehydration solutions, which are gested times for tissue immersion are as follows.
a series of mixtures of alcohol and water with increasing al-
cohol concentration. The final solution in the series is dehy-
Pharmacopeial Forum
Embedding Procedure—-Pour the tissue with the paraffin

Alcohol Removal Solution Time (hours)
to an embedding boat. Paraffin has to completely cover the
A mixture of dehydrated alcohol and tissue by about 3 to 5 mm. Place the embedding boat on top
xylene (3:1) of a preheated warming platform that is designed for histol-
A mixture of dehydrated alcohol and ogy work. Adjust the tissue in the boat to its proper orienta-
xylene (1:1) tion for sectioning. Slowly cool the paraffin by sliding the
A mixture of dehydrated alcohol and boat down to the cool side of the platform until the paraffin
xylene (1:3) has solidified. Immerse the paraffin block in ice water to ra-
Xylene pidly cool the block and to prevent paraffin crystals from
Xvlene forming. Store the paraffin block at 4°.
Sectioning and Mounting—Cut the paraffin block into

XYLENE REMOVAL—Once xylene has completely re- pieces, each containing one tissue sample. Trim the paraffin
placed alcohol, paraffin is added slowly to infiltrate the tis- block, as close to the tissue mass as possible, to form a rec-
sue and remove xylene. Proceed as follows: tangle or a slight trapezoid. Such trimming will prevent sec-
1. For each mL of xylene add about 1 paraffin chip to the tioning problems due to excess paraffin around the tissue.
tissue vial, cap, and allow to stand at room temperature To make transverse sections, orient the tissue at a right angle
for 4 hours. Add additional paraffin chips until no more to a wooden tissue block whose face has been soaked in
chips dissolve. melted paraffin. Affix the paraffin block to the face of the
2. Place tissue in an oven maintained at 42° to 45°. Add 2 tissue block. Add a small amount of melted paraffin to the
to 3 paraffin chips every hour until no more chips dis- base of the paraffin block to help form a tighter seal. Cool
solve at that temperature. the block to 4°.
3. Pour off one-third of the volume, and replace with an Properly mount and adjust the tissue and paraffin block in
equal volume of melted paraffin. Do not cap, and trans- a microtome. Use a sharp stainless-steel microtome knife
fer vial to an oven maintained at 58° to 60°. that has been properly honed. Set the microtome to cut sec-
4. After the paraffin re-melts (about 4 hours later) pour off tions 8 to 15 /im thick (10-/im thickness is optimal for most
one-half of the volume, and replace with equal volume tissues). Cut individual or serial sections. Prepare a micro-
of melted paraffin. Transfer vial to the oven maintained scope slide as follows. An adhesive may be prepared as a
at 58° to 60° if paraffin begins to solidify. solution containing 1% of gelatin and 0.5% of sodium ben-
5. Repeat step 4 twice more, then pour off the entire vol- zoate that is heated to 30° to 35° to dissolve the gelatin.
ume of paraffin-xylene. Replace with pure melted par- Smear a thin film of the adhesive so obtained onto the slide,
affin. About 4 hours later, pour off paraffin, and replace allow to dry, rinse with a 4% solution of formaldehyde TS,
with fresh pure melted paraffin. Repeat the pouring off and add a small amount of water. Plate the cut sections up-
and replacement 4 hours later, and allow to stand over- side down on the slide, so that they float on water, and flood
night. [NOTE—Transfer vial to the oven maintained at with a 4% solution of formaldehyde TS. The sections will
58° to 60° if paraffin begins to solidify at any point.] immediately spread out and wrinkles will disappear.
Pharmacopeial Forum
Place the slide on a warming platform, maintained at 42°, PROCEDURE—Once the tissue has been rehydrated to 70
to relax the sections. Pipet, and blot the excess water and percent alcohol as described wider Preparation for Staining,
formaldehyde solution. Dry overnight in an oven at 42° to immerse for 2 to 24 hours, depending on the tissue, in Sa-
ensure adherence of the tissue section to the slide. franin O Staining Solution. Remove excess stain by immer-
Staining— sing the slide in water several times. Transfer slide to an
Preparation for Staining—Immerse the microscope slide alcohol solution containing 0.5% of picric acid for 2 to 10
with the affixed tissue twice into xylene, each time for 10 to seconds to further remove excess stain from the section and
15 minutes, to remove paraffin. Then immerse the slide into to assist in differentiation of the tissue structures. To stop the
several solutions, leaving it in each solution for 5 minutes action of the picric acid, transfer slide for 10 seconds to 1
and taking care not to dislodge the tissue, the following se- minute to an alcohol solution containing 4 drops of ammo-
quence of solutions being used: a mixture of dehydrated al- nium hydroxide in each 100 mL of alcohol. Transfer slide to
cohol and xylene (1:1), dehydrated alcohol, alcohol, and a dehydrated alcohol for 10 seconds. Visually inspect the
70 percent alcohol solution. The tissue is bleached prior to stained tissue under a microscope to see if further destaining
staining if it is opaque because of the presence of tannins or with picric acid is necessary. Counterstain for 10 to 15 sec-
other ergastic materials. To bleach, dip the slide into a 1% onds in Fast Green Staining Solution. Transfer slide through
potassium permanganate solution for 1 minute, rinse with two changes of a mixture of methyl salicylate, dehydrated
water, dip into a 5% oxalic acid solution for 1 minute, and alcohol, and xylene (2:1:1), each change lasting for 5 to
rinse thoroughly with water. The material is ready for stain- 10 seconds. Then transfer slide to a mixture of xylene and
ing. One of the following two staining procedures is recom- dehydrated alcohol (95:5) for 1 minute. Transfer through
mended for most botanical identification work. The first two changes of xylene. Store in xylene until ready to mount
staining procedure uses safranin O counterstained with fast the coverslip. Chromosomes, nuclei, and lignified, cuti-
green. An alternative staining procedure uses safranin 0 nized, or suberized cell walls will be stained red. Cytoplasm
counterstained with orange G. and cellulosic cell walls will be stained green to blue, de-
pending on the pH of the tissue.
Safranin O—Fast Green Staining—
SAFRANIN O STAINING SOLUTION—Prepare a mixture of Safranin O-Orange G Staining—
methoxyethanol, dehydrated alcohol, water, and formalde- SAFRANIN O STAINING SOLUTION—Prepare a 0.004% so-
hyde solution (50:25:25:2). Add a sufficient quantity of solution of safranin O.
dium acetate to obtain a solution containing 1% of sodium ORANGE G STAINING SOLUTION—Dissolve 2 g of orange
acetate, and mix. Add a sufficient quantity of safranin O to G, 5 g of tannic acid, and 4 drops of hydrochloric acid in
obtain a solution containing 1% of safranin O, and mix. water, and dilute with water to 100 mL.
FAST GREEN STAINING SOLUTION—Prepare a mixture of PROCEDURE—Once the tissue has been rehydrated to 70
methoxyethanol, dehydrated alcohol, and methyl salicylate percent alcohol as described under Preparation for Staining,
(1:1:1) containing 0.05% of fast green FCF. sequentially transfer slide through the following series of
solutions.
Pharmacopeial Forum
Chemical identification typically employs chromatographic

Solution Time procedures ouoh ao thin layer ohromatography, liquid
o h r o m a t o g r a p h y , or gaa o h r o m a t o g r a p h y (ooc
35 percent alcohol 5 minutes
Chromatography (€H)) to detect the presence of marker
A filtered 2% zinc chloride solution 1 minute
compounds specified in the individual monograph. Spectro-
Water 5 seconds
scopic or chromatographic profiles can be used to achieve
Safranin 0 Staining Solution 5 minutes
chemical identification by fingerprint comparison against
Water 5 seconds
that of a reference sample or standard. Examples of spectro-
Orange G Staining Solution 1 minute
scopic method include UV, IR, and Fourier transformed IR
Water 5 seconds
(see Spectrophotometric Identification Tests (197)). Exam-
A filtered 5% tannic acid solution 5 minutes
ples of chromatographic methods include high-pressure li-
Water 3 seconds
quid chromatography (HPLC), thin-layer chromatography
A 1% ferric ammonium sulfate solution 2 minutes
(TLC), 2-dimensional-TLC, and gas chromatography (see
Water 15 seconds
Chromatography (621)). Analytical methods used for fin-
45 percent alcohol 10 seconds
gerprinting should be capable of detecting as many chemical
90 percent alcohol 10 seconds
constituents as possible. Multiple fingerprints, using a com-
Dehydrated alcohol 10 seconds
bination of analytical methods with different separation
A mixture of dehydrated alcohol and 1 to 2 minutes
principles and test conditions, may be useful. In addition
xvlene O:H
to the spectroscopic chromatographic methods, qualitative
Finally, store in xylene until ready to mount the coverslip.
wet-chemistry methods may also be specified in the indivi-
Cellulosic cell walls will stain blue-black, nuclei will stain
dual monograph.
yellow, starch grains will stain black, and lignified cell walls
will stain red.
Chemotaxonomy
Mounting the Coverslip—The mounting of a coverslip
Low molooular woight Chemotaxonomy is the classifica-
over the tissue completes the preparation of the slide. Cana-
tion of the plants based on their chemical constituents and it
da balsam, diluted with a small portion of xylene, can be
may be useful in botanical articles identification. Metabolic
used as an adhesive. Other mountants are also commercially
compounds found within plant tissues can be divided into
available. Upon drying of the mountant, the slide can then
two broad categories based on their functions. Thefirstca-
be examined under a microscope. The entire process of
tegory comprises primary metabolites—metabolites in-
making permanent microscope slides can be expected to
volved in the physiological plant processes that are
take 5 or more days.
absolutely necessary for life and ubiquitous throughout
CHEMICAL IDENTIFICATION the plant kingdom. These processes include photosynthesis,
To help ensure the authenticity of the botanical raw mate respiration, and nucleic acid, protein, carbohydrate, and li-
ftftl? article, chemical identification is performed in conjunc- pid metabolism. The second category comprises secondary
tion with biologioal botanical identification outlined above. metabolites—compounds that are thought not to be abso-
Pharmacopeial Forum
lutely necessary for Ofe? plant processes, although they may on certain considerations. Currently, the following types
have important functions in the plant's interactions with of marker compounds are specified in compendial mono-
other organisms, such as allelopathic interactions; in chemi- graphs and may be identified in raw materials:
cal defense against herbivores and plant pathogens; and in Active Principles—These are constituents that have
signaling to attract pollinating and seed-dispersing animals. known proven clinical activity. A minimum content or range
Many secondary metabolites are known to have pharmaco- for the active principles is usually specified in the individual
logical activity. They are also the basis for the chemotaxon- monograph. A quantitative determination of active princi-
omy of plants. Secondary metabolites fall into several ples during stability studies of botanical dosage forms pro-
different chemical classes such as nonprotein amino acids, vides necessary information for arriving at suitable
flavonoids, xanthones, coumarins, polyacetylenes, cyclic expiration dates.
polyketides, monoterpenes, sesquiterpenes, iridoids, triter-
Active Markers—These are constituents that have some
penes, sterols, nitrogen-containing terpenes, and alkaloids.
known pharmacological activity contributing in some extent
These chemical classes are not ubiquitous throughout the
to efficacy. Thoao oonstituontflmay or may not have- clini
plant kingdom, but tend to be specific to certain botanical
cally proven efficacy. However, the clinical efficacy for
classes, orders, and families. Moreover, many chemical sub-
these constituents may not be proven. A minimum content
classes and individual secondary compounds are specific to
or range for active markers is usually specified in individual
certain subfamilies, genera, or species. It is these chemical
monographs. A quantitative determination of active markers
subclasses and individual compounds that can be used as
during stability studies of botanical dosage forms provides
marker compounds to aid in the proper identification of
necessary information for arriving at suitable expiration
plant material.
dates.
Analytical Markers—Where neither defined active prin-

Active Principles and Marker Compounds ciples nor active markers are known, other constituents of
For chemical identification ofrawmatoriala, botanical ar- the botanical extract amenable to quantitative determination
ticles, extracts are prepared. Such extracts are usually com- are chosen. These markers aid in the positive identification
plex mixtures of several chemical constituents. For a large of the article under test. In addition, maintaining a minimum
majority of botanical extracts it is not known with certainty content or a specified range of the analytical markers helps
which of the various components is responsible for the re- to achieve standardization of the plant extract and to arrive
ported pharmacological effect. It is generally believed that at a suitable expiration date during stability studies.
several constituents act synergistically to provide the re-
Negative Markers—These are constituents that may
ported effect. For articles for which compendial mono-
have allergenic or toxic properties, rendering their presence
graphs are provided, certain chemical constituents of the
in the botanical extract undesirable. For example pyrrolizi
article are chosen and quantitative test procedures for deter-
dino alkaloido from oortain botanioalo ouoh as oomfroy gink-
mining their content are provided. The choice of such con-
golic acids from ginkgo belong to this category. A stringent
stituents, known generally as marker compounds, is based
limit for these negative markers may be specified in indivi-
dual monographs.
Pharmacopeial Forum
Use of USP Reference Articles (565) BOTANICAL EXTRACTS

Reference articles are used to assist in the identification of
In the pharroaeoutieal
marker compounds within the test article. Reference articles
A.USP26
are either USP Authenticated Reference Materials or USP extraction
i practice for articles of botanical origin, the constituents
of interest are completely or partially separated from the interfering
Reference Standards (see USP Reference Standards (11)), A
other AUSretf
components with the aid of
whichever is specified in the individual monograph. USP
,At/m5
Reference Standards used to identify marker compounds alcohol, alcohol-water mixtures, or other suitable solvents. This
extraction process involves the removal of the desired constituents
in the test articles may be a single purified chemical entity, from the plant or animal
•
a mixture of purified chemical entities, or a standardized ex- A.VSP26
matter with suitable menstrua, the evaporation of all or nearly all of
tract prepared from the authenticated plant article. USP Ref- the solvent, and the adjustment of the residual fluids, masses, or
powders with tho aid of auitablo inert materials
erence Standards may also be used to quantitate marker •
A.USP26
compounds, as specified in the individual monograph. to the prescribed standards. At tho ond of oxtraotion^ unwanted
matter 19 removed.
A pulverized test article undergoes a specified extraction A
Suitable inert substances may be added as carriers or dilu-
procedure (see Methods of Extraction under Botanical Ex- ents to improve physical characteristics. Suitable antimicro-
tracts (565)) and is prepared for chromatographic or wet- bials and other preservatives may be added to preserve the
chemistry analysis. If a USP Authenticated Reference Mate- integrity. Extracts may be subjected to processes that in-
crease the content of characterized constituents, decrease
rial is available, then it undergoes the same extraction pro-
the content of unwanted constituents, or both. Extracts with
cedure as the test article. The test preparation and reference
no added inert substances and no processing beyond the ex-
articles then undergo the same chromatographic or wet-
traction are called native extracts.ACOT>2<;
chemistry procedure specified in the individual monograph.
In some preparations, the plant or animal
The response of the test preparation is compared to the re- •
AUSP26
sponse of reference articles to determine the presence of the matter may be pretreated by mactivation of enzymes
A
and microbial contaminants,AUS.W(f
marker compounds in the test article. AkUSP26 grinding, defatting, or a AVSP26
similar procedure.
Extracts may be defined as oonoontratod
A.USP26
preparations with liquid, solid, or intormodiato
BRIEFING u v i i i i k } u n u . USP26
consistency. Tho principal methods of oxtraotion are percolation,
(565) Botanical Extracts, USP 25 page 1958. References to maceration, digootion, infusion, and dooootion.
water as one of the solvents used in preparation of botanical ex- •
tracts are being added where appropriate. This chapter addresses A.USP26
botanical extracts, so references to animal matter are being deleted The products obtained by extraction are fluidextracts, powdered
to clearly reflect this emphasis. A clarification is provided to iden- extracts, semisolid extracts, and tinctures.
tify the types of additives permitted in botanical extracts. The de-
finition and labeling requirements for native extracts are
introduced. The cross-reference to Solvent Residue—The Tripartite METHODS OF EXTRACTION
Guidelines (1194), a chapter that has not been added to USP, is
being replaced with a reference to ICH guidelines on residual sol-
vents. Other changes are editorial. Percolation
In the manufacture of extracts, percolation is tho moat
AUSP26
commonly used method. The crude material being extracted is re-
duced to pieces of suitable size, if necessary, then mixed thor-
oughly with a portion of the specified solvent, and allowed to
Pharmacopeial Forum
stand for about 15 minutes. The mixture is transferred to a perco- Standardized powdered extracts are adjusted to the defined content
lator, sufficient amount of the specified solvent is added to cover of constituents, using suitable inert materials or a powdered extract
the entire solid mass, and the mixture is allowed to percolate of the plant matter used for preparation. Where applicable, a limit
slowly for the solvent used for extraction is specified in the individual
A monograph.
(at a rate of not more than 1 mL per minute for 1000 g of
material)AUS.P2(j
, the matter to be extracted being always covered with a layer of
solvent. The residue may be pressed, and the obtained fluid is com- Semisolid Extracts
bined with the percolate. The entire percolates are concentrated, SEMISOLID EXTRACTS, also known as soft extracts or pillular ex-
generally by distillation under reduced pressure, so as to subject tracts, are preparations having consistencies between those of
the constituents of interest in the article under extraction to as little fluidextracts and those ofpowdered extracts, and are obtained by
heat as possible. partial evaporation of the solvent,
alcohol, or hydroalcoholic mixtures being used as extracting sol-

Maceration vents. They may contain suitable antimicrobial or other preserva-
tives. A semisolid extract and a powdered extract obtained from the
Unless otherwise specified, the crude material being extracted is same material are interchangeable as drugs or as supplements, but
reduced to pieces of suitable size, mixed thoroughly with the spe- each has its own advantages.
cified extracting solvent, and allowed to stand at room temperature
in a closed container for an appropriate time, with frequent agita-
tion until soluble matter is dissolved. The mixture isfiltered,the
insoluble material is washed with the same solvent used for ma- General Pharmacopeial Requirements
ceration, and the filtrates are combined and concentrated, usually
under reduced pressure, to the desired consistency. Unless otherwise specified in the individual monographs, Phar-
macopeial requirements for the fluidextracts, powdered extracts,
and semisolid extracts are as follows.
PREPARATIONS
Packaging and Storage—Store in tight, light-resistant contain-
ers. [NOTE—See Preservation, Packaging, Storage, and Labeling
Fluidextracts under General Notices and Requirements.]
FLUIDEXTRACTS, also known as liquid extracts, are preparations Labeling—Label it to indicate the name of the plant part used;
of plant matter, containing alcohol as a solvent or as a preservative, the names of solvents, other than the hydroalcoholic solvents, used
or both, and are so made that each mL contains the extracted con- in preparation; the content of tho oonotituonta of intoroot and tho
stituents of 1 g of the crude material that it represents, unless other- ratio of starting material to final product;
wise specified in the individual monograph. They may be prepared
A
from suitable extracts and may contain suitable antimicrobial or , in percentage, of active principles or marker compounds
other preservatives.
Pharmacopeial fluidextracts are made by percolation, often fol- identified in the individual monograph;ÛSP26
lowing a period of maceration. The required solvent is specified in and the name and concentration of any added antimicrobial or
the individual monograph. The common manufacturing procedure other preservative. [NOTE—For somiaolid oxtraota and powdorod
includes concentration of the more diluted portion of percolate by oxtraoto, any addod oxoipiont ia aloo indioatodij
evaporation or distillation under vacuum at temperatures below A
60°. The time of maceration and the rate offlowduring percolation Where active principles are unknown, the ratio of starting
may be varied to adjust for the quantity and nature of the crude
material under extraction, provided that the composition of the ex- material tofinalproduct is stated. For semisolid extracts and
tracted constituents of interest is not adversely affected.
The rate offlowof the percolate can be slow, moderate, or rapid. powdered extracts, the identity and quantity of any added
With reference to the extraction of 1000 g of the starting material,
at a slow rate, not more than 1 mL of percolate is produced per excipient is also indicated. In such cases the percentage of
minute; at a moderate rate, between 1 and 3 rnL per minute is pro-
duced; and at a rapid rate, between 3 and 5 mL per minute is pro- native extract may also be stated.
duced. A fluidextract that tends to deposit sediment may be aged
and filtered, or the clear portion may be decanted, provided that the
resulting clarified liquid conforms to the Pharmacopeial standards. Residue on Evaporation—Transfer promptly about 2 mL, ac-
curately measured, of Fluidextract, about 0.5 g of Powdered Ex-
tract, or about 2 g of Semisolid Extract to a suitable tared,
round-bottom flask. Evaporate to dryness on a water bath, and
dry the residue at 100° to 105° for 3 hours. Allow to cool in a de-
Powdered Extracts siccator over phosphorus pentoxide, and determine the weight of
the residue obtained: not less than 95% of Powdered Extract speci-
POWDERED EXTRACTS are solid preparations having a powdery men remains as residue; or not less than 70% of Semisolid Extract
consistency obtained by evaporation of the solvent used for extrac- specimen remains as residue.
tion. They may contain suitable oxoipionta. A
A
[NOTE—Limits for Fluidextracts are specified in the indi-
added substances such as excipients, stabilizers, and pre-
vidual monographs.]AD37,2(j
servatives. AUSP26
Pharmacopeial Forum
Residual Solvents—If prepared with solvents other than alco- top of the percolator. When the liquid is about to drip from the per-
hol, water, or alcohol-water mixtures, it meets the requirements for colator, close the lower orifice, and allow the drug to macerate for
Method VI under Organic Volatile Impurities (467). NOTE—See 24 hours or for the time specified in the monograph. If the Assay
Solvent Residue The Tripartite Guidelines'(4444) A
test for content of active principles or marker com-
A
ICH document Impurities: Residual Solvents AUSP26
for related information. pAayP2(5
is not required in the individual monograph, allow the percolation
Pesticide Residues—Proceed as directed under Articles of Bo- to proceed slowly or at the specified rate (for definitions of flow
tanical Origin (561): meets the requirements. rates, see under Fluidextracts), gradually adding sufficient quantity
of extracting solvent to produce 1000 mL of tincture, and mix. If a»
Heavy Metals, MethodII (231): 0.002%.
A
A a test for content of active principles or marker com-
20 ng per g.AUSP26
pounds^^
Alcohol Content, Method II (611) (if present): between 90% is required, collect only 950 mL of percolate, mix, and test a por-
and 110% of the labeled amount of C2H5OH is found in Fluidex- tion of it as directed in the individual monograph. Dilute the re-
tract and Semisolid Extract. mainder of the percolate with as much of the prescribed
extracting solvent as calculation from the Assay
A
content testAUSP2g
indicates is necessary to produce a tincture that conforms to the
TINCTURES requirements, and mix.
TINCTURES are liquid preparations usually prepared by extract-
ing plant materials with alcohol or hydroalcoholic mixtures, ^^be
concentration of thoso preparations is not uniform; it varioa accord
ing to tho ootabliahod standarda for oaoh. MACERATION PROCESS
A
AUSP26 Macerate the drug with 750 mL of the prescribed extracting sol-
Traditionally, tinctures of potent articles of botanical origin repre- vent in a closed container, and put in a warm place. Agitate it fre-
sent the activity of 10 g of the drug in each 100 mL of tincture, the quently during 3 days or until the soluble matter is dissolved.
strength being adjusted following the Assay Transfer the mixture to a filter. When most of the liquid has
A drained, wash the residue on the filter with a sufficient quantity
test for content of active principles or marker com- of the prescribed extracting solvent, combining the filtrates, to pro-
duce 1000 mL of tincture, and mix.
p A t / 5 m
Most other plant tinctures represent 20 g of the respective plant
material in each 100 mL of tincture.
A GENERAL PHARMACOPEIAL REQUIREMENTS
Different tinctures are not always diluted to obtain the
Unless otherwise specified in the individual monographs, Phar-
same ratio of starting plant material to final tincture. This macopeial requirements for the tinctures are as follows.
ratio will depend on the requirements prescribed in the spe- Packaging and Storage—Store in tight, light-resistant contain-
ers, and avoid exposure to direct sunlight and excessive heat.
cific tests for content of active principles or marker com- [NOTE—See Preservation, Packaging, Storage, and Labeling un-
der General Notices and Requirements.]
p o u n d s i n c l u d e d in the i n d i v i d u a l m o n o g r a p h s . As
tinctures are being prepared, they are assayed in accordance Labeling—Label it to indicate the name of the plant part used
for preparation; the name of the solvent or solvent mixture used for
with these content tests. Using the values obtained from extraction; and the content of the constituents of interest and the
ratio of starting material to final product.
such assays, the final concentration of a tincture is adjusted
by adding more solvent or by evaporating part of the

Physical Tests and Determinations
solvent.Al/SW(f
Unless otherwise specified, tinctures are usually prepared from
coarse powder or fine cuttings of plant materials either by a perco-
lation process or a maceration process.
PERCOLATION PROCESS
BRIEFING
Carefully mix the ground mixture of ingredients with a sufficient
quantity of the prescribed extracting solvent to render it evenly and
distinctly damp, allow it to stand for 15 minutes, transfer it to a (661) Containers, USP 25 page 1999 and page 2817 of PF
suitable percolator, and pack the mass firmly. Pour on enough of 27(4) [July-Aug. 2001]. Comments have been received in re-
the specified extracting solvent to saturate the drug, and cover the sponse to the publications in PF 24(5), PF 26(4), and PF 27(4)
Pharmacopeial Forum
of the proposal to add a new section, Polypropylene Containers, to of molded polypropylene containers may be altered when
this general test chapter. A new section, Polypropylene Containers
for Ophthalmics, has been added in response to some of the com- reground polymer is incorporated, depending on the propor-
ments. Also see the article, Polypropylene Containers: Status and
Comments Received, published in the Stimuli to the Revision Pro- tion of reground material in the final product. Other proper-
cess section of this PF that describes the comments raised and the
Packaging, Storage, and Distribution Expert Committee's re- ties that may affect the suitability of polypropylene used in
sponses to those concerns.
containers for packaging drugs are the following: oxygen
(PSD: C. Okeke) RTS—35779-1
and moisture permeability, modulus of elasticity, melt in-
dex, environmental stress crack resistance, and degree of
Add the following:
crystallinity after molding. The requirements in this section
are to be met when dosage forms are to be packaged in a
POLYPROPYLENE CONTAINERS container defined by this section.
The standards and tests provided in this section character-
Multiple Internal Reflectance—
ize polypropylene containers, produced from either homo-
APPARATUS—Use an IR spectrophotometer capable of cor-
polymers or copolymers, that are interchangeably suitable
recting for the blank spectrum and equipped with a multiple
for packaging dry and liquid oral and ophthalmic dosage
internal reflectance accessory and a KRS-5 internal reflec-
forms.
tion plate. A KRS-5 crystal 2-mm thick having an angle
Where stability studies have been performed to establish
of incidence of 45° provides a sufficient number of reflec-
the expiration date of a particular dosage form in the appro-
tions.
priate polypropylene container, then any other polypropy-
PREPARATION OF SPECIMEN—Cut 2 flat sections, representa-
lene container meeting these requirements may be
tive of the average wall thickness of the container, and trim
similarly used to package such dosage form, provided that
them as necessary to obtain segments that are convenient for
the appropriate stability programs are expanded to include
mounting in the internal reflectance accessory. Taking care
the alternative container, in order to assure that the identity,
to avoid scratching the surfaces, wipe the specimens with
strength, quality, and purity of the dosage form are main-
dry paper, or if necessary with a soft cloth dampened with
tained throughout the expiration period.
methanol, and permit them to dry. Securely mount the speci-
Propylene polymers are long-chain polymers synthesized
mens on both sides of the KRS-5 internal reflection plate,
from propylene or propylene and other olefins under con-
ensuring adequate surface contact. Prior to mounting the
trolled conditions of heat and pressure, with the aid of cat-
specimens on the plate, they may be compressed toflatuni-
alysts. Examples of other olefins most commonly used
form films by exposure to temperatures between 220° and
include ethylene and butene. The propylene polymers, the
240°. The specimen's time/temperature history during this
ingredients used to manufacture the propylene polymers,
operation should be limited to that necessary to mold the
and the ingredients used in the fabrication of the containers
films.
conform to the applicable sections of the Code of Federal
PROCEDURE—Place the mounted specimen sections within
Regulations, Title 21.
the multiple internal reflectance accessory, and place the as-
Polypropylene has a distinctive IR spectrum and pos-
sembly in the specimen beam of the IR spectrophotometer.
sesses characteristic thermal properties. It has a density be-
Adjust the specimen position and mirrors within the acces-
tween 0.880 and 0.913 g per cm3. The permeation properties
Pharmacopeial Forum
sory to permit maximum light transmission of the unattenu- Test the containers as described under Containers—Per-
ated reference beam. (For a double beam instrument, upon meation (671). The containers meet the requirements if
completing the adjustment in the accessory, attenuate the the moisture permeability exceeds 15 mg per day per liter
reference beam to permit full-scale deflection during the in not more than one of the 10 test containers and exceeds
scanning of the specimen.) Determine the IR spectrum from 25 mg per day per liter in none of them.
3500 to 600 cm~'. The corrected spectrum of the specimen Heavy Metals and Nonvolatile Residue—Prepare ex-
exhibits major absorption bands only at the same wave- tracts of specimens for these tests as directed for Procedure
lengths as the spectrum of the USP Reference Standard under Physicochemical Tests—Plastics, except that for each
for either a polypropylene homopolymer or copolymer, si- 20 mL of Extracting Medium the portion shall be 60 cm2,
milarly determined. regardless of thickness.
Thermal Analysis—Cut a section weighing about 12 HEAVY METALS—Containers meet the requirements for
mg, and place it in the test specimen pan. Intimate contact Heavy Metals under Physicochemical Tests—Plastics.
between the pan and the thermocouple is essential for repro- NONVOLATILE RESIDUE—Proceed as directed for Nonvola-
ducible results. Determine the thermogram under nitrogen at tile Residue under Physicochemical Tests—Plastics, except
temperatures ranging from ambient to 30° above the melting that the blank shall be the same solvent used in each of the
point. Maintain the temperature for 10 minutes, then cool to tests set forth below. The difference between the amounts
50° below the peak crystallization temperature at a rate of obtained from the specimen and the blank does not exceed
10° to 20° per minute, using equipment capable of perform- 10.0 mg when water maintained at a temperature of 70° is
ing the determinations as described under Thermal Analysis used as the extracting medium, does not exceed 60.0 mg
(891). The thermogram of the specimen is similar to the when alcohol maintained at a temperature of 70° is used
thermogram of the appropriate USP Reference Standard as the extracting medium, and does not exceed 225.0 mg
for polypropylene. The temperatures of the endotherms when hexanes maintained at a temperature of 50° is used
and exotherms in the thermogram do not differ from those as the extracting medium. Containers meet these require-
of the USP Reference Standard for homopolymers by more ments for Nonvolatile Residue for all of the above extracting
than 12° or from those of the USP Reference Standard for media. [NOTE—Hexanes and alcohol are flammable. When
copolymers by more than 6°. evaporating these solvents, use a current of air with the
Light Transmission—Polypropylene containers in- water bath; when drying the residue, use an explosion-proof
tended to provide protection from light meet the require- oven.]
ments under Light Transmission. Buffering Capacity—Prepare extracts of the specimen as
Water Vapor Permeation—Fit the containers with im- described for Procedure under Physicochemical Tests—
pervious seals obtained by heat-sealing the bottles with an Plastics. Containers meet the requirements for Buffering
aluminum foil-polyethylene laminate or other suitable seal. Capacity under Physicochemical Tests—Plastics. AUSP26
Pharmacopeial Forum
Add the following: Labeling—It is the responsibility of the dispenser, taking into
account the nature of the drug repackaged, any packaging and be-
yond-use dating information in the manufacturer's product label-
ing, the characteristics of the containers, and the storage
^POLYPROPYLENE CONTAINERS FOR conditions to which the article may be subjected, to place a suitable
beyond-use date on the label. Repackaged dosage forms must bear
OPHTHALMICS on their labels beyond-use dates as determined from information in
the product labeling. Each single-unit or unit-dose container bears
Factors such as plastics composition, processing and a separate label, unless the device holding the unit-dose form does
not allow for the removal or separation of the intact single-unit or
cleaning procedures, contacting media, inks, adhesives, ab- unit-dose container therefrom.
sorption, adsorption and permeability of preservatives, and Storage—Store the repackaged article in a humidity-controlled
environment and at the temperature specified in the individual
conditions of storage may also affect the suitability of a monograph or in the product labeling. Where no temperature or
humidity is specified in the monograph or in the labeling of the
plastic for a specific use. The suitability of a specific poly- product, controlled room temperature and a relative humidity cor-
responding to 75% at 23° are not to be exceeded during repacka-
propylene must be established by appropriate testing. ging or storage.
A refrigerator or freezer shall not be considered to be a humid-
Biological Test—Polypropylene containers for ophthal- ity-controlled environment, and drugs that are to be stored at a cold
temperature in a refrigerator or freezer shall be placed within an
mics meet the requirement set forth in the section for Bio- outer container that meets the monograph requirements for the
drug contained therein.
logical Tests—Plastics and Other Polymers in addition to
the requirements in this section.
•Reprocessing—Reprocessing of repackaged unit-dose
Multiple Internal Reflectance, Thermal Analysis,
containers (i.e., removing dosage unit from one unit-dose
Light Transmission, Water Vapor Permeation, Heavy
container and placing dosage unit into another unit-dose
Metals and Nonvolatile Residue, and Buffering Ca-
container) shall not be done. However, reprocessing of the
pacity—Proceed as directed for the above tests under Poly-
secondary package (e.g., removing the blister card from the
propylene Containers, except to use polypropylene
cardboard carrier and placing the blister card into another
containers for opththalmics.AWWtf
cardboard carrier) is allowed provided that the original be-
Change to read:
yond-use date is maintained.B1
REPACKAGING INTO SINGLE-UNIT

CONTAINERS AND UNIT-DOSE CONTAINERS
FOR NONSTERILE SOLID AND LIQUID
DOSAGE FORMS BRIEFING
An official dosage form is required to bear on its label an expira-
tion date assigned for the particular formulation and package of the (671) Containers—Permeation, USP 25 page 2005. A clari-
article. This date limits the time during which the product may be fication is being provided in the procedure for evaluating the mois-
dispensed or used. Because the expiration date stated on the man- ture-permeation characteristics of single-unit and unit-dose con-
ufacturer's or distributor's package has been determined for the tainers. It is intended that the test and control containers or packs
drug in that particular package and is not intended to be applicable be weighed every 24 hours and this is now specifically stated.
to the product where it has been repackaged in a different contain- Other changes are editorial.
er, repackaged drugs dispensed pursuant to a prescription are ex-
empt from this expiration date labeling requirement. It is necessary, (PSD: C. Okeke) RTS—35916-1
therefore, that other precautions be taken by the dispenser to pre-
serve the strength, quality, and purity of drugs that are repackaged
for ultimate distribution or sale to patients.
The following guidelines and requirements are applicable where
official dosage forms are repackaged into single-unit or unit-dose
containers or mnemonic packs for dispensing pursuant to prescrip-
tion.
Pharmacopeial Forum
Change to read: so tested are tight containers if not more than one of the test con-
tainers exceeds 10 mg per day per liter in moisture permeability,
and none exceeds 25 mg per day per liter.
For containers used for drugs being dispensed on prescription,
MULTIPLE-UNIT CONTAINERS FOR the containers are well-closed containers if not more than one of
CAPSULES AND TABLETS the 10 test containers exceeds 2000 mg per day per liter in moisture
permeability, and none exceeds 3000 mg per day per liter.
Desiccant—Place a quantity of 4- to 8-mesh, anhydrous cal- Torque Applicable to Screw-Type Container

cium chloride1 in a shallow container, taking care to exclude any
fine powder, then dry at 110° for 1 hour, and cool in a desiccator. Suggested Tightness Range with
Manually Applied
Procedure—Select 12 containers of a uniform size and type, Closure Diameter1 (mm) Torque;2(inch-pounds)
clean the sealing surfaces with a lint-free cloth, and close and open 8 5
each container 30 times. Apply the closure firmly and uniformly 10 6
each time the container is closed. Close screw-capped containers 13 8
with a torque that is within the range of tightness specified in the 15 5-9
accompanying table. Add Desiccant to 10 of the containers, desig- 18 7-10
nated test containers, filling each to within 13 mm of the closure if 20 8-12
the container volume is 20 mL or more, or filling each to two-thirds 22 9-14
of capacity if the container volume is less than 20 mL. If the inter- 24 10-18
ior of the container is more than 63 mm in depth, an inert filler or 28 12-21
spacer may be placed in the bottom to minimize the total weight of 30 13-23
the container and Desiccant; the layer of Desiccant in such a con- 33 15-25
tainer shall be not less than 5 cm in depth. Close each immediately 38 17-26
after adding Desiccant, applying the torque designated in the ac- 43 17-27
companying table when closing screw-capped containers. To each 19-30
of the remaining 2 containers, designated controls, add a sufficient 48
53 21-36
number of glass beads to attain a weight approximately equal to 23^*0
that of each of the test containers, and close, applying the torque 58
63 25^13
designated in the accompanying table when closing screw-capped 26-45
containers. Record the weight of the individual containers so pre- 66
70 28-50
pared to the nearest 0.1 mg if the container volume is less than 20 32-65
mL; to the nearest mg if the container volume is 20 mL or more but 83
86 40-65
less than 200 mL; or to the nearest centigram (10 mg) if the con- 40-70
tainer volume is 200 mL or more; and store at 75 ± 3% relative 89
100 45-70
humidity and a temperature of 23 ± 2°. [NOTE—A saturated sys- 45-70
tem of 35 g of sodium chloride with each 100 mL of water placed 110
120 55-95
in the bottom of a desiccator maintains the specified humidity. 60-95
Other methods may be employed to maintain these conditions.] 132
After 336 ± 1 hours (14 days), record the weight of the individual
1
containers in the same manner. Completely fill 5 empty containers The torque designated for the next larger closure diameter is to be applied in testing
of the same size and type as the containers under test with water or containers having a closure diameter intermediate to the diameters listed.
2
a noncompressible, free-flowing solid such as well-tamped fine A suitable apparatus is available from Owens-Illinois, Toledo, OH 43666. (Model
glass beads, to the level indicated by the closure surface when in 25 torque tester is used for testing between 0 and 25; Model 50 for testing between 0
and 50; and Model 100 for testing between 0 and 100 inch-pounds of torque.) The
place. Transfer the contents of each to a graduated cylinder, and torque values refer to application, not removal, of the closure. For further detail re-
determine the average container volume, in mL. Calculate the rate garding instructions, reference may be made to "Standard Mothod of Moaouwng Ap
of moisture permeability, in mg per day per liter, by the formula: plication and Removal Toyquo of Throadod Cloauroo," STM Dooigiiation D 3198 73,
A
" Standard Test Method for Application and Removal
Torque of Threaded or Lug-Style Closures", ASTM Meth-
in which Fis the volume, in mL, of the container, (Tj— T,) is the od D3198-97, AVSnf
difference, in mg, between the final and initial weights of each test published by the American Society for Testing and Materials, 1916 Race
container, and (Cy- C,) is the difference, in mg, between the aver- St., Philadelphia, PA 19103.
age final and average initial weights of the 2 controls. For contain-
ers used for drugs being dispensed on prescription, the containers Change to read:
so tested are tight containers if not more than one of the 10 test
containers exceeds 100 mg per day per liter in moisture permeabil-
ity, and none exceeds 200 mg per day per liter. For multiple-unit
containers used by manufacturers or distributors where the pro-
ducts are repackaged prior to distribution or sale, the containers SINGLE-UNIT CONTAINERS AND UNIT-DOSE
CONTAINERS FOR CAPSULES AND TABLETS
To permit an informed judgment regarding the suitability of the
packaging for a particular type of product, the following procedure
and classification scheme are provided for evaluating the moisture-
permeation characteristics of single-unit and unit-dose containers.
Inasmuch as equipment and operator performance may affect the
1 moisture permeation of a container formed or closed, the moisture-
Suitable 4- to 8-mesh, anhydrous calcium chloride is available commer- permeation characteristics of the packaging system being utilized
cially as Item JT1313-1 from VWR Scientific. Consult the VWR Scientific shall be determined.
catalog for ordering information or call 1-800-234-9300.
Pharmacopeial Forum
Desiccant—Dry suitable desiccant pellets2 at 110° for 1 hour the controls. Store all of the containers at 75 + 3% relative humid-
prior to use. Use pellets weighing approximately 400 rng each ity and at a temperature of 23 + 2°.[NOTE—A saturated system of
and having a diameter of approximately 8 mm. [NOTE—If nec- 35 g of sodium chloride with each 100 mL of water placed in the
essary due to limited unit-dose container size, pellets weighing less bottom of a desiccator maintains the specified humidity. Other
than 400 mg each and having a diameter of less than 8 mm may be methods may be employed to maintain these conditions.] After
used.] 24 hours, and at
A
each multiple thereofA6W>2(5
Procedure— (see Results), remove the packs from the chamber, and allow them
to equilibrate forabout 45 minutes. Record the weights of the indi-
Method I—Seal not less than 10 unit-dose containers with 1 pel- vidual packs, and return them to the chamber. Weigh the control
let in each, and seal 10 additional, empty unit-dose containers to packs as a unit, and divide the total weight by the number of con-
provide the controls, using finger cots or padded forceps to handle trol packs to obtain the average empty pack weight. [NOTE—If any
the sealed containers. Number the containers, and record the indi- indicating pellets turn pink during the procedure, or if the average
vidual weights3 to the nearest mg. Weigh the controls as a unit, and pellet weight increase in any pack exceeds 10%, terminate the test,
divide the total weight by the number of controls to obtain the aver- and regard only earlier determinations as valid.] Calculate the aver-
age. Store all of the containers at 75 ± 3% relative humidity and at age rate of moisture permeation, in mg per day, for each unit-dose
a temperature of 23 ± 2°. [NOTE—A saturated system of 35 g of container or blister in each pack taken by the formula:
sodium chloride with each 100 mL of water placed in the bottom of
a desiccator maintains the specified humidity. Other methods may (\/NX)[(WF-WI)-(CF-CI)],
be employed to maintain these conditions.] After a 24-hour inter-
val, or a multiple thoroof in which N is the number of days expired in the test period (begin-
ning after the initial 24-hour equilibration period); X is the number
A
and at each multiple therQofAUSP26 of separately sealed units per pack; {Wf- W,) is the difference, in
(see Results), remove the containers from the chamber, and allow mg, between the final and initial weights of each test pack; and (CF
them to equilibrate for 15 to 60 minutes in the weighing area. - Cj) is the difference, in mg, between the average final and aver-
Again record the weight of the individual containers and the com- age initial weights of the control packs, the rates being calculated to
bined controls in the same manner. [NOTE—If any indicating pel- two significant figures.
lets turn pink during this procedure, or if the pellet weight increase
exceeds 10%, terminate the test, and regard only earlier determina- Results—The individual unit-dose containers as tested in Meth-
tions as valid.] Return the containers to the humidity chamber. Cal- od I are designated Class A if not more than 1 of 10 containers
culate the rate of moisture permeation, in mg per day, of each tested exceeds 0.5 mg per day in moisture permeation rate and
container taken by the formula: none exceeds 1 mg per day; they are designated Class B if not more
than 1 of 10 containers tested exceeds 5 mg per day and none ex-
ceeds 10 mg per day; they are designated Class C if not more than
in which N is the number of days expired in the test period 1 of 10 containers tested exceeds 20 mg per day and none exceeds
A
40 mg per day; and they are designated Class D if the containers
( b e g i n n i n g after t h e initial 2 4 - h o u r e q u i l i b r a t i o n tested meet none of the moisture permeation rate requirements.
The packs as tested in Method II are designated Class A if no
period);.^* pack tested exceeds 0.5 mg per day in average blister moisture per-
(WF — Wj) is the difference, in mg, between the final and initial meation rate; they are designated Class B if no pack tested exceeds
weights of each test container; and {CF — Q) is the difference, in 5 mg per day in average blister moisture permeation rate; they are
mg, between the average final and average initial weights of the designated Class C if no pack tested exceeds 20 mg per day in
controls, the data being calculated to two significant figures. average blister moisture permeation rate; and they are designated
[NOTE—Where the permeations measured are less than 5 mg per Class D if the packs tested meet none of the above average blister
day, and where the controls are observed to reach equilibrium with- moisture permeation rate requirements.
in 7 days, the individual permeations may be determined more ac- With the use of the Desiccant described herein,
curately by using the 7-day testcontainer and control container A
weights as Wt and Ch respectively, in the calculation. In this case, as stated for Method I and Method II, after every 24 hours,
a suitable test interval for Class A (see Results) would be not less
than 28 days following the initial 7-day equilibration period (a total the test and control containers or packs are weighed;
of 35 days).]
&nd>USp26
Method II—Use this procedure for packs (e.g., punch-out cards) suitable test intervals for the final weighings, WF and CF, are as
that incorporate a number of separately sealed unit-dose containers follows: 24 hours for Class D; 48 hours for Class C; 7 days for
or blisters. Seal a sufficient number of packs, such that not less than Class B; and not less than 28 days for Class A.
4 packs and a total of not less than 10 unit-dose containers or blis-
ters filled with 1 pellet in each unit are tested. Seal a corresponding
number of empty packs, each pack containing the same number of
unit-dose containers or blisters as used in the test packs, to provide
2 BRIEFING
Suitable moisture-indicating desiccant pellets are available commercially
from sources such as Medical Packaging, Inc., 470 Route 31, Ringoes, NJ
08551-1409 [Telephone 800-257-5282; in NJ, 609-466-8991; FAX 609- (795) Pharmacy Compounding, USP 25 page 2053 and page
466-3775], as Indicating Desiccant Pellets, Item No. TK-1002. 3078 of PF 27(5) [Sept.-Oct. 2001]. It is proposed to revise the
3
Accurate comparisons of Class A containers may require test periods in chapter title to Pharmaceutical Compounding—Nonsterile Pre-
excess of 28 days if weighings are performed on a Class A prescription parations to make it consistent with the proposed title of a related
balance (see Prescription Balances and Volumetric Apparatus (1176)). chapter, Pharmaceutical Compounding—Sterile Preparations
The use of an analytical balance on which weights can be recorded to 4 (797), which appears elsewhere in this PF (see revision proposal
or 5 decimal places may permit more precise characterization between con- under Sterile Drug Products for Home Use (1206)). Where appro-
tainers and/or shorter test periods. priate, cross-references to the new proposed chapters Good Com-
Pharmacopeia! Forum
pounding Practices (1075) and Pharmaceutical Calculations in relationships; the quantity of medication prepared in anticipation of
Prescription Compounding (1160), which also appear in this PF, receiving a prescription or a prescription order; and the conditions
are being added. Several references to compounders are also being of sale, which are limited to specific prescription orders.
clarified to distinguish where the expertise of a pharmacist is nec- The pharmacist's
essary. A statement about the usual tolerance limits for com-
pounded preparations is also being added under Compounded
Preparations. compoundor's
responsibilities in compounding drug preparations are to dispense

(CRX: C. Okeke) RTS—35643-1 the finished preparation in accordance with a prescription or a pre-
scriber's order or intent and to dispense those preparations in com-
pliance with requirements established by Boards of Pharmacy and
other regulatory agencies. Pharmaoioto
Change to read:
C ompounders AUSP26
must be familiar with statutes and regulations that govern com-
pounding because these requirements vary from state to state.
The pharmaoiat
(795) PHARMACY
p A a s m
COMPOUNDING is responsible for compounding preparations of acceptable
strength, quality, and purity with appropriate packaging and label-
^PHARMACEUTICAL COM- ing in accordance with good pharmaoy
A
compoundingAOT>2(J
POUNDING—NONSTERILE practices
PREPARATIONS Ausm A
(see Good Compounding Practices (^075))AUSP26
, official standards, and relevant scientific data and information.
Pharmacists
Change to read: A
Compounders Aas . W(5
A engaging in compounding ohould
For the purposes of this chapter, the licensed health care
A
h a v e to A t / i S M < f
professional responsible for the preparation preparing the continually expand their compounding knowledge by participating
in seminars, studying appropriate literature, and consulting collea-
compounded preparationsis referred to as "compoun- gues.
Add the following:

Compounding is an integral part of pharmacy practice and is es-
sential to the provision of health care. The purpose of this chapter
and applicable monographs on formulation is to help define what A
RESPONSIBILITY OF THE COMPOUNDER
constitutes good pharmacy
A compounder dispensing any compounded preparation
p g A L 5 p 2 ( 5
practices and to provide general information to enhance the phar
is responsible for ensuring that the product has been pre-
p pared, labeled, controlled, stored, dispensed, and distributed

ability in the
properly. This includes the responsibility of ensuring that
Compounding facilityAaS7,2«j
to extemporaneously compound preparations that are of acceptable the compounded preparation is kept under appropriately
strength, quality, and purity.
Compounding is different from manufacturing, which is guided controlled conditions at the location of use and that it is ad-
by GMPs (see Good Manufacturing Practices for Bulk Pharma-
ceutical Excipients (1078)) . Some of the characteristics or criteria ministered properly through adequate labeling and verbal or
that differentiate compounding from manufacturing include the ex-
istence of specific practitioner-patient-pharmacist written instructions. The compounder is also responsible for
oompoundor ensuring that the compounded preparation retains its quality

attributes within acceptable limits through a written quality
1
The Food and Drug Administration Modernization Act of 1997 (FDA- assurance program. This program ensures that for the entire
MA) adds Section 5O3A, "Pharmacy Compounding," to the Federal Food,
Drug, and Cosmetic Act. This law describes the conditions for pharmacy labeled life of the product, or until manipulated by the clin-
compounding of drugs, exempts the finished compounded product from the
FD&C Act's requirements for good manufacturing practices [§ ician, patient, or caregiver, the potency, pH, sterility if ap-
501(a)(2)(B)], new drug applications (§505), and "adequate directions for
use" on the drug label [§502(f)]. The new law addresses only the com- plicable, freedom from pyrogens, particulate limits,
pounding of drugs but not dietary supplements or cosmetics.
Pharmacopeial Forum
container integrity, appearance, and other qualities or char- (6) Appropriate stability evaluation is performed or deter-
acteristics that the compounded preparation is expected to mined from the literature or follows the individual pre-
have do exist. The quality assurance program encompasses paration described in the monograph or Pharmacy
every compounded preparation under the compounding fa- Compounding—Nonsterile Pi«cparations (295) in this
cility's control and includes all phases of their preparation, chapter.
distribution, storage, administration, and use. The com- (7) There is assurance that processes are always carried out
pounding facility employs proper analytical testing, where as intended or specified and are under control.
appropriate, to ensure the microbiological, chemical, and (8) Compounding conditions and procedures are adequate
physical quality of all compounded preparations. These re- for preventing errors.
sponsibilities apply equally to commercially available in- (9) Thoroare Adequate procedures and records exist for in-
jectable drug products that are dispensed to patients vestigating and correcting failures or problems in com-
without compounding or other manipulation and to compounding, testing, or in the preparation itself.AUSP26
pounded preparations that have been repackaged, reconsti- Change to read:
tuted, diluted, admixed, blended, or otherwise manipulated
(collectively referred to as "compounded") in any way prior COMPOUNDING ENVIRONMENT
to dispensing. The compounder is responsible for ensuring
that the quality is built into the compounded preparations of
Facilities
products, with key factors including at least the following

AUSP26
general principles. (See also Good Compounding Areas designated for compounding have adequate space for the or-
derly placement of equipment and materials to prevent mixups be-
Practices (1075).) tween ingredients, containers, labels, in-process materials, and
finished preparations. The compounding area is also to be de-
(1) Personnel are capable and qualified to perform their assigned, arranged, used, and maintained to prevent adventitious
cross-contamination. Areas used for sterile preparations are to be
signed duties. separate and distinct from the nonsterile compounding area (see
Sterile Drug Products for Home Use
(2) Ingredients used in compounding have their expected
Sterile Preparations Pharmacy Practices
identity, quality, and purity.
(3) Compounded preparations are of acceptable strength, A
Environmental Quality and Control under Pharmaceutical
quality, and purity, with appropriate packaging and la- Compounding—Sterile Preparations {797}).AUSp26
The entire compounding area is to be well-lighted. Heating, venti-
beling, with good compounding pmotioea; and prepared lation, and air conditioning systems are to be controlled to avoid
decomposition of chemicals (see Storage Temperature under Pre-
in accordance with good compounding practices, offi- servation, Packaging, Storage, and Labeling in the General No-
tices and Requirements and the manufacturers' labeled storage
cial standards, and relevant scientific data and informa- conditions). Storage areas provide an environment suitably con-
trolled to ensure quality and stability of bulk chemicals and fin-
tion. ished preparations.
Potable water is to be supplied for hand and equipment washing.
(4) Critical processes are validated to ensure that proce- This water meets the standards prescribed in the EPA's National
Primary Drinking Water Regulations (40 CFR Part 141). Purified
dures, when used, will consistently result in the ex- Water must be used for compounding nonsterile drug preparations
when formulations indicate the inclusion of water. Purified Water
pected qualities in the finished preparation. must also be used for rinsing equipment and utensils. In those cases
when a water is used to prepare a sterile preparation, Water for In-
(5) The compounding environment is suitable for its injection, Sterile Water for Injection, or Bacteriostatic Water for In-
jection must be used (see Water for Pharmaceutical Purposes
tended purpose. (1231) and Sterile Drug Products for Home Use (4306)
Pharmacopeial Forum
Sterile Preparations—Pharmacy Practices (1206))r oompoundor's

knowledge of the chemical reactions by which drugs degrade pro-
A vides a means for establishing conditions under which the rate of
Pharmaceutical Compounding—Sterile Preparations degradation is minimized. The factors that influence the stability of
preparations compounded by pharmacists
(191)).AUSP26
Compounding areas are to be maintained in a clean and sanitary
condition. Adequate washing facilities are to be provided, includ- oompoundoro
ing hot and cold water, soap or detergent, and air driers or single-
service towels. Sewage, trash, and other refuse in the compounding
area is to be disposed of in a safe, sanitary, and timely manner. ^compounded preparationsAasw<5
Equipment is to be thoroughly cleaned promptly after use to avoid are generally the same as those for manufactured drug products
cross-contamination of ingredients and preparations. Special pre- (see Factors Affecting Product Stability and Responsibility of the
cautions are to be taken to clean equipment and compounding areas Pharmacist under Stability Considerations in Dispensing Practice
meticulously after compounding preparations that contain aller- (1191)).
genic ingredients (e.g., sulfonamides or penicillins).
Primary Packaging
Equipment
Compounded preparations should be packaged in containers
Equipment is to be of appropriate design and size for compound- meeting USP standards (see Containers under Preservation,
ing and suitable for the intended uses. The types and sizes of equip- Packaging, Storage, and Labeling in the General Notices and Re-
ment will depend on the dosage forms and the quantities quirements, Containers (661), and Containers—Permeation
compounded (see Weights and Balances (41), Prescription Bal- (671)). The container used depends on the physical and chemical
ances and Volumetric Apparatus (1176), and equipment manufac- properties of the compounded preparation. Container-drug interac-
turers' instruction manuals). All equipment is to be constructed so tion is to be considered with substances such as phenolic com-
that surfaces that contact pharmaceutical components, in-process pounds and sorptive materials (e.g., polypeptides and proteins).
materials, or finished preparations are not reactive, additive, or ad-
sorptive to avoid altering the safety, identity, strength, quality, or
purity of the preparation. Equipment and accessories uaod in com
pounding should bo inspected, maintained, and cleaned at appro Sterility
priato intervals to ensure the accuracy and reliability of their
performance. Assurance of sterility in a compounded sterile preparation is
A
mandatory. Compounding and packaging of sterile drugs, such
The use of micropipets, electronic or analytical balances, as ophthalmic solutions, will require strict adherence to guidelines
presented in the general information chapter Sterile Drug Products
or triturations or dilutions shall be considered when needed for Home Use (306)
quantities are too small to accurately measure with standard
Sterile Preparations—Pharmacy Practices
equipment required by a state Board of Pharmacy. Equip-
A
ment and accessories used in compounding are to be in- Pharmaceutical Compounding—Sterile Preparations
spected, maintained, cleaned, and validated at appropriate <797) A W r e ,

and in the manufacturers' labeling instructions.
intervals to ensure the accuracy and reliability of their per-
formance. A.USP26
Stability Criteria and Beyond-Use Dating
Change to read: The beyond-use date is the date after which a compounded pre-
paration is not to be used and is determined from the date the pre-
paration is compounded. Because compounded preparations are
intended for administration immediately or following short-term
storage, their beyond-use dates may be assigned based on criteria
STABILITY OF COMPOUNDED different from those applied to assigning expiration dates to man-
PREPARATIONS ufactured drug products.
Pharmacists
"Stability" is defined as the extent to which a preparation re- A
tains, within specified limits, and throughout its period of storage Compounders AtAS . m
and use, the same properties and characteristics that it possessed at are to consult and apply drug-specific and general stability docu-
the time of compounding. See the table Criteria for Acceptable Le- mentation and literature when available, and are to consider the
vels of Stability under Stability Considerations in Dispensing nature of the drug and its degradation mechanism, the container
Practice (1191). in which it is packaged, the expected storage conditions, and the
The oompounding pharmacist intended duration of therapy when assigning a beyond-use date
(see Expiration Date and Beyond-Use Date underLabeling in the
p A t 5 P 2 ( 5 General Notices and Requirements). Beyond-use dates are to be
must avoid formulation ingredients and processing conditions that assigned conservatively. When using manufactured solid dosage
would result in a potentially toxic or ineffective preparation. The forms to prepare a solution or aqueous suspension, the pharmacist
pharmacist's
Pharmacopeial Forum
A
compounder. USP26 For Water-Containing Formulations (prepared from ingredi-
is also to consider factors such as hydrolysis and the freeze-thaw ents in solid form)—The beyond-use date is not later than 14 days
property of the final preparation before assigning a beyond-use A
date. In assigning a beyond-use date for a compounded drug pre- for liquid preparationsA(/57>2($
paration, in addition to using all available stability information, the when stored at cold temperatures
pharmacist A
between 2° and 8° (36° and 46° V).AUSP26
p A U s W f i
is also to use his or her pharmaceutical education and experience. For All Other Formulations—The beyond-use date is not later
When a manufactured product is used as the source of active in- than the intended duration of therapy or 30 days, whichever is ear-
gredient for a nonsterile compounded preparation, the product ex- lier. These beyond-use date limits may be exceeded when there is
piration date cannot be used to extrapolate directly a beyond-use supporting valid scientific stability information that is directly ap-
date for the compounded preparation. However, a pharmacist plicable to the specific preparation (i.e., the same drug concentra-
tion range, pH, excipients, vehicle, water content, etc.). See also
compounderA^yW(j the beyond-use dating information in the Labeling section under
may refer to the literature or to the manufacturer for stability infor- Repackaging Into Single-Unit Containers and Unit-Dose Contain-
mation. The pharmacist ers for Nonsterile Solid and Liquid Dosage Forms under
A Containers (661).
compounder A a s r a j
may also refer to applicable publications to obtain stability, com-
patibility, and degradation information on ingredients. All stability
data must be carefully interpreted in relation to the actual com-
pounded formulation. BEYOND-USE LABELING
At all steps in the compounding, dispensing, and storage pro-
cess, the pharmacist Federal law requires that manufactured drug products be labeled
A with an expiration date. Some state laws may require a beyond-use
compounder. a s r a j date. The label on the container or package of an official com-
is to observe the compounded drug preparation for signs of in- pounded preparation must bear a beyond-use date. Good pharmacy
stability. For more specific details of some of the common physical
signs of deterioration, see Observing Products for Evidence of In- Compounding USP26
stability under Stability Considerations in Dispensing Practice practice dictates beyond-use labeling for all compounded prepara-
(1191). However, excessive chemical degradation and other drug tions.
concentration loss due to reactions may be invisible more often
than they are visible. Change to read:
In the absence of stability information that is applicable to a spe-
cific drug and preparation, the following maximum beyond-use
dates are recommended for nonsterile compounded drug prepara-
tions2 that are packaged in tight, light-resistant containers and DEFINITIONS
stored at controlled room temperature unless otherwise indicated
A For purposes of this chapter, the following terms shall have these
(see Preservation, Packaging, Storage, and Labeling in meanings.
PREPARATION is a drug product,
the General Notices and Requirements).AUSP26
A
dosage foTm,AUSP26
a nutritional supplement, or a finished device. It is thefinishedor
For Nonaqueous Liquids and Solid Formulations— partially finished preparation of one or more official
Where the Manufactured Drug Product is the Source of Active •
Ingredient—The beyond-use date is not lator than 25% of the- timo AUSP26
remaining until tho product'3 expiration date- or 6 months, which substances formulated for use on or for the patient or consumer
ever io earlier. (see General Notices and Requirements).
OFFICIAL SUBSTANCE includes an active drug entity, a recog-
A nized nutrient, or a pharmaceutic ingredient (see also NF 19)
one year or the time remaining until the product's expira-
A
NF21)AUSP26
tion date.AWSK(f or a component of a finished device.
ACTIVE INGREDIENT usually refers to chemicals, substances, or
Where a USP or NF Substance is the Source of Active Ingredi- other components of articles intended for use in the diagnosis, cure,
ent—The beyond-use date is not later than 6 months. mitigation, treatment, or prevention of diseases in humans or other
A
one year or the time remaining until the product's expira- animals or for use as nutritional supplements.
ADDED SUBSTANCES are ingredients that are necessary to prepare
tion date.AKSM<f the preparation but are not intended or expected to cause a human
pharmacologic response if administered alone in the amount or
concentration contained in a single dose of the compounded pre-
paration. The term added substances is usually used synonymously
2
For guidelines applicable to dating sterile compounded preparations, see with the terms inactive ingredients, excipients, and pharmaceutic
Storage and Expiration Dating undor Sterile Drug Products for Home Use ingredients.
Sterile Preparation Pharmacy Practices

A
Storage and Beyond-Use Dating under Pharmaceutical
Compounding—Sterile Preparations {797).AUSP26
Pharmacopeial Forum
Change to read: on an FDA liat of drug products dovolopod through rulo making
which present domonstrablo difficulties in compounding that ad
vorsoly affoot tho safety or effectiveness of tho drug.
INGREDIENT SELECTION AUSP26
CALCULATIONS
AVSP26
Compounding Non-Drug Requirements

Sources If the product
Official compounded preparations are prepared from ingredients p p y p
A U 2 5
that meet requirements of the compendial monograph for those in- is intended for use as a dietary
dividual ingredients for which monographs are provided.
A USP or an NF grade substance is the preferred source of in-
gredients for compounding all other preparations. If that is not or nutritional
available, or when food, cosmetics, or other substances are or must supplement (to supplement the diet) or cosmetic (e.g., to beautify),
be used, then the use of another high-quality source, such as ana- then the pharmacist
lytical reagent (AR), certified American Chemical Society (ACS),
or Food Chemicals Codex (FCC) grade, is an option for profes- p A j ; 5 W ( 5
sional judgment. For any substance used in compounding not pur- must adhere to this chapter on good compounding practices, but
chased from a registered drug manufacturer, the pharmacist the pharmacist
A
A
compounderAUS;/,2(j compoundQTAUSP26
must establish purity and safety by reasonable means, which may is not restricted to compounding limitations described in section
include lot analysis, manufacturer reputation, or reliability of 503AoftheFD&C Act.
source. Pharmacists who compound dietary supplements must comply
A manufactured drug product may be a source of active ingre- with the federal labeling requirements, some of which are complex,
dient. Only manufactured drugs from containers labeled with a and any state requirements.
batch control number and a future expiration date are acceptable
as a potential source of active ingredients. When compounding
with manufactured drug products, the pharmacist
Calculations
^compounder.^s
must consider all ingredients present in the drug product relative to Tho pharmacist must bo able to oaloulato tho amount or oonoon
the intended use of the compounded preparation. tration of drug substances in each unit or dosage portion of a com
pounded preparation at tho timo it is disponsod. Pharmacists must
perform calculations and measurements to obtain, theoretically;
100% of the amount of oaoh ingredient in compounded formula
Compounding—U.S. Food and Drug Law tion3. Calculations must aooount for tho active ingredient, or active
Requirements moiety; and water oontont of drug substances, which inoludos that
in tho chemical formulas of hydrates. Offioial drug sub3tanoos and
Section 503A requires that a pharmacist uoo bulk drug sub added 3ubstanoos must moot tho requirements under Loss on
stances whioh are: (1) subject to a USP NF monograph, if it exists, •Drying (?^4-), whioh must bo inoludod in tho oaloulations of
and tho USP chap tor on Pharmacy Compounding (395); (2) if a amounts and concentrations of ingredients. The pharmacist should
monograph does not exist, a component of a drug approved by oonsider tho offoot of ambient humidity on tho gain or loss of water
FDA; or (3) if no monograph exists or tho substance is not a com from drugs and added substances in containers subjootod to inter
ponont of a drug approved by FDA, a substance which appears on a mittont opening over prolonged storage. Each container should bo
list approved through rule making for compounding by FDA, after opened for tho shortest duration nooossary and then olosod tightly
consultation with USP. A pharmacist must use bulk drug sub immediately after use.
stances prepared by a manufacturer registered with FDA. The bulk Tho nature of tho drug substance that is to bo weighed and used
drug substances must bo accompanied by a valid certificate of ana in compounding a proscription must bo known oxaotly. If tho sub
lysis. For ingredients other than bulk drug substances, pharmacists stance is a hydrate, its anhydrous equivalent weight may need to be
should use ingredients that comply with an applicable USP NF calculated. On the other hand, if there is adsorbed moisture present
monograph and tho USP chapter on Pharmacy Compounding that is either spooifiod on a certificate of analysis or that is dotor
(?9§). USP has published monographs on individual bulk drug mined in the pharmacy immediately before the drug substance is
substances and ingredients in addition to those on compound for used by tho proooduro under Loss on Drying (?34-), this informa-
mulations. tionmust bo used when calculating tho amount of drug 3ubstanoo
•
that is to bo weighed in order to determine tho oxaot amount of
AUSP26 anhydrous drug substance required-
A pharmacist There arc oases in whioh tho required amount of a dose is spo
A oifiod in terms of a cation [e.g., Li( I), nctilmioin (n+)], an anion
compounder AC/5W5 [e.g., F( )], or a molecule (e.g., thoophyllino in aminophyllino). In
may not compound a drug product those instanoos, tho drug substance woighod is a salt or oomplox, a
portion of whioh represents tho pharmacologically aotivo moiety.
p p A ( / ^ 2 6 Thus, tho oxaot amount of such substances woighod must bo oalou
that appears on a list of drug products withdrawn or removed from latod on tho basis of tho required quantity of tho pharmaoologioal
the market because they are found to be unsafe or not effective, fe
addition, a pharmacist may not compound a product which appears j
Tho following formula may bo used to oaloulato tho exact thoo
rotical weight of an ingredient in a compounded preparation:
Pharmacopeia! Forum
W-abide, Example 4: Aoouratoly weigh an amount of Notilmioin Sulfato

in which W'\a tho aotual weighed Qmount; a io tho progoribod or USP, equivalent to 2.5 g of notilmioin. [NOTE—Uoing tho prooo
pharmacist determined weight of tho aotivo or functional moioty duro under Loss on Diying (334-), tho Notilmioin Sulfato USP that
of drug or added oubstanoo; b ia tho ohomioal formula weight of waa woighod loot 12% of ito woight.]
tho ingrodiont, including watoro of hydration for hydrous ingro
dionts-e/ is tho fraction of dry weight when the percent by weight Equation Factor Numerical Value
of adsorbed moisture content ia known from tho I033 on drying pro
ooduro (see Loss on Diying(T^4-)); and e ia tho formula weight of W woight, in g, of Notilmioin Sulfato USP
tho aotivo or funotional moioty of a drug or addod oubotanoo that ia 3$ g
provided in tho formula weight of tho weighed ingredient. b 11-12 g/molo
TIT 7 O ©
Example 1: Triturate Morphine Sulfato USP and Lactose NF to ob- e 951 g/molo
tain 10 g in which there are 30 mg of Morphine Sulfato USP for
each 200 mg of the morphino laotoso mixture. NOTE—Clinioal do- W- (2.5 g (1112 g/molo))/(0.88 (951 g/molo)) - 131 g.
oagos of morphine mean Morphine Sulfato USP, which io tho pen
AVSP26
Equation Factor Numerioal Value Change to read:

W weight, in g, of Morphino Sulfato USP
1.5 g of morphino sulfatc pontahydrato in tho
proooription
759 g/molo CHECKLIST FOR ACCEPTABLE STRENGTH,
QUALITY, AND PURITY
e 759 g/molo
The following questions are to be considered carefully before
compounding.
W- (1.5 g (759 g/molo))/(1.0 (759 g/molo)) - 1.5 g. 1. Have the physical and chemical properties and medicinal,
dietary, and pharmaceutical uses of the drug substances been
reviewed?
2. Is the quantity and quality of each active ingredient identifi-
Example 2: Aoouratoly woigh an amount of Aminophyllino USP to able?
obtain 250 mg of anhydrous thoophyllino. NOTE—Tho powdered 3. Will the active ingredients be effectively absorbed, locally or
aminophyllino dihydrato woighod contains 0.1% w/w adaorbod systemically according to the prescribed purpose, from the
moioturo ao stated in tho Certificate of Analyaio. preparation and route of administration?
4. Are there added oubstanooo
Equation Factor Numerical Valuo
pharmaceutical cxcipicnt3
W woight, in mg, of Aminophyllino USP (dihy-
0 250 mg of thoophyllino
^substances (see Definitions)AUSP26
b 156 g/molo (confirmed or potentially present) from manufactured pro-
A n c\nc ducts that may be expected to cause an allergic reaction, irri-
Vf \J * J J \J
tation, toxicity, or undesirable organoleptic response from the

€ 360 g/molo patient? Are there added oubotancoo
W- (250 mg (156 g/molo))/(0.996 (360 g/molo)) - 318 mg. pharmaceutical oxoipiont3
Example 3: Aoouratoly weigh an amount of Lithium Citrate USP A

substances (see Definitions)AUSP26
(containing 2.5% moisture as stated in tho Certificate of Analysis) (confirmed or potentially present) that may be unfavorable
to obtain 200 mEq of lithium (Li+). NOTE One mEq of Li+4s (e.g., unsuitable pH or inadequate solubility)?
equivalent to 0.00691 g of Li-K 5. Were all calculations and measurements confirmed to ensure
that the preparation will be compounded accurately
Equation Faotor Numorioal Value A
(see Pharmaceutical Calculations in Prescription
W weight, in g, of Lithium Citrato USP (tetra
Compounding (11 60))1AUSP26
200 mEq of Li I or 1.39 g of Li+
b 282 g/molo Change to read:
4
e 3 )( 6.91 g/molo or 20.8 g/molo
COMPOUNDED PREPARATIONS
W- (1.39 g (282 g/molo))/(0.975 (20.8 g/molo)) - 19.3 g.
The term compounded preparations includes the terms com-
pounded dosage forms, compounded drugs, and compounded for-
mulations, and means finished forms that are prepared by or under
the direct supervision of a licensed pharmacist.
Pharmacopeial Forum
compounder.A ysp26 quantitatively to a calibrated dispensing bottle or graduate.

When controlled substances are used, check with state and The preparation may be homogenized to ensure a uniform fi-
federal authorities concerning their policies. nal dispersion.
A
Unless otherwise indicated or appropriate, compounded Reducing solid ingredients to the smallest reasonable particle
size.
preparations are to be prepared to ensure that each prepara- Solutions shall contain no visible undissolved matter when
dispensed. [NOTE—An exception may occur with supersatu-
tion shall contain not less than 90.0 percent and not more rated solutions such as Potassium Iodide Oral Solution.]
Emulsions and suspensions are labeled, "Shake well before
than 110.0 percent of the theoretically calculated and la- using."
beled quantity of active ingredient per unit weight or vol-
ume and not less than 90.0 percent and not more than
110.0 percent of the theoretically calculated weight or vol- Suppositories
ume per unit of the preparation.ACOT.2is When compounding suppositories, the pharmacist
Compounded preparations include, but are not restricted to, the fol- p A [ / i S p 2 (5
is to prepare an excess amount of total formulation to allow the
lowing pharmaceutical dosage forms described under Pharmaceu- prescribed quantity to be accurately dispensed. Selected practices
tical Dosage Forms (1151). and precautions for compounding these dosage forms include the
following:
• not using ingredients that are caustic or irritating, and thor-
oughly comminute solids that are abrasive to the mucous
membranes;
Capsules, Powders, Lozenges, and Tablets • selecting a base that allows active ingredients to provide the
intended local or systemic therapeutic effect;
When compounding these dosage forms, the pharmacist • reducing solid ingredients to the smallest reasonable particle
compounderA [/s/^,5 size; and
is to prepare an amount of the total formulation sufficient to allow • weighing a representative number of suppositories to ensure
the prescribed amount or quantity to be accurately dispensed. Se- that each is not less than 90% and not more than 110% of the
lected practices and precautions for compounding these dosage average weight of all suppositories in the batch.
forms include the following:
• reducing solid ingredients to the smallest reasonable particle
size;
• implementing appropriate checks to ensure that all ingredients
are blended to achieve a homogeneous mixture; Creams, Topical Gels, Ointments, and Pastes
• monitoring humidity if moisture might cause hydrolysis, do-
sage form adhesion to containers, or softening or partial dis- When compounding semisolid dosage forms, the pharmaoist
solution of capsule shells; A
compounder AUSW6
• accurately performing weighings to ensure that each unit shall is to prepare an excess amount of total formulation to allow the
be not less than 90% and not more than 110% of the theore- prescribed quantity to be accurately dispensed. Selected practices
tically calculated weight for each unit [NOTE—Preparations and precautions for compounding these dosage forms include the
classified as dietary supplements are required by the U.S. following:
Food and Drug regulations to be not less than 100% of the • not using ingredients that are caustic, irritating, or allergenic
declared potency.]; and to the skin or other application sites unless they are necessary
• packaging dosage units according to container specifications for a treatment;
for capsules and tablets of the specific active ingredient unless • selecting a base or vehicle that allows active ingredients to
specified otherwise in individual monographs (see Containers provide the intended local or systemic therapeutic effect;
(661)). • reducing solid ingredients to the smallest reasonable particle
size;
• geometrically incorporating the active ingredients with the
added substances to achieve a uniform liquid or solid disper-
sion in the dosage form; and
Emulsions, Solutions, and Suspensions • observing the uniformity of the dispersion by spreading a thin
film of finished formulation on a flat transparent surface (e.g.,
When compounding these dosage forms, the pharmaoiot clear glass ointment slab).
compounder. [/^p^g
is to prepare a 2% to 3% excess amount of the total formulation to Change to read:
allow the prescribed amount to be accurately dispensed. Selected
practices and precautions for compounding these dosage forms in-
clude the following.
• For single-unit containers, the weight of each filled container, COMPOUNDING PROCESS
corrected for tare weight, shall be the equivalent of not less
than 100% and not more than 110% of the labeled volume. The pharmacists
• Aqueous suspensions are prepared by levigating the powder A
mixture to a smooth paste with an appropriate wetting agent. compoundersAl!SW<j
This paste is converted to a free-flowing fluid by adding ade- are to consider using the following steps to minimize error and
quate vehicle. Successive portions of the vehicle are used to maximize the prescriber's intent.
wash the mortar, or other vessel, to transfer the suspension
Pharmacopeia! Forum
Judge the suitability of the prescription to be compounded in Formulation Record

terms of its safety and intended use. Determine what legal
limitations, if any, are applicable. The formulation record is afileof individually compounded pre-
2. Perform necessary calculations to establish the amounts of in- parations. This record must list the name, strength, and dosage
gredients needed (see form of the preparation compounded, all ingredients and their
quantities, equipment needed to prepare the preparation, when ap-
* Pharmaceutical Calculations in Prescription propriate, and mixing instructions. Mixing instructions should in-
clude the order of mixing, mixing temperatures or other
Compounding (11 60)).AUSP26 environmental controls, such as the duration of mixing, and other
3. Identify equipment needed. factors pertinent to the replication of the preparation as com-
4. Don the proper attire and wash hands. pounded. The formulation record must include an assigned be-
5. Clean the compounding area and needed equipment. yond-use date, the container used in dispensing, the storage
6. Only one prescription should be compounded at one time in a requirements, and any quality control procedures.
specified compounding area.
7. Assemble all necessary materials to compound the prescrip-
tion.
8. Compound the preparation following the formulation record Compounding Record
or prescription (see Compounding Records and Documents
below), according to the art and science of pharmacy. The compounding record contains documentation of the name
9. Assess weight variation, adequacy of mixing, clarity, odor, and strength of the compounded preparation, the formulation re-
color, consistency, and pH as appropriate. cord reference for the preparation, and the sources and lot numbers
10. Annotate the compounding log and describe the appearance of ingredients. The compounding record also includes information
of the formulation. on the total number of dosage units compounded, the name of the
11. Label the prescription containers to include the following person who prepared the preparation and the name of the pharma
items: a) the name of the preparation; b) the internal identifi-
cation number; c) the beyond-use date (see Beyond-Use La- A
beling); d) the initials of the pharmacist compounder. [/5?26
A
who approved the preparation, the date of preparation, the assigned
compounder. [/5W( j internal identification number or the prescription number and an
who prepared the label; e) any storage requirements; and f) assigned beyond-use date, and the prescription number. For all
any other statements required by law. compounded preparations, results of quality control procedures
12. Sign and date the prescription affirming that all procedures are to be recorded (e.g., weight range of filled capsules).
were carried out to ensure uniformity, identity, strength, quan- A
tity, and purity. When compounding problems occur with preparations
13. Thoroughly and promptly clean all equipment and store prop-
erly. prepared according to USP compounding monographs, the
compounder must complete a USP Monograph Experience
Change to read:
Reporting Form and submit the form to USP for evalua-
tion.A.VSP26
COMPOUNDING RECORDS AND
DOCUMENTS
All pharmacists
MSDS File
compoundersAUSp;?(s
who dispense prescriptions must comply with the record keeping Tho MSDS Filo oontains tho Material Safety Data Shoota for any
requirements of their individual states. If the pharmacist drug sub 3tanoo or bulk ohomical located on tho pharmacy promises
A not in a solid dosage form; Tho MSDS ohould bo requested from
compounder AUSP:M tho aupplior of oaoh subotanoe and kopt on filo in tho pharmacy
compounds a preparation according to the manufacturer's labeling Employees should bo instruoted aa to tho location of tho filo and
instructions, then further documentation is not required. All other its content.
compounded preparations require further documentation. Such
A
compounding documents are to list the ingredients and the quantity MSDS are to be readily accessible to all employees
of each in the order of the compounding process.
The objective of the documentation is to allow another pharma working with drug substances or bulk chemicals located
on the compounding facility premises. Employees are to
p A C / f f ^
to reproduce the identical prescription at a future date. The formu- be instructed on how to retrieve and interpret needed
lation record provides a consistent source document for preparing
the preparation (recipe), and the compounding record documents information.
the actual ingredients in the preparation and the person responsible
for the compounding activity. These records are to be retained for
the same period of time that is required for any prescription under
state law. The record may be a copy of the prescription in written or
machine readable form that includes a formulation record, a com-
pounding record, and a Material Safety Data Sheets (MSDS) file.
©2002 The United States Pharmacopeia! Convention, Inc. All Rights Reserved.
Pharmacopeia! Forum
Change to read:
GENERAL CHAPTERS
QUALITY CONTROL
The safety, quality, and performance of compounded prepara-
tions depend on correct ingredients and calculations, accurate
and precise measurements, appropriate formulation conditions
General Information
and procedures, and prudent pharmaceutical judgment. As a final
check, the pharmaoiot
compounder.^.^
is to review each procedure in the compounding process. To ensure
accuracy and completeness, the pharmaoiot
BRIEFING
is to observe the finished preparation to ensure that it appears as
expected and is to investigate any discrepancies and take appropri- (1146) Packaging Practice—Repackaging a Single Solid
ate corrective action before the prescription is dispensed to the pa- Oral Drug Product into a Unit-Dose Container, page 2827 of
tient (see the Checklist for Acceptable Strength, Quality, and PF 27(4) [July-Aug. 2001]. A definition for the package is being
Purity, the appropriate pharmaceutical dosage form under Com- added under Nomenclature and Definitions. Several notes about
pounded Preparations, and the steps under Compounding Pro- the temperature conditions in the packaging facility and the plastic
cess). material used in packaging are being added under Beyond-Use
Date. A few minor editorial changes are also included.
Add the following:
^VALIDATION
Add the following:
Compounding procedures that are routinely performed,
including batch compounding, shall be completed and vali-
dated according to written procedures. The act of validation •(1146) PACKAGING
of a compounding procedure involves checking to ensure PRACTICE—REPACKAGING A
that calculations, weighing and measuring, order of mixing,
SINGLE SOLID ORAL DRUG
and compounding techniques were appropriate and accu-
PRODUCT INTO A UNIT-DOSE
CONTAINER
rately performed. AVSP26
INTRODUCTION
PATIENT COUNSELING
Repackaging of solid oral drug products, such as tablets
The patient or the patient's agent should be counseled about
proper use, storage, and evidence of instability in the compounded and capsules, into unit-dose configurations is common prac-
preparation at the time of dispensing (see Responsibility of the
Pharmacist under Stability Considerations in Dispensing Practice tice both for the pharmacy that is dispensing drugs pursuant
(1191)).
to a prescription and for the pharmaceutical repackaging
firm. This general chapter contains minimum standards to
be used as a guideline for repackaging practices. This guide-
line is not intended to replace or supplant the requirements
of regulatory agencies.
Repackaging preparations into unit-dose configurations
is an important aspect of pharmaceutical care and of optimi-
zation of patient compliance. For purposes of this chapter,
Pharmacopeial Forum
there are two types of repackaging: the first involves phar- MATERIALS
macies that dispense prescription drugs; the second con- Blister packages offer a wide array of designs of both
cerns commercial pharmaceutical repackaging firms. functionality and appearance. Various packaging materials
Change to read: are utilized to create blisters that are tailored to provide op-
timum performance. The blister container consists of two
NOMENCLATURE AND DEFINITIONS components: the blister, which is the formed cavity that
holds the product, and the lid stock, which is the material
DISPENSER—A dispenser is a licensed or registered prac-
that seals to the blister, as shown below. Because of the vari-
titioner who is legally responsible for providing a prepara-
ety of blister films available, film selection should be based
tion for patient use, with a specific patient label, pursuant to
upon the degree of protection required. The choice of lid
a prescription or a medication order. In addition, dispensers
stock depends on how the blister is to be used, but generally
may prepare limited quantities in anticipation of a prescrip-
the lid stock is made of aluminum foil. The material used to
tion or medication order from a physician. Dispensers are
form the cavity is typically a plastic, which can be designed
governed by the board of pharmacy of the individual state.
to protect the dosage form from moisture. There are widely
A
PACKAGE—The term "package" is synonymous with
varying degrees of moisture protection now available. For
the term "container." See Containers under Preservation,
purposes of this general chapter, they are referred to as nom-
Packaging, Storage, and Labeling in the General Notices
inal, medium, high, and extreme moisture barrier properties.
and Requirements.AUSP26
PHARMACY—A pharmacy is an establishment that is leg-

Lidding stock
ally responsible for providing the drug preparation for pa-
tient use, with a specific patient label, pursuant to a Blister
prescription or a medication order. The terms dispenser

and pharmacy are used interchangeably. Schematic Presentation of a Typical Blister Pack
REPACKAGING—Repackaging is the act of removing a

preparation from its original primary container and placing
it into another primary container, usually of smaller size.
REPACKAGER—A repackager is an establishment that re- Polyvinyl Chloride—The most commonly used blister
packages drugs and sends them to a second location in an- material is polyvinyl chloride (PVC). This material, which
ticipation of a need. Repackaging firms repackage provides a nominal or zero barrier to moisture, is used when
preparations for distribution (e.g., for resale to distributors, the product does not require effective moisture protection.
hospitals, or other pharmacies), a function that is beyond the PVC is available in a range of gauges and can be made opa-
regular practice of a pharmacy. Distribution is not patient que or can be tinted with pigments to block out specific light
specific in that there are no prescriptions. Unlike dispensers, wavelengths.
repackaging firms are required to register with the FDA and The thickness of the PVC used is determined by the depth
to comply with the Current Good Manufacturing Practice and size of the cavity to be formed. Because the plastic thins
regulations in 21 CFR 210 and 211. during the blister-forming process, care should be taken to
Pharmacopeial Forum
ensure that the finished blister provides sufficient protection PVCIPVdC Laminations—PVC/PVdC is a film in which
from light (if required) and that it is strong enough to ade- the PVC is coated with an emulsion of polyvinylidene chlo-
quately protect the dosage form. Common gauges of PVC ride (PVdC). The PVdC layer is specified in g per m2 and
used in the pharmaceutical industry range from 7.5 to 15 can be constructed to providemeof/wm to high barrier protec-
mil (0.0075 to 0.015 inch). tion. The coating weights commonly used in the pharmaceu-
tical industry are 40, 60, and 90 g per m2, and the film is
Barrier Films—Many drug preparations are extremely
offered with or without a middle layer of polyethylene.
sensitive to moisture and therefore require high barrier
The polyethylene is used with heavier coating weights, such
films. Several materials may be used to provide moisture
as 60 and 90 g per m2, to improve the thermoforming char-
protection. Barrier films commonly used in the pharmaceu-
acteristics of the blister cavity.
tical industry are described below.
P VCIPCTFE Laminations—Poly chlorotrifluoroethy lene Adhesive
(PCTFE) film1 is a thermoplastic film made from polychlor-

Duplex Structure
otrifluoroethylene fluoropolymer. The PCTFE film is lami-
nated to the PVC by an adhesive layer between the PVC and
the PCTFE film (duplex structure) or by a layer of polyethy-
lene between the PVC-adhesive and the PCTFE-adhesive
layers (triplex structure). By using various gauges of the
PCTFE film, medium to extreme moisture barriers can be
PVC
obtained.
Triplex Structure
Adhesive
Duplex Structure Polypropylene—Because of its morphology, polypropy-

lene (PP) serves as a good moisture barrier, its spherulitic
structure creating an arduous path for water molecules to
traverse. Although not commonly used as a pharmaceutical
blister film in the U.S., PP provides an economical alterna-
tive to medium barrier materials and is used in Europe as an
PYC
alternative to PVC.
Triplex Structure
Cold Form Foil—This material is used for products that

are extremely hygroscopic or light sensitive. It is an extreme
moisture barrier and consists of three layers: PVC, alumi-
num foil, and nylon.
1
PCTFE film is available from Allied Signal (as Aclar) and
from other sources.
Pharmacopeial Forum
pushed through the remaining aluminum foil. It is important
Nylon
to note that use of this type of foil structure helps make the
package more child resistant. However, if child-resistant
packaging is required, the package design should be tested
Cold Form Foil
in accordance with the protocol described in 16 CFR 1700,
the Poison Prevention Packaging Act.
Laminating—__^ Paper
Lid Stock—Lid stock is sealed to the molded blister as Adhesive
Foil *
described above. Different designs of lid stocks are avail- Laminating
Adhesive
able, and selection of a particular design depends on how

Child-Resistant Foil
the package will be used. Standard designs—peelable,

push-through, and child-resistant—are described below.
The primary component of lid stock is typically aluminum
Push-Through—There are two commonly used types of
and its gauge varies from 18 to 25 urn (0.0078 to 0.001
push-through foil: one with a paper outer layer separated
inch). The side of the aluminum foil laminate in contact with
from the aluminum by a layer of adhesive and one without
the product provides the heat-sealable layer that forms the
paper (see diagrams below). The paper outer layer serves as
seal to the blister material. The heat-seal coating should
an aesthetic and makes it possible to print on the back of the
be capable of forming an adequate seal with the blister film
blister.
to which it is intended to seal. The materials used in the ma-
keup of the heat-seal layer meet 21 CFR 175 and 177.
Peelable—Peelable foil, commonly used in an institu-

Push-Through Foil (with paper)
tional setting, consists of several layers, as shown below,
and can be peeled away from the blister. [NOTE—For
child-resistant peelable foil, a layer of polyester with the ap-
propriate adhesives would be added.] With the peelable foil
lid stock, which is used in conjunction with blister tooling, a
three-step process is required to open the blister.
Push-Through Foil (no paper)
Laminating
Adhesive
Feelable Foil Construction

Other Package Styles—Other types of packages used
for unit-dose packaging of solid dosage forms are strip
First, the blister cavity must be separated from the rest of packs, pouches, and sachets.
the blister card. Next, the paper and polyester layers are
pulled back from an unsealed area. Finally, the product is
Pharmacopeial Forum
on the blister material used and on the speed at which that

material travels through the heating station, is a critical para-
Polyester {48 ga)
Aluminum (0.0035) meter for optimal performance. At the forming station the
Linear Low Density
Polyethylene {150 g)
blister material is heated to the point where the plastic soft-
Pouch Material Structure
ens sufficiently to allow the cavity to be formed. The blister
material is drawn from a reel-mounted roll (referred to as the
Change to read: web) and pulled through the machine. A splicing table is lo-
cated at the reel unwind to provide room for a second roll of
PROCESS blister material to be readily available for splicing and re-
Unit-dose packages can be formed and sealed in a variety sumption of the packaging process. An unwind device
of ways. Larger scale repackagers may use thermoformers may be installed to aid in moving the blister material from
that accomplish these functions in-line, while smaller re- the roll as adjusted for a specific index.
packagers may purchase preformed blister material. This Once the blister material is properly heated, compressed
section begins with an overview of the process involved air is generally used to form the blister cavity. Upper and
in thermoforming a blister, the fundamental process that lower forming dies close on the blister material as air is in-
also applies to other unit-dose package types such as troduced, forming a blister that corresponds to the size of the
pouches. The overview is not intended to be all encompass- cavity. A plug assist may be necessary depending on the ma-
ing, but it highlights the major operations along with their terial and size of the cavity. The plug assist ensures a uni-
critical parameters. form thinning of the blister material to optimize the
protective characteristics of the formed material. Once the
Thermoforming a Blister Unit-Dose Package—The
blister material is formed into the desired blister configura-
complete thermoforming process consists of four basic sta-
tion, it is advanced to the filling station.
tions where the following operations occur: forming, filling,
sealing, and finishing. Thermoforming requires the use of Filling Station—The product is loaded into the blister
heat and air in forming the blister. The lid stock material cavity at this station. An automated filling device may be
is sealed to the blister cavity material for a defined time used or the cavities may be hand filled. The critical para-
(the stroke of the machine) at the point where the heat plate meter at this station is proper filling of the formed blisters.
closes on the two materials.
Sealing Station—At this station, the lid stock is sealed to
Forming Station—Prior to entering the forming station, the filled blister cavity, using heat and pressure for a defined
the blister material passes through a heating unit where dwell time. The critical parameters to be considered at this
the blister material is heated uniformly in stages, to ensure station are temperature, pressure, and dwell time.
proper formation. Because different plastics have different The lid stock material is staged on a roll above the blister
softening points, careful attention must be paid to determin- cavity and may be preprinted or printed on-line. Lot num-
ing the proper temperature of the heating station, which of- bers and expiration dates may be applied at this point. Pre-
ten has multiple temperature zones. The temperature, based printed lid stock materials will require a print registration
© 2002 The United Slates Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
system to control the position of the printing relative to the be cut later during the equipment processing or roll continu-
blister cavity. The critical parameters at this part of the sta- ously and be manually cut. Temperature and dwell time are
tion include legible and correct labeling. the main critical factors for this equipment.
Finishing Station—The finishing station encompasses all Preformed Unit-Dose Packages—Preformed containers
other steps in the packaging process, including embossing, are sealed either by heat or adhesion. Heat sealers may be
perforation, and cutting. Embossing involves application of manual units requiring hand pressure application or auto-
a lot number and expiration date to the package. Steel type is mated units that provide a more controlled pressure for seal-
used to emboss information on the edges of the blister packing.
age. One of the critical parameters at this station is package Heat sealing may be accomplished through the use of
integrity. It is important that the embossing, perforation, and manual tabletop equipment. This equipment is generally op-
cutting processes do not compromise the blister, lid, or seal. erated at a set pressure. Critical parameters with these de-
The quality of the embossing is another critical parameter in vices are pressure and v temperature control because
the process. The embossing must be legible, correct, and in- undesirable variation in these parameters may yield inade-
clude all required information. quate seals.
Pouch Unit-Dose Packages—The pouch process is also Critical Parameters—In order to ensure that the finished
a form, fill, and seal operation, but it does not provide a de- container performs as intended, qualification of critical para-
fined, formed cavity as does the thermoforming process. meters should be determined. Typically, validation of a
Although the equipment used to form pouch unit-dose packaging line consists of qualification of the installation,
packages may function differently from that described for operation, and performance of a packaging system.
thermoforming a blister, the main operations (form, fill,
Installation Qualification—Equipment should be in-
and seal) and critical parameters at those stations are quite
stalled and found to be in proper working condition prior
similar. [NOTE—See the aforementioned critical parameters
to use.
defined in the section on thermoforming.]
The strip-pack process involves the drug product being Operation Qualification—Operational qualification
dosed into a three-sided, formed pouch. Once filled with should be performed to establish that the equipment oper-
the drug, the machine seals the pouch, forming a strip of ates within the manufacturer's specified ranges. Incoming
sealed unit-dose pouches. The basic flow of the process be- utilities for the equipment, such as air, electricity, etc.,
gins with the drug situated above the pouch material. One should be monitored and checked periodically.
roll of strip-pack material is used to form the pouch. This
Performance Qualification—Performance qualification
is accomplished by moving the material over a device that
should be done to ensure that the equipment is performing
forces the material to fold into two equal sides. The sides
properly with the required materials to produce a container
and bottom are sealed prior to dosing. The strip pack may
that functions as intended. The critical parameters include
forming temperature and pressure, sealing temperature and
pressure, and dwell time at the seal station. Qualified ranges
Pharmacopeial Forum
should be readily available in a reference source for the set Change to read:
up of equipment. Re-evaluation may be necessary with

changes to equipment, materials, or the process. PERFORMANCE
The primary purpose of the unit-dose package used in the
In-Process Inspections—Strict controls covering the packaging of a drug preparation is to ensure that throughout
packaging and labeling processes shall be in place. The final its intended expiration dating there is adequate protection
container should be evaluated for performance in each of the from the environment as the dosage form is distributed
stations described above. Specifically, the formed container and stored. It is also essential that the materials used do
should be inspected visually to ensure that it is properly not interact with the dosage form.
formed. Evaluation of the filling station should include a When determining what type of package to use in the re-
check to ensure that the unit-dose is properly filled (i.e., packaging operation, consideration must be given to the do-
the correct product is present). The sealing station should sage form's sensitivities (if any) to the storage and
be evaluated to ensure that a proper seal has been made distribution environments (e.g., temperature, light, and
and that the moisture permeation specifications of the sealed moisture).
container have been met. A visual examination of the pack-
The materials used in constructing the unit-dose container
age should be performed to ensure that the final steps of the
as well as the process of forming and sealing the container
packaging process are acceptable.
all together define the properties of the finished container.
Repackagers and dispensers should use a standard inspec- As discussed in Materials, there is a wide variety of com-
tion plan to verify the adequacy of the package. A visual in- mercially available film structures that provide unit-dose
spection should be performed to verify that the correct containers with a range of moisture and light protection.
product is in the proper packaging materials with correct la- Suppliers of these materials typically provide quantitative
beling. Seal integrity should be evaluated, using vacuum data obtained from well-established test methods, to high-
testing,2 helium testing, tear testing, eter Aand other testing light the protective properties of their material. These data
methods suitable to establish whether seal integrity is main- are based on flat sheets of the film, not on the formed con-
tained.^/^ tainer.
It is critical to understand that once the film is formed,
protective properties change because the overall thickness
of the film decreases as the blister cavity is formed. Usually
2
Vacuum testing consists of placing samples from the the change is a decrease, especially in the case of barrier
packaging operation into a jar filled with water. A lid is
placed over the samples to fully immerse them in the water. properties. However, the extent of change will vary with
A container lid is applied to create a seal effective enough to
create approximately 25 cm of vacuum. The vacuum pump the type of film structure used and is also highly dependent
is set and the samples are tested for approximately 1 minute,
removed from the water, wiped down, and opened to deter- on the container-forming process used (see Process).
mine if the inside of the unit-dose cavity or pouch is wet.
This process should be adjusted until it is under control Further, a suboptimal seal on the formed container will de-
and additional testing may be performed to ensure that the crease the protective properties of the container. Insufficient
seal integrity is consistently acceptable. Wetness indicates a
defective seal and therefore the potential for the drug to de- temperature, time, or pressure during a heat-seal operation
grade when exposed to the atmosphere. Defective packages
must be removed from further use. may enable the passage of moisture or oxygen through the

Pharmacopeia! Forum
A
seal area over time and may have an effect on the dosage As stated in the General Notices and Requirements, the
form. In addition, if the seal area is designed with insuffi- dispenser must maintain the facility where the dosage forms
cient surface area, the same problem may occur. To ensure are packaged and stored at a temperature such that the mean
A
a good seal, a minimum SQa\mgAUSP26 distance of 3 mm kinetic temperature is not greater than 25°. The plastic ma-
from the edge of the blister cavity to the nearest edge or per- terial used in packaging the dosage forms must afford better
foration is recommended. Therefore, it is important to mea- protection than polyvinyl chloride, which does not provide
sure the performance of the formed and sealed container adequate protection against moisture permeation. Records
rather than the performance of the flat sheet. must be kept of the temperature of the facility where the do-
Moisture is a critical factor in preparation integrity.Con- sage forms are stored, and of the plastic materials used in
tainers—Permeation (621) describes how to determine and packaging.^™
classify moisture permeation rates. If the manufacturer's la- Change to read:
beling includes "Protect From Moisture", the repackager
MINIMUM REQUIREMENTS
shall utilize a high barrier film.
The previous sections serve as a general introduction to
If light protection is required for a drug preparation, the
repackaging by providing a basic understanding of materials
repackager should follow the requirements for light trans-
selection, the form-fill-seal process, and the importance of
mission established under Containers (661). Again, this
performance of the sealed container. In this section, certain
testing should be conducted on the formed container, be-
minimum requirements for repackaging, which must be
cause the light protective properties of the film are compro-
met, are described in more detail.
mised once the film is thinned during the forming process. It
is recommended that these tests, in conjunction with any Personnel—Each person with responsibility for the re-
guidance provided by the manufacturer, be considered ap- packaging of a preparation shall have the education, train-
propriate for any container closure system used in repacka- ing, and experience, or any combination thereof, to
ging a drug preparation. perform assigned functions in a manner such that the safety,
Change to read: identity, strength, quality, purity, Apotency,AU5W(J and phar-
maceutical elegance of the drug dosage form are retained.
BEYOND-USE DATE
Training should be documented.
In the absence of stability data for the drug product in the
Personnel engaged in the repackaging of a preparation
repackaged container, the beyond-use dating period is one
shall wear clean clothing appropriate for the duties or pro-
year or the time remaining of the expiration date, whichever
cesses performed.
is shorter. If current stability data are available for the drug
product in the repackaged container, the length of time es- Facility—The repackaging facility may require areas of
tablished by the stability study may be used to establish the low relative humidity, and temperature conditions should
beyond-use date but must not exceed the manufacturer's ex- meet controlled room temperature requirements specified
piration date. in the General Notices.
Pharmacopeial Forum
Equipment—Equipment used in the repackaging of a manufacturer, lot number, expiration date, date of repacka-
preparation shall be of appropriate design and suitably lo- ging, and designation of persons responsible for repacka-
cated to facilitate operations for its intended use. Its design ging and for checking. The repackager or dispenser will
should allow for cleaning to preclude cross-contamination use documented controls to prevent labeling errors.
as well as for maintenance to be performed. Equipment shall
Materials—The repackager or dispenser shall place an
be constructed so those surfaces that contact components or
appropriate beyond-use date on the label and package in ap-
a preparation are not reactive, additive, or absorptive.
propriate materials. Materials used by the repackager shall
Any substances required for operation, such as lubricants
not be reactive, additive, or absorptive, and must meet the
or coolants, shall not come into contact with components or
requirements described in 21 CFR 175 and 177.
a preparation.
Equipment and utensils shall be cleaned, maintained, and Storage—The dispenser shall rotate and monitor stock
sanitized at appropriate intervals to prevent malfunctions or closely to ensure that the dispensing of preparations is on
contamination. Preventive maintenance should be per- a first-in-first-out (FIFO) basis. The repackager or dispenser
formed at appropriate intervals in accordance with the shall store preparations under required environmental con-
equipment manufacturer's recommendation. Any instru- ditions (e.g., controlled room temperature with a mean ki-
ments used to monitor critical parameters should be cali- netic temperature not higher than 25°).
brated on a defined schedule.
Drug Product—The repackager or dispenser shall exam-
Process—Steps should be taken to determine the critical ine preparations for evidence of instability such as change in
process parameters (e.g., seal temperature, dwell time, etc.) color or odor, and shall exercise professional judgment as to
in operating the equipment. Set points for these parameters the acceptability of a package.
should be documented and procedures established to ensure
that they are adhered to each time the equipment is operated. Complaints—The repackager or dispenser will maintain
written procedures describing the handling of written and
Labeling—The labeling requirements for a commercial oral complaints regarding a drug product and will ensure
: A
repackager and a pharmacist are different. Fke For exam- that complaints are investigated and appropriately resolved.
ple, theAUSP26 commercial repackager must comply with 21
CFR 201.1, but the pharmacist or dispenser does not have to Returned Goods—Policies and procedures relating to
comply with this requirement. If stability data are unavail- returned goods should be developed to ensure proper hand-
able, the dispenser shall repackage only an amount of stock ling.
sufficient for a limited time and shall include product name

Reprocessing—Reprocessing of repackaged unit-dose
and strength, lot number, manufacturer, and appropriate be-
containers (i.e., removal of medication from one unit-dose
yond-use date on the label. When quantities are repackaged
container and placing it into another unit-dose container)
in advance of immediate needs, each preparation must bear
shall not be done. However, reprocessing of the secondary
an identifying label, and the dispenser is required to main-
package (e.g., removing the blister card from the cardboard
tain suitable repackaging records showing the name of the
carrier and placing the blister card into another cardboard
Pharmacopeial Forum
carrier) is allowed provided the original beyond-use date is pharmaceutical article (see Pharmaceutical Compound-
maintained, and provided the integrity of the blister is en- ing—Nonsterile Preparations (795), Pharmaceutical Com-
sured. pounding—Sterile Preparations (797), and Good
Compounding Practices (1075)) or when simply dispensing
Special Considerations—If a product is known to be
prescriptions (see Stability Considerations in Dispensing
oxygen sensitive or if it exhibits extreme moisture or light
Practice (1191)).
sensitivity (e.g., cold form foil), it shall not be repackaged. If
a product is refrigerated, it shall not be repackaged unless Correct pharmaceutical calculations can be accomplished
proper environmental conditions and suitable materials are by using, for example, proper conversions from one mea-
available. Certain drug products (such as oncologic agents, surement system to another and properly placed decimal
hormones, or penicillin derivatives) require special handling points, by understanding the arithmetical concepts, and by
because they are considered very potent or toxic, and be- paying close attention to the details of the calculations. Be-
cause transfer of any portion of these products to another fore proceeding with any calculation, pharmacists should do
product could have deleterious effects.B1 the following: (a) read the entire formula or prescription
carefully; (b) determine which materials are needed; and
then (c) select the appropriate methods of preparation and
the appropriate calculation.
BRIEFING
There are often several ways to solve a given problem.
(1160) Pharmaceutical Calculations in Prescription Com- Logical methods that require as few steps as possible should
pounding, page 1658 of PF 26(6) [Nov.-Dec. 2000]. This new
chapter, which previously appeared in Pharmacopeial Previews,
is now forwarded to In-Process Revision with a title change and be selected in order to ensure that calculations are done cor-
editorial changes. This general information chapter provides guide-
lines for calculations commonly used in pharmaceutical com- rectly. The best approach is the one that yields results that
pounding and incorporates the section on Calculations in
Pharmaceutical Compounding—Nonsterile Preparations (795). are accurate and free of error. The pharmacist must double-
The chapter is designed to be a companion chapter to Pharmaceu-
tical Compounding—Nonsterile Preparations (795), Pharmaceu- check each calculation before proceeding with the prepara-
tical Compounding—Sterile Preparations (797) (formerly Sterile
Drug Products for Home Use (1206)), and Good Compounding tion of the article or prescription order. One way of double-
Practices (1075).
checking is by estimation. This involves rounding off the
(CRX: C. Okeke) RTS—33725-1 quantities involved in the calculation, and comparing the es-
timated result with the calculated value.
Add the following: Finally, the following steps should be taken: the dosage of
each active ingredient in the prescription should be checked;
all calculations should be doubly checked, preferably by an-
* (1160) PHARMACEUTICAL
CALCULATIONS IN other pharmacist; and where instruments are used in com-
PRESCRIPTION COMPOUNDING pounding, they should be carefully checked to ascertain

that they will function properly. See USP general chapters
INTRODUCTION Aerosols, Metered-Dose Inhalers, and Dry Powder Inhalers
The purpose of this chapter is to provide general informa-
(601) and Water-Solid Interactions in Pharmaceutical Sys-
tion to guide and assist pharmacists in performing the nec-
tems (1241) for information on specific instruments.
essary calculations when preparing or compounding any
Pharmacopeial Forum
BASIC MATHEMATICAL CONCEPTS A zero in a quantity such as 298.0 mL is a significant figure

and implies that the measurement has been made within the
SIGNIFICANT FIGURES limits of 297.95 and 298.05 with a possible error calculated
Expressed values are considered significant to the last di- as follows:
git shown (see Significant Figures and Tolerances in the
General Notices). Significant figures are digits with practi-
0.05 mL
xl00% = 0.017%
cal meaning. The accuracy of the determination is implied 298.0 mL
by the number of figures used in its expression. In some cal-
culations zeros may not be significant. For example, for a
measured weight of 0.0298 g, the zeros are not significant;
they are used merely to locate the decimal point. In the ex- EXAMPLES—
ample, 2980 g, the zero may also be used to indicate the dec-
1. 29.8 mL = 29.8 ± 0.05 mL (accurate to the nearest 0.1
imal point, in which case the zero is not significant.
mL)
Alternately, however, the zero may indicate that the weight
2. 29.80 mL = 29.80 ± 0.005 mL (accurate to the nearest
is closer to 2981 g or 2979 g, in which case the zero is sig-
0.01 mL)
nificant. In such a case, knowledge of the method of mea-
3. 29.800 mL = 29.800 ± 0.0005 mL (accurate to the
surement would be required in order to indicate whether the
nearest 0.001 mL)
zero is or is not significant. In the case of a volume measure-
ment of 298 mL, all of the digits are significant. In a given The degree of accuracy in the last example is greatest.
result, the last significant figure written is approximate but Thus, the number of significant figures provides an estimate
all preceding figures are accurate. For example, a volume of both of true value and of accuracy.
29.8 mL implies that 8 is approximate. The true volume falls EXAMPLES OF SIGNIFICANT FIGURES—
between 29.75 and 29.85. Thus, 29.8 mL is accurate to the
Measurement Number of Significant Fig-
nearest 0.1 mL, which means that the measurement has been
ures
made within ± 0.05 mL. Likewise, a value of 298 mL is
2.98
accurate to the nearest 1 mL and implies a measurement fall-
2.980
ing between 297.5 and 298.5, which means that the mea-
0.0298
surement has been made within ± 0 . 5 mL and is subject
0.0029
to a maximum error calculated as follows:
Calculations—All figures should be retained until the

0.5 mL
xl00% = 0.17% calculations have been completed. Only the appropriate
298mL
number of significant figures, however, should be retained
in the final result.
Pharmacopeia! Forum
Determining the number of significant figures— pH = -log [H+], and pKa = -log Ka, where [H+] is the
Sums and Differences hydrogen ion concentration in an aqueous solution and Ka
When adding or subtracting, the number of decimal is the ionization constant of the acid in an aqueous solution.
places in the result shall be the same as the number of dec- The [H+] = the antilogarithm of (-pH), and the Ka = the an-
imal places in the component with the fewest decimal tilogarithm of (-pKa).
places. The pH of an aqueous solution containing a weak acid
EXAMPLE— may be calculated using the Henderson-Hasselbalch equa-

tion:
11.5 + 11.65+9.90 = 33.1
pH = pKa + log [salt]/[acid]
Products and Quotients

EXAMPLE—
When multiplying or dividing, the result shall have no
A solution contains 0.020 moles per liter of sodium ace-
more significant figures than the measurement with the
tate and 0.010 mole per liter of acetic acid, which has a pKa
smallest number of significant figures entering into the cal-
value of 4.76. Calculate the pH and the [H+] of the solution.
culation.
Substituting into the above equation, pH = 4.76 + log
EXAMPLE—
(0.020/0.010) = 5.06, and the [H+] = antilogarithm of (-
4.266 x 21 = 90
5.06) = 8.69 x 10~«.
BASIC PHARMACEUTICAL CALCULATIONS

Rounding Off—For rules on rounding off measurements
The remainder of this chapter will focus on basic pharma-
or calculated results, see Interpretation of Requirements un-
ceutical calculations. It is important to recognize the rules
der Significant Figures and Tolerances in the General No-
involved when adding, subtracting, dividing, and multiply-
tices. Note, however, that in the example above, if 21 is an
ing values. The interrelationships between various units
absolute number, e.g., the number of doses, then the answer,
within the different weighing and measuring systems are
89.586, is rounded off to 89.59 which has 4 significant fig-
also important and have to be understood.
ures.
CALCULATIONS IN COMPOUNDING
LOGARITHMS
The pharmacist must be able to calculate the amount or
The logarithm of a number is the exponent or the power to
concentration of drug substances in each unit or dosage por-
which a given base must be raised in order to equal that
tion of a compounded preparation at the time it is dispensed.
number.
Pharmacists must perform calculations and measurements
Definitions—
to obtain, theoretically, 100% of the amount of each ingre-
dient in compounded formulations. Calculations must ac-
pH = -log [H+], and
count for the active ingredient, or active moiety, and water
content of drug substances, which includes that in the che-
pKa = -log Ka
Pharmacopeia! Forum
mical formulas of hydrates. Official drug substances and in which FFis the actual weighed amount; a is the prescribed
added substances must meet the requirements under Loss or pharmacist-determined weight of the active or functional
on Drying (731), which must be included in the calcula- moiety of drug or added substance; b is the chemical formu-
tions of amounts and concentrations of ingredients. The la weight of the ingredient, including waters of hydration for
pharmacist should consider the effect of ambient humidity hydrous ingredients; d is the fraction of dry weight when the
on the gain or loss of water from drugs and added sub- percent by weight of adsorbed moisture content is known
stances in containers subjected to intermittent opening over from the loss on drying procedure (see Loss on Drying
prolonged storage. Each container should be opened for the (731)); and e is the formula weight of the active or func-
shortest duration necessary and then closed tightly immedi- tional moiety of a drug or added substance that is provided
ately after use. in the formula weight of the weighed ingredient.
The nature of the drug substance that is to be weighed and Example 1: Triturate Morphine Sulfate USP and Lactose
used in compounding a prescription must be known exactly. NF to obtain 10 g in which there are 30 mg of Morphine
If the substance is a hydrate, its anhydrous equivalent Sulfate USP for each 200 mg of the morphine-lactose mix-
weight may need to be calculated. On the other hand, if there ture. [NOTE—Clinical dosages of morphine mean Morphine
is adsorbed moisture present that is either specified on a cer- Sulfate USP, which is the pentahydrate.]
tificate of analysis or that is determined in the pharmacy im-
mediately before the drug substance is used by the Equation Factor Numerical Value
procedure under Loss on Drying (731), this information
W weight, in g, of Morphine Sulfate
must be used when calculating the amount of drug sub-
USP
stance that is to be weighed in order to determine the exact
a 1.5 g of morphine sulfate pentahy-
amount of anhydrous drug substance required.
drate in the prescription
There are cases in which the required amount of a dose is b 759 g/mole
specified in terms of a cation [e.g., Li(+), netilmicin (n+)], d 1.0
an anion [e.g., F(-)], or a molecule (e.g., theophylline in e 759 g/mole
aminophylline). In these instances, the drug substance
weighed is a salt or complex, a portion of which represents
the pharmacologically active moiety. Thus, the exact
1.5g(759g/mole)
amount of such substances weighed must be calculated on 1.0(759 g/mole) "
the basis of the required quantity of the pharmacological
moiety.
The following formula may be used to calculate the exact
theoretical weight of an ingredient in a compounded pre-
paration:
W= abide,
Pharmacopeia! Forum
Example 2: Accurately weigh an amount of Aminophyl- 1.39g(282g/mole)

_
line USP to obtain 250 mg of anhydrous theophylline. 0.975 (20.8g/mole)
[NOTE—The powdered aminophylline dihydrate weighed

contains 0.4% w/w adsorbed moisture as stated in the Cer-
tificate of Analysis.]
Example 4: Accurately weigh an amount of Netilmicin
Equation Factor Numerical Value Sulfate USP, equivalent to 2.5 g of netilmicin. [NOTE—
Using the procedure under Loss on Drying (731), the Ne-
W weight, in mg, of Aminophylline
tilmicin Sulfate USP that was weighed lost 12% of its
USP (dihydrate)
weight.]
a 250 mg of theophylline
b 456 g/mole
Equation Factor Numerical Value
d 0.996
e 360 g/mole W weight, in g, of Netilmicin Sulfate
USP
a 2-5 g
b 1442 g/mole
w=250mg(456g/mole) =
0.996 (360g/mole) d 0.88
e 951 g/mole
Example 3: Accurately weigh an amount of Lithium Ci- 2.5g(1442g/mole)

trate USP (containing 2.5% moisture as stated in the Certi- 0.88(951g/mole) '
ficate of Analysis) to obtain 200 mEq of lithium (Li+).

[NOTE—One mEq of Li+ is equivalent to 0.00694 g of Li+.]

BUFFER SOLUTIONS
W weight, in g, of Lithium Citrate
USP (tetrahydrate)
a 200 mEq of Li+ or 1.39 g of Li+ Definition—A buffer solution is an aqueous solution that
b 282 g/mole resists a change in pH when small quantities of acid or base
d are added, when diluted with the solvent, or when the tem-
0.975
e perature changes. Most buffer solutions are mixtures of a
3 x 6.94 g/mole or 20.8 g/mole
weak acid and one of its salts or mixtures of a weak base
Pharmacopeial Forum
and one of its salts. Water and solutions of a neutral salt such EXAMPLE—
as sodium chloride have very little ability to resist the The addition of 0.01 gram equivalents of sodium hydrox-
change of pH and are not capable of effective buffer action. ide to 0.25 liter of a buffer solution produced a pH change of
0.50. The buffer capacity of the buffer solution is calculated
Preparation, Use, and Storage of Buffer Solutions—
as follows:
Buffer solutions for pharmacopeial tests should be prepared
(0.01/0.25)70.50 = 0.08(Eq/L)/(pH change)
using freshly boiled and cooled water (see Standard Buffer
Solutions under Buffer Solutions in Reagents, Indicators,
and Solutions. They should be stored in containers such as
Type I glass bottles and used within three months of pre-
DOSAGE CALCULATIONS
paration..
Buffers used in physiological systems are carefully cho-
Special Dosage Regimens—Geriatric and pediatric pa-
sen so as not to interfere with the pharmacological activity
tients require special consideration when designing dosage
of the medicament or the normal function of the organism.
regimens. In geriatric patients, the organs are often not func-
Commonly used buffers in parenteral products for example
tioning efficiently as a result of age-related pharmacokinetic
are acetic, citric, glutamic, and phosphoric acids and their
changes or disease. For these patients, modifications in dos-
salts and should be freshly prepared.
ing regimens are available in references such as USP Drug
The Henderson-Hasselbalch equation, noted above, al-
Information.
lows the pH of a buffer solution of a weak acid and its salt
For pediatric patients, where organs are often not fully
to be calculated. Appropriately modified, this equation may
developed and functioning, careful consideration must be
be applied to buffer solutions composed of a weak base and
applied during dosing. Modifications in dosing regimens
its salt.
for pediatric patients are also available in references such
Buffer Capacity—The buffer capacity of a solution is
as USP Drug Information. General rules for calculating
the measurement of the ability of that solution to resist a
doses for infants and children are available in pharmacy cal-
change in pH upon addition of small quantities of a strong
culation textbooks. These rules are not drug-specific and
acid or base. An aqueous solution has a buffer capacity of 1
should be used only in the absence of more complete infor-
when 1 liter of the buffer solution requires 1 gram- equiva-
mation
lent of strong acid or base to change the pH by 1 unit. There-
The usual method for calculating a dose for children is to
fore, the smaller the pH change upon the addition of a
use the information provided for children for the specific
specified amount of acid or base, the greater the buffer ca-
drug. The dose is frequently expressed as mg of drug per
pacity of the buffer solution. Usually, in analysis, much
kg of body weight for a 24-hour period, and is then usually
smaller volumes of buffer are used in order to determine
given in divided portions.
the buffer capacity. An approximate formula for calculating
The calculation may be made using the following equa-
the buffer capacity is gram equivalents of strong acid or base
tion:
added per liter of buffer solution per unit of pH change, i.e.,
(Eq /L)/(pH change).
Pharmacopeial Forum
(mg of drug per kg of body weight) x (kg of body weight) PERCENTAGE CONCENTRATIONS
= dose for an individual for a 24-hour period Percentage concentrations of solutions are usually ex-
pressed in one of three common forms:
A less frequently used method of calculating the dose is
based on the surface area of the individual's body. The dose
Volume of solute
is expressed as amount of drug per body surface area in m2, Volume percent (v/v) =
Volume of solution
as shown in the equation below:
(amount of drug per m2 of body surface area) x (body

surface area in m2) = dose for an individual for a 24-hour
period. „, . , . , . N Weight of solutexl00%
Weight percent (w/w) =
Weight of solution
The body surface area (BSA) may be determined from no-
mograms relating height and weight in dosage handbooks.
The BSA for adult and pediatric patients may also be deter-
mined using the following equations: „, . . . . . •/ / \ Weight of solute (ing) .nno/
Weight in volume percent (w/v) = ^———xl00%
BSA (m2) = square root of {[Height (in) x Weight (lb)] / Weight of solution (in mL)
3131}
See also Percentage Measurements under Concentrations in
or
the General Notices. The above three equations may be used
2
BSA (m ) = square root of {[Height (cm) x Weight (kg)]/ to calculate any one of the three values (i.e., weights, vo-
3600}. lumes or percentages) in a given equation if the other two
values are known.
Note that weights are always additive, i.e., 50 g plus 25 g
EXAMPLE—
= 75 g. Volumes of two different solvents or volumes of sol-
Rx for Spironolactone Suspension 25 mg/tsp. Sig: 9 mg
vent plus a solid solute are not strictly additive. Thus 50 mL
BID for an 18 month-old child who weighs 22 lbs.
of water + 50 mL of pure alcohol do not producea volume of
The USPDI2001, 21st ed., states that the normal pediatric
100 mL. Nevertheless, it is assumed that in some pharma-
dosing regimen for Spironolactone is 1 to 3 mg per kg per
ceutical calculations, volumes are additive, as discussed be-
day. In this case, the weight of the child is 22 lbs, which
low under Reconstitution of Drugs Using Volumes Other
equals 22 lbs/(2.2 lbs/kg) = 10 kg. Therefore the normal
than Those on the Label.
dose for this child is 10 to 30 mg per day and the dose or-
dered is 18 mg per day as a single dose or divided into 2 to 4 EXAMPLES—
doses. The dose is acceptable based on published dosing 1. Calculate the percentage concentrations (w/w) of the
guidelines. constituents of the solution prepared by dissolving
2.50 g of phenol in 10.00 g of glycerin. Using the
Pharmacopeial Forum
weight percent equation above, the calculation is as follows. Weight percent of starch = (15 g starch/60 g ointment)
Total weight of the solution = 10.00 g + 2.50 g = 12.50 g. x 100% = 25%.
Weight percent of phenol = (2.50 g x 100%)/12.50 g =
Weight percent of white petrolatum = (30 g white pet-
20.0% of phenol.
rolatum/60 g ointment) x 100% = 50%.
Weight percent of glycerin = (10 g x 100%)/12.50 g =
80.0% of glycerin.
2. A prescription order reads as follows:
SPECIFIC GRAVITY
Eucalyptus Oil 3% (v/v) in Mineral Oil.
The definition of Specific Gravity is usually based on the
Dispense 30.0 mL.
ratio of weight of a substance in air at 25° to that of the
What quantities should be used for this prescription?
weight of an equal volume of water at the same temperature.
Using the volume percent equation above, the calcula-
The weight of 1 mL of water at 25° is approximately 1 g.
tion is as follows.
The following equation may be used for calculations.
Amount of Eucalyptus Oil:
Specific Gravity = (Weight of the substance)/(Weight of an
3% = (VolumeofoilinmL/30.0mL) x 100%
equal volume of water)
Solving the equation, the volume of oil = 0.90 mL.
Amount of Mineral Oil:
EXAMPLES—
To 0.90 mL Eucalyptus Oil add sufficient Mineral Oil to
1. A liquid weighs 125 g and has a volume of 110 mL.
prepare 30.0 mL.
What is the specific gravity?
The weight of an equal volume of water is 110 g.
Zinc oxide 7-5 g Using the above equation, specific gravity = 125 g/110
Calamine 7.5 g g=1.14.
Starch 15 g 2. Hydrochloric Acid NF is approximately 37% (w/w) so-
White petrolatum 30 g lution of hydrochloric acid (HC1) in water. How many
grams of HC1 are contained in 75.0 mL of HC1 NF?
Calculate the percentage concentration for each of the (Specific gravity of Hydrochloric Acid NF is 1.18.)
four components. Using the weight percent equation Calculate the weight of HC1 NF using the above equa-
above, the calculation is as follows. tion.
Total weight = 7.5 g + 7.5 g + 15 g + 30 g = 60.0 g. The weight of an equal volume of water is 75 g.
Specific Gravity 1.18 = weight of the HC1 NF g /75.0 g.
Weight percent of zinc oxide = (7.5 g zinc oxide/60 g Solving the equation, the weight of HC1 NF is 88.5 g.
ointment) x 100% = 12.5%. 3. Now calculate the weight of HC1 using the weight per-
Weight percent of calamine = (7.5 g calamine/60 g oint- cent equation.
ment) x 100%= 12.5%. 37.0 % (w/w) = (weight of solute g/88.5 g ) x 100.

Solving the equation, the weight of the HC1 is 32.7 g.
Pharmacopeial Forum
DILUTION AND CONCENTRATION mg to g. One mg of drug in 1 Og of mixture is the same

A concentrated solution can be diluted. Powders and as 0.001 g in 10 g.
other solid mixtures can be triturated or diluted to yield less Let (g,) = 10 g, (C,) = (1 in 100), and (C2) = (0.001 in
concentrated forms. Because the amount of solute in the di- 10).
luted solution or mixture is the same as the amount in the Using the equation for dilution, lOg x (1/100) = (Q2)g
concentrated solution or mixture, the following relationship x (0.001/10).
applies to dilution problems: Solving the above equation, (Q2) = 1000 g.
The quantity of Solution 1 (£),) x concentration of Solution Because 10 g of the final mixture contains all of the
1 (C,) = the quantity of Solution 2 (Q2) x concentration of drug and some diluent, (1000 g - 10 g) or 990 g of dil-
Solution 2 (C2), or uent is required to prepare the mixture at a concentra-
tion of 0.001 g of drug in 10 g of final mixture.
(QOiCO = (<22)(C2). 3. Calculate the percentage strength of a solution obtained
by diluting 400 g of a 5.0% solution to 800 g.
Almost any quantity and concentration terms may be used.
Let (Q{) = 400 g, (C,) = 5%, and (Q2) = 800 g.
However, the units of the terms must be the same on both
Using the equation for dilution, 400 g x 5% = 800g x
sides of the equation.
(C2)%.
EXAMPLES— Solving the above equation, (C2) = 2.5%.
1. Calculate the amount (Q2), in g, of diluent that must be
added to 60 g of a 10% ointment to make a 5% oint-
ment. USE OF POTENCY UNITS
Let (£>,) = 60 g, (C,) = 10%, and (C2) = 5%. See Units of Potency in the General Notices.
Using the above equation, Because some substances may not be able to be defined
60 g x 10% = (Q2) x 5%. by chemical and physical means, it may be necessary to ex-
press quantities of activity in biological units of potency.
Solving the above equation, the amount of diluent EXAMPLES—
needed, Q2, is 120 g. The initial amount of diluent 1. One mg of Pancreatin contains not less than 25 USP
added was 60 g, and therefore an additional 60g of dil- Units of amylase activity, 2.0 USP Units of lipase activ-
uent must be added to the initial amount to give a total ity, and 25 USP Units of protease activity. If the patient
of 120 g. takes 0.1 g (100 mg) per day, what is the daily amylase
2. How much diluent should be added to 10 g of a tritura- activity ingested?
tion (1 in 100) to make a mixture that contains 1 mg of 1 mg of Pancreatin corresponds to 25 USP Units of
drug in each 10 g of final mixture? amylase activity.
Determine the final concentration by first converting 100 mg of Pancreatin corresponds to 100 x (25 USP
Units of amylase activity) = 2500 Units.
Pharmacopeia! Forum
2. A dose of penicillin G benzathine for streptococcal in- 1 g of testosterone corresponds to 412.6/288.4 g of tes-
fection is 1.2 million units intramuscularly. If Bicillin tosterone cypionate.
L-A contains 1180 units per mg, how many milligrams 60.0 mg or 0.0600 g of testosterone corresponds to
would be in the dose? (412.6/288.4) x .0.0600 = 0.0858 g or 85.8 mg of tes-
1180 units of penicillin G benzathine are contained in 1 tosterone cypionate.
mg.
1 unit is contained in 1/1180 mg.
RECONSTITUTION OF DRUGS USING VOLUMES OTHER
1,200,000 units are contained in (1,200,000 x l)/1180 THAN THOSE ON THE LABEL
units =1017 mg. Occasionally it may be necessary to reconstitute a powder
in order to provide a suitable drug concentration in the final
product. This may be accomplished by estimating the vol-
BASE VS SALT OR ESTER FORMS OF DRUGS ume of the powder and liquid medium required.
Frequently the base form of a drug is administered in an
EXAMPLES—
altered form such as an ester or salt for stability or other rea-
1. If the volume of 250 mg of ceftriaxone sodium is 0.1
sons such as taste or solubility. This altered form of the drug
mL, how much diluent should be added to 500 mg of
usually has a different molecular weight (MW), and at times
ceftriaxone sodium powder to make a suspension hav-
it may be useful to determine the amount of the base form of
ing a concentration of 250 mg per mL?
the drug in the altered form.
Volume of the 250 mg per mL suspension required to
EXAMPLES— contain 500 mg of ceftriaxone sodium powder =
1. Four hundred milligrams of erythromycin ethylsucci-
nate (molecular weight, 862.1) is administered. Deter-
l m L
500 m g x =2mL.
mine the amount of erythromycin (molecular weight, 250 mg
733.9) in this dose.
862.1 g of erythromycin ethylsuccinate corresponds to
733.9 g of erythromycin. Volume of 500 mg of ceftriaxone sodium =
1 g of erythromycin ethylsuccinate corresponds to

(733.9/862.1) g of erythromycin.
5 0 0 m g x ° ' l m L =0.2mL
0.400 g erythromycin ethylsuccinate corresponds to 250 mg
(733.9/862.1) x 0.400 g or 0.3405 g of erythromycin.
2. The molecular weight of testosterone cypionate is
412.6 and that of testosterone is 288.4. What is the dose
Volume of the diluent required = (2 mL of suspension)
of testosterone cypionate that would be equivalent to
- (0.2 mL of Ceftriaxone Sodium) = 1.8 mL.
60.0 mg of testosterone?
288.4 g of testosterone corresponds to 412.6 g of testos- 2. What is the volume of dry powder cefonicid, if 2.50 mL
terone cypionate. of diluent is added to 1 g of powder to make a solution
Pharmacopeial Forum
having a concentration of 325 mg per mL? EXAMPLES—

Volume of solution containing 1 g of the powder 1. How much ointment having a 12% drug concentration
and how much ointment having a 16% drug concentra-
1 mL of solution = 3 tion must be used to make 1 kg of a preparation contain-
1 e of cefonicid x
lg 325 mg of cefonicid
ing a 12.5% drug concentration?
(higher) 16% 0.5 parts of 16%
'12.5%'
Volume of dry powder cefonicid = 3.08 mL of solution (desired)
2.50 mL of diluent = 0.58 mL.

(lower) 12%' ' 1 5 parts of 12%
4.0 parts of 12.5%
ALLIGATION ALTERNATE AND A L G E B R A In a total of 4.0 parts of 12.5% product, 3.5 parts of
12% ointment and 0.5 parts of 16% ointment are
Alligation—Alligation is a rapid method of determining needed.
the proportions in which substances of different strengths 4 parts correspond to 1 kg or 1000 g.
are mixed to yield a desired strength or concentration. Once 1 part corresponds to 250 g.
the proportion is found, the calculation may be performed to 3.5 parts correspond to 3.5 x 250 g or 875 g.
find the exact amounts of substances required. Set up the 0.5 parts correspond to 0.5 x 250 g or 125 g.
problem as follows: 2. How many mL of 20% dextrose in water and 50% dex-
trose in water are needed to make 750 mL of 35% dex-
1. Place the desired percentage or concentration in the
trose in water?
center.
(higher) 50% ^ 15 parts of 50%
2. Place the percentage of the substance with the lower
x
35%
strength on the lower left-hand side. (desired),
3. Place the percentage of the substance with the higher

(lower) 20% 15 parts of 20%
strength on the upper left-hand side. 30 parts of 35%
4. Subtract the desired percentage from the lower percen-
tage, and place the obtained difference on the upper
In a total of 30 parts of 35% dextrose in water, 15 parts
right-hand side.
of 50% dextrose in water and 15 parts of 20% dextrose
5. Subtract the higher percentage from the desired percen-
in water are required.
tage, and place the obtained difference on the lower
30 parts correspond to 750 mL.
right-hand side.
The results obtained will determine how many parts of the
two different percentage strengths should be mixed to pro-
duce the desired percentage strength of a drug mixture.
Pharmacopeial Forum
Thus use 375 mL of the 20% solution and 375 mL of the (20/100)* + (50/100)(750 -x) = (35/100)(750).
50% solution to prepare the product.
Solving the equation, x equals 375 mL of the 20% solution
and (750 -JC) equals (750 - 375) or 375 mL of the 50% solu-
Algebra—Instead of using alligation to solve the above
tion.
problems, algebra may be used, following the scheme out-
lined below.
In order to represent the total amount (weights, parts or
MOLAR, MOLAL, AND NORMAL CONCENTRATIONS
volumes) of the final mixture or solution, 1 or a specified
See Concentrations in the General Notices.
amount is used.
Molarity—The molar concentration, M, of the solution is
Let x be the amount of one portion and [1 (or the specified
the number of moles of the solute contained in one liter of
amount) - x] be the remaining portion. Set up the equation
solution.
according to the statement below, and solve.
Molality—The molal concentration, m, is the number of
The amount in one part plus the amount in the other part
moles of the solute contained in one kilogram of solvent.
equals the total amount in the final mixture or solution.
Normality—The normal concentration, N, of a solution
EXAMPLES— expresses the number of milliequivalents (mEq) of solute
1. How much ointment having a 12% drug concentration contained in one mL of solution or the number of equiva-
and how much ointment having a 16% drug concentra- lents (Eq, gram-equivalent weight) of solute contained in
tion must be used to make 1 kg of a preparation contain- one liter. When using normality, the pharmacist must apply
ing a 12.5% drug concentration? quantitative chemical analysis principles using molecular
Let 1 kg be the total amount of ointment to be prepared, weight (MW). Normality depends on the reaction capacity
let JC be the quantity, in kg, of the 12% ointment, and let of a chemical compound and therefore the reaction capacity
(1 — x) be the quantity in kg of the 16% ointment. The must be known. For acids and bases, reaction capacity is the
equation is as follows: number of accessible protons available from, or the number
of proton binding sites available on, each molecular aggre-
gate. For electron transfer reactions, reaction capacity is the
(12/100) x + (16/100)(l -*) = (12.5/100)(l).
number of electrons gained or lost per molecular aggregate.
Solving the equation, x equals 0.875 kg of the 12% EXAMPLES—
ointment and (1 -x) equals (1 - 0.875) or 0.125 kg of 1. How much sodium bicarbonate powder is needed to
the 16% ointment. prepare 50.0 mL of a 0.07 N solution of sodium bicar-
2. How many mL of 20% dextrose in water and 50% dex- bonate (NaHCO3)? (MW of NaHCO 3 is 84.0 g per
trose in water are needed to make 750 mL of 35% dex- mol.)
trose in water? In an acid or base reaction, because NaHCO3 may act as
Let x be the volume, in mL, of the 20% solution, and let an acid by giving up one proton, or as a base by accept-
(750 -x) be the volume in mL of the 50% solution. The ing one proton, one Eq of NaHCO3 is contained in each
equation is as follows: mole of NaHCO3. Thus the equivalent weight of NaH-
Pharmacopeia! Forum
CO3 is 84 g. [NOTE—The volume, in liters, x normal- MlLLIEQUIVALENTS AND MlLLIMOLES

ity of a solution equals the number of equivalents in the NOTE—This section addresses milliequivalents (mEq)
solution.JThe number of equivalents of NaHCO3 re- and millimoles (mmol) as they apply to electrolytes for do-
quired = (0.07 Eq/L)(50.0 mL/1000 mL /L) = 0.0035 sage calculations.
equivalents. The quantities of electrolytes administered to patients are
1 equivalent weight is 84.0 g. usually expressed in terms of mEq. This term must not be
0.0035 equivalents equals 84.0 g/Eq x 0.0035 Eq = confused with a similar term used in quantitative chemical
0.294 g. analysis as discussed above. Weight units such as mg or g
2. A prescription calls for 250 mL of a 0.1 N hydrochloric are not often used for electrolytes because the electrical
acid (HC1) solution. How many mL of concentrated hy- properties of ions are best expressed as mEq. An equivalent
drochloric acid are needed to make this solution? is the weight of a substance (equivalent weight) that sup-
[NOTE—The specific gravity of concentrated hydro- plies one unit of charge. An equivalent weight is the weight,
chloric acid is 1.18, the molecular weight is 36.46, in g, of an atom or radical divided by the valence of the atom
and the concentration is 37.5% (w/w). Because hydro- or radical. A milliequivalent is one-thousandth of an equiva-
chloric acid functions as an acid and reacts by giving up lent (Eq). Because the ionization of phosphate depends on
one proton in a chemical reaction, 1 Eq is contained in several factors, the concentration is usually expressed in
each mole of the compound. Thus the equivalent millimoles, moles, or milliosmoles which are described be-
weight is 36.46 g.]The number of equivalents of HC1 low. [NOTE—Equivalent weight (Eq.wt) = wt. of an atom or
required is 0.250 L x 0.1 N = 0.025 equivalents. radical (ion) in g/valence (or charge) of the atom or radical.
1 equivalent is 36.46 g. Milliequivalent weight (mEq.wt) = [Eq.wt. (g)]/1000.]
0.025 equivalents correspond to 0.025 Eq x 36.46 g/
EXAMPLES—
Eq = 0.9115 g.
1. Potassium (K+) has a gram-atomic weight of 39.10. The
37.5 g of pure HC1 are contained in 100 g of concen-
valence of K+ is 1+. Calculate its milliequivalent weight
trated HC1.
(mEq wt).
Thus 1 g of pure HC1 is contained in (100/37.5) g
Eqwt = 39.10 g/1 = 39.10 g
=2.666 g of concentrated acid, and 0.9115 g is con-
mEq wt = 39.10 g/1000 = 0.03910 g = 39.10 mg
tained in (0.9115 x 2.666) g or 2.43 g of concentrated
2. Calcium (Ca2+) has a gram-atomic weight of 40.08.
acid.
Calculate its milliequivalent weight (mEq wt).
In order to determine the volume of the supplied acid
Eq wt = 40.08 g/2 = 20.04 g
required, use the definition for specific gravity as
mEq wt. = 20.04 g/1000 = 0.02004 g = 20.04 mg
shown below.
Specific gravity = (weight of the substance)/(weight of
an equal volume of water).
1.18 = 2.43 g/(weight of an equal volume of water).
The weight required is 2.056 g or 2.06 g.
Pharmacopeial Forum
NOTE—The equivalent weight of a compound may be The number of mEq may be calculated as follows.
determined by dividing the molecular weight in g by The mEq wt = Eq wt (g)/1000 = (123.24 g/Eq)/1000 =
the product of the valence of either relevant ion and 0.12324 g.
the number of times this ion occurs in one molecule The number of milliequivalents of magnesium ion in 1
of the compound. g is lg/0.12324 g/mEq = 8.114 mEq.
+
3. How many milliequivalents of potassium ion (K ) are For the sulfate ion:
there in a 250-mg Penicillin V Potassium Tablet? The number of equivalents is calculated as follows:
[NOTE—Molecular weight of penicillin V potassium 246.48/[2(valence) x 1 (number of ions in the com-
is 388.48 g per mol; there is one potassium atom in pound)] = 123.24 g/Eq of sulfate ion.
+
the molecule; and the valence of K is l.]Eq wt = The number of equivalents in 1 g is lg/123.24 g/Eq =
388.48 g/[l(valence) x 1 (number of charges)] = 0.008114 Eq.
388.48 g. The number of mEq may be calculated as follows.
mEq wt = 388.48 g/1000 = 0.38848 g = 388.48 mg. The mEq wt = Eq wt (g)/1000 = (123.24 g/Eq)/1000 =
(250 mg per Tablet)/(388.48 mg per mEq) = 0.644 mEq 0.12324 g.
ofK + per Tablet. The number of milliequivalents of sulfate ion in 1 g is
4. How many equivalents of magnesium ion and sulfate lg/0.12324 g/mEq = 8.114 mEq.
ion are contained in 2 mL of a 50% Magnesium Sulfate 5. A vial of Sodium Chloride Injection contains 3 mEq of
Injection? (Molecular weight of MgSO 4 -7H 2 O is sodium chloride per mL. What is the percentage
246.48 g per mol.) strength of this solution? (Molecular weight of sodium
Amount of magnesium sulfate in 2 mL of 50% Magne- chloride is 58.44 g per mol.)
sium Sulfate Injection = 1 mEq = 1 Eq/1000 = 58.44 g/1000 = 0.05844 g =
58.44 mg.
_ T _T . . 50 g of magnesium sulfate . Amount of sodium chloride in 3 mEq per mL = 58.44

= 2 mL of Inj ection x — = 1 g. mg per mEq x 3 mEq per mL = 175.32 mg per mL.
lOOmLoflnjection
175.32 mg 17532mg 17.532g

Eq wt of MgSO4.7H2O = MW (g)/(valence of specified = 17.5%
lmL 100 mL lOOmL
ion x number of specified ions in one mole of salt).
For the magnesium ion:

The number of equivalents is calculated as follows:
246.48/2[(valence) x 1 (number of ions in the com- Using mols and mmols—
pound)] = 123.24 g/Eq of magnesium ion. A number of countries have adopted the International
The number of equivalents in 1 g is lg/ 123.24 g/Eq = System of Units and no longer calculate doses using mEq
0.008114 Eq. as described above, but instead use the terms moles (mol)
Pharmacopeial Forum
and millimoles (mmol). In USP 25-NF 20, the International many solutions which are isoosmotic with body fluids are
System of Units is used except for the labeling of electro- not necessarily isotonic with body fluids, e.g., a solution
lytes. of urea. Nevertheless many pharmaceutical products are
prepared using freezing point data or related sodium chlo-
Definitions—
ride data to prepare solutions that are isoosmotic with the
A mole equals one gram atomic weight or gram molecular
body fluids. A closely related topic is osmolarity (see
weight of a substance.
Osmolarity (785)).
A millimole equals 1/1000 of a mole.
Freezing point data or sodium chloride equivalents of
EXAMPLES—
Pharmaceuticals and excipients (see Table 1 below) may
1. Potassium (K) has a gram-atomic weight of 39.10. Cal- be used to prepare isoosmotic solutions, as shown in the ex-
culate its weight in millimoles (mmol). amples below.
The weight of one mole is 39.10 g and the weight in

millimoles is 39.10 g/1000 =0.0391 g or 39.1 mg. Table 1. Sodium Chloride Equivalents (E) and Freezing
2. How many millimoles of Penicillin Vare in a tablet that Point (FP) Depressions for a 1% Solution of the Drug or
contains 250 mg of Penicillin V Potassium? (Molecular Excipient
weight of penicillin V potassium is 388.48 g per mol.)
Drug or Excipient FP Depression
The weight of one mole is 388.48 and the weight in
Atropine sulfate 0.13 0.075
millimoles is 388.48/1000 = 0.3848 g or 388.48 mg.
Sodium chloride 1.00 0.576
Thus there are 250 mg/388.48 mg/mmol = 0.644 mmol
of Penicillin V ion per tablet.
EXAMPLE—
Determine the amount of sodium chloride required to pre-
ISOOSMOTIC SOLUTIONS
pare 60 mL of an isoosmotic solution of atropine sulfate
The following discussion and calculations have thera- 0.5% using the sodium chloride equivalent values and also
peutic implications in preparations of dosage forms in- the freezing point depression values.
tended for ophthalmic, subcutaneous, intravenous,

Using the sodium chloride equivalent values—
intrathecal and neonatal use.
The total amount of substances equivalent to sodium chlo-
Cells of the body, such as erythrocytes, will neither swell
ride (for a 0.9% solution) = (0.9 g/100 mL) x 60 mL =
nor shrink when placed in a solution that is isotonic with the
0.54 g.
body fluids. However, the measurement of tonicity, a phy-
The amount of atropine sulfate required = (0.5 g/100 mL) x
siological property, is somewhat difficult. It is found that a
60 mL = 0.3 g.
0.9% (w/v) solution of sodium chloride, which has a freez-
1 g of atropine sulfate is equivalent to 0.13 g of sodium
ing point of- 0.52°, is isotonic with body fluids and is said
chloride.
to be isoosmotic with body fluids. In contrast to isotonicity,
0.3 g atropine sulfate is equivalent to 0.3 x 0.13 g = 0.039 g
the freezing point depression is a physical property. Thus
of sodium chloride.
Pharmacopeial Forum
Vol. 28(2) [Man-Apr. 2002] IN-PROCESS REVISION 491
Thus the required amount of sodium chloride is 0.54 - 0.039 1 mL = 20 drops.

= 0.501 g or 0.50 g. 1.04 mL =1.04 x 20 drops = 20.8 drops.
Thus in 1 minute, 20.8 or 21 drops are administered.
Using freezing point depression values—
2. A 14.5 kg patient is to receive 50 mg of Sodium Nitro-
The freezing point depression required is 0.52°.
prusside in 250 mL of dextrose 5% in water (D5W) at
A 1% solution of atropine sulfate causes a freezing point de-
the rate of 1.3 ug per kg per minute. The set delivers 50
pression of 0.075°.
drops per mL.
A 0.5% solution of atropine sulfate causes a freezing point
Calculate the flow rate in mL per hour.
depression of 0.075° x 0.5 = 0.0375°.
The dose for 1 kg is 1.3 ug per minute.
The additional freezing point depression required is 0.52° -
The 14.5 kg patient should receive 14.5 x 1.3 ug =
0.0375° = 0.482°.
18.85 ug per minute.
A 1% solution of sodium chloride causes a freezing point
50 mg or 50000 ug of drug are contained in 250 mL of
depression of 0.576°.
D5W.
A (1%/ 0.576) solution of sodium chloride causes a freezing
18.85 ug are contained in 250 mL x 18.85/50000 =
point depression of 1°.
0.09425 mL D5W, which is administered every minute.
A (1%/0.576) x 0.482 = 0.836% solution of sodium chlo-
In 1 minute, 0.09425 mL are administered.
ride causes a freezing point depression of 0.482°.
In 1 hour or 60 minutes, 60 x 0.09425 mL = 5.655 or
The required amount of sodium chloride is (0.836 g/100
5.7 mL are administered.
mL) x 60 mL. = 0.502 g or 0.50 g.
Calculate the flow rate in drops per minute.
1 mL provides 50 drops per minute.
0.09425 mL provides 0.09425 x 50 = 4.712 or 4.7
FLOW RATES IN INTRAVENOUS SETS
drops per minute.
Some calculations concerning flow rates in intravenous
sets are provided below. [NOTE—Examples below are not
to be used for treatment purposes.]
TEMPERATURE
EXAMPLES—
The relationship between Celsius degrees (°C) and Fah-
1. Sodium Heparin 8,000 units in 250 mL Sodium Chlo-
renheit degrees (°F) is expressed by the following equation:
ride Injection 0.9% solution are to be infused over 4
9(°O = 5(°F)-160,
hours. The administration set delivers 20 drops per mL.
What is the flow rate in mL per hour? in which °C and °F are the numbers of Celsius degrees and
In 4 hours, 250 mL are to be delivered. Fahrenheit degrees, respectively.
In 1 hour, 250 mL/4 = 62.5 mL are delivered.
EXAMPLES—
What is the flow rate in drops per minute?
1. Convert 77 °F to Celsius degrees.
In 60 minutes, 62.5 mL are delivered.
9(°Q = 5(°/0-160
In 1 minute, 62.5 mL/60 = 1.04 mL are delivered.
°C = [5(°F) - 160]/9 = [(5 x 77) - 160]/9 = 25 °C
Pharmacopeial Forum
number of temperatures recorded. The mean kinetic tem-

2. Convert 30 °C to Fahrenheit degrees.
perature is calculated from average storage temperatures re-
9(°Q = 5(°F)-160
corded over a one-year period, with a minimum of twelve
°F = [9(°C) + 160]/5 = [(9 x 30) + 160]/5 = 86 °F
equally spaced average storage temperature observations
being recorded (see Pharmaceutical Dosage Forms
The relationship between the Kelvin and the Celsius (1151). This calculation can be performed manually with
scales is expressed by the equation: a pocket calculator or electronically with computer soft-
ware.
K=°C+ 273.1,
in which K and °C are the numbers of Kelvin degrees and EXAMPLES—
Celsius degrees, respectively. 1. The means of the highest and lowest temperatures for
52 weeks are 25 °C each. Calculate the MKT.
« = 52
APPLICATION OF MEAN KINETIC TEMPERATURE
AH/R = 10,000 K
See Stability under Pharmaceutical Dosage Forms
Tv T2, ...,Tn = 25 °C = 273.1 + 25 = 298.1 K
(1151) for the definition of mean kinetic temperature
R = 0.0083144 kJK-'mol"1
(MKT). MKT is usually higher than the arithmetic mean
AH = 83.144 kJ per mol
temperature and is derived from the Arrhenius equation.
MKT addresses temperature fluctuations during the storage
period of the product. The mean kinetic temperature,^, is
-AH
calculated by the following equation:
T>,= R
-AH/RTt , -AH/RT2 -AH/RTn
"l H I™ • • • I ' t
-AH n
T = R
e-AH/RTt +e-AH/RT2
-10,000K
in which AH is the heat of activation, which equals 83.144 A////fx298
/ 2xe-
5 '
kJ per mol (unless more accurate information is available 52
from experimental studies); R is the universal gas constant,
which equals 8.3144 x 10~3 kJ per degree per mol; Tx is the
average temperature, in degrees Kelvin, during the first time
period, e.g., the first week; T2 is the average temperature, in
-10,000K
degrees Kelvin, during the second time period, e.g., second
week; and Tn is the average temperature, in degrees Kelvin
52
during the «th time period, e.g., nth week, n being the total
Pharmacopeial Forum
be substituted individually into the equation. The re-

maining two examples illustrate such calculations, ex-
cept that the monthly averages are used]
-10,000K
= 298.1K = 25.0°C
-33.5458 2. A pharmacy recorded a yearly MKT on a monthly ba-
sis, starting in January and ending in December. Each
month, the pharmacy recorded the monthly highest
temperature and the monthly lowest temperature, and
The calculated MKT is 25.0 °C. Therefore the controlled
the average of the two was calculated and recorded
room temperature requirement is met by this pharmacy.
for the MKT calculation at the end of the year.
[NOTE—If the averages of the highest and lowest weekly
temperatures differed from each other and were in the al- From these data the MKT may be estimated or it may
lowed range of 15 °C to 30 °C (see Controlled Room Tem- be calculated. If more than half of the observed tem-
perature under Preservation, Packaging, Storage, and peratures are lower than 25 °C and a mean lower than
Labeling in the General Notices), then each average would 23 °C is obtained, the MKT may be estimated without
performing the actual calculation.
Table 2. Data for Calculations of MKT
Lowest Highest
Tem- Tem- Average Average
perature perature Temperature Temperature
n Month (in °C) (in °C) (in °C) (inK) AH/RT Q-AH/RT
1 Jan. 15 21 294.1 34.002 1.710 x lO-'5

27
2 Feb. 20 25 22.5 295.6 33.830 2.033 x 10-15
3 Mar. 17 25 21 294.1 34.002 1.710 x 10-15
4 Apr. 20 25 22.5 295.6 33.830 2.033 x 10-15
5 May 22 27 24.5 297.6 33.602 2.551 x 10-15
6 June 15 25 20 293.1 34.118 1.523 x IO-15
7 July 20 26 23 296.1 33.772 2.152 x 10-15
8 Aug. 22 26 24 297.1 33.659 2.411 x IO-15

9 Sept. 23 27 25 298.1 33.546 2.699 x IO-15
10 Oct. 20 28 24 297.1 33.659 2.411 x 10-15
11 Nov. 20 24 22 295.1 33.887 1.919 x 10-15

12 Dec. 22 28 25 298.1 33.546 2.699 x 10-15
Pharmacopeia! Forum
a. To estimate the MKT, the recorded temperatures The calculated MKT is 23.0 °C, so the controlled room
are evaluated and the average is calculated. In this temperature requirement is met. [NOTE—These data
case, the calculated arithmetic mean is 22.9 °C. and calculations are used only as an example.]
Therefore, the above requirements are met and it
3. An article was stored for one year in a pharmacy where
can be concluded that the mean kinetic temperature
the observed monthly average of the highest and lowest
is lower than 25 °C. Therefore, the controlled room
temperatures was 25 °C (298.1 K), except for one
temperature requirement is met.
month with an average of 28 °C (301.1 K). Calculate
b. The second approach is to perform the actual cal-
the MKT of the pharmacy.
culation.
n= 12 n= 12
-AH
R -AH
T = -AH/RT, . -AH/RT2 -AH/RT.
R
Tr = -AH/RT, +e-AHfRT2
-10.000K
+ 2.033xl0- 15 +1.710xl0" 15 +... -AH
R
12
-10,000K
12 -10,000K
12
-10,000K
= 296.11K = 23.0°C
-33.771
Pharmacopeial Forum
-10,000K
2.9692xl0" I 4 +3.7705xl0" 1 \ BRIEFING
12 (1186) Shipping and Storage of Labile Preparations, page

9248 of PF25(6) [Nov.-Dec. 1999]. At the July 31, 2001 Packa-
ging, Storage, and Distribution Expert Committee working meet-
ing, the Committee members evaluated and discussed all the
comments received on this general information chapter. The fol-
lowing comments were received:
1. The temperature and humidity conditions specified for testing
the product should correspond with those established and
agreed to in the International Conference on Harmonization
-10,000K (ICH) process, e.g., 40 ± 2° and 75 ± 5% relative humidity.
,3.3463x10"" 2. The statement that "an article must be shipped bearing a
time-temperature indicator" should be removed because
time-temperature monitoring devices are not validated, reli-
12 able, or of high quality.
3. For clarity, revise the following statement under Exemptions:
"shipped and received in not more than 48 hours." This state-
ment does not allow sufficient time to generate the necessary
data. A number of correspondences raised concern with the
48-hour limit in shipping.
4. Manufacturers develop detailed labeling information in con-
sultation with FDA; therefore labeling, storage, and shipping
-10,000K requirements within the chapter are unnecessary.
5. The implementation of documentation tracking will become
/«(2.7886xl0" 13 ) costly and will entail many distribution partners currently
not involved.
6. Some editorial and organizational changes were suggested.
In response, the Expert Committee made the following revi-
sions:
1. The specific test criteria for the different dosage forms in de-
termining whether a product is a Labile Preparation has been
modified to include ICH intermediate testing conditions.
2. The accelerated stability testing conditions have been revised
-10,000K to provide a +2° or ± 5 % acceptability for temperature and
= 298.39K=25.29°C humidity, as indicated.
-33.513 3. The exemption criteria have been slightly revised based on
manufacturers' comments.
4. The use of monitoring devices or insulated packaging is en-
couraged but is subject to the manufacturers discretion. The
Expert Committee is hopeful that implementation of this
chapter in USP 26 will challenge suppliers of these devices
to increase their reliability, which in turn would increase the
The controlled room temperature requirement is not met be- assurance for patients, pharmacists, and within the distribu-
tion system that these products were protected. The Expert
cause the calculated MKT exceeds 25 °C. (See Note in Ex- Committee plans to recommend the adoption of suitable tests
to characterize time-temperature monitors and to pursue the
ample 2 above.)AKSratf issue of affixing devices to outer packing.
5. The Expert Committee believes that the revised proposal con-
cerning the labeling of the beyond-use date period accommo-
dates concerns raised over this issue.
6. As indicated in the General Notices and Requirements, USP
uses the term "Preparation" to mean a drug product, not ex-
cipients or official drug substances. These materials are other-
wise treated in the General Notices and Requirements. No
intent was expressed at the last meeting of the Expert Com-
mittee to pursue these articles in the context of this test.
7. This general chapter is not prescriptive with regard to docu-
mentation tracking; it does encourage communication among
the various participants. Based on our preliminary observa-
tions, the need for documentation tracking would be the unu-
sual situation.
Pharmacopeial Forum
c. Or, for semisolids and heterogeneous liquids, such as

8. Other changes in this proposed chapter are intended to clarify
the content. creams, transdermal systems, gels, emulsions, and sus-
pensions, and for sterile solids for injection: 6 months at
a temperature of 30° and 60% relative humidity in the
market container.
Add the following:
d. Or, for solid oral dosage forms: 30 days at a temperature
A of 25° and 60% relative humidity in an open dish
(1186) SHIPPING AND
STORAGE OF LABILE (namely, container without closure, coil, or desiccant
PREPARATIONS or unsealed blisters).
Labile Preparations (Temperature- or Humidity-Sen- If a preparation does not moot a monograph requirement
sitive Preparations)—An individual preparation is a Labile after exposure to conditions specified for -a; rotost as dirootod
Preparation if, based on lots representative of the marketed for b, c, or d, as appropriate.
product, data indicate the failure of that preparation to con- Exemptions—

form to a monograph requirement after exposure to one of 1. The following preparations are exempt from the above
the following sets of conditions. [NOTE—The dosage forms considerations: those labeled that they must be stored
may be protected from light during the studies.] and transported refrigerated or frozen; labeled radio-
If a preparation does not meet a monograph requirement pharmaceuticals; and those shipped and received in
after exposure to conditions specified under a below, retest not more than 48 hours [48 houro] the time period spe-
as directed for b, c, or d, as appropriate. cified on the outer package, provided data are available
a. For any dosage form: 3 months at a temperature of £7^ to show that the stability of the article is not compro-
te-4©^ 40 ±2° and 95% 75 + 5% relative humidity in mised during that period under the expected conditions
the market container,"1" or 30 ± 2° and 60 ± 5% relative of temperature and humidity.
humidity for 6 months. 2. For classifying a preparation as a Labile Preparation,
b. Or, for solutions: 3 months at a temperature of 37° to the requirements of the test for Uniformity of dosage
40^ 40 + 2° and ambient humidity in the market con- units (905) do not apply.
tainer. Labeling, Storage, and Shipping—Decisions regarding
the labeling of a product as a Labile Preparation are the re-
sponsibility of the packager and are based on the product's
characteristics and stability history.
1. Where data establish that a preparation is a Labile Pre-
paration, the following labeling and shipping arrange-
ments should be considered:
4
a. Shipping the article in a manner that ensures its ef-
~Produoto ontoring multiplo olimatio eonoo (BOO Stability undor Pharma
ooutioal Doaago Forma (1151)) may alao bo toatcd in an open diah for 30 ficacy and safety based on product information,
dayo at a tomperaturo of 30° and 70% relative humidity. For aovoro oondi •
tiono of product diotribution, WHO propoaea the following atrooa tooting packaging data, and the distribution system used.
conditional 30 daya at a temperature of 50° and 75% relative humidity.
Pharmacopeia! Forum
d. Label tho patient's oontainors with a beyond UGO

b. Shipping in suitable insulated packaging.
date of 35 days. Label the patient's container to
c. Shipping* the article with a validated time-tem-
state that the contents should be used within 35
perature monitoring device (see Monitoring De-
days from the first day that the individual container
vices—Time, Temperature, and Humidity (1118)
is opened. The beyond-use period starts on the day
and Packaging, Storage, and Distribution of Phar-
when the patient first opens the individual con-
macopeia! Articles (1141)). The monitoring device
tainer.
is affixed either to the outer shipping package or to
In an institutional setting, store packages of Labile Pre-
the packaging of individual containers (for exam-
parations at controlled room temperature. Packages dis-
ple, for mixed shipments).
pensed for use by a particular patient should bear a
d. Moving unopened packages through the distribu-
beyond-use date of 3 months or 90 days and a statement
tion chain with the monitoring device intact.
"Store at 20°C to 25°C (68°F to 77°F)", unless data support
e. Including instructions that the article is not to be
other labeling, or other manufacturers recommendations are
used if the monitoring device discloses a history
applicable.
of exposure equivalent to more than 48 hours at
For preparations Labile Preparations for which data sup-
or above a temperature of 40°. A manufacturer
port other labeling, beyond-use dates, or exposure equiva-
may make other assurances based on product infor-
lents, the manufacturer should include labeling and
mation and data and on packaging and distribution
information suitable for optimal handling by the practitioner
arrangements.
and the patient. Product development or stability data can be
2. Identifying a Labile Preparation to the pharmacist or
used to determine appropriate labeling and shipping state-
dispensing repackager with appropriate instructions.
ments that will properly inform patients and practitioners.
For example, the labeling of a manufacturer's multi-
Decisions regarding tho labeling of a product as a Labile
ple-unit package (or market repackage) of a humidity-
Preparation are tho responsibility of tho manufacturer and
sensitive Labile Preparation may include one or more
are based on tho produot'o oharaotoristiog and stability his
of the following statements:
tef=y? Related product information for certain challenging
a. Do not dispense more than a 35-day supply of the
distribution situations may be valuable if documentation
prescription in one multiple-unit container.
trails tracking exists. Means of establishing such trails such
b. Dispense it in a tight or Class A container (see
tracking systems should involve all parties taking part in
Containers—Permeation (671)) if it is not dis-
distribution. See a diagram representing the channels of dis-
pensed in a market package.
tribution [To oomo.] under Packaging, Storage, and Distri-
c. "Do not repackage" if the medication is not to be
bution of Pharmacopeial Articles (1141).
repackaged.
When repackagers and pharmacists, including hospital,
emergency medical services, mail service, Internet-based,
^Shipping inoludoa transportation in a common oarrior (for and other practitioners, request information about product
example, through tho mail, including package- express sys
toma) and uninaulatod storage in a vohiolo.
Pharmacopeial Forum
behavior upon exposure to various temperature and humid- Change to read:
ity conditions, pharmaceutical manufacturers are encour-

aged to provide such information.
(4306) STERILE DRUG
PRODUCTS FOR HOME USE
PREPARATIONS PHARMACY
PRACTICES
BRIEFING
(1206) Sterile Drug Products for Home Use, USP 25 page

2234 and page 812 of PF 26(3) [May-June 2000]. In a previous A
revision proposal for this chapter, it was proposed to extend the (797) PHARMACEUTICAL
scope of the chapter to all areas of pharmacy-prepared sterile pre-
parations. At the August 2001 meeting of the USP Expert Commit-
COMPOUNDING—STERILE
tee on Parenteral Products—Compounding and Preparation, it was
decided to propose a change in this chapter's status from an infor-
PREPARATIONS^™
mational chapter to a general tests chapter, making its provisions
mandatory. Therefore, it is proposed to rename the chapter Phar-
maceutical Compounding—Sterile Preparations (797) to corre-
spond with a currently proposed name of a related general tests Change to read:
chapter, Pharmaceutical Compounding—Nonsterile Preparations
(795), which appears elsewhere in this PF. These changes are
partly due to the recommendation of the FDA Advisory Committee A homo U3O storilo drug produot (SP) is a drug product requiring
on Compounding that Sterile Drug Products for Home Use (1206) sterility, such as injootabloo and ophthalmiosv that 13 proparod in
be recognized as the national standard and the guiding chapter on and dispensed from a licensed pharmaoy for intended administra
compounded sterile preparation techniques and practices. Addi- tion by tho patient or by a family member or other oarogivor in a
tional revisions were made on the basis of the FDA Advisory Com- sotting other than an organized, professionally staffed health oaro
mittee's comments. faoility. Tho rosidonoo or other location to which an SP is delivered
The content of the chapter has been reevaluated to reflect its typically is not equipped to ensure injoetablo drug quality as do
proposed mandatory status. Several sections are being extensively 3oribod in this ohaptor and is not under tho direct supervision of
revised, and a couple of new sections are being added. One of these tho dispensing pharmacist.
new sections, Medium-Risk Level, describes medium-risk condi- This ohaptor explains in detail various proooduros necessary to
tions under which sterile preparations may be compounded. An- prepare and dispense sterile drug products intended for homo use:
other new section, Validation of Automated Compounding tho validation of sterilization and asoptio prooossos, tho quality and
Devices for Parenteral Nutrition Compounding, is being added control of environmental conditions for asoptio operations, person
to address the validation of automated compounding devices, nol training, aseptic toohniquos, finished produot release testings
which are widely used by pharmacists in the hospital and other storage, expiration dating and beyond use dating, tho oontrol of
health care settings with the intent to streamline the labor-intensive produot quality beyond tho pharmaoy, patient or oarogivor training,
process involved in compounding of multi-component parenteral patient monitoring and oomplaints, and finally, a quality assurance
nutrition admixtures. program. This information is not prescriptive, nor docs it oxoludo
In view of the extent of this revision proposal, public comments altornato praotioos. However, alternatives whon used should bo
are encouraged and should be addressed to Dr. Claudia Okeke. shown, on the basis of valid evidence; to bo at least as suitable,
effective, and reliable as tho praotioos provided horoin.
(PPC: C. Okeke) RTS—32414-1 A sterile preparation (SP) is a drug produot requiring sterility,
suoh as injootablos and ophthalmioa, that is prepared in and dig
ponsod from a lioonsod pharmaoy for intended administration to
or by tho pationt in an organized, professionally staffed health oaro
faoility or homo oaro sotting.
This ohaptor explains in detail various proooduros nooessary to
prepare, dispense, and oontrol tho post dispensing quality of storilo
preparations. Tho following contents apply equally to sterile pro
ducts for use in an organized health oaro sotting and to thoso in a
homo oaro sotting: tho validation of sterilization and asoptio pro
oossos, tho quality and oontrol of environmental conditions for
asoptio operations, personnel training, asoptio toohniquos, finished
produot roloaso testing, 3torago and expiration dating, and a quality
assurance program. In addition, proooduros necessary to maintain
produot quality and oontrol are explained for both an organized
health care setting and for a homo oaro sotting.
Pharmacopeial Forum
Change to read:
A INTRODUCTION
This chapter provides procedures and requirements for
compounding sterile preparations. Sterile compounding RESPONSIBILITY OF THE DISPENSING
PHARMACIST
must be performed or supervised by a qualified licensed
A pharmacist dispensing any SP ia responsible for ensuring that
healthcare professional, usually a pharmacist or a physician, tho product haa boon prepared, labeled, oontrollod, stored, dig
ponood, and distributed properly. Thia inoludeo tho responsibility
using the appropriate components and ingredients, effective for onauring that tho SP i3 kept under appropriate oontrollod eon
ditiona at tho looation of use and that it is administorod properly
procedures, and accurate measurements in high air-quality through adequate labeling and verbal or writton instructions. Tho
dispensing pharmacist is also roaponsiblo for ensuring that tho SP
environments. Sterile compounding is different from non- retains its quality attributes within aoooptablo limits through a writ
ton quality assurance program. This program should ensure that for
sterile compounding, which is described under Pharmaceu- tho ontiro labeled life of tho produot, or until manipulated by tho
clinician, patient, or oarogivor, tho potonoy, pH, sterility, freedom
tical Compounding—Nonsterile Preparations (795) and from pyrogono, partioulato limits^ container integrity, appoaranoo,
and other qualities or characteristics that tho SP is expected to havo
Good Compounding Practices (1075). do exist. Tho quality assuranoo program should encompass ovory
SP under tho phannaoy's oontrol and includes all phasos of its pro
In this chapter, emphasis is on the quality control of the paration, distribution, storage, administration, and use. Tho dispon
sing pharmacy should employ proper analytical testing; whore
components and processes utilized, the responsibilities and appropriate, to ensure tho microbiological, chemical, and physical
quality of all SPs. Thoso responsibilities apply equally to oommor
performance of compounding personnel, and the environ- oially available injootablo drug products that are dispensed to pa
tiont3 without compounding or other manipulation and to SPo that
mental conditions under which sterile preparations are com- have boon ropaokagod, reconstituted, dilutod, admixod, blended, or
othorwiao manipulated (oollootivoly referred to as "Com
pounded and the associated processes performed. pounded") in any way prior to dispensing. Tho pharmaoist is re
sponsiblo for ensuring that quality i3 built into tho preparation of
Compounded sterile preparations (CSPs) are intended to products, with koy factors inoluding at loast tho following general
principles:
be sterile when administered. For the purposes of this chap- {4}—Porsonnol aro oapablo and qualifiod to porform thoir assigned
ter, CSPs include the following: {3}—Ingrodionts uood in compounding have their oxpootod idon
tity, quality, and purity.
a. Preparations obtained from any manipulation of a man- {3}—Critical processes aro validated to ensure that procedures,
whon uaod, will consistently rosult in tho oxpootod qualities
ufactured sterile product that is not included in the la- in tho finished product.
(1) Tho production environment i3 suitable for its intended pur
beling of the product. pose (addressing such matters as environmental cleanliness,
oontrol, monitoring, and the sotting of action limits, as appro
b. Preparations containing nonsterile ingredients or em-
(5) Appropriate roleaso chocks or testing procedures aro per
ploying nonsterile components and devices that must formed to onsuro that finished produots havo thoir oxpootod
potonoy, purity, quality, and characteristics at tho time of ro
be sterilized before administration.
{6)—Appropriate stability evaluation is performed or determined
c. Biologies, diagnostics, drugs, nutrients, and radiophar- from tho literature for ostabliohing reliable boyond use dating
to ensure that finished produots havo thoir oxpootod potonoy,
maceuticals that possess either of the above two char- purity, quality, and characteristics at Ioa3t until tho labeled bo
yond use dato.
acteristics, and which include, but are not limited to, f?3—There is assurance that processes aro always carried out as
intended or specified and aro undor oontrol.
baths and soaks for live organs and tissues, implants, {&)—Preparation conditions and procedures are adequate for pro
venting mixups.
inhalations, injections, powders for injection, irriga- (9)—There aro adequate procedures and records for investigating
and correcting failures or problems in preparation, testing, or
tions, metered sprays, and ophthalmic and otic prepar- in tho produot itself.
QQ)—There 13 adequate separation of quality oontrol functions and
ations.^,^ decisions from those of production-
Emphasis in this chapter is placed upon tho quality and tho eon
trol of tho processes utilized, porsonnol performance, and the on
vironmontal conditions undor which tho processes aro performed.
Othor factors, suoh as to3ting and stability, aro addressed to tho ox
tent noooaaary for tho limited quantities of produots with relatively
Pharmacopeial Forum
short beyond uoo dating periods normally associated with home 1. Compounding personnel is adequately skilled, edu-
oaro pharmacy praotioo. This ohaptor is not intended to address is
sues concerning the manufacture of sterile drug products. cated, and instructed. Personnel is trained to properly
perform antiseptic hand washing; disinfection of non-
^RESPONSIBILITY OF COMPOUNDING
sterile compounding surfaces; selection and wearing
PERSONNEL
of protective gowns, gloves, and masks; accurate and
Compounding personnel is responsible for ensuring that
aseptic physical manipulations; sterilization of high-
CSPs are accurately identified, measured, diluted, and
risk CSPs; and evaluation of the quality of components
mixed; and correctly purified, sterilized, packaged, sealed,
and ingredients.
labeled, stored, dispensed, and distributed. These perfor-
2. Ingredients have their correct identity, quality, and pur-
mance responsibilities include maintaining appropriate
ity.
cleanliness conditions and providing labeling and supple-
3. Opened, partially used packages of nonsterile bulk in-
mentary instructions for the proper clinical administration
gredients for CSPs are stored under tamper-evident
of CSPs.
conditions in the compounding facility, and evaluated
All CSPs for administration by injection shall meet the
to ensure they retain their correct qualities before each
purity and labeling requirements under Injections (1) and
use.
Particulate Matter in Injections (788). The dispenser shall
4. To minimize the generation of bacterial endotoxins,
ensure CSPs maintain their correct strength within 10% of
water-containing preparations that are nonsterile during
their labeled values, unless a narrower limit is specified in
any phase of the compounding process are sterilized
the official monograph, until either the beyond-use date is
within 4 hours of the initiation of the compounding pro-
reached or the CSP is manipulated for clinical administra-
cess.
tion before the beyond-use date.
5. Sterilization methods achieve sterility of CSPs, main-
A written quality assurance protocol shall include specific
tain the labeled strength of active ingredients, and do
in-process checks for accuracy and precision of measuring
not result in production of toxic substances or damage
and weighing; the requirement for sterility; methods of ster-
to packaging.
ilization and purification; safe limits and ranges for strength
6. Measuring, mixing, and purifying devices are properly
of ingredients, bacterial endotoxins, particulate matter, and
cleaned and validated to be accurate and effective.
pH; labeling accuracy and completeness; beyond-use date
7. Potential harm from added substances and differences
assignment; and packaging and storage requirements. The
in rate and extent of bioavailability of active ingredients
dispenser shall, when appropriate and practicable, obtain
for other than oral route of administration are carefully
and evaluate results of testing for identity, strength, purity,
evaluated before such CSPs are dispensed and adminis-
and sterility before CSP is dispensed. Qualified licensed
tered.
health care professionals who supervise compounding and
8. Packaging is proven to be compatible and effective.
dispensing of CSPs shall ensure that the following objec-
9. While being used, the compounding environment
tives are achieved.
maintains the sterility or the presterilization purity,
whichever is appropriate, of the CSP.
Pharmacopeial Forum
10. Appropriate tests and inspections are performed prior to Change to read:
dispensing to ensure that the CSPs have their labeled

identity, strength, purity, and sterility. RISK LEVELS
11. Beyond-use dates are assigned based on direct testing With reference to tho miorobiologioal quality (i.o., sterility) of
tho finished drug product, an SP, in general, is compounded undor
or extrapolation from reliable literature sources and either relatively low risk or high risk conditions, as determined by
tho potential for tho introduction of miorobial contamination. This
other documentation (see Stability Criteria and Be- contamination may result from the use of nonotorilo components;
novel, complex, or prolonged aseptic processes; or open exposure
yond-Use Dating under Pharmaceutical Compound- of tho drug product or product containment devices to tho atmo-
aphoro. In addition; long storage time between compounding and
ing—Nonsterile Preparations (795)). initiation of administration may affect tho miorobiologioal quality
of tho finished drug product.
12. Procedures for measuring, mixing, dilution, purifica- Tho characteristics itomizod bolow to distinguish between tho
high risk and low risk lovols aro intondod to provido conceptual
tion, sterilization, packaging, and labeling conform to guidanoo and arc not intended to bo prosoriptivo. Tho pharmacist
is expected to exoroiso professional judgment on a case by ease
the correct sequence and quality established for the spe- basis when dotormining tho risk lovol that would bo appropriate
for a particular process.
cified CSP.
13. Deficiencies in compounding, labeling, packaging, and

Low Risk
quality testing and inspection can be rapidly identified
An SP is considered to bo asoptically processed under low risk
and corrected. conditions when all of tho following conditions prevail:
^)—Tho finished product is compounded with commercially
14. Compounding procedures and manipulations are available, sterile drug products.
(3)—Compounding involves only basic, and relatively fow, aooptio
clearly separated from quality testing and inspection. manipulations that aro promptly executed.
{3}—"Closed sy3tom" transfers are used: tho oontainer closure
This chapter emphasizes the need to maintain high stan- system remains essentially intact throughout tho asoptio pro
cess, compromised only by tho penetration of a sterile, pyro
dards for the quality and control of processes, components, gen froo noodle or oannula through tho designated 3toppor or
port to affect transfer, withdrawal, or delivery in accordance
and environments; and skill and knowledge of personnel with tho labolod instructions for tho portinont, commercially
availablo dovioos. Oponod ampuls should bo regarded as if
who prepare CSPs. The rigor of in-process quality-control they aro closed systems for purposes of this chapter.
Examples of low risk processes include tho following:
checks and of postcompounding quality inspection and test- (1) Transferring sterile drug products from vials or ampuls into
sterile final containers using a sterile ncodlo and syringe.
ing increases corresponding to the potential hazard of the {2}—Transferring sterile drug products into storilo olastomorio in
fusion containers with tho aid of a moohanioal pump and an
route of administration. For example, nonsterility and large appropriate 3terilo transfor tubing dovioo, with or without tho
subsequent addition of storilo drug products to tho infusion
strength-of-ingredient errors are more dangerous with intra- container with a sterile noodle and syringe:
{3}—Compounding storilo nutritional solutions by combining Bex
venous injections than with subcutaneous injections. Unlike tmsc Injection and Amino Acids Injection via gravity transfer
into storilo empty oontainors; with or without tho subsequent
the case for nonsterile compounding (see Pharmaceutical addition of storilo drug products to tho final container with a
storilo noodle and 3yringo.
Compounding—Nonsterile Preparations (795)), CSPs such
as total parenteral nutrition and palliative hospice care pre-
High Risk
parations may be necessary in larger quantities for longer
Category I—A high risk SP may fall into oithor of two subolassi
fioations. High risk SPs in Category I aro thoao prepared from
commercially availablo, storilo components whore one or more
of tho following conditions prevail:
(1) Compounding involves tho intermediate closed system pool
ing of sterile drug products. Pooling of additives is defined a3
a highor risk process than performing multiplo single addi •
tivoQ booau3o contamination of tho pool oould result in oon
tamination of units filled from tho pool, thus potentially
causing opidomio infection.
Pharmacopeia! Forum
)—Compounding includes complex and/or numerous aseptic The characteristics described below for low-risk, med-
manipulations oxooutod ovor a prolongod poriod.
)—An individual finished produot is administered as a multi day ium-risk, and high-risk CSPs are intended as a guide to
infusion via a portable pump or reservoir.
Examples of high risk category I processes include the follow the breadth and depth of care necessary in compounding,
Compounding sterile nutritional solutions using an auto but they are neither exhaustive nor prescriptive. The li-
mated compounding device involving ropoatod attachment
of fluid containers to proximal openings of the oompoundor censed health care professionals who supervise compound-
tubing 3Ot and of empty final containers to the distal opening.
The process oonoludog with the transfer of additiveg into the ing are responsible to determine the procedural and
filled final container from individual drug produot containers
or from a pooled additive solution. environmental quality practices and attributes that are nec-
{2)—Preparing ambulatory pump reservoirs by adding more than
one drug produot with tho evacuation of air from the reoorvoir essary for the risk level they assign to specific CSPs.
prior to dispensing.
(3}—Preparing ambulatory pump reservoirs for multi day (i.o:; These risk levels apply to the quality of CSPs immedi-
ambient temperature) administration-
ately after the final aseptic mixing or filling or immediately
Category II—High risk SPs in Category II are those involving
after the final sterilization. Upon subsequent storage and
cither of tho following:
ft)—A nonstorilo drug substance or an inj actable drug produot pro shipping of freshly finished CSPs, an increase in the risks
pared in house from a nonstcrilo substance is used to com
pound tho SP. of chemical degradation of ingredients, contamination from
(2) "Open systems" aro usod, for example, when combining in
gredionts in a nonscalod reservoir before filling or when fluid physical damage to packaging, and permeability of plastic
passes through tho atmosphere during a fill seal operation.
Examples of high risk category II processes inoludo tho follow and elastomeric packaging is expected. In such cases, addi-
iftgr-
ft)—Compounding injeotablo morphine solutions from nonstorilo tional evidence must be obtained to ensure that the intended
morphine substance and suitable vehicles.
(3}—Compounding oterilo nutritional solutions from nonatorilo in quality limits and attributes of the CSP are maintained for
gradients with initial mixing in a nonscalod or nonstorilo re
the particular storage or shipping duration and conditions
throughout the assigned beyond-use date.
A
CSP RISK LEVELS
Low-Risk Level
The appropriate risk level—low, medium, or high—is as-
CSPs compounded under all of the following conditions
signed according to the corresponding probability of con-
are at a low risk of contamination.
taminating a CSP with (1) microbial contamination
Low-Risk Conditions—
(microbial organisms, spores, and endotoxins) and (2) che-
1. The CSPs are compounded entirely under Class 100 air
mical and physical contamination (foreign chemicals and
conditions, only from manufactured sterile products
physical matter). Potential sources of contamination in-
and components, and in a manner other than that in
clude, but are not limited to, solid and liquid matter from
the approved labeling of the products.
compounding personnel and objects; nonsterile components
2. The compounding involves only transfer, measuring,
employed and incorporated before terminal sterilization; in-
and mixing manipulations with closed or sealed packa-
appropriate conditions within the restricted compounding
ging systems that are performed promptly and atten-
environment; prolonged presterilization procedures with
tively.
aqueous preparations; and nonsterile dosage forms used to
compound CSPs.
Pharmacopeia! Forum
3. Manipulations are limited to aseptically opening am- 4. The sterile CSPs do not contain broad-spectrum bacter-
puls, penetrating sterile stoppers on vials with sterile iostatic substances, and they are administered over sev-
needles and syringes, and transferring sterile liquids eral days (for example, an externally worn or implanted
in sterile syringes to sterile administration devices and infusion device).
packages of other sterile products. 5. The CSPs are stored or shipped for periods longer than
4. The CSPs are stored for less than 48 hours at less than 48 hours, at less than 30°, and in locations where they
30° in locations where they are protected from damage are protected from damage before being administered.
before being administered. Examples of medium-risk compounding include the fol-
lowing:
Examples of low-risk compounding include the follow-
1. Compounding of total parenteral nutrition fluids using
ing:
manual or automated devices during which there are
1. Single transfers of sterile dosage forms from ampuls,
multiple injections, detachments, and attachments of
bottles, bags, and vials using sterile syringes with ster-
nutrient source products to the device or machine to de-
ile needles, other administration devices, and other ster-
liver all nutritional components to a final sterile con-
ile containers.
tainer.
2. Manually measuring and mixing no more than three
2. Filling of reservoirs of injection and infusion devices
manufactured products to compound drug admixtures
with multiple sterile drug products, and evacuation of
and nutritional solutions.
air from those reservoirs before the filled device is dis-
pensed.
Medium-Risk Level
3. Filling of reservoirs of injection and infusion devices
When CSPs are compounded aseptically under Low-Risk
with volumes of sterile drug solutions that will be ad-
Conditions, and one or more of the following conditions ex-
ministered over several days at ambient temperatures
ists, such CSPs are at a medium risk of contamination.
between 25° and 40°.
Medium-Risk Conditions—
4. Transfer of volumes from multiple ampuls or vials into
1. Multiple individual or small doses of sterile products
a single, final sterile container or product.
are combined or pooled to prepare a CSP that will be
administered either to multiple patients or to one patient
High-Risk Level
on multiple occasions.
CSPs compounded under all of the following conditions
2. The compounding process includes complex aseptic
are at a high risk of contamination.
manipulations other than the single-volume transfer.
High-Risk Conditions—
3. The compounding process requires unusually long
1. Nonsterile ingredients, including manufactured pro-
duration, such as that required to complete the dissolu-
ducts for routes of administration other than those listed
tion or homogeneous mixing.
under C in the Introduction, are incorporated, or a non-
sterile device is employed before terminal sterilization.
Pharmacopeia! Forum
2. Sterile ingredients, components, devices, and mixtures 4. Assuming, without appropriate evidence or direct de-
are exposed to air quality inferior to Class 100. termination, that packages of bulk ingredients contain
3. Initially nonsterile preparations are terminally steri- at least 95% by weight of their active chemical moiety
lized, but are not tested for sterility (see Sterility Tests and have not been contaminated or adulterated between
(71))- uses.
4. Intravenous solutions prepared using nonsterile ingre- 5. Using manufactured oral dosage forms as the source of
dients and devices are terminally sterilized, but are active ingredients in CSPs.At/5.P2(5
not tested for bacterial endotoxins (see Bacterial Endo-
toxins Test (85)).
5. It is assumed, and not verified by examination of label- VALIDATION
•The sterilization or aseptic processingof an SP ohould bo in ao
ing and documentation from suppliers or by direct de- oordanco with properly designed and validated written proooduros:
The act of validation of a sterilization or aseptic process involvoa
termination, that the chemical purity and content planned testing designed to demonstrate that mioroorganisms will
be effectively destroyed, removed, or prevented from inadvertently
strength of ingredients meet their original or compen- being introduced by personnel or by process related activities.
dial specifications in unopened or in opened packages
of bulk ingredients (see Ingredient Selection under
Sterilization Processes
Pharmaceutical Compounding—Nonsterile Prepara-
A high riak SP prepared from nonatorilo ingredients or oompo
tions (795)). nento should be storilizod uoing an appropriate sterilization pro
cess, such as filtration or heat sterilization. In general, each
6. The CSPs are stored or shipped for periods longer than sterilization process should bo validated to demonstrate suitability
for its intended purpose and specific manner of intended uoos.
48 hours, at less than 30°, and in locations where they
are protected from damage before being administered.
STERILIZATION BY FILTRATION
All nonsterile measuring, mixing, and purifying devices
A atorilizing filtration prooooa ohould bo oapablo of removing
are rinsed thoroughly with sterile, pyrogen-free water, and microorganisms from the liquid SP. Commercially available pro-
storilizod filtration devices should bo certified to bo appropriate
then thoroughly drained or dried immediately before use for human use in storilo pharmaceutical applications^ havo a poro
size of 0.2 um or smaller (generally recognized as a sterilizing fil
for high-risk compounding. All high-risk CSP solutions tor), and have boon lot tested for retention of Pscudomonas dimin
uta at a minimum concentration of 10* organisms per cm' under
are passed through a filter having a 0.45-um nominal poros- spooifiod operating parameters. The individual devices ahould be
tooted for membrane and housing integrity, nonpyrogenioity, and
ity before use when terminal steam sterilization will be em- oxtraotablos by tho manufacturer. Suoh devices should bo capable
of 3torilizing an SP (see Sterilisation and Sterility Assurance of
ployed. Compcndial Articles (1211)). Before uoing suoh devices, tho phar-
macist should thoroughly evaluate their suitability for tho intended
Examples of high-risk compounding include the follow- SP and conditions of use.
Tho sizo and configuration of filtration dovioos should aooom
ing: modato tho volume being filtered to permit complete filtration
within a roaoonablo period of time and without ologging to tho
1. Dissolving nonsterile bulk drug and nutrient powders to point where mid prooo33 filter ohangoo would bo required.
Filtoro and aooooiatod doviooo and apparatuo (housing, gaslcoto;
make solutions, which will be terminally sterilized. oto:) should bo physically and chemically compatible with tho pro
duet to bo filtered and should bo capable of withstanding tho tern
2. Exposing sterile ingredients, components, devices, and poraturoo, prooouroo, and hydrostatic otros303 imposed on tho
oyotem. Thooo capabilities are to bo ootablishod through 'appropri-
preparations to ambient environments in which air ate produot opooifio tooting. To ootabliah compatibility, tho phar
maoy may rely on vendor certification or on definitive evidence;
quality is significantly inferior to Class 100. opeoifio to produot and filter, obtained from a oritioal review of
tho literature or from reliable unpublished roaoaroh.
3. Measuring and mixing sterile ingredients in nonsterile Validation should bo ootablishod experimentally-for-all filtration
apparatuo involving aooombly in tho pharmaoy of tho mombrano
devices before sterilization is performed. (filtration medium) into its housing or holder. Tho pharmacy may
Pharmacopeial Forum
roly on vondor oortifioation of validation for oommoroially avail

ablo prostorilizod roady to uao filter doviooa or for pharmaoy ao VALIDATION OF COMPOUNDING
aomblod apparatu3. (The sterilization process used for pharmaoy
assembled apparatus must bo proporly validated.) When initially ACCURACY AND S T E R I L IZATION
selecting a oommoroially available, atcrilo, pro assembledfilterdo
vioo, tho pharmacist should onauro that tho vondor hao validated tho The compounding procedures and sterilization methods
filter for the intended conditions of use and that an adequate ohal
longo was used (minimum concentration of 10* organisms Pscudo for CSPs shall correspond to correctly designed and vali-
monas diminuta per em* of filter 3urfaoo). Validation should
encompassthe filtration apparatus and configuration, duration of dated written documentation in the compounding facility.
filtration, filtration operating conditions (filtration rate and torn
poraturo), and tho critical product formulation parameters (pH, Validation requires planned testing designed to demonstrate
viscosity, ionic strength, and oomolarity) usod to generate tho 3up
plied data arc representative of tho pharmaoy'3 product, apparatus, effectiveness of all procedures critical to the accuracy and
specified operating paramotors, oto.; in regard to the faotora that
might physically or ohomioally alter filter integrity, affect miorobial purity of finished CSPs. For example, sterility testing (see
capture moohanisms, or shrink tho mioroorganism during filtration-
Each filter device usod for product sterilization should bo Test Procedures under Sterility Tests (11)) may be applied
cheeked for integrity at tho time of uso. Integrity testing of oom
moroially available, sterile, solf contained filter dovioos requiring to specimens of low- and medium-risk CSPs, and standard
no prouso assembly may bo porformod at tho conclusion of tho fil
tration process. Filter integrity tost kits suitable for phannaoy uoo nonpathogenic bacterial cultures may be added to nondis-
(for example, thoao consisting of a small gauge and a three way
stopcock assembly) aro oommoroially available for testing tho bub pensable specimens of high-risk CSPs before terminal ster-
bio point of small disk typo filters. For pharmaoy assembled appa
ratu3, ao defined above, prefiltration integrity tooting ia ilization for subsequent evaluation by sterility testing.
recommended in addition to po3tfiltration testing. Quantitative in
togrity testing, such as tho bubble point or forward flow tests (000 Packaged and labeled CSPs are visually inspected for phy-
Sterilization and Sterility Assurance of Compendia! Articles
(1211)) should bo U3od, aa appropriate for larger filtration devices sical integrity and expected appearance, including final fill
or when Category II high risk SPs aro sterilized.
Filtration should bo porformod in accordance with written pro amount. To ensure that the identities and concentrations of
ooduros that list those filters determined to bo acceptable for tho
various SPs to bo filtorod in tho pharmaoy or in aooordanoo with ingredients are accurate, and in the absence of reliable ob-
master batoh formulas that include definitive filter specifications.
Filtration procedures and master batch formulas should also do servations and data to confirm and extrapolate those para-
aoribo acceptable techniques for using and for chocking tho intog
rity of all liotod filtors. Fluid filter compatibility must bo meters, samples of CSPs are assayed.
established prior to the filtration of any SP not included in tho pro
Sterilization Methods
HEAT STERILIZATION The licensed health care professionals who supervise
Terminal sterilization should bo used whon sterilizing Category compounding are responsible to determine that the selected
II high risk SPs. Sterilization may bo accomplished in tho final
sealed container as a validated, oontrollod moist hoat proooss sterilization method (see Methods of Sterilization under
(000 Sterilisation and Sterility Assurance of Compcndial Articles
(1211)). In tho absence of hoat sterilization capabilities, or where Sterilization and Sterility Assurance of Compendial Articles
hoat labile drug products or oontainor closure systems preclude
hoat sterilization, an SP may bo sterilized by filtration and asepti (1211)) both sterilizes and maintains the strength, purity,
oally processed and oontrollod in aooordanoo with tho standards sot
forth in this chapter. quality, and packaging integrity of CSPs. The selected ster-
Hoat sterilization prooosao3 should bo validated to ensure that
tho likelihood of survival of tho most resistant mioroorganisms ilization process should achieve a 0.0001% probability, or
likely to constitute product bioburden is no greater than 10"* under
the specified operating conditions and parameters, 3uoh as sterili no more than one chance in one million opportunities, that
zation time and temperature, size and nature of load, and chamber
loading configuration. Tho validation and monitoring of hoat stor viable bacterial vegetative forms and spores will remain in
ilization prooos3O3 should bo in writing with all critical paramotors
specified, should bo followed oaoh time of use, and should bo su CSPs. General guidelines for matching CSPs and compo-
porviood by a pharmacist knowledgeable of tho technology in
volvcd in tho sterilization of drug produots. Monitoring data nents to appropriate sterilization methods include the fol-
ahould bo rooordod proporly to ensure, retrospectively, that tho pro
cesses were carried out as specified and that all critical paramotors lowing:
were within specified limits during processing.*
j
~PDA Technical Monograph No. 1, Validation of Steam Sterilisation Cy
Pharmacopeia! Forum
1. Colloidal fluid dispersions, emulsions, solutions, and used. Sterilizing filters with 0.2-um and 0.45-um nominal
suspensions that have been proven to remain physically porosities will not remove bacterial endotoxins and viruses
and chemically stable in their containers are sterilized by physical retention.
by steam sterilization. The supervising health care professional must ensure, di-
2. Glass and metal devices may be covered tightly with rectly or from appropriate documentation, that thefiltersare
aluminum foil, then exposed to dry heat in an oven at chemically and physically stable at the pressure and tem-
a mean temperature of 250° for 2 hours to achieve steri- perature conditions to be used, and that the filters will
lity and depyrogenation (see Dry-Heat Sterilization un- achieve sterility and maintain prefiltration pharmaceutical
der Sterilization and Sterility Assurance of Compendial quality of the specific CSP. The filter dimensions and mate-
Articles (1211)). Such items are either used immedi- rial shall permit the sterilization process to be completed ra-
ately or stored until use in an environment suitable pidly without the replacement of the filter during the
for compounding low- and medium-risk CSPs. process. When CSPs are known to contain excessive pani-
3. Solutions may be filtered through sterile membranes culate matter, a prefilter or larger porosity membrane should
having 0.2-jxm nominal porosity, which includes be placed upstream from the sterilizing filter to remove
0.22-um porosity. It must be demonstrated, by testing gross particulate contaminants, so as to maximize the effi-
or by documentation from appropriate sources, that ciency of the sterilizing filter.
CSPs to be sterilized by microporous membrane filtra- When sterilizing filter devices are assembled from sepa-
tion will retain their intended physical quality attri- rate components by compounding personnel, such as-
butes, such as emulsion droplet-size limits, and their sembled devices are tested to validate their sterility and
full strength of all ingredients. sterilizing effectiveness under relevant conditions before
they are used to process CSPs. For example, a standard non-
pathogenic bacterial culture may be combined with a sterile,
STERILIZATION BY FILTRATION
growth-promoting fluid medium, filtered under aseptic con-
Commercially available sterile filters should be approved
ditions into an evacuated sterile vial, and incubated to ob-
for human use applications in sterilizing pharmaceutical
serve for turbidity that indicates colonization or for clarity
fluids. Both filters that must be sterilized before processing
that indicates sterility. On the other hand, when commer-
CSPs and commercially available, disposable, sterile, pyro-
cially available, sterile, disposable filter devices are used,
gen-free filters shall have a nominal porosity of 0.2 jam,
the compounding personnel may accept the written certifi-
which includes 0.22-um porosity. They should be certified
cation from suppliers that the units retain at least 107 micro-
by the manufacturer to retain at least 107 microorganisms of
organisms of the strain of Pseudomonas diminuta on each
a strain of Pseudomonas diminuta on each cm2 of upstream
cm2 of filter surface. In both cases, the sterile filters are
filter surface under conditions similar to those in which the
tested under conditions of duration, fluid flow rate, osmolar-
CSPs will be sterilized. In emergency situations when sterile
ity, pH, pressure, process sequence, solvent composition,
0.2-um porosity membranes are not available, filters of the
temperature, and viscosity that are similar to those of the
same composition and 0.45-um nominal porosity may be
CSP to be sterilized. Large deviations from the CSP chemi-
Pharmacopeial Forum
cal and physical characteristics carry risk of not disclosing tion under Sterilization and Sterility Assurance of
damage to filter integrity or shrinkage of microorganisms to Compendial Articles (1211)). To achieve sterility, it is nec-
less than the nominal filter-porosity limit. essary that all materials be exposed to steam at 121°, under a
Except in a medical emergency, the integrity of sterilizing pressure of about one atmosphere or 15 pounds per square
filters must be ensured before CSPs subjected to sterilization inch, for the duration proven by testing to achieve sterility of
by filtration are dispensed. In cases when sterility testing of the items, which is usually 20 to 60 minutes for CSPs. An
either a single CSP or a statistical sample of multiple units of allowance must be made for the time required for the mate-
a CSP (see Methods of Sterilization under Sterilization and rial to reach 121° before the sterilization exposure duration
Sterility Assurance of Compendial Articles (1211)) will be is timed.
employed after sterilizing filtration, the negative result of Items that are not directly exposed to pressurized steam
that testing shall be construed to mean that the filter integrity may result in survival of microbial organisms and spores.
was maintained. Before their sterilization, plastic, glass, and metal devices
Sterile, commercially available sterilizing filter devices are tightly wrapped in low particle shedding paper or fab-
for use on handheld syringes may be checked by feeling rics, or sealed in envelopes that prevent poststerilization mi-
for greater resistance on the plunger when filtering air after crobial penetration. Immediately before filling ampuls and
an aqueous fluid has been filtered. Immediately following vials that will be steam sterilized, solutions are passed
sterilization by filtration, a standard nonpathogenic bacterial through filters having 0.45-um nominal porosities. Sealed
culture in a sterile, growth-promoting fluid medium may be containers must be able to generate steam internally; thus,
passed through the same filter under aseptic conditions into stoppered and crimped empty vials must contain a small
an evacuated sterile vial, and incubated to observe for tur- amount of moisture to generate steam. For small items
bidity and for clarity (see Test Procedures under Sterility and vials, in the absence of an autoclave, a household pres-
Tests (71)). In the absence of a standard nonpathogenic bac- sure cooker may be used, provided the effectiveness of the
terial culture, a swab from a human mouth or palm that has sterilization duration has been previously validated.
not been disinfected within the past 12 hours may be intro- The description of steam sterilization conditions and
duced into the sterile, growth-promoting fluid medium (see duration for specific CSPs is included in written documen-
Test Procedures under Sterility Tests (71)); and then filtered, tation in the compounding facility. The effectiveness of
incubated, and evaluated as described. steam sterilization is validated by sterility testing of nondis-
pensable samples to which a standard nonpathogenic bacte-
STEAM STERILIZATION rial culture was added. 1 In the absence of a standard

The process of thermal sterilization employing saturated nonpathogenic bacterial culture, a swab from a human
steam under pressure, or autoclaving, is the preferred meth- mouth or palm that has not been disinfected within the past
od to terminally sterilize aqueous preparations that have 12 hours may be introduced into the nonsterile CSP, fol-
been proven to maintain their full chemical and physical sta- lowed by steam sterilization and by sterility testing (see Test
bility under the conditions employed (see Steam Steriliza- Procedures under Sterility Tests {71)).AUSp26
1
PDA Technical Monograph No. 1, Validation of Steam Sterilization Cy-
cles, 1978.
Pharmacopeial Forum
Change to read:
Minimum Validation Requirements
High Risk
A A
Low- and Medium- CSPs*AUSP26
Validation
Purpose Risk CS?sAUSP26
ASEPTIC PROCESSING
Failure Revali- 3 consecutive media-fill 3 consecutive media-
All aseptic processing operations and configurations should be dation runs without contamina- fill runs without con-
adequately established by media-fill validation? Media fills should tion tamination
simulate as closely as possible actual aseptic operations. All ma-
nipulations, handling, environmental conditions, and other factors NOTE—Personnel should have first passed low fiolc
likely to influence the risk of process-associated contamination
should be represented by the media-fill simulations. The intensity A
low- and mediu
of such challenges should represent the greatest risk that would be validation.
expected during normal production. Media-fill validations should
be repeated with sufficient frequency to ensure the ongoing cap- Change to read:
ability of performing properly each aseptic processing operation
used in the pharmacy
Authorized facility.Aas.w<$
The frequency and results of media-fill runs should be documen- LOW-RISK OPERATIONS
ted. A
The culture medium selected should be capable of supporting A quality assurance program should include a system
the growth of abroad spectrum of microorganisms likely to be pro- that incorporates validation and monitoring processes that
duction-associated contaminants in the pharmacy. ensure a compounded sterile preparation meets predeter-
Authorized facility.AUSP2S mined, specific criteria of quality.Al/SP2(5
Commercially available media can be obtained that, when recon- The primary objective of the validation of aseptic processing invol-
stituted as directed by the manufacturer, are certified to have
growth-promoting properties. Soybean-Casein Digest Medium is ving low-risk operations is to ensure that personnel are capable of
acceptable (see Sterility Tests (71)). Incubation of medium-filled using effective aseptic technique to compound an SP successfully
units should take at least 14 days and may be at room temperature under the most rigorous conditions encountered during normal
for 14 days or may be at room temperature for the first 7 days, with
the final 1 to 7 days at 30° to 35°. Alternate suitable incubation work assignments. In oarrying out validation of the prooosa; por
schedules may be used as determined by the pharmacy to ensure 3onnol should perform
enough growth of any potential contaminating microorganisms to A
be visually detectable. Microorganisms in all medium-filled units The validation program should include a system of proofs
showing visible evidence of microbial growth should be promptly
identified, and if this growth exceeds the action limits, an immedi- that show that processes and operators are appropriate for
ate investigation should be made with prompt correction of any
identifiable causes of the failure. Review of environmental moni- achieving predefined product-quality conditions and per-
toring data obtained during the media fill should be included in the
investigation, as well as a review of the cleaning, sanitizing, disin- sonnel have skills to perform those compounding activities
fection, production procedures, aseptic technique, personnel prac-
tices, and other factors as appropriate. Revalidation should occur reproducibly and repeatedly. The validation of the process
after all media-fill failures (see Table 1).
media fills consisting of a planned repetitive sequence of com-
Table 1. pounded or repackaged units. The number of manipulations of
each unit and the number of units in each media fill should reflect
Validation of Aseptic Processing the most complex and prolonged aseptic manipulations likely to be
encountered by an operator as a normal workload requirement. The
Minimum Validation Requirements number of units per media-fill run should be enough to ensure that
the operator is capable of replicating acceptable aseptic procedures.
High Risk A sampling plan and validation requirements (aoo Table 1) should
A A fee
Low- and Medium- CSPs* 1USP26
Validation AUSP26
Purpose Risk defined in written procedures. Media transfers could be used to re-
General Personnel validation Process validation present procedures such as syringe transfers, use of automated
Initial 3 consecutive media-fill 3 consecutive media- compounding devices, multiple additive procedures, and various
runs without contamina- fill runs without con- aseptic assemblies and connections. An example of a validation
tion tamination procedure for low-risk operations is as follows.
Revalidation 1 media-fill run quar- annual media-fill run
terly without contamina- without contamina- Scenario—A pharmacy prepares antibiotics, hydration solu-
tion tion tions, and parenteral nutrition solutions, for homo uso. The moat
oomplox and prolonged asoptio manipulations arc required for
FDA Guideline on Sterile Drug Products Produced by Aseptic Proces- tho parontoral nutrition solutions. Tho paronteral nutrition oolution
sing, June 1987, pp. 20-27; PDA Technical Monograph No. 2, Validation is mado by combining tho amino aoid and doxtroso by gravity
of Aseptic Filling for Solution Drug Products, 1980. transfer into 2 liter empty flexible bags, and thon adding a maxi
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] JN-PROCESS REVISION 509
A
mum of 10 additivos to a bag via syringo transfer. Typically, tho evidence of contamination before resuming preparation of
pharmacy proparoo no moro than a 2 or 3 woolc gupply of tho solu
tiona at one timo.
for patients. Operators should also be re validated if the nature of
A
Low-risk CSP processing would include the reconstitution their aseptic compounding assignments changes to the extent that
their previous media fills are not representative of their revised as-
and preparation of antibiotics for administration of single signments.
A
units at set intervals. Many of these products are prepared Quality assurance programs for low-risk CSPs also in-
in batches and stored in anticipation of future use. Operators clude a system that employs routine methods to ensure that
should be trained and their techniques validated using a ster- the finished products are reviewed for compounding accu-
ile culture medium to simulate the syringe transfer of diluent racy and potential hazards, such as particulate matter, micro-
to reconstitute lyophilized antibiotics, the transfer of that organisms, pyrogens, allergens, and cross-contamination
product to an empty sterile bag, bottle, or syringe; and from other drugs that may have been introduced into the
any other manipulations that may be routine in the admix- compounding environment. Final products are inspected
ture processes.AUSras for particulate matter and leakage before release. A predeter-
Example of a Validation Procedure—Ono hundred mL of ator mined percentage of compounded products could be se-
ilo Soybean Casein Digest Medium is tranoforrod via gravity into
plaatio bags: Twonty units are oomplotod in this mannor, to approx questered for routine sterility and pyrogen testing.
imato tho number of units typically compounded at one time. After
all twenty unita have boon filled, tho media containers are lined up Allergens and cross-contamination are best controlled
in pairs. Ono mL of media is drawn from ono container and trans
forrod aseptioally by syringo transfer to another media unit and re through the strict adherence to proper procedures, which
poated for a total often transfers. Then modia from tho other unito
is oyringo transferred to tho first unit for a total often syringe trans limit or eliminate the introduction of the allergens, and to
fors. This process is continued until all twenty units have under
gone ten syringe transfers. Tho modia fill units are incubated at frequent cleaning to reduce the potential of lingering drug
room tomporaturo for a total of fourtoon days, with froquont ohooks
for growth: residues in the work area. Personnel are trained in the proper
A
Six 25-mL aliquots of sterile Soy-Casein Digest Medium methods of eliminating allergens and cleaning and disinfect-
are aseptically transferred to separate, empty 30-mL sterile ing the workstation. That training is reviewed periodical-
vials. Ten milliliters of sterile Soy-Casein Digest Medium is ly- A VSP26
removed from one of the vials and added to a vial of sterile, Add the following:
lyophilized Polyethylene Glycol. Four 2.5-mL aliquots of
the resulting solution are added to 30-mL vials already con- ^MEDIUM-RISK OPERATIONS
taining 25-mL sterile Soy-Casein Digest Medium, and the In the case of medium-risk CSPs, procedures and manip-
vials are labeled. The six 30-mL vials are incubated at room ulations employed in the preparation processes may be more
temperature for a total of 14 days, with frequent checks for complex than those for low-risk operations, and because
growth.AUSWtf long-term storage may be required, more stringent require-
Media fills should be representative of peak periods of fatigue,
stress, and pacing demands. For example, media fills could be ments for quality control and quality assurance are appropri-
scheduled immediately after normal production activity has ended.
Media fills should not be performed during normal production. ate. The more complex and prolonged aseptic manipulations
Operators should pass an initial validation, performing three
media fills with no contamination, before they are allowed to malco are required for parenteral nutrition solutions. Quality assur-
^compound CSPsAl/sw<f
ance programs for medium-risk operations include all as-
for patients. Subsequently, each operator should perform at least pects of the low-risk CSP program and also include
one media fill involving low-risk operations quarterly. If one con-
taminated unit results from a media fill, the operator should be revalidation processes that simulate medium-risk conditions.
trained and then perform three consecutive media fills with no
contaminated unit before again being allowed to compound SPs
Pharmacopeial Forum
Scenario—A pharmacy prepares hydration solutions and during production involving the process being validated. However,
the fill volume of media-fill units need not equal the fill volume of
parenteral nutrition solutions. The parenteral nutrition solu- finished product units.
A media-fill run should be performed at least annually for each
tion is prepared by combining amino acid solution and dex- unique high-risk batch processing procedure and configuration. A
media-fill failure for most homo oaro
trose solution by gravity transfer into empty flexible bags,
AUSP26
and then several additives are introduced into the bag by sy- operations (less than 1000 units) is one or more contaminated units
after incubation. For batches equal to or greater than 1000 units, a
ringe transfer. The pharmacy prepares no more than a 2- or media-fill failure is greater than one contaminated unit. When a
media-fill failure occurs, three consecutive successful media fills
3-week supply of the solutions at one time. should occur before the process failing the media fill may be used
for the preparation of a CSP for patients. An example of a valida-
Example of a Validation Procedure—One hundred tion procedure for a high-risk operation is as follows:
milliliters of sterile Soybean-Casein Digest Medium is Scenario—A pharmacy prepares individual cassettes of mor-
phine for epidural use from morphine powder. The nonsterile pow-
transferred via gravity into empty flexible bags. Twenty der is weighed, and then placed in the barrel of a 60-mL syringe.
After replacing the syringe plunger, sterile 5% dextrose solution is
units are completed in this manner, to approximate the num- drawn into the syringe to make a total volume of 50 mL. After
shaking to dissolve the powder, a 0.22-um disk filter is placed
ber of units typically compounded at one time. After all on the syringe, and the solution is pushed through the filter into
a drug reservoir cassette for an ambulatory infusion pump. Typi-
twenty units have been filled, the media containers are cally, the pharmacy prepares a week's supply of two to three cas-
settes at one time.
aligned in pairs. One milliliter of the medium is drawn from
Example of a Validation Procedure—A small quantity of an
one container and transferred aseptically by syringe transfer inert powder (for example, lactose or sugar) is placed in the barrel
of a 60-mL syringe. After replacing the syringe plunger, sterile 5%
to the other medium unit of the pair for a total of 10 syringe dextrose solution is withdrawn into the syringe to make a total vol-
ume of 50 mL. A sterile 0.22-um filter is connected to the syringe
transfers. The media-fill units are incubated at room tem- tip. After shaking to dissolve the powder, the solution is pushed
through the filter: the first 5 mL are aseptically introduced into a
perature for a total of 14 days, with frequent checks for test tube containing 10 mL of sterile Soybean-Casein Digest Med-
ium; the next 40 mL are discarded in a sterile container; and the last
growth. AVSP26 5 mL are aseptically introduced into another tube containing 10 mL
of sterile Soybean-Casein Digest Medium. At least three syringes
Change to read: should be evaluated in this manner. The inoculated tubes of Med-
ium should be incubated at 20° to 25° for 14 days, with frequent
visual observations made for growth of microorganisms.
HIGH-RISK OPERATIONS Change to read:

In the case of high-risk operations, the focus of validation is on
the process as well as personnel capability. Thus, the primary ob-
jective of the validation of aseptic processing for high-risk CSP ENVIRONMENTAL QUALITY AND CONTROL
operations is to ensure that the aseptic process is capable of being
carried out consistently under control by any qualified operator, be- Achieving and maintaining sterility and overall freedom from
fore the process is utilized for production of units intended for ad- contamination of a pharmaceutical product is dependent upon the
ministration to patients. Accordingly, each type of high-risk quality status of the components incorporated, the process utilized,
personnel performance, and the environmental conditions under
which the process is performed. The standards required for the en-
lS
AUSP26 vironmental conditions depend upon the amount of exposure of the
validated independently, rather than having operators perform re- CSP to the immediate environment anticipated during processing.
presentative sets of aseptic activities, as is the case with low-risk The quality and control of environmental conditions for low riak
A
and and high riok oporationo
aseptic operations. A
Personnel assigned to high-risk aseptic operations should be va- each risk level of operation . ^ t f
lidated for low-risk is explained in this section. In addition, operations using nonsterile
components require the use of a method of preparation designed to
A
and medium-riskA[/5.Wfi produce a sterile product.
operations as described above. In addition, this personnel should
participate, at least annually, in the validation of each high-risk
aseptic operation to which they are assigned.
For example, for high-risk operations involving nonsterile com- Critical Site Exposure
ponents, the media-fill run should simulate as closely as possible
the most intensive conditions likely to be encountered during the The degree of exposure of the product during processing will be
normal production activities. The number of units in a media-fill affected by the length of time of exposure, the size of the critical
run should be no less than the largest number of units encountered site exposed, and the nature of the critical site.
Pharmacopeia! Forum
A critical site is any opening providing a direct pathway between tho Buffer Room. Howovor, unito can bo installed to draw in frooh
a sterile product and the environment or any surface coming in di- outside air through an HEPA filter and provido positive air proa
rect contact with the product and the environment. The risk of such sure, but they oannot bo movable:
a site picking up contamination from the environment increases Tho direction of flow may bo horizontal or vertical. (A auitablo
with time of exposure. Therefore, the processing plan and the in- biological aafoty cabinet with vertical airflow should bo used for
tent of the operator should give due consideration to organization, prooosoing oytotoxio and othor hazardous agonto to protoot the op
efficiency, and speed in order to keep such exposure time to a mini- orator ao woll a3 tho product.) The air quality within tho LAFW
mum. For example, an ampul should not be opened unnecessarily adjacent to oritioal oitos should moot a M3.5 (Class 100) oloan
in advance of use. room specification during normal work aotivity. (Soo Table 2 for
The size of the critical site affects the risk of contamination en- tho definition of clean room olasoeo.)
tering the product: the greater the exposed area, the greater the risk. Tho environmental quality within the Buffer Room should bo
An open vial or bottle exposes to contamination a critical site of domonstrably better than that of adjacent areas, ouoh as tho main
much larger area than the tip of a 26-gauge needle. Therefore, pharmaoy, to roduoo tho risk of contaminants boing blown,
the risk of contamination when entering an open vial or bottle is dragged, or otherwise introduced into tho LAFW. For oxamplo,
much greater than during the momentary exposure of a needle tip. strong air currents from briefly opened doors, poroonnol walking
The nature of a critical site also affects the risk of contamination. past tho LAFW, or tho airatream from tho heating, ventilating,
The relatively rough, permeable surface of a rubber and air conditioning (HVAC) system oan oaaily oxoood tho volooity
A
of oloan air from tho LAFW. Also, operators introducing supplies
an elastomericûsp^ into tho LAFW or reaching in with their arms oan drag oontami
closure retains microorganisms and other contaminants, after nanto along with thooo movements.
swabbing with an alcohol pad, more readily than does the smooth Tho level of cleanliness of tho air in tho Buffer Room, in eon
glass surface of the neck of an ampul. Therefore, the surface dis- junction with tho expertise of tho operator, i3 oritioal to maintaining
infection can be expected to be more effective for an ampul. tho M3.5 (Class 100) conditions within tho LAFW. Tho air entering
A tho Buffer Room should bo froah, HEPA filtered, oonditionod air.
Once the ampul is open, the critical site of exposure is Tho air in tho Buffer Room should moot tho roquiromcnts for at
least a M6.5 (Class 100,000) (ooo Table 2) oloan room for low risk
greatly increased, creating a pathway with the potential operations and a M5.5 (Class 10,000) for high riok oporations. In
addition to cleaning tho inflowing air and providing at loaot 10 air
for introduction of glass, fiber, and dust into the fluid con- changes per hour, cooling is essential because of tho continual
buildup of hoat from the circulation of air through tho blower
tained in the ampul. .VSp26 and HEPA filter of tho LAFW. It should bo noted that tho oiroula
The prevention or elimination of airborne particles must be gi- tion of air from tho Buffer Room through tho HEPA filter of tho
ven high priority. Mobile or LAFW onhanoos tho eloanlinosa of tho air, particularly during non
• U30 periods.
4.USP26
Airborne contaminants are much more likely to reach critical sites
than contaminants that are adhering to the floor or other surfaces
below the work level. Further, particles that are relatively large or
of high density settle from the airspace more quickly and thus can
be removed from the vicinity of critical sites. A
Clean Rooms and Barrier Isolators
In general, sterile product preparation facilities utilize la-
ENVIRONMENTALLY CONTROLLED
minar airflow workbenches (LAFWs) to provide an ade-
WORKSPACES
quate critical site environment. A discussion of the
LAFW AND-BUFFER-ÔOM
necessary facilities and proper procedures for preparing ster-
An onvironmontally oontrollod workopaoo suitable for tho asep
tio processing of an SP consists of a ouitably oonstruetod, properly ile products using LAFWs in clean rooms is presented be-
functioning, and regularly certified device, which swoops tho
workopaoo or an entire room with HEPA filtered air at a velocity low. The use of alternative systems in clean rooms that have
of 90 foot per minuto ± 20%, suoh as a laminar airflow workbench
(LAFW). Such a workspace is required for both low risk and high been validated to achieve the same or better level of envir-
riok oporationa. Tho air blower for tho workspace should bo opor
atod without interruption in ordor to owoop tho workspaoo oontinu onmental quality as that achieved by properly operated
ally. Since tho airflow volooity is relatively gentle, an LAFW muot
bo located in an onvironmontally controlled room or a spaeo other LAFWs may also be utilized. An emerging alternative tech-
wise ooparatod from loss oontrollod work aroasj such as tho main
pharmaoy, by partitions, plaatio curtains^ or preferably, a solid wall. nology utilizes barrier isolator systems to minimize the ex-
Hereinafter, this area surrounding an LAFW shall bo called tho
"Buffer Room." (Figuiv 1 shows an example of a floor plan for tent of personnel contact and interaction, to separate the
an onvironmontally oontrollod workspace and adjacent areas, as a
basio for illustrating tho following dioouasion.) Cloan and sanitized external environment from the critical site, and to provide
supplies may bo aooumulatod and stored for a limited period of
time in the Buffer Room in ordor to bo conveniently available a suitable M3.5 (Class 100) clean air environment at the cri-
for uoo in preparing produoto in tho LAFW.
Sinoo an LAFW i3 normally a self contained unit, tho air oirou tical site for preparing sterile products. A well-designed po-
latod is drawn from tho Buffer Room and does not oontributo frosh
air. Thoroforo, suoh a unit doos not oroate positive air pressure in sitive pressure barrier isolator, supported by adequate
Pharmacopeial Forum
procedures for its maintenance, monitoring, and control, ap- zontal flow clean benches, vertical flow clean benches, bio-
pears to offer an acceptable alternative to the use of conven- logical safety cabinets, and barrier isolators. Primary
tional LAFWs in clean rooms for aseptic processing. engineering control must provide an M3.5 (Class 100) en-
vironment. (See Table 2 for a review of SI designations and
Environmental Controls class limits.) Secondary engineering controls generally pro-
Engineering controls reduce airborne contamination po- vide a buffer zone or buffer room as a core for the location of
tential in workspaces by limiting the amount and size of the workbenches or isolators,
contaminants in the CSP processing environment. Primary
engineering controls are used and generally include hori-
Table 2. Class Limits in Particles per Cubic Meters and Cubic Feed.
(Actual Particle sizes may be equal to or greater than those shown)*

Class Name Measured Particle Size
U.S. 0.1 um 0.2 um 0.3 um 0.4 (am 0.5 um
SI Customary (m3) (ft3) (m 3 ) (ft3) (m3) (ft3) (m3) (ft3) (m3) (ft3)
M1.5 Class 1 1,240 35 265 7.50 106 3.0 35.3 1.00
M2.5 Class 10 12,400 350 2,650 75.0 1,060 30.0 353 10.0 — —
M3.5 Class 100 . 26,500 750 10,600 300 3,530 100 — —
M4.5 Class 1,000 — — — — — — 35,300 1,000 247 7.0
M5.5 Class 10,000 — — — — — — 353,000 10,000 2,470 70.0
M6.5 Class 100,000 — — — — — — 3,530,000 100,000 24,700 700
The class limits shown in this Table are defomed for classification purposes only, and do not necessarily represent the size distribution that could be found in any particular
situation. Adapted from the Federal Standard No. 209E, General Services Administration, Washington, DC 20407 (September 11, 1992).
Airflow through high-efficiency particulate air (HEPA) In general, the CSP work environment is designed to have
filters is unidirectional or columnar, and because of the pore the cleanest work surfaces (horizontal or vertical clean
size of the filter the "first air" at the face of the filter is, for benches, biological safety cabinets, or isolators) located in
the purposes of aseptic sterile preparation (SP) compound- a buffer area, which is preceded by an anteroom that pro-
ing, free from airborne particulate contamination. Barrier vides a clean area for donning personnel barriers, such as
isolators provide a suitable environment by restricting any hair covers, gloves, gowns, or full clean-room attire. The
ambient air from the work chamber. These systems are not class limit of the buffer or core room has to be demonstrably
as sensitive to external environments as the HEPA-filtered better than that of ambient air to reduce the risk of contami-
unidirectional airflow units. nants being blown, dragged, or otherwise introduced into
Several aspects of barrier isolation and filtered unidirec- the filtered unidirectional airflow environment. For exam-
tional airflow in work environment must be understood ple, strong air currents from opened doors, personnel traffic,
and practiced in the SP compounding process. Policies or air streams from the heating, ventilating, and air-condi-
and procedures for maintaining and working in the pre- tioning systems can easily disrupt the unidirectional, colum-
scribed conditions for aseptic processing must be prepared, nar airflow in the open-faced workbenches. The operators
updated, maintained, and implemented and are determined may also introduce disruptions in flow by their own move-
by the scope and risk levels of the activities undertaken in ments and by the placement of objects onto the work sur-
the SP compounding operation. face.
Pharmacopeial Forum
The class limit of the air in the buffer area, in conjunction from contaminating substances, while permitting supplies and per-
sonnel to enter the area from relatively uncontrolled storerooms,
with the expertise of the operator, is critical to maintaining from the main pharmacy, or from administrative areas. Access
should be strictly limited to only designated, qualified personnel.
the M3.5 (class 100) conditions within the workstation. The The number of personnel in the buffer area at any one time should
not exceed those essential to perform the required tasks.
air entering the buffer area should be fresh, HEPA-filtered, An anteroom or other separated area should be available for the
decontamination of supplies, equipment, and personnel before they
conditioned air. The air in the buffer area should meet the enter the buffer area. (This decontamination area is hereafter re-
ferred to as the Anteroom
requirements for at least an M6.5 (Class 100,000) clean A
and the buffer area as the Buffer Room,AUSP2<f
room for low- and medium-risk operations and for at least as shown in Figure 1.) The size of the room should be sufficient to
accommodate this activity with the heaviest work load anticipated.
an M5.5 (Class 10,000) clean room for high-risk operations. Minimally this would require space for two or more carts and space
for personnel to clean, sanitize, and transfer supplies from the
Appropriate air-conditioning and humidity controls should stockroom cart to the clean room cart. A floor demarcation should
identify the maximum distance into the room that stockroom carts
be in place for the buffer area.AUyw<$ can penetrate.
Tasks carried out within the buffer area should be limited to
those for which a controlled environment is necessary. Only the
furniture, equipment, supplies, and other goods required for the
tasks to be performed may be brought into this room, and they Shelving
should be nonpermeable, nonshedding, and resistant to disinfec-
tants. Whenever such items are brought into the room, they should
first be cleaned and sanitized. Whenever possible, equipment and
other items used in the buffer area should not be taken from the
room except for calibration, servicing, or other activity associated Buffer Room
with the proper maintenance of the item.
The surfaces of ceilings, walls, floors, fixtures, shelving, coun- ©
ters, and cabinets in the buffer area should be smooth, impervious,
free from cracks and crevices, and nonshedding, thereby promot-
ing cleanability and minimizing spaces in which microorganisms Counter
and other contaminants may accumulate. The surfaces should be
Shelving
resistant to damage by sanitizing agents. Junctures of ceilings to
walls should be coved or caulked to avoid cracks and crevices
where dirt can accumulate. If ceilings consist of inlaid panels, Table
the panels should be impregnated with a polymer to render them
impervious and hydrophobic, and they should be caulked around Air Dryer .
each perimeter to seal them to the support frame. Walls may be of Sink—p"
panels locked together and sealed or of epoxy-coated gypsum
board. Preferably, floors are overlaid with wide sheet vinyl flooring Anteroom
with heat-welded seams and coving to the sidewall. Dust-collect- Coat *
Hooks
ing overhangs, such as ceiling utility pipes, or ledges, such as win-
dowsills, should be avoided. The exterior lens surface of ceiling
lighting fixtures should be smooth, mounted flush, and sealed.
Any other penetrations through the ceiling or walls should be Shelving Uniform
sealed. Storage
The buffer area should contain no sinks or floor drains. Work
surfaces should be constructed of smooth, impervious materials,
such as stainless steel or molded plastic, so that they are readily
cleanable and sanitizable. Carts should be of stainless steel wire
or sheet metal construction with good quality, cleanable casters
to promote mobility. Storage shelving, counters, and cabinets Fig. 1. Example of a floor plan. (Encircled letters are suggested
should be smooth, impervious, free from cracks and crevices, non- environmental sampling sites.)
shedding, cleanable, and sanitizable. Their number, design, and
manner of installation should promote effective cleaning and sani- The Anteroom should also be designed for uncartoning and dis-
tizing. infecting large-volume injection (LVI) bottles, pouches of hypo-
dermic syringes, ampuls, vials, pouches of LVI bags, transfer set
packages, and other required supplies. Here, also, carts for use in
the Buffer Room should be cleaned and disinfected.
ACCESS CONTROL TO THE BUFFER ROOM AND One or more sinks and a forced air hand dryer or disposable non-
shedding towels should be available near the entrance door to the
ANTEROOM Buffer Room so that personnel can scrub their hands and arms be-
fore donning hair covers, shoe covers, clean gowns, and face
Access to the buffer area should be planned and strictly con- masks. After donning hair and shoe covers, foamed alcohol may
trolled because of the need to protect the aseptic operations per- be used to resanitize the hands. Faucet handles should be designed
formed in an LAFW so that they can be shut off with the elbows or feet. An alternate
A
a suitably controlled enviroment procedure being used increasingly is to disinfect the hands and
arms with a foamed alcohol, or other effective sanitizer, instead
of scrubbing with detergent and water. The hot air hand dryer is
Pharmacopeial Forum
then not needed. A means of demarcation should be provided be- contamination. Alternatively, if supplies are planned to be received
tween the Buffer Room side and the general entry side of the Ante- in sealed pouches, the pouches can be removed as the supplies are
room to enhance the gowning procedure. One option, a movable introduced into the Buffer Room without the need to sanitize the
bench (preferably of stainless steel), shown in Figure 1, provides individual supply items. No shipping or other external cartons may
a barrier and place for personnel to sit down to don shoe covers just be taken into the Buffer Room. Cleaning and sanitizing of the
before entering the Buffer Room. A storage area for clean gowning Anteroom should be performed at least weekly by trained and su-
supplies should be conveniently located nearby. The door into the pervised custodial personnel, in accordance with written proce-
Buffer Room should remain automatically, positively closed and dures. However, floors are cleaned and sanitized daily, always
capable of being opened with elbow hooks or other means without proceeding from the Buffer Room to the Anteroom. Storage shel-
using clean hands. The Anteroom should be designed to reduce to ving should be emptied of all supplies and cleaned and sanitized at
as low as possible the risk of recontamination of cleaned and sani- planned intervals, preferably monthly.
tized supplies and personnel prior to entry into the Buffer Room. These cleaning and sanitizing procedures apply to both low-risk
An Anteroom as just described is necessary for high-risk opera- and high-risk operations.
tions. For low-risk operations, a carefully controlled area adjacent
to the Buffer Room but without rigid walls may be acceptable.
However, essentially the same attention for organization and clean-
liness of the anteroom area is to be given in conjunction with both Personnel and Gowning
high-
A Personnel are critical keys to the maintenance of asepsis when
, medium-, AUSnp carrying out their assigned responsibilities. They must be thor-
and low-risk operations. oughly trained in aseptic techniques and be highly motivated to
maintain these standards each time they prepare a sterile product.
Prior to entering the Buffer Room, operators should remove out-
er lab jackets or the like, makeup, and jewelry and should thor-
Cleaning and Sanitizing the Workspaces oughly scrub hands and arms to the elbow. After drying hands
and arms they should properly don clean, nonshedding uniform
The cleaning, sanitizing, and organizing of the LAFW components, including hair covers, shoe covers, knee-length coats
SCE.USP26 or coveralls, and Qtorilo latox
should oe the responsibility of trained operators (pharmacists and Appropriate sterile protectiveAas.P2(5
technicians) following written procedures and should be performed gloves, in that order. The coats should fit snugly at the wrists and be
at the beginning of each shift. All items should be removed from zipped or snapped closed in the front. Shoe covers should be
the LAFW donned so that feet then touch the floor only on the clean side of
SCEAUSP26 the bench or other demarcation. Face masks should be donned just
and all surfaces wiped clean with a freshly prepared mild detergent prior to beginning work at the horizontal LAFW,
followed by an approved sanitizing agent,3 allowing sufficient time SCE,AUSP26
for the agent to exert its antimicrobial effect. The chosen sanitizing as talking, sneezing, or coughing normally generates an air velocity
agent should be rotated with one of a different action at least quar- that exceeds the velocity of air from the LAFW.
terly. Recleaning should be performed if spillage or other events
indicate the need. A W S P 2<?
Work surfaces near the LAFW When working at a vertical LAFW,
SCEAUSP26 SCE,Ai/SP2s
in the Buffer Room should be cleaned in a similar manner, includ- the wearing of a mask is optional where a solid transparent shield
ing counter tops and supply carts. Storage shelving should be emp- establishes a physical barrier between the face of the operator and
tied of all supplies and then cleaned and sanitized at least weekly, the workspace. However, any facial hair should be completely cov-
using approved agents. ered in all instances.
Floors in the Buffer Room should be cleaned by mopping once Storilo latex
daily when no aseptic operations are in progress. Mopping may be A
performed by trained and supervised custodial personnel using ap- Appropriate sterile protective AUSP26
proved agents described in the written procedures. Only approved gloves should be put on, aseptically—being sure to protect the out-
cleaning and sanitizing agents should be utilized, with careful con- er surfaces from contamination—as the last uniform component.
sideration of compatibilities, effectiveness, and inappropriate or Latox glovoo are
toxic residues. Their schedules of use and methods of application A
The gloves must beAUSP26
should be in accord with written procedures. All cleaning tools, effective in containing oacteria, skin scales, and other particles
such as wipers, sponges, and mops, should be nonshedding and shed by the most scrupulously scrubbed hands. However, the outer
dedicated to use in the Buffer Room. Floor mops may be used in sterile
both the Buffer Room and the Anteroom, but only in that order.
Most wipers should be discarded after one use. If cleaning tools g A U S P 2 6
are reused, their cleanliness should be maintained by thorough rin- surfaces do not remain sterile since they will contact the room air,
sing and sanitization after use and by storing in a clean environ- sanitized supply items, work counters, and other surfaces that,
ment between uses. Trash should be collected in suitable plastic while clean, are not sterile. Therefore, operators must perform
bags and removed with minimal agitation. aseptic manipulations in a manner designed to prevent touching
In the Anteroom, supplies and equipment removed from ship- critical sites with the gloved fingers or hands. Further, operators
ping cartons should be wiped with a sanitizing agent, such as sterile should attempt to maintain gloved hand surfaces as free from con-
70% isopropyl alcohol (IPA)4 , which is checked periodically for tamination as possible by repeated rinsing with a sterile sanitizing
3
agent, such as IPA, during use.
Approved by the pharmacist in charge. Storilo latox
4 A
NOTE—70% isopropyl alcohol (IPA) may harbor resistant microbial Appropriate sterile protectiveAUS.W6
spores. Therefore, IPA used in aseptic areas should always be filtered
through a 0.2-um hydrophobicfilterto render it sterile.
Pharmacopeial Forum
gloves must be worn when operator protection as well as product AUSP26

protection is essential, such as during operations involving cyto- prepared and brought into the Buffer Room, preferably on one
toxic or otherwise hazardous sterile products. or more movable carts. Supplies that are required for back-up
Proper scrubbing and gowning immediately prior to entry into or general support of operations may be stored on the desig-
the Buffer Room is required of all personnel, without exception. nated shelving in the Buffer Room, but excessive accumula-
Should the operator find it necessary to leave the room, the coat tion of supplies should be avoided.
may be carefully removed at the entrance and hung inside out (6) Objects that shed particles ahould not
for redonning upon re-entry, but only during the same shift. How- A
ever, hair covers, masks, shoe covers, and gloves should be dis- cannot USP26
carded and new ones donned prior to re-entry. be brougnt into the Buffer Room, including pencils, card-
For high-risk operations, it is especially critical to minimize the board cartons, paper towels, and cotton items.
risk of contamination on lab coats, coveralls, and other garb to be A
worn in the Buffer Room. Preferably, fresh clean garb should be Only nonshedding paper-related products (boxes,
donned upon each entry into the Buffer Room to avoid liberating
contaminants from previously worn garb. Alternatively, garb that work records, and so forth) can be brought into the
has been worn may be removed with the intention of regarbing for
re-entry into the Buffer Room and stored during the interim under Buffer Room. AUSP26
proper control and protection in the Anteroom. Garb worn or taken (7) Traffic flow in and out of the Buffer Room
outside the confines of the Anteroom should not be worn in the A
Buffer Room. has to be,
'AUSP26
Dispersion of particles from body surfaces, such as from skin minimized.
rashes, sunburn, or cosmetics, increases the risk of contamination (8) Personnel preparing to enter the Buffer Room should
of critical sites and should be appropriately controlled or mini- A
mized. If severe, the operator should be excluded from the Buffer have to.aSP26
Room until the condition is remedied, especially for high-risk op- remove all jewelry from hands and arms.
erations. (9) Personnel entering the Buffer Room should
A
have to*usp26
first scrub nands and arms with soap, including using a scrub
Suggested Standard Operating Procedures brush on the fingers and nails. An air dryer or disposable non-
shedding towels should bo
The pharmacy should have written, properly approved standard are
operating procedures (SOPs) designed to ensure the quality of the ALOT2<5
environment in which a CSP is prepared. The following procedures used to dry hands and arms after washing.
are recommended: (10) Personnel entering the Buffer Room, after scrubbing, should
(1) Access to the Buffer Room should bo don attire as described under Personnel and Gowning.
(11) No chewing gum, candy, or food items may be brought into
A.USP26
the
restricted to qualified personnel with specific responsibilities A
Anteroom o
or assigned tasks in the area. Buffer Room.
(2) All cartoned supplies ahould bo
(12) At the beginning of each shift and when spillage occurs, the
TAClli
T3nnr
Al/SW6
decontaminated in the Anteroom by removing them from A
SCE_A.USP26
shipping cartons and wiping surface
A
or s p r a y i n g ^ ™
with a disinfecting agent, such as sterile IPA, while being AlfSP26
transferred to a clean, sanitized cart or other conveyance for wiped with a clean, nonlinting wiper or sponge dampened
introduction into the Buffer Room. Individual pouched sup- with distilled water. The entire inside of the LAFW should
plies need not be wiped because the pouches can be removed
as these supplies are introduced into the Buffer Room. A
SCE is thenAmP26
(3) Supplies required frequently or otherwise needed close at wiped with another clean wiper wet with an approved disin-
hand but not necessarily needed for the scheduled operations
of the shift should bo fectant, such as IPA.
(13) The blower of the LAFW ahould bo
areAUSP26 SCE IS^SP^
i
decontaminated and stored on the shelving in the Anteroom. operated continuously. However, in the event of a long period
(4) Carts used to bring supplies from the storeroom ohould not of nonuse, the blower may be turned off and tho opening oov
crod with a plastio ourtain or othor shield.
cannotAuSP26
be rolled oeyond the demarcation line in the Anteroom, and A
carts used in the Buffer Room ahould not access to the Buffer Room is prohibited.Al/5.Wd
Before reuse, all internal surfaces ahould bo
be rolled outward beyond the demarcation line unless cleaned AUSP26

and sanitized before returning. sanitized and the blower operated for a minimum of 30 min-
(5) Generally, supplies required for the scheduled operations of utes or as individual testing or studies support.
lllw o i l 1 XL rfTiT7TriTT"""T7\?
Pharmacopeial Forum
(14) Traffic in the area of the LAFW ohould bo Environmental Control and Monitoring Program
oCfci IS»(JSP26 Because achieving or maintaining sterility is essential in the pre-
minimized and controlled. The LAFW ahould bo paration of sterile products, the assessment of the level of control of
the environment in which those products are prepared is rooom
l 4
shielded from all less clean air currents that are of higher ve-
locity than the clean laminar airflow. required.. c/5P ^
(15) Supplies to be utilized in the LAFW The level of environmental control achieved may be evaluated by
measuring the viable and the total (viable and nonviable) number
of particles in the environment. Viable particle counting is recom-
AySp26
mended for environmental assessment. Total particle counting is
for the planned procedures recommended for facility classification.
areAUSP26 Viable particle counts are indicative of the portion of the total
accumulated and then decontaminated by wiping particle counts that represent microorganisms, normally reported
as colony-forming units (cfu), since typical viable particle counting
A
or spraying AKSM , results do not distinguish between single microorganisms and clus-
the outer surface with IPA or removing the outer wrap at the ters. The difficulties in obtaining consistent and quantitative
edge of the LAFW growth of microorganisms and the time lag between sampling
and obtaining results because of growth time are important envir-
ÛSP26
onmental monitoring limitations.
as the item is introduced into the aseptic work area. Total particle counts are usually performed by means of electro-
(16) After proper introduction into the LAFW nic instruments that give results instantly, based upon the measure-
ment of particles in a prescribed volume of air. Clean room
SCEJ.(JSP26 classifications (see Table 2) are based upon such measurements.
of supply items required for and limited to the assigned opera- A number of different types of instruments are available. Measure-
ments can be made one at a time, or, with most instruments, auto-
matically obtained on a planned, ongoing schedule. Instantaneous
AUSP26
results permit assessment of environmental particulates at any gi-
so arranged that a clear, uninterrupted path of HEPA-filtered ven time and permit rapid changes in the control program should
air will bathe all critical sites at all times during the planned the results indicate a problem. However, these results do not dis-
procedures. That is, no objects may be placed behind an ex- tinguish between viable and nonviable particulates.
posed critical site in a horizontal position or above in the ver- This section focuses on the measurement and monitoring of pro-
tical laminar flow workbench. grams for viable particles.5
(17) All supply items should bo arrangod in tho LAFW
A
are arranged in the SCE so asAUsP26
to reduce clutter and to provide maximum efficiency and or- TESTING PROGRAM
der for the flow of work.
(18) All procedures should bo A testing program is based upon the use of various methods for
collecting an environmental sample on a nutrient, usually solid,
AUSK(J culture medium, incubating at a temperature and for a time period
performed in a manner designed to minimize the risk of touch conducive to the multiplication of any collected microorganisms,
contamination. Gloves ahould bo and then counting the discrete colonies that have developed on the
surface of the medium. The count, reported as cfu, is a measure of
?AUSP26 . microbial contamination of the environment at the time and under
sanitized with adequate frequency the conditions of sampling.
A
In general, test methods for airborne environmental microbial
with an approved disinfectant., USP26 contaminants either determine the number of cfu collected in a
(19) All rubber stoppers of vials and bomes and the neck of ampuls measured volume of air ("quantitative" or "volumetric") or dur-
should bo ing a specified period of time. Any test method sensitive enough to
show trends in environmental quality under specified conditions of
AUSP26 the sampling used is acceptable. In general, quantitative methods
sanitized with IPA prior to the introduction of a needle or are preferred over nonquantitative methods
spike for the removal of product. A
(20) After the preparation of every admixture, the contents of the , but an organization has to consider suitable options in or-
der to select a methodology and implement it consisten-

At/5W<5
thoroughly mixed and then inspected for the presence of partly- A USP26
ticulate matter, evidence of incompatibility, or other defects. When using either approach, the sample size should be sufficient to
(21) After procedures are completed, used syringes, bottles, vials, give a result of statistical significance. The testing program also
and other supplies ohould bo includes surface sampling.
Dynamic monitoring, that is, testing under operating conditions
arQ
AUSP26 during work activity, should be used routinely in order to give a cfu
removed, but with a minimum of exit and re-entry into the count during the processing of an SP
T_A_E117
nnnr
to minimize the risk of introducing contamination into the 5

The PDATechnical Report No. 13,1990, may be consulted for details and
aseptic workspace. monitoring methods not covered in this section.
©2002 The United States Pharmacopeia! Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
that demonstrates the critical effects of the presence and movement (or room) will average less than one per 10 cubic feet, even under
of operators. The latter is possible when comparing results from dynamic testing conditions. However, culture media exposed to the
dynamic monitoring with results from static monitoring when no airstream tend to dry and, therefore, should not be exposed for
processing is being performed. Static monitoring generally evalu- more than 1 hour. Table 3 provides examples of microbial environ-
ates the status of the facilities, operating equipment, and house- mental test limits, and is presented as a guide.6
keeping.
The greatest value of ongoing microbial monitoring is achieved Table 3. A Sample Dynamic Environmental Microbial
when microbial recoveries show trends. For a given environmental Monitoring Program
area, a baseline count is determined under the best environmental
control believed to be possible for the area. Sampling Low-Risk High-Risk
Baseline Action Action
A Site cfu Level Level
is performed AKSWtf
in selected locations and in a manner intended to reflect best the Settling Plates'1
environmental conditions in the area A 0,1 3 2
A D 2,3 6 4
(that is, after a thorough cleaning of the area to be test- E 4,5 10 6
J 5 10 7
)AisP26 L 8 15 10
The encircled letters on Figure 1 illustrate possible sampling loca- Contact Plates
tions. To establish the baseline count, a large number of samples D 2,3 6 4
should be taken in multiple locations over a period of time to reflect E 4,6 10 7
time of day and week, workload conditions, and, preferably, sea- J 6 12 8
sonal variations. Analysis of these results would give counts nor- L 8 15 10
mally expected to be achievable and the identification of a reduced Slit-to-Agar or Impac-
number of selected sites expected to reflect the environmental con- tion Sampler15
ditions in the area with subsequent monitoring. This analysis then A 0,1 3 2
becomes the basis for ongoing monitoring. The baseline count lim- E 5 10 7
its may be slightly higher for low-risk operations than for high-risk H 8 15 10
operations. Subsequently, any significant change in the counts ob-
tained, either as a single spike or a gradual rise in the cfu count,
Based on 3-hour exposure, except 1-hour for "A". See Fig. 1 for site locations.
would require investigation into the cause.
' Based on 10-ft.! samples.
When counts exceed the established baseline count by a deter-
mined amount (the action level), a written plan of action ohouldbo
, f+.USP26
initiated. The plan would usually call for a repeat of the monitoring
tests the next day and an investigation into the cause, and may in- TEST METHODS
clude such actions as review of decontamination procedures, resa- A well-known test method is the exposure of settling plates, that
nitization of the LAFW is, petri dishes with solid nutrient agar medium congealed in the
bottom section of the plate. These 100-mm diameter plates are sim-
ply opened and allowed to rest on a surface for a planned period of
AUSP26
and the Buffer Room, a change to a different sanitizing agent, or time. They do not sample a known volume of air; rather, viable
retraining of operators. It should be remembered that microbial particles collect on the agar surface as they fall from the environ-
monitoring results are not available until after incubation, usually ment or are impacted by the movement of air currents. Three-hour
48 hours, thus causing a delay in taking any corrective action. exposure of settling plates in a room is an appropriate, easy, and
Therefore, trends should bo inexpensive way to obtain a representation of the contamination
that could be expected to settle from the air at the sampling site.
A Well-known volume-of-air samplers include the slit-to-agar
have to ^
"A.USP26 (STA) sampler and the Reuter centrifugal air sampler (RCS). The
detected as early as possible. Action levels would be slightly higher STA sampler utilizes a revolving nutrient agar plate under a slit
for low-risk operations than for high-risk operations. orifice to impinge the air sample particles on the surface of the nu-
The workspace in an LAFW trient agar in the plate. While the unit is portable, it requires a va-
cuum and an electrical source. The unit can be sanitized but not
AySP26 sterilized. The RCS draws air with an impeller into the head of
is the only environment required to meet M3.5 (Class 100) condi- the unit and centrifugally impacts any particles on a nutrient agar
tions, with the exception of specialized rooms (e.g., laminar flow strip around the perimeter of the head. The unit samples in multi-
rooms) specifically designed to achieve M3.5 (Class 100) condi- ples of 40 liters per minute and is sanitizable and portable, with a
tions. To ensure that M3.5 (Class 100) conditions are met continu- self-contained battery power unit. Both of these units are relatively
ously, the LAFW expensive but, unlike settling plates, have the advantage of quan-
titative sampling.
SCE A us Surface sampling is most frequently done with contact plates7 to
detect accumulated microbial contamination on a flat surface.
1S
These plates are 60 mm in diameter and filled with nutrient agar
AUSP26
certified after installation and recertified at least annually and after
the unit is moved. This certification process includes testing for These test limits were compiled from suggested values in Technical
HEPA filter leaks and the laminar airflow velocity. The microbial Monograph No. 2, the Parenteral Society (Great Britain), 1989, and other
counts normally anticipated within the LAFW sources.
7
Dishes meeting these specifications are obtainable from laboratory supply
houses as Rodac brand, or use the equivalent.
Pharmacopeia! Forum
medium to form a convex surface. The agar usually contains addi- neoossary to perform tho aooignod taoko proporly. Eaoh porson as
tives to help neutralize residues of disinfectants that may be on the oignod to tho aooptio aroa must ouooooofully oomploto spooializod
test surface. The agar is pressed onto a flat surface lifting any mi- training in asoptio technique and aaoptio aroa practices.
croorganisms present onto the surface of the agar. This method can Training should include didaotio material and practical skills aO"
be considered to be relatively quantitative when contaminants are tivitios. Evaluation should inoludo written testing and a written pro
residing superficially on a flat, smooth surface. However, residual toool of frequent routino porformanoo ohooks involving random
agar must be thoroughly removed from the test surface. diroot observation of oritioal operations and adheronoo to all asoptio
aroa procedures and oodoo. Prompt appropriate aotion should ooour
to oorroot porforcnaneo deviations, whether doteotod during a por
formanoo ohook or informally. At six month intervals oaoh por
AN EXAMPLE OF AN ENVIRONMENTAL MONITORING oon'a continuing training nocd3 should bo roa9SO33od, then
documented^ to ensure that 3kill lovols are maintained:
PROGRAM
The following is a suggestion for one possible environmental
monitoring program consisting of multiple tests to determine the
baseline count and subsequent reduced testing for ongoing moni-
toring of the environmental control conditions.8 Aseptic Technique
Settling plates should be uncovered at sites A-N (see Fig. 1) and All oritioal operations aro carried out by appropriately trained
exposed for 3 hours (except 1 hour at site A), both under static and and qualified personnel in an LAFW uaing proper aooptio toohni
dynamic conditions. This test should be repeated each day and quo dosoribod in a written proooduro (ooo tho sootion Suggested
each shift for at least one week, preferably two weeks. If STA or Standard Operating Procedures). Asoptio technique is equally ap
RCS air samplers are used, at least 10 cu. ft. (280 liters) air samples plioablo to tho preparation of storilo sensitizing and ohomotoxio
should be taken at sites B, D, E, J, K, and L. The nutrient agar agents. Howovor, it ohould bo rooognizod that additional prcoau
plates or strips are then incubated at 30° to 35° for 48 hours and tiono must bo usod to protoot tho oompoundor and tho oompound
the colonies counted. These tests should be repeated about six ing environment from tho adverse offoots of tho agents boing
months later. The average number of colonies at each site is com- processed. A vortioallaminar flow workbench (VLFW) with bio
puted to give baseline counts, being sure that housekeeping and hazard oontrol oapabilitioo, tho protective oapabilitioo of garb and
other environmental control procedures are functioning at maxi- gloves, spraybaok and spill control techniques, tho use of 3pooia
mum efficiency. lizod compounding devices, and proper disposal aro oomo of tho
Similarly, at the end of each shift and before any clean-up sani- additional measures to bo considered.
tization is done, perform surface sampling with contact plates at the
same sites, being careful to remove any residual medium from the A
A written description of specific training and perfor-
surfaces with an alcohol wipe. In addition, at least the gloved index
finger of each operator should be rolled on a contact plate. mance evaluation program for individuals involved in the
The results of these evaluations are critically reviewed. Using
the data given in Table 3 as an example, a reduced number of sites use of aseptic techniques for the preparation of sterile pro-
for monitoring, which give the best evidence of the level of micro-
bial control maintained during facility operation, can be selected. ducts has to be developed for each site. This program equips
Monitoring tests under dynamic conditions should then be per-
formed at least weekly during the shift of highest activity at the the personnel with the appropriate knowledge and trains
selected sites (i.e., sites D, E, J, and L, or other sites that give evi-
dence of being more representative of the true environmental con-
trol conditions). At least monthly another shift should be them in the required skills necessary to perform the assigned
monitored in the same manner. Volume-of-air samples might be
reduced to one site in each room weekly. However, the number tasks. Each person assigned to the aseptic area in the pre-
of monitoring sites or the sampling frequency should be increased
if there is any indication that the monitoring program is inadequate. paration of sterile products must successfully complete spe-
Action levels are determined by making a reasoned judgment. A
50% increase above the baseline count is probably reasonable cialized training in aseptic techniques and aseptic area
for high-risk operations. For low-risk operations an increase of
100% probably would be acceptable. However, whenever a rising practices prior to preparing products or working in this area.
trend appears to be in progress, the operations ohould be
The evaluation process includes a written test of the funda-
are
AUSP26
mental knowledge of aseptic techniques and the preparation
closely monitored with more frequent sampling being performed to
confirm whether or not a trend is occurring.
of sterile products, and a performance assessment of aseptic
Change to read: techniques involving direct observation of critical steps and
of adherence to all aseptic techniques and codes. The results

PROCESSING
of this testing process are made available for review. Person-
Personnel Training and Evaluation
Tho pharmacy ohould follow a written program of training and
performance evaluation designed to on3uro that oaeh person work
ing in tho asoptio aroa hao tho appropriate knowledge) and olcilla
See also Am. J. Hosp. Pharm. 1980; 37:668.
Pharmacopeial Forum
nel are tested at six-month intervals to determine continuing NONSTERILE COMPONENTS

training needs, and these results and actions are documented Drug oomponontsshould moot oompondial standards. Certifi
oatoa of analysis from reputable manufacturers of bulk drug sub
to ensure that all skill levels are maintained. Prompt and ap- stances may bo uaod to O3tabliah that oaoh lot of bulk drug
oubatanoo roooivod by tho pharmaoy mooto ito opooifioationo. Bulk
propriate actions are taken to correct performance devia- drug substances atorod properly in the pharmacy oan bo oxpootod to
retain thoir quality until tho manufacturer 'a labolod expiration date:
tions whenever the evaluation process detects them. Bulk drug aubstanoos that arc not labolod with a manufacturer'a
expiration dato should bo dated upon roooipt, atorod properly, dated
when opening tho container, used within a roaaonablo period of
time, and visually inapootod by tho pharmaoiat upon uao. Tho con
Aseptic Technique ditiona undor whioh containers of bulk drug substances are oponod
and tho toohniquo of tho contents' withdrawal ahould bo strictly
Critical operations are carried out by appropriately trained controlled. Additionally, tho dovioog uaod to withdraw' tho contents
ahould bo oloan to prooludo contamination of tho remaining con
and qualified personnel in an SCE using proper aseptic tech- tents. Tho pharmaoy may ropaolcago bulk drug substaneoa into
smaller, ouitablo, and properly soalod containers (o.g., using a
nique described in a written procedure (see Suggested Stan- shrink seal) to minimize tho risk of contamination. Upon roooipt
of oaoh lot of bulk drug 3ubstanoo U3od to compound an SP, tho
dard Operating Procedures). Aseptic technique is equally pharmacy ahould perform an inspection of tho lot for any visual
ovidonoo of deterioration, other typos of unaoooptablo quality,
applicable to the preparation of sterile sensitizing and che- and wrong identity. Visual inspection of bulk drug subatancoa
should bo performed routinoly.
motoxic agents. However, it is essential to recognize that ad- A
Drug components must meet the compendial standards if
ditional precautions must be utilized to protect the personnel
available. Certificates of analysis from manufacturers of
and the compounding environment from the potential ad-
bulk drug substances or excipients may be used to establish
verse effects of these chemotoxic products. The minimum
that each lot of the bulk drug substance or excipient meets
requirements for this process include the following: work-
the required specification prior to its use. Bulk drug sub-
ing and validated vertical laminar flow workbench (VLFW)
stances or excipients have to be stored properly. If properly
with biohazard control capabilities; the protective capabil-
stored, it is assumed that the bulk drug substance or excip-
ities of gowns, masks, bouffants, and gloves; sprayback
ient will retain its quality until the manufacturer's labeled
and spill control techniques and equipment; the use specia-
expiration date. Bulk drug substances or excipients not la-
lized compounding devices and equipment; and proper dis-
beled with a manufacturer's labeled expiration date have to
be strictly controlled. This control process includes the fol-
lowing: a log indicating the date of receipt and lot number;
Components and a log of product use including dates when the container
The pharmacy should is opened, conditions under which the container can be
A
has to AUSP26 opened, specific devices required to withdraw the contents
follow written procedures to ensure that all items used to com-
pound sterile drug products retain their purported or expected qua- to prevent contamination of the remaining contents, proper
lities at the time of administration.
storage of the container, use within a reasonable period of
time (6 or 12 months), and visual inspection upon removal
STERILE COMPONENTS and prior to use. The bulk drug substance or excipient may
Commercially available sterile drug products, sterile ready-to-
use containers and devices are examples of sterile components. be repackaged into smaller and properly sealed containers
A written procedure for unit-by-unit physical inspection prepara-
lory to (e.g., using shrink seal) to minimize the risk of contamina-
IS AVSP26 tion. Upon receipt of each lot of the bulk drug substance or
followed to ensure that these components are sterile, free from de-
fects, and otherwise suitable for their intended use. excipient used for CSPs, the individual compounding the
Pharmacopeial Forum
product performs a visual inspection of the lot for evidence Change to read:
of deterioration, other types of unacceptable quality, and
wrong identification. The bulk drug substance or excipient FINISHED PRODUCT RELEASE CHECKS AND
TESTS
visual inspection is performed on a routine basis as de-
All SPs ohould bo
scribed in the written protocol.AL,5W<5
Because finished CSPs are not usually tested for pyrogens, non- CSPs areA[/sp2«
sterile bulk drug substances subjected to appropriate checks or tests to ensure that only those
A SPs free from defects and meeting all quality specifications
or excipientsAUSW« A
could impart pyrogenic properties to the finished product. There- as outlined in the product documentation Af/5W «
fore, the pharmacy should will be distributed. An SP ahould not
A
has to A W W t f
have a procedure to ensure that the final product does not exceed be released until all quality specifications have been reviewed, and
specified endotoxin limits. See Bacterial Endotoxins Test (85) for it is determined that all release requirements are met.
procedural details concerning endotoxin testing.
Physical Inspection
EQUIPMENT
AH finishod SPo ohould be individually inopootod in aooordanoo
Tho pharmacy should onauro that equipment, apparatus;and do with written proooduroa after compounding and, if not distributed
viooo usod to compound an SP aro oapablo of oonoiatontly oporat promptly, prior to leaving tho pharmacy.
ing properly and within aooopttible toloranoe limita. Written
proooduroa ahould bo oatabliahod and followed that inoludo oquip A
mont calibration, annual maintonanoc, monitoring, and control. Finished CSPs are individually inspected in accordance
Routine maintenance ohooko ohould bo documontod. Poroonnol
3hould be qualified through on appropriate combination of specific with written procedures after compounding. If not distribu-
training and experience to operate or manipulate any itom of oquip •
mont, apparatuo, or device to whioh thoy will bo aaaignod to U3O ted promptly, these products are individually inspected just
when preparing drug products forpationta. Training should inoludo
tho ability to determine whether any itom of oquipmont ia operating prior to leaving the storage area. Those products that are not
properly or ia malfunctioning.
immediately distributed are stored in an appropriate location
A
It has to be ensured that equipment, apparatus, and de-
as described in the written p ^ / ^
vices used to compound an SP are consistently capable of Immediately after compounding and as a condition of release, each
product unit, where possible, should be inspected against lighted
operating properly and within acceptable tolerance limits. white and black backgrounda
A
Written procedures outlining required equipment calibra- or black background or bothAas.P25
for evidence of visible participates or other foreign matter. Pre-re-
tion, annual maintenance, monitoring for proper function, lease inspection should alao inoludo
A
also i ^ p ^
controlled procedures for use of the equipment and specified container-closure integrity and any other apparent visual defect.
Products with observed defects should be immediately discarded
time frames for these activities are established and followed. or marked and segregated from acceptable products in a manner
that prevents their administration. When products are not distribu-
Routine maintenance and time intervals are also outlined in ted promptly after preparation, a predistribution inspection ohould
be
these written procedures. Results from the equipment cali-
1S
AUSP26
bration, annual maintenance reports, and routine mainte- conducted to ensure that a CSP with defects, such as precipitation,
cloudiness, and leakage, which may develop between the time of
nance are kept on file for the lifetime of the equipment. release and the time of distribution, is not released.
Personnel is prepared through an appropriate combination
of specific training and experience to operate or manipulate Compounding Accuracy Checks
any piece of equipment, apparatus, or device they may use Written procedures for double-checking compounding accuracy
ohould bo followed for every SP
when preparing CSPs. Training includes gaining the ability A
have to be followed for every CSP during preparation and
to determine whether any item of equipment is operating
immeditely AUSKM
properly or is
Pharmacopeial Forum
prior to release. The double check system should meet state regu- reliable as the USP Membrane Filtration Methodox the
lations and include label accuracy and accuracy of the addition of
all drug products or ingredients used to prepare thefinishedpro- USP Direct Transfer Method where the membrane filtration
duct and their volumes or quantities. The used additive containers
and, for those additives for which the entire container was not ex- method is not feasible.
pended, the syringes used to measure the additive, should be quar-
antined with the final products until the final product check is Normally, the CSPs cannot be released for use until test
completed. Syringe plungers should be drawn back to the volume
mark used for each additive, if the additive volume was not results show no evidence of microbial contamination of
checked prior to the addition. Automated pump settings should
be verified just prior to or just after pumping and mixing, and the product. However, when a CSP must be released prior
the volumes of each ingredient actually pumped should be checked
or the addition otherwise appropriately confirmed to establish that to the completion of the sterility testing, the CSP can be con-
the accuracy of the automated pump is within the limits set by the
manufacturer. Written procedures for accountability of all drug ditionally released. In such a case, a written procedure re-
product units used in the preparation of SPs ohould bo
A quiring daily observation of the media and requiring an
CSPs have to beAUSP26
followed. immediate recall if there is any evidence of microbial
Additional finished product tests ohould bo
growth must be available. In addition, the physicians of
performed on high-risk CSPs, as follows.
those patients to whom a potentially contaminated CSP
was administered and those patients are notified of the po-
Sterility Testing tential risk to the patient. Positive sterility test results should
Storility testing should bo porformod on Category II high risk prompt a rapid and systematic investigation of aseptic tech-
SPs. Sampling for tho storility tost should ooour promptly upon
tho oomplotion of preparation. Tho storility toat, including tho sam nique, environmental control, and other sterility assurance
pling oohomo, should bo oonduotod aooording to ono of tho USP
methods (soo Sterility (T^-)). Membrane filtration is tho method
of ohoioo whoro feasible. A method not dosoribod in tho USP controls to identify sources of contamination and correct
may bo used if validation results demonstrate that tho alternative
is at loast as effective and roliablo a3 tho USP mombrano filtration problems in the methods or processes.AUS.W(S
method or tho diroot transfer method whoro tho mombrano filtration
method is not feasible.
Normally, tho SP ohould not bo roloasod for pationt uso until tost
results show no ovidonoo of miorobial contamination of tho pro
duet. However, whon tho SP mu3t bo released prior to tho oomplo Pyrogen Testing
tion of tho storility tooting, tho SP oan bo conditionally roloasod. In
ouoh a oaso, tho pharmacy should havo a procedure requiring daily Each CSP prepared from nonsterile drug components
observation of tho media and requiring an immodiato rooall if there A
is any ovidonoo of miorobial growth. In addition, tho physicians of or excipients,Al/Sp2tf
those patients to whom a potentially oontaminatod SP was adminis or from an intermediate compounded from a nonsterile component
torod should bo notified as to tho potential risk to tho pationt. Po
sitivo sterility tost results should prompt an investigation of aaoptio AUSP26
technique, environmental control, and othor storility assurance tested for pyrogen or endotoxin according to the recommended
oontrols to identify and oorroot probloms as muoh as possible. methods (see Bacterial Endotoxins Test (85)). The product she«W
^Sterility testing is performed on high-risk CSPs. Sam-
A
pling for the sterility test should occur promptly upon the cannotA[/iSP2(S
be released until it has been determined that the endotoxin limit
completion of compounding. The sterility test, including specified for the product is not exceeded.
the sampling scheme, is conducted according to one of the
USP methods (see Sterility Tests (71)). Membrane Filtra- Potency Testing
tion Method is the method of choice where feasible (e.g., The pharmacy should have a procedure for a pre-release check of
the potency of the active ingredients in SPs prepared from nonster-
components are compatible with the membrane). A method ile bulk active ingredients. The procedure should include at least
the following verifications by a pharmacist:
not described in the USP may be used if validation results
demonstrate that the alternative is at least as effective and
Pharmacopeia! Forum
A
A written procedure for a pre-release check of the po- produot is ultimately uoed by tho pationt. Tho original boyond uso
date assigned by tho pharmaoist oould easily bo invalidated undor
tency of the active ingredients in CSPs prepared from non- these circumstances. A procedure should bo in plaoo that details
what is to bo done whon this situation ooours. Should this situation
sterile bulk active ingredients must be available. The arise, tho pharmaoist noods to determine what the aotual stability of
tho produot will bo, lcooping in mind tho oumulativo offoots of room
procedure includes at least the following verifications by a temperature storage upon tho produot.
A
pharmacist or their agent:AC/5/>2(5 The effect of "cumulative" room temperature storage on
1. The lot of the active ingredient used for compounding has the the physical-chemical stability and characteristics of the
necessary identity, potency, purity, and other relevant quali-
ties. For example, this can be established for official drug sub- CSP has to be considered as well. For example, a CSP
stances by comparing the information stated on the lot's
certificate of analysis with the requirements specified in the may be removed from the refrigerator and allowed to equi-
USP monograph for the substance.
2. All weighings, volumetric measurements, and additions of in- librate at room temperature, only to be placed back into the
gredients were carried out properly. This can be established
by reviewing compounding records to ensure that these steps refrigerator. This could happen any number of times before
were confirmed and initialed by a second person during com-
pounding. the product is ultimately administered. The original beyond-
3. The compounding or control records include documentation
that the fill volumes of all units available for release were use date assigned to the CSP could easily be invalidated un-
checked and were correct.
4. The final yield is confirmed to be consistent with the theore- der these circumstances, because the required storage con-
tical yield.
Because beyond-use dating periods established from product- ditions have not been met. A written procedure has to be in
specific data acquired from an appropriate instrumental analysis
are clearly more reliable than those predicted theoretically, the for- place that details what is to be done when this situation oc-
mer approach is strongly urged to support dating periods exceeding
30 days. curs. Should this situation arise, the actual stability of the
product has to be determined, keeping in mind the cumula-
Change to read:
tive effects of room temperature storage upon the prod-
UCt..USp26
STORAGE AND BEYOND-USE DATING The drug product's manufacturer or other credible stability ref-
Each finished drug product unit should boar labeling that 3pooi- erence source should be consulted, particularly for expensive bio-
fioo tho produot's storage roquiromonta, manufacturer'a expiration technology or chemotherapeutic drugs.
date or tho boyond use dato, and, whoro appropriate, tho timo of Additionally, some CSPs may be subjected to elevated tempera-
day boyond which tho product i3 not to bo usod. ture conditions, (e.g., body temperature) for continuous or novel
drug delivery devices such as ambulatory infusion pumps, implan-
A
Each CSP unit shall bear labeling that specifies the pro- table infusion devices, and elastomeric infusion devices. Pharma
oiats should have
duct's storage requirements, manufacturer's expiration date •
AUSP26
or assigned beyond-use date according to the written proce- Adequate stability reference data
A
has to exist. VSP26
dure and, where appropriate, the time of day beyond which to ensure that the product's potency characteristics are maintained
when stored at these elevated temperatures during the labeled per-
the product is not to be \ised.AUSP2s iod of time chosen. CSPs may be frozen if adequate stability evi-
Unless otherwise indicated, CSPs should be refrigerated until the dence to support freezing is available.
time of use, with allowance for adequate time to equilibrate to All light-sensitive products should be suitably protected from
room temperature before administration. CSPs intended for admin- light from the time of preparation until the time of use or, where
istration promptly after compounding may be retained at room indicated, until the conclusion of administration.
temperature from the time of compounding.
Even under the best of conditions, there is always the likelihood
that unsuspected microorganisms might inadvertently gain entry
into the CSP during aseptic processing. Thus, as an adjunct sterility Determining Beyond-Use Dates
assurance measure, CSPs not intended for prompt use should be
stored at a temperature no higher than 4°, that is, at a temperature Whoro possible; tho boyond use date should bo in aooordanoo
expected to inhibit microbial growth. Multi-day CSPs (injections with allowanoos opooifiod in tho approved labeling. Howovor, roli
prepared for administration by a portable infusion pump or reser- ablo, publishod stability information ia oometimeo looking for
voir system) should be started promptly after preparation, and ad- many typos of drugs: In tho3o instances, pharmacists ohould oon
ministration should be completed within 7 days. Pharmaoiota suit with tho drug'3 manufacturer to establish a boyond-u3o date.
ohould also consider tho offoot of "cumulative" room temperature Booauao of compelling pationt oaro noodo, a pharmaoiot may bo un
storage on tho physical ohomioal stability and oharaotoristios of tho ablo to 3tay within tho approved labeling and produot guidelines
SP. For example, an SP may bo removed from tho rofrigorator and stated in tho package insert. For oxamplo, a higher concentration
allowed to equilibrate to room temperature, only to bo rcplaood into of drug may bo proscribed; different diluont; oontainor; oto., may
tho rofrigorator. This oould happen any number of timoo before the
Pharmacopeial Forum
bo nooosoary; or tho pationt may roquiro tho SP for longor poriodo od is supported by only marginal ovidonoo; or whore a significant
of timo. Tho pharmaoiot should oommunioato tho doviationa from margin of safety oannot bo vorifiod for tho proposed thoorotioal bo
tho pookago insert to tho manufacturer whon requesting stability yond uso dating period.
information. Otherwise, tho pharmaoiat should ensure that tho man Additionally, whon prepared for administration in a homo oaro
ufaoturor's stability information is produot spooifio, that is, tho OK sotting; conditions to which tho finished produot may bo subjected
aot otrongth; diluent, fill volumo, and oontainor typo (PVC bag, during in homo uso (o.g., in homos without air conditioning in a
plastic syringo, olastomorio infusion device, etc.) will bo used by hot climate) should bo oonsidorod on a pationt by pationt basis.
tho pharmaoiot whon preparing tho SP. Pharmaoists should obtain a Thus, tho possiblo nood to shorten a general boyond use date
letter from tho manufacturer certifying tho boyond uao dating por should bo oonsidorod at the timo of dispensing basod on tho parti-
iod provided. Information provided by tho manufacturer is usually cularoiroumstanoos of tho patient.
for tho SP'a chemical and physical stability only and would there In all instanoos where alternate informational resources aro usod
fore not bo relevant to sterility assurance imparted by tho pharma to establish a boyond uso date for a drug produot, tho pharmacist
cist oaoh timo tho produot is madoi Therefore, it i3 tho pharmaoiot^s should onauro that thoso resources havo undergone oritioal ovalua
rooponsibility to ensure that compounding methods are validated to tion in conjunction with tho spooifio produot for whioh a boyond-
en3urofinalproduot 3torility. Boyond use dating not opooifioally ro U3O date is established. Boyond uae dates prediotod from alternate
foronood in tho produot'a approved labeling, or not established by informational rosouroos should bo conservative and not extend bo
produot speoifio instrumental analysis, should bo limited to 30 yond tho roalistio and praotioal pationt oaro nood3 of the pharmacy?
Pharmaoists should subsequently maintain a rooord of tho spooifio
To ensure consistent practices in dotormining and assigning bo basis used to establish the boyond uso date for each oompoundod
yond uso dates, tho pharmaoy shouldfaavowritten policies and pro drug produot. Pharmacists 3hould provido a written rooord of ox
ooduros governing tho determination of tho boyond use dates for all ooptions for produot3 with boyond uso dates that fall outsido of the
of ito oompoundod produots. Tho following information may bo pharmacy's established SOPs on stability' and boyond uso dating.
helpful in providing a basis for those policies and procedures: Alternatively, tho exceptional reasons for changing tho product's
Produot spooifio, oKporimontally determined stability data basod boyond uso date may also bo documented in tho pationt'o ohart.
on sound stability evaluation protoools are preferable to published A
stability information for tho prediction of boyond uoo dat03. Phar The beyond-use date is a defined period of time that
maoists should consult tho gonoral information chapter Phaima
ccutical Dosage Forma (1151) for tho appropriate stability starts from the original date the parenteral admixture was
paramotoro to bo oonsidorod when initiating or evaluating a pro
duet spooifio stability study. However, tho uso of professional judg made until it is deemed unacceptable for clinical use, after
ment basod on aooumulatod information may also bo aoooptablo for
dotormining boyond use dates. which the compounded sterile product should not be used.
When attempting to prodiot a thoorotioal boyond uso date; a
oompoundod or an admixed produot should bo oonsidorod as a un Where possible, the beyond-use date should be in accor-
iquo system that can have physical ohomioal proportios and stabi
lity characteristics that differ from its components. For example, dance with the allowances specified in the approved label-
antioxidant, buffering, or antimicrobial proportios of an SVI might
bo lost upon ito dilution; with tho potontial of soriously oompromio ing. Because of compelling patient-care needs, the
ing tho ohomioal stability '0f tho SVI's active ingredient or tho phy
sioal or microbiological stability of tho SVI formulation in general. compounding clinician may be unable to stay within the ap-
Thus, tho properties stabilized in tho SVI formulation usually can
not bo automatically expected to bo carried over to tho oom proved labeling and product guidelines stated in the package
pounded or admixed produot.
It should bo recognized that tho only truly valid evidence of sta insert. The beyond-use dates may be assigned based on cri-
bility for predicting boyond uao dating is from produot spooifio
(appropriate braokoting is aoooptablo) experimental studios. Pro teria different from those applied to assigning the expiration
diotiono baood on other ovidonoo, such ao publications, oharts, ta
bloa, oto., would rooult in thoorotioal boyond uso dates. dates to manufactured drug products. For example, a higher
Thoorotioally prodiotod boyond uso dating introduces varying do
groo3 of assumption;} and honoo a likelihood of error, or at least concentration of drug may be described; different diluent or
inaccuracy. Tho degree of error or inaccuracy would be dependent
upon tho extant of difforonoo3 botwoon tho SP'o oharaotoristios container may be necessary; or the patient may require the
(e.g., composition, concentration of ingredients, fill volumo, con
tainor typo and material, oto.) and tho oharaotoristios of tho produots CSP for longer periods of time. In these instances, a phar-
from which stability data or information arc to bo extrapolated.
Thus; tho greater tho doubt of tho aoouraey of theoretically pro macist must be consulted to ascertain a reasonable extension
dieted boyond uso dating; tho greater tho need to determine dating
periods experimentally: Thoorotioally prodiotod boyond use dating of the product's beyond-use life outside of the approved
periods should bo soriously oonsidorod for SPs prepared from non
storilo bulk active ingredients having therapeutic activity, O3po package insert. In assigning a beyond-use date for a CSP,
oially whore those SPs are oxpootod to bo oompoundod routinely.
Somiquantitativo procedures, such as thin layer ohromatography pharmacists should use their pharmaceutical education and
(TLC), may bo aoooptablo for many SPsi However, quantitative
stability indicating assays, such as high performance liquid experience.
ohromatography (HPLC), would bo more appropriate for certain
oritioal SPo. Examples inoludo SPs with a narrow thorapoutio do The pharmacist must consult with the manufacturer to as-
sago range or a narrow thorapoutio index where oleao monitoring or
titoring is required to ensure therapeutic effeetivonoso or to avoid sist in establishing information to assign a beyond-use date.
toxioity; where a thoorotioally established boyond use dating peri
The pharmacist should communicate the deviations from
Pharmacopeial Forum
the package insert to the manufacturer when requesting sta- ences between the CSP's characteristics (such as composi-
bility information. Otherwise the pharmacist must ensure tion, concentration of ingredients, fill volume, or container
that the manufacturer's stability information is product-spe- type and material) and the characteristics of the products
cific, that is, the exact strength, diluent, fill volume, and con- from which stability data or information are to be extrapo-
tainer type (PVC bag, plastic syringe, elastomeric infusion lated. The greater the doubt of the accuracy of theoretically
device, and so forth) will be used by the clinician when pre- predicted beyond-use dating, the greater the need to deter-
paring and infusing the CSP. If possible, pharmacists should mine dating periods experimentally. Theoretically predicted
obtain a letter from the manufacturer certifying the beyond- beyond-use dating periods should be carefully considered
use dating period in cases where it differs from that in the for CSPs prepared from nonsterile bulk active ingredients
package insert. Information provided by the manufacturer having therapeutic activity, especially where these CSPs
usually pertains to CSP's chemical and physical stability are expected to be compounded routinely. Beyond-use dates
only. Therefore, it would not be relevant to guarantee that should be conservatively assigned, and where such dating is
compounding methods are validated to ensure final product not established by the product-specific instrumental analy-
sterility. This guarantee is then the pharmacist's responsibil- sis, limited to 30 days. However, when prepared for admin-
ity. Beyond-use dating not specifically referenced in the istration in a home-care setting, conditions to which the
package insert should not exceed 30 days. finished product may be subjected during in-home use (for
In addition, the pharmacist may refer to applicable publi- instance, in homes without air-conditioning in a hot climate)
cations to obtain relevant stability, compatibility, and degra- should be considered on a patient-by-patient basis. Thus, the
dation information regarding the drug or its congeners. possible need to shorten a general beyond-use date should
When assigning a beyond-use date, pharmacists should con- be considered at the time of dispensing based on the parti-
sult and apply drug-specific and general stability documen- cular circumstances of the patient.
tation and literature where available, and they should It should be recognized that the truly valid evidence of
consider the nature of drug and its degradation mechanism, stability for predicting beyond-use dating can be obtained
the container in which it is packaged, the expected storage only through product-specific experimental studies. Semi-
conditions, and the intended duration of therapy (see Ex- quantitative procedures, such as thin-layer chromatography
piration Date and Beyond-Use Date under Labeling in the (TLC), may be acceptable for many CSPs. However, quan-
General Notices and Requirements). Stability information titative stability-indicating assays, such as high performance
must be carefully interpreted in relation to the actual com- liquid chromatographic (HPLC) assays, would be more ap-
pounded formulation and conditions for storage and use. propriate for certain CSPs. Examples include CSPs with a
Predictions based on other evidence, such as publications, narrow therapeutic index, where close monitoring or dose
charts, tables, and so forth would result in theoretical be- titration is required to ensure therapeutic effectiveness and
yond-use dates. Theoretically predicted beyond-use dating to avoid toxicity; where a theoretically established beyond-
introduces varying degrees of assumptions, and hence a use dating period is supported by only marginal evidence; or
likelihood of error or at least inaccuracy. The degree of error where a significant margin of safety cannot be verified for
or inaccuracy would be dependent on the extent of differ- the proposed beyond-use dating period. In short, because
Pharmacopeial Forum
beyond-use dating periods established from product-speci- the a beyond-use date is established. Pharmacists should
fic data acquired from the appropriate instrumental analyses subsequently maintain a record of the specific basis used
are clearly more reliable than those predicted theoretically, to establish the beyond-use date for each CSP that deviates
the former approach is strongly urged to support dating per- from the approved package insert. Pharmacists should pro-
iods exceeding 30 days. vide a written record of exceptions for products with be-
To ensure consistent practices in determining and assign- yond-use dates that fall outside of the established SOPs on
ing beyond-use dates, the pharmacy should have written po- stability and beyond-use dating. Alternatively, the excep-
licies and procedures governing the determination of the tional reasons for changing the products beyond-use date
beyond-use dates for all compounded products. When at- may also be thoroughly documented in the patient's chart.
tempting to predict a theoretical beyond-use date, a com- If multiple-dose parenteral medication vials (MDVs) are
pounded or an admixed product should be considered as a used, refrigerate the MDVs after they are opened unless
unique system that has physical and chemical properties and otherwise specified by the manufacturer. Discard the MDVs
stability characteristics that differ from its components. For when empty, when suspected or visible contamination oc-
example, antioxidant, buffering, or antimicrobial properties curs, or when the manufacturer's stated expiration date is
of a sterile vial for injection (SVI) might be lost upon its di- reached, provided the manufacturer's storage conditions
lution, with the potential of seriously compromising the che- have been adhered to. Expiration dating not specifically re-
mical stability of the SVPs active ingredient or the physical ferenced in the package insert should not exceed 30 days
or microbiological stability of the SVI formulation in gen- once the vial has been opened.A[/5/,2(5
eral. Thus, the properties stabilized in the SVI formulation
usually cannot be expected to be carried over to the com-
Monitoring Controlled Storage Areas
pounded or admixed product. Product-specific, experimen-
To ensure that product potency is retained through the manufac-
tally determined stability data evaluation protocols are turer's labeled expiration date, pharmacists must monitor the drug
storage areas within the pharmacy. Controlled temperature storage
preferable to published stability information. Pharmacists areas in the pharmacy (refrigerators, 2° to 8°; freezers, -20° to
-10°; and incubators, 30° to 35°; etc.) should be monitored at least
should consult the general information chapter Stability un- once daily and the results documented on a temperature log. Ad-
ditionally, pharmacy personnel should note the storage temperature
der Pharmaceutical Dosage Forms (1151) for the appropri- when placing the product into or removing the product from the
storage unit in order to monitor any temperature aberrations. Suit-
ate stability parameters to be considered when initiating or able temperature recording devices may include a calibrated con-
tinuous recording device or an NBS calibrated thermometer that
evaluating a product-specific stability study. has adequate accuracy and sensitivity for the intended purpose
and should be properly calibrated at suitable intervals. If the phar-
In all instances where alternate informational resources macy uses a continuous temperature recording device, pharmacy
personnel should verify at least once daily that the recording device
are used to establish a beyond-use date for a CSP (defined itself is functioning properly.
The temperature sensing mechanisms should be suitably placed
in consultation with the manufacturer, in view of the theore- in the controlled temperature storage space to reflect accurately its
true temperature. In addition, the pharmacy should adhere to ap-
tical predications, or from product-specific instrumental propriate procedures of all controlled storage spaces to ensure that
such spaces are not subject to significantly prolonged temperature
analysis), the pharmacist must ensure that those references fluctuations as may occur, for example, by leaving a refrigerator
door open too long.
have been critically evaluated for the specific CSP for which
Pharmacopeial Forum
Change to read:
VALIDATION OF AUTOMATED COMPOUNDING
DEVICES FOR PARENTERAL NUTRITION

MAINTAINING PRODUCT QUALITY AND
CONTROL AFTER ff COMPOUNDING
A
Automated compounding devices (ACDs) for the pre-
THE CSP
LEAVES THE PHARMACY paration of parenteral nutrition admixtures are widely used
by pharmacists in hospitals and other health care settings.
They are designed to streamline the labor-intensive pro-
A
Sterile Preparations for Institutional Use
cesses involved in the compounding of these multiple-com-
This section pertains to the responsibilities of the phar-
ponent formulations by automatically delivering the
macy for maintaining product quality and control after the
individual nutritional components in a predetermined se-
CSP leaves the pharmacy for distribution and use within the
quence under computerized control. Parenteral nutrition ad-
organized health care system to which the pharmacy be-
mixtures often contain 20 or more individual additives
longs. The pharmacy is responsible for the quality of all
representing as many as 50 or more individual components
CSPs prepared by or dispensed from the pharmacy, through-
(for example, 15 to 20 crystalline amino acids, dextrose
out the life cycle of the CSP, regardless of where the CSP
monohydrate, and lipids; 10 to 12 electrolyte salts; 5 to 7
exists physically within the organized health care system.
trace minerals; and 12 vitamins). Thus, the ACDs can im-
In fulfilling this general responsibility, the pharmacy is re-
prove the accuracy and precision of the compounding pro-
sponsible for the proper packaging, handling, transport, and
cess compared to the traditional, manual compounding
storage of CSPs prepared by or dispensed from it, including
methods. Pharmacists should consult the general informa-
the appropriate education, training, and supervision of phar-
tion chapter Validation of Compendial Methods (1225) for
macy personnel assigned to these functions. The pharmacy
validation parameters to be considered when evaluating an
should assist in the education and training of non-pharmacy
ACD.
personnel responsible for carrying out any aspect of these
Accuracy—The accuracy of an ACD can be determined
functions.
in various ways to ensure the correct quantities of nutrients,
Establishing, maintaining, and assuring compliance with
electrolytes, or other nutritional components are delivered to
comprehensive written policies and procedures encompass-
the final infusion container. Initially, the ACD is tested for
ing these responsibilities is a further responsibility of the
its volume and weight accuracy. For volume accuracy, a
pharmacy. Where non-pharmacy personnel are assigned
suitable volume of Sterile Water for Injection, which repre-
tasks involving any of these responsibilities, the policies
sents a typical additive volume (e.g., 40 mL for small-vol-
and procedures encompassing those tasks should be devel-
ume range of 1 to 100 mL; or 300 mL for large-volume
oped by the pharmacy in consultation with other institu-
range of 100 to 1000 mL), is programmed into the ACD
tional departments as appropriate. Activities or concerns
and delivered to the appropriate volumetric container. The
that should be addressed as the pharmacy fulfills these re-
pharmacist then consults Volumetric Apparatus (31) for ap-
sponsibilities are as follows.
propriate parameters to assess the volumetric performance
of the ACD. For gravimetric accuracy, the balance used in
Pharmacopeia! Forum
conjunction with the ACD is tested using various weight sulfate, potassium chloride, and so forth. The critical point
sizes that represent the amounts typically used to deliver is the use of USP references and the possible laboratory pro-
the various additives. The pharmacist consults Weights cedural differences.
and Balances (41) for acceptable tolerances of the weights Precision—The intermediate precision of the ACD can
used. In addition, the same volume of Sterile Water for In- be determined on the basis of the day-to-day variations in
jection used to assess volumetric accuracy is then weighed performance of the accuracy measures. Thus, the pharmacist
on the balance used in conjunction with the ACD. For ex- has to keep a daily record of the above-described accuracy
ample, if 40 mL of water was used in the volumetric assess- assessments and review the results over time. This review
ment, its corresponding weight should be about 40 g has to occur at least at weekly intervals to avoid potentially
(assuming the relative density of water is 1.0). In addition, clinically significant cumulative errors over time. This is
during the use of the ACD, certain additives, such as potas- especially true for additives with a narrow therapeutic index,
sium chloride (corrected for density differences) can also be such as potassium chloride.
tested in the same manner as an in-process test.
Finally, additional tests of accuracy may be employed that PACKAGING, HANDLING, AND TRANSPORT
determine the content of certain ingredients in the final vol- Inappropriate processes or techniques involved with
ume of the parenteral nutrition admixture. Generally, phar- packaging, handling, and transport can adversely affect pro-
macy departments do not have the capability to routinely duct quality and package integrity. While pharmacy person-
perform chemical analyses such as analyses of dextrose or nel routinely perform many of the tasks associated with
electrolyte concentrations. Consequently, hospital or institu- these functions, some tasks, such as transport, handling,
tional laboratories may be called upon to perform these and placement into storage, may be fulfilled by non-phar-
quality assurance tests. However, the methods in such la- macy personnel who are not under the direct administrative
boratories are often designed for biological, not pharmaceu- control of the pharmacy. Under these circumstances, appro-
tical, systems. Thus, their testing procedures must be priate written policies and procedures have to be established
validated to meet the USP requirements stated in the indivi- by the pharmacy with the involvement of other departments
dual monograph for the component being tested. For exam- or services whose personnel are responsible for carrying out
ple, under Dextrose Injection, the following is stated: It those CSP-related functions for which the pharmacy has a
contains not less than 95.0 percent and not more than direct interest. The performance of the non-pharmacy per-
105.0 percent of the labeled amount of C 6 H 12 O 6 -H 2 O. sonnel is monitored for compliance to established policies
The hospital or institutional chemistry laboratories have to and procedures.
validate their methods to apply to this range and correct for The critical requirements that are unique to CSPs and are
their typical measurement of anhydrous dextrose versus necessary to ensure product quality and packaging integrity
dextrose monohydrate. Similar ranges and issues exist, for have to be addressed in written procedures. For example,
example, for injections of calcium gluconate, magnesium techniques should be specified to prevent the depression
of syringe plungers or dislodging of syringe tips during
handling and transport. Additionally, disconnection of sys-
Pharmacopeial Forum
tern components (for example, where CSPs are dispensed Pneumatic transport of nonevaluated packaging alternatives
with administration sets attached to them) must be pre- should be avoided. Additional references should be con-
vented throughout the life cycle of the product. Foam pad- sulted as necessary for further information on handling che-
ding or inserts are particularly useful where CSPs are motoxic and other hazardous drugs.
transported by pneumatic tube systems. Regardless of the
methods used, the pharmacy has to evaluate their effective- USE AND STORAGE
ness and the reliability of the intended protection. Evalua- The pharmacy is responsible for ensuring that CSPs in the
tion should be continuous, for example, through a patient-care setting maintain their quality until adminis-
surveillance system, including a system of problem report- tered. The immediate labeling of the CSP container will dis-
ing to the pharmacy. play prominently and understandably the requirements for
Inappropriate transport and handling can adversely affect proper storage and expiration dating. Delivery and patient-
the quality of certain CSPs having unique stability concerns. care-setting personnel must be properly trained to deliver
For example, the physical shaking that might occur during the CSP to the appropriate storage location. Outdated and
pneumatic tube transport, or undue exposure to heat or light, unused CSPs must be returned to the pharmacy for disposal
have to be addressed on a product-specific basis. Alternate or possible reuse.
transport modes or special packaging measures might be Written procedures have to exist to ensure that storage
needed for the proper assurance of quality of these CSPs. conditions in the patient-care setting are suitable for the
The use of tamper-proof closures and seals on CSP ports CSP-specific storage requirements. Procedures should in-
can add an additional measure of security to ensure product clude daily monitoring and documentation of drug storage
integrity regardless of transport method used. refrigerators to ensure temperatures between 2° and 8° and
Chemotoxic and other hazardous CSPs require safeguards the monthly inspection of all drug storage locations by phar-
to maintain the integrity of the CSP and to minimize the ex- macy personnel. Inspections should confirm compliance
posure potential of these products to the environment and with appropriate storage conditions, separation of drugs
the personnel who may come in contact with them. Special and food, proper use of multiple-dose containers, and the
requirements associated with the packaging, transport, and avoidance of using single-dose products as multiple-dose
handling of these agents include the prevention of accidental containers. CSPs, as well as all other drug products, must
exposures or spills and the training of personnel in the event be stored in the patient-care area in such a way as to secure
of an exposure or spill. Examples of special requirements of them from unauthorized personnel, visitors, and patients.
these agents also include exposure-reducing strategies such
as the use of Luer lock syringes and connections, syringe ADMINISTRATION
caps, the capping of container ports, sealed plastic bags, im- Procedures essential for generally ensuring product qual-
pact-resistant containers, and cautionary labeling. Appropri- ity, especially sterility assurance, when readying a CSP for
ate cushioning for pneumatic tube transport should be its subsequent administration include proper hand-washing,
selected and evaluated to ensure that the products so con- aseptic technique, site care, and change of administration
veyed can withstand the stresses induced by the system. sets. Additional procedures may also be essential for certain
Pharmacopeial Forum
products, devices, or techniques. Examples where such spe- should design, implement, and maintain a formal education,
cial procedures are needed include in-line filtration, the op- training, and competency assessment program that encom-
eration of automated infusion control devices, and the passes all the functions and tasks addressed in the foregoing
replenishment of drug product into the reservoirs of implan- sections and all personnel to whom such functions and tasks
table or portable infusion pumps. are assigned. This program should include the assessment
and documentation of procedural breaches, administration
RE-DISPENSED C S P S mishaps, side effects, allergic reactions, and complications

The pharmacy must have the sole authority for determin- associated with dosage or administration, such as extravasa-
ing whether a CSP not administered as originally intended tion. This program should be coordinated with the institu-
can be used for an alternate patient or under alternate con- tion's adverse-event and incident reporting programs.AC/5P2(j
ditions. All CSPs that are not used as originally intended
must be returned to the pharmacy for appropriate disposi-
OFF glTE-GOMPOUNDING PHARMACIES
tion, which may include redispensing, but only if adequate
When the SP is prepared in a lioonsod oompounding pharmacy
continuing quality can be fully ensured. The following may separate from tho pharmacy at the uae site in an organized, profca
sionally ataffod health care facility, the off site compounding phar
provide such assurance: the CSP was maintained under con- maoy must moot all of tho requirements for quality assurance for
oompounding SPs cited in this chapter undor Pharmacy Practices.
tinuous refrigeration and protected from light, if required; Tho receiving pharmacy in tho health oaro facility is responsible for
ensuring that the off aito compounding pharmacy moots all of tho
no evidence of tampering or any readying for use outside quality requirements for tho preparation of SPs cited in thio chapter
before tho off sito oompounding pharmaoy's services arc engaged
the pharmacy exists; and there is sufficient time remaining and through periodic evaluations. Tho receiving pharmacy at tho
health oaro facility is also responsible for all aspects of proper sto
until the originally assigned beyond-use time and date will rago, distribution, handling, and use of tho finished SPs oited under
Pharmacy Practices and Institutional Use Sterile Dmg Products
be reached. Thus, initial preparation and thaw times should after tho products aro roooivod in tho hoalth oaro facility. If there
is no pharmacy in tho receiving health oaro facility, thon tho off sito
be documented and reliable measures should have been ta- oompounding pharmaoy assumes all responsibility for proper oto
rago, distribution, handling, and uao of tho finished SPs. The fol
ken to prevent and detect tampering. Compliance with all lowing guidelines are provided to ensure produot quality and
control after tho SPs loavo tho oompounding pharmaoy during tran
procedures associated with maintaining product quality is sit to tho receiving pharmacy in tho hoalth care facility.
essential. In the absence of adequate assurance that product

quality and packaging integrity (including the connections A
NONINSTITUTIONAL COMPOUNDING
of devices, where applicable) were continuously maintained PHARMACIES
between the time the CSP left and was returned to the phar- Noninstitutional compounding pharmacies (NICPs) that
macy, the CSP must not be redispensed. Additionally, CSPs prepare CSPs must meet all of the requirements for quality
must not be redispensed if redispensing cannot be supported assurance for compounding CSPs cited under Responsibility
by the originally assigned beyond-use time. of Compounding Personnel. The NICP is responsible for
meeting all of the quality requirements for the preparation
EDUCATION AND TRAINING of CSPs and all the requirements for proper storage, distri-
The assurance of CSP quality and packaging integrity is bution, handling, and use of the CSPs. The following guide-
highly dependent upon the proper adherence of all person-
nel to the pertinent written procedures. The pharmacy
Pharmacopeia! Forum
lines are provided to ensure product quality and control after locations. Additional precautions should be used to protect
the CSPs leave the NICP and are in transit to the pat- the shipper and recipients from the adverse effects from any
leakage of sensitizing, chemotoxic, or hazardous agents.
Although the procedures should also ensure that biohazard
PACKING controls are adequate for transit conditions and for meeting
Both the off site compounding pharmacy and tho pharmacy at all OSHA and local requirements, this topic is beyond the
tho health care facility aro equally responsible for ensuring that
the SFs are suitably paokod for transport. If there is no pharmacy scope of the chapter, and other references should be con-
at the health care facility, then the off site compounding pharmacy
all roaponoibility for suitable packing: sulted.
A
The NICP is responsible for ensuring that the CSPs are The patient should have written procedures that specify
suitably packed for transport. Packing should provide ade- the expected packing techniques, configurations, and mate-
quate control of the conditions under which CSPs are trans- rials for the products obtained from an NICP. The proce-
ported to the patient. Packing specifications, including dures should specify the required packing for groups of
configuration and materials, should be appropriate, as deter- products with common storage characteristics and for speci-
mined on a product-by-product basis, to maintain the sto- fic products where unique storage conditions are required to
rage conditions necessary to protect against adverse retain adequate stability and product quality. The required
physical conditions such as temperatures beyond the range packing should be adequate to protect the shipper and the
allowable for the CSP and, where indicated, exposure to patient from the adverse effects from any leakage of sensi-
light. Packing should retain adequate effectiveness for the tizing, chemotoxic, or hazardous agents.
duration of, and under the environmental conditions ex- The NICP should ensure that transit specifications and
pected during, transit. procedures are effective. For example, posttransit determi-
In-transit temperatures of a CSP should be maintained nations of internal pack temperatures following several trial
near the midpoint of the CSP's specified upper and lower shipments of goods packed with new or modified materials,
limits, recognizing that some temperature excursions, not configurations, or techniques provide an indicator of pack-
to exceed the product's specified limits, are permissible during suitability under actual transit conditions. Following the
ing transit. Under no circumstances may excursions exceed initial determination of packing suitability to each use, oc-
the limits specified under Storage Temperatures in the Gen- casional shipments should be subsequently checked, espe-
eral Notices and Requirements for the defined temperature cially whenever transit conditions vary, such as in
conditions. seasonal temperature changes or transit times. This would
The NICP should have written procedures that specify even include relatively brief transport because temperatures
packing techniques, configurations, and materials for in vehicles can easily rise out of the range of acceptability
groups of products with common storage characteristics during summer months. Because different packing config-
and for specific products where unique storage conditions urations, pack size, internal packing matrices (such as, insu-
are required to retain adequate stability and product quality. lated coolers or containers, styrofoam, bubble wrap, and
The written procedures should be appropriate for each trans-
portation mode and duration of transit and may include dif-
ferent requirements for health care facilities with differing
Pharmacopeial Forum
freezer packs) and pack thickness differ in their resistance to Both the NICP and the receiving pharmacy in the health
heat penetration or loss, packing should not vary from estab- care facility should have effective systems for the routine
lished procedures and specifications without evaluation. evaluation of shipping performance. For example, each
pharmacy might periodically review delivery receiving
TRANSIT times or conduct periodic shipping follow-ups. Delivery

Whenever possible, the NICP and the receiving pharmacy time, internal temperature (temperature indicators such as
at the health care facility should control the mode of transit, strips or probes inside packages provide objective evidence
transit time, and transit conditions to ensure that at no time for determining the adequacy of temperature control), con-
are the limits specified under Storage Temperatures in the dition of goods upon receipt, and courteousness of person-
General Notices and Requirements for the defined tempera- nel are some key determinants of acceptable shipping
ture conditions exceeded. In some situations, neither phar- performance.
macy may have complete control over the transit time and
conditions. However, both the NICP and the receiving phar- Home-Use Sterile Preparations
macy in the health care facility can establish reasonable ex- When the CSP is prepared in and dispensed from a li-
pectations of transit time and conditions and can carry out censed pharmacy for intended administration by the patient
procedures to ensure that expectations are routinely met. or by a family member or other caregiver in a setting other
The determination of packing suitability is based on these than an organized, professionally staffed health care facility,
expectations. Where possible, delivery personnel should and is not under the direct supervision of the dispensing
be trained by the pharmacist on how to transport CSPs. pharmacist, the following guidelines are provided to ensure
When common carriers are utilized, the NICP and the re- product quality and control after it leaves the pharma-
ceiving pharmacy are jointly responsible for choosing a re- cy- A USP26
liable carrier capable of consistently fulfilling the

requirements for delivery schedules, transit time duration,
PACKING
handling, care, external temperature controls, and special
The pharmacy is responsible for ensuring that the SPs
handling that may be required. The carrier should be pro-
vided with a written statement of shipping requirements are suitably packed for transport. Packing should provide adequate
control of the conditions under which SPs
and the carrier should provide written assurance of capabil-
AUSP26
ity and commitment to fulfilling these requirements before are transported to the patient. Packing specifications, including
configuration and materials, should be appropriate, as determined
the carrier's services are engaged. on a product-by-product basis, to maintain the storage conditions
necessary to protect the product against adverse physical condi-
Delivery personnel, whether pharmacy employees, em- tions, such as temperatures beyond the range allowable for the SP
pp
ployees of a parent organization, or a common carrier, ^^ÂUSP26
and, where indicated, exposure to light. Packing should retain ade-
should know the shipping requirements of each package quate effectiveness for the duration of, and under the environmen-
tal conditions expected during, transit.
consigned. Printed labels, prominently displayed on the ex- In-transit temperatures f
CSPs.y^d
terior of each package, are usually sufficient. Supplementary should be maintained near the midpoint of the SPa'
printed instructions may be necessary in some instances.
Pharmacopeial Forum
specified upper and lower limits, recognizing that some tempera- IN THE HOME
ture excursion, not to exceed the product's specified limits, is per-
missible during transit. Under no circumstances may excursions The pharmacy's basic responsibilities for ensuring that SPs
exceed the limits specified in the General Notices and Require-
ments under Storage Temperatures for the defined temperature AKSW(j
conditions. in the home maintain their quality until administered include the
The pharmacy should have and follow written procedures that following:
specify packing techniques, configurations, and materials for (1) The immediate labeling of the SP
groups of products with common storage characteristics and for
specific products where unique storage conditions are required to ±USP2g
retain adequate stability and product quality. It must be recognized container displays prominently and understandably the re-
that additional precautions should be used to protect the shipper, quirements for proper storage and beyond-use dating.
patient, and caregiver from adverse effects from any leakage of (2) Adequate information is obtained to assure the pharmacist
sensitizing or chemotoxic agents. Although written procedures that the storage conditions existing in the home are suitable
should also ensure that biohazard controls are adequate for transit for h SP%
conditions and for meeting all OSHA and local requirements, this
topic is beyond the scope of this chapter, and other references USP26
should be consulted. specified storage requirements. (It is acceptable for the phar-
macist to obtain this information through documentation by
The pharmacy should ensure that transit specifications and pro- nursing or delivery personnel.)
cedures are effective. For example, post-transit determinations of (3) The patient has an acceptable temperature measurement de-
internal pack temperatures following several trial shipments of vice in the refrigerator and understands the importance of
goods packed with new or modified materials, configurations, or its use for maintaining proper storage temperature.
techniques provide an indicator of packing suitability under actual (4) Written information, in addition to the immediate labeling,
transit conditions. Following the initial determination of packing should be issued explaining proper storage, interpretation of
suitability, occasional shipments should be subsequently checked, the beyond-use dating, and how to look for signs of unsuit-
especially whenever transit conditions vary, such as from seasonal ability for use.
temperature changes or transit times. Because different packing The patient or caregiver should be informed of the need to notify
configurations, pack size, internal packing matrices (insulated the pharmacy promptly of any actual or suspected malfunction of
coolers or containers, styrofoam, bubble wrap, freezer packs, the refrigerator, freezer, or temperature measurement device. The
etc.), and pack thickness differ in their resistance to heat penetra- pharmacy should assist patients or caregivers as necessary to en-
tion or loss, packing should not vary from established procedures sure that proper storage conditions for SP§
and specifications without evaluation.
AUSP26
are maintained with little or no interruption.

The pharmacy is responsible for ensuring that the home is vis-
TRANSIT ited or the patient is contacted by other means at regular intervals to
confirm compliance with appropriate drug storage conditions,
Unlike the selection of the adherence to packing specifications, cleanliness, separation of food and drug items, avoidance of impro-
the pharmacy may lack complete control over transit time and con- per re-use of multiple dose containers or supplies such as tubing or
ditions. However, the pharmacy can establish reasonable expecta- syringes, avoidance of the use of single-dose products as multiple-
tions of transit time and conditions and can carry out procedures to dose containers, and product inventory as indicative of product
ensure that expectations are usually met. The determination of usage compliance. Inappropriately stored, exteriorly soiled, ex-
packing suitability is based on these expectations. Where possible, pired, or visibly defective drug products should be removed from
delivery personnel should be trained by the pharmacist on how to the patient's possession, using the opportunity to instruct the pa-
transport SPsr tient or caregiver or to reinforce storage and handling responsibil-
ities. Similarly, the home visit should also assess compliance with
AWy/2(j
waste containment and disposal. The pharmacy may entrust the
When common carriers are utilized, the pharmacy is responsible home visit to another health professional or paraprofessional.
for choosing a reliable carrier capable of consistently fulfilling the
pharmacy's requirements for delivery schedules, transit time dura- Change to read:
tion, handling, care, external temperature controls, and special
handling that may be required. The pharmacy should provide the
carrier with a written statement of shipping requirements and PATIENT OR CAREGIVER TRAINING
should obtain from the carrier an assurance of capability and com-
mitment for fulfilling these requirements before the pharmacy en- A formal training program should be provided as a means to en-
gages the carrier's services. sure understanding and compliance with the many special and
Delivery personnel, whether employees of the pharmacy, the complex responsibilities placed upon the patient or caregiver for
parent organization, or the common carrier, should know the ship- the storage, handling, and administration of SP
ping requirements of each package consigned. Printed labels, pro-
minently displayed on the exterior of each package, are usually AUSP26
sufficient. Supplementary printed instructions may be necessary The instructional objectives for the training program should in-
in some instances. clude all home care responsibilities expected of the patient or care-
The pharmacy should have an effective system for the routine giver and should be specified in terms of patient or caregiver
evaluation of shipping performance. For example, the pharmacy competencies.
might periodically review delivery receipts or conduct periodic Upon the conclusion of the training program, the patient or care-
shipment follow-ups by telephoning patients or caregivers. Deliv- giver should, correctly and consistently, be able to do the follow-
ery time, internal temperature (temperature indicators such as strips ing:
or probes inside packages provide objective evidence for determin- (1) Describe the therapy involved, including the disease or con-
ing the adequacy of temperature control), condition of goods upon dition for which the SP
receipt, and courteousness of personnel are some key determinants
A
of acceptable shipping performance. CSP A.USP26
Pharmacopeial Forum
is prescribed, goals of therapy, expected therapeutic outcome, bilities. Post-training verbal counseling should also be used peri-
and potential side effects of the Sft odically, as appropriate, to reinforce training and to ensure
continuing correct and complete fulfillment of responsibilities.
(2) Inspect all drug products, devices, equipment, and supplies on Change to read:
receipt to ensure that proper temperatures were maintained
during transport and that goods received show no evidence
of deterioration or defects.
(3) Handle, store, and monitor all drug products and related sup- PATIENT MONITORING AND COMPLAINT
plies and equipment in the home, including all special require- SYSTEM
ments related to same.
(4) Visually inspect all drug products, devices, and other items The pharmacy must have written policies and procedures de-
the patient or caregiver is required to use immediately prior scribing the monitoring of patients using SPs
to administration in a manner to ensure that all items are ac-
ceptable for use. For example, SPs CSPS. *USP26
and the handling of reports of adverse events.
should be free from leakage, container cracks, particulates,
precipitate, haziness, discoloration, or other deviations from
the normal expected appearance, and the immediate packages Outcome Monitoring
of sterile devices should be completely sealed with no evi-
dence of loss of package integrity. The pharmacy is responsible for developing a patient monitoring
(5) Check labels immediately prior to administration to ensure plan, which includes written outcome measures and systems for
the right drug, dose, patient, and time of administration. routine patient assessment. The outcome monitoring system should
(6) Clean the in-home preparation area, scrub hands, use proper provide information suitable for the evaluation of the quality of pa-
aseptic technique, and manipulate all containers, equipment, tient care and of pharmaceutical services. Examples of assessment
apparatus, devices, and supplies used in conjunction with ad- parameters include infection rates, rehospitalization rates, inci-
ministration. dence of adverse drug reactions, catheter complications, and other
(7) Employ all techniques and precautions associated with Si* variables that may serve as meaningful indicators of the effective-
ness and suitability of the home use of SPs?
^.USP26
administration, for example, preparing supplies and equip- CSPS. jûsp26
ment, handling of devices, priming the tubing, and disconti- In selecting suitable outcome measures, the focus should be on
nuing an infusion. high-risk, high-volume, or problem-prone factors.
(8) Care for catheters, change dressings, and maintain site pa-
tency as indicated.
(9) Monitor for and detect occurrences of therapeutic complica-
tions such as infection, phlebitis, electrolyte imbalance, and Reports
catheter misplacement.
(10) Respond immediately to emergency or critical situations such The pharmacy should have policies and procedures for the re-
as catheter breakage or displacement, tubing disconnection, ceipt, documentation, handling, and disposition of reports of pa-
clot formation, flow blockage, and equipment malfunction. tient problems, complaints, adverse drug reactions, drug product
(11) Know when to seek and how to obtain professional emer- or device defects, and other adverse events reported by patients,
gency services or professional advice. caregivers, family members, pharmacists, or other health profes-
(12) Handle, contain, and dispose of wastes, such as needles, syr- sionals. The pharmacy should have a procedure to ensure that
inges, devices, biohazardous spills or residuals, and infectious the patient receives prompt and appropriate medical attention as
substances. necessary in response to all adverse incidents from SPs
Training programs should include hands-on demonstration and
practice with actual items that the patient or caregiver is expected AUSP26
to use, such as SP or devices. When a complaint or problem prompts a suspicion that

nn cp
LUX wl
AUSP26
containers, devices, and equipment. The patient or caregiver ÛSP2S
should practice aseptic and injection technique under the direct ob- or a device may be defective, the pharmacy should also be able to
servation of a health professional. identify and recall the potentially defective item to the patient level
The pharmacy, in conjunction with nursing or medical person- whenever appropriate.
nel, is responsible for ensuring initially and- on an ongoing basis Procedures should also include a mechanism for periodic review
that the patient or caregiver understands, has mastered, and is cap- of reports received to determine any need for correction of under-
able of and willing to comply with all of these home care respon- lying systems problems. All reports received should be maintained
sibilities. This should be achieved through a formal, written for a reasonable period of time in a log, file, or binder dedicated for
assessment program. All specified competencies in the patient or this purpose and readily retrievable as needed for subsequent ana-
caregiver's training program should be formally assessed. The pa- lysis, legal or regulatory inquiry, or quality assurance audit. Stan-
tient or caregiver should be expected to demonstrate to appropriate dardized forms or formats for the reporting and recording of
health care personnel their mastery of their assigned activities be- incidents, complaints, and so forth should be used. Reports should
fore being allowed to administer SPs be completed and signed by the individual receiving it or by the
individual involved in the situation. Procedures should depict the
classification, documentation, investigation, and resolution of all
unsupervised by a health professional. reports and should provide a mechanism for participation in var-
Printed material such as checklists or instructions provided dur- ious federal and state reporting programs such as USP or FDA pro-
ing training may serve as continuing post-training reinforcement of grams for reporting reaction problems, or defects with drug
learning or as reminders of specific patient or caregiver responsi- products or medical devices.
Pharmacopeial Forum
is to incorporate those provisions. Other revisions include chan-

Change to read: ging the term "should" to "shall" where the Expert Committees
determined that a requirement is mandatory.
(DSB, DSN; G. Giancaspro) RTS—36116-2

THE QUALITY ASSURANCE PROGRAM
A provider of SPs
Change to read:
should nave in place a formal Quality Assurance (QA) Program
intended to provide a mechanism for monitoring, evaluating, cor-
recting, and improving the activities and processes described in
this chapter. Emphasis in the QA Program should be placed on
maintaining and improving the quality of systems and the provi-
(2750) MANUFACTURING
sion of patient care. In addition, the QA program should ensure that
any plan aimed at correcting identified problems also includes ap-
PRACTICES FOR NUTRITIONAL
propriate follow-up to make certain that effective corrective actions
were performed.1
Characteristics of a QA plan include the following: ±DIETARYAm,
(1) Formalization in writing;
(2) Consideration of all aspects of the preparation and dispensing SUPPLEMENTS
of products as described in this chapter, including environ-
mental testing, validation results, etc.;
(3) Description of specific monitoring and evaluation activities; As is indicated in the General Notices under Significant Figures
(4) Specification of how results are to be reported and evaluated; and Tolerances, tolerances are based upon the consideration that
(5) Identification of appropriate follow-up mechanisms when ac- the article is produced under recognized principles of good manu-
tion limits or thresholds are exceeded; and facturing practice. Many of the principles in this general informa-
(6) Delineation of the individuals responsible for each aspect of tion chapter are basic in that they apply equally to various types of
the QA program. products and levels of technology, and that they are derived from
In developing a specific plan, focus should be on establishing the current good manufacturing practices for drugs. However, the
objective, measurable indicators for monitoring activities and pro- practical application of these principles to nutritional produoto
cesses that are deemed high-risk, high-volume, or problem-prone. A
dietary pp
Appropriate evaluation of environmental monitoring might in- may be different.
clude, for example, the trending of an indicator such as settling
plate counts. In general, the selection of indicators and the effec- The principles set forth in this general chapter contain recom-
tiveness of the overall QA plan should be reassessed on an annual mended minimum current good manufacturing practices for the
basis. methods to be used in, and the facilities and controls to be used
for, the manufacture of a nutritional
yA6,ym
supplement to assure that such a product meets the requirements of
safety, and has the identity and strength and meets the quality and
purity characteristics that it is represented to possess.
BRIEFING
Establishments engaged solely in the harvesting, storage,
(2750) Manufacturing Practices for Nutritional Supple-
ments, USP 25 page 2484. This general chapter was introduced or distribution of one or more "raw agricultural commod-
in 1993 to support the monographs for multivitamin and mineral
preparations and other nonbotanicals only. The Dietary Supple- ities" as defined in section 201(r) of the Dietary Supple-
ments Health and Education Act of 1994 (DSHEA) recognized bo-
tanical preparations, in addition to vitamins and minerals. Thus, ments Health and Education Act of 1994, which are
there is a need to introduce provisions pertaining to botanical pre-
parations in the general chapter. The present proposal for revision ordinarily cleaned, prepared, treated, or otherwise processed
before being marketed to the consuming public are excluded
from this chapter.A£/5W(5
A glossary of terms used in this general chapter is presented at
the end.
9
Other accepted terms that describe activities aimed at assessing and im-
proving the quality of care rendered include Continuous Quality Improve-
ment, Quality Assessment and Improvement, and Total Quality
Management.
10
The use of additional resources, such as die Accreditation Manual for
Home Care from the Joint Commission on Accreditation of Healthcare Or-
ganizations, may prove helpful in the development of a QA plan.
Pharmacopeial Forum
Change to read: An adequate number of qualified personnel to perform and

supervise the manufacture of each nutritional
A
dietary A ( / 5 m
ORGANIZATION AND PERSONNEL product snould be provided.
Responsibilities of Quality Control Unit

Personnel Responsibilities
A quality control unit should
Porsonnol ongagod in tho manufacture of a nutritional produot
shall. usp26 should woar oloan clothing appropriate for tho duties thoy perform.
be established that has the responsibility and authority to approve Protective apparel, ouoh as hoad and hand covering, should bo
or reject all components, worn, as nooossary, to protoot produots from oontamination.
A
raw materials, A[/ ^ 2(5 All porsonnol should praotioo good sanitation and health habits.
product containers, closures, in-process materials, packaging mate- Anyone having an apparent illnooo or open looion (shown by mod-
rial, labeling, and finished nutritional produota, ioal examination or supervisory obsorvation) that may adversely
affoot tho safoty or quality of produots should be oxoludod from
^dietary supplements,AUSP26 direct oontaot with components, produot containers, closures, in
and the authority to review production records to ensure that no process materials, and finished produota until tho condition is oor
errors have occurred or, if errors have occurred, that they have been rooted or determined by competent modioal personnel not to joo
fully investigated. The quality control unit should be responsible pardizo tho safety or quality of those products. All porsonnol should
for approving or rejecting products manufactured, processed, report to supervisory porsonnol any health conditions that may
packed, or held under contract by another company. havo an adverse offoot on 3uoh products.
Adequate laboratory facilities for the testing and approval (or Personnel working in diroot oontaot with ingredients, in proooss
rejection) of oompononta, materials, or finished produots should wash thoir hands thoroughly
A
before starting work, after an absonoo from tho work station, and at
raw materials, Aaswtf other timos whon tho hands havo booomo soiled or oontaminatod.
product containers, closures, packaging materials, in-process mate- Those persons should also remove all insoouro jewelry and remove
rials, and nutritional produota from hands any jowolry that cannot bo sanitized proporly.
A
dietary supplements Aas/ , 26 If glovos aro used, porsonnol should maintain thorn in an intaot,
should be available to the quality control unit. clean; and sanitary oondition. Suoh gloves should bo of an im
The quality control unit should have the responsibility for ap- pormoablc material oxoopt whore thoir usage would bo inappropri
proving or rejecting all procedures or specifications that impact ato or incompatible with tho work involved.
on the identity, strength, quality, and purity of the nutritional pro Porsonnol should not storo olothing or othor personal belong
ings, oat or drink beverages, or use tobacco in any form in any
manufacturing area; or in aroas whore produots or ingredients aro
A
dietary supplement. AWSp2(5 exposed, or in areas used for washing equipment or utonsila.
All responsibilities and procedures applicable to the quality control All porsonnol should tako any othor nooossary precaution to pro
unit should vont oontamination of produots with microorganisms or foreign
substanoos including, but not limited to, perspiration, hair, cos
motios, tobaooo, ohemioals, and modioants.
be in writing.
A
The company management shall take all reasonable
Personnel Qualifications measures and precautions to assure the following:

Each person engaged in the manufacture of a nutritional produot (a) Disease control. Any person who, by medical exam-
A
dietary supplementAt/5/,2(5 ination or supervisory observation, is shown to have, or ap-
should have the proper education, training, and experience (or any
combination thereof) needed to perform the assigned functions. pears to have, an illness, open lesion, including boils, sores,
Training should be in the particular operation(s) that the employee
performs and should bo based on current good manufacturing prao or infected wounds, or any other abnormal source of micro-
bial contamination by which there is a reasonable possibility
AUSP26
as they relate to the employee's functions. of an in-process or finished dietary product becoming adult-
A
Appropriate documentation of training shall be retained by erated, or processing equipment, utensils or packaging ma-
the company. AUSP26 terials becoming contaminated, shall be excluded from any
Each person responsible for supervising the manufacture of a
nutritional produot operations which may be expected to result in such adultera-
A
dietary productAUS.,,2(j tion or contamination until the condition is corrected. Per-
should have the proper education, training, and experience (or any
combination thereof) to perform assigned functions in such a man- sonnel shall be instructed to report such health conditions
ner as to provide assurance that the product has the safety, identity,
strength, quality, and purity that it is represented to possess. to their supervisors.
Pharmacopeia! Forum
(b) Cleanliness. All persons working in direct contact — Wearing, where appropriate, in an effective manner,
with raw materials, in-process or finished dietary products, hair nets, caps, beard covers, or other effective hair re-
processing equipment, utensils or packaging materials shall straints.
conform to hygienic practices while on duty to the extent — Storing clothing or other personal belongings in areas
necessary to protect against adulteration or contamination other than where in-process or finished product is ex-
of such materials. The methods for maintaining cleanliness posed or where processing equipment or utensils are
include, but are not limited to: washed.
— Confining the following to areas other than where in-
— Wearing outer garments suitable to the operation in a
process or finished product may be stored or exposed,
manner that protects against the adulteration of raw ma-
or where processing equipment or utensils are washed:
terials, in-process or finished dietary products, or con-
eating food, chewing gum, drinking beverages, or using
tamination of processing equipment, utensils or
tobacco.
packaging materials.
— Taking any other necessary precautions to protect
— Maintaining adequate personal cleanliness.
against adulteration of raw materials, in-process or fin-
— Washing hands thoroughly (and sanitizing if necessary
ished product, or contamination of processing equip-
to protect against contamination with undesirable mi-
ment, utensils, or packaging materials with micro-
croorganisms) in an adequate hand-washing facility be-
organisms or foreign substances including, but not lim-
fore starting work, after each absence from the work
ited to, perspiration, hair, cosmetics, tobacco, chemi-
station, and at any other time when the hands may have
cals, and medicines applied to the skm.AUSp26
become soiled or contaminated.
Change to read:
— Removing all unsecured jewelry and other objects that
might fall into raw materials, in-process or finished
dietary product, equipment, or containers, and remov-
BUILDINGS, AND FACILITIES
ing hand jewelry that cannot be adequately sanitized
during periods in which in-process or finished product A
Grounds
is manipulated by hand. If such hand jewelry cannot be
The grounds about a dietary product manufacturing plant
removed, it may be covered by material which can be
under the control of the operator shall be kept in a condition
maintained in an intact, clean, and sanitary condition
that will protect against the adulteration of dietary products.
and which effectively protects against the adulteration
The methods for adequate maintenance of grounds include,
of dietary product or contamination of processing
but are not limited to:
equipment, utensils or packaging materials.
— Maintaining gloves, if they are used in raw materials, — Properly storing equipment, removing litter and waste,
in-process or finished product handling, in an intact, and cutting weeds or grass within the immediate vici-
clean, and sanitary condition. The gloves should be of nity of the plant building or structures that may consti-
a material that adequately protects the product from tute an attractant, breeding place, or harborage for
contamination. pests.
Pharmacopeia! Forum
— Maintaining roads, yards, and parking lots so that they product containers, closures, labeling, in-process materials, or fin-
ished products, and to prevent contamination. Theflowof oompo-
do not constitute a source of adulteration in areas where
A
raw ,AWs/2tf
product is exposed. product containers, closures, labeling, in-process materials, and
products through the building or buildings should be designed to
— Adequately draining areas that may contribute to pro- prevent contamination.
Operations should bo performed within apooifioally defined
duct adulteration by seepage, foot-borne filth, or pro- areas of adoquato giao to provont contamination OF mixupo. Those
separate or defined areas are a3 follows:
viding a breeding place for pests.
— Operating systems for waste treatment and disposal in Ôperations should be performed within specifically de-
an adequate manner so that they do not constitute a fined areas of adequate size to prevent contamination or
source of adulteration in areas where product is ex- mixups or adulterations of in-process or finished dietary
posed. If the plant grounds are bordered by grounds product, or contamination of processing equipment, uten-
not under the operator's control and not maintained in sils, or packaging materials with microorganisms, chemi-
the manner described above, care shall be exercised in cals, filth, or other extraneous material. The potential for
the plant by inspection, extermination, or other means mixups and product adulteration may be reduced by ade-
to exclude pests, dirt, and filth that may be a source of quate product safety controls and operating practices or ef-
product adulteration. A[/5m fective design, including the separation of operations in
which contamination is likely to occur, by one or more of
A the following means: location, time, partition, airflow,en-
BuHding
closed systems, or other effective means. There should be
Any building or buildings used in the manufacture of a nutri
separate or defined areas as follows:
UIVIU1 Y A.USP26
product snould be of suitable size, construction, and location to fa 1. An area for the receipt, identification, storage, and with-
eilitato cleaning, maintenance, and proper operations.
A holding from use of components, product containers,
and shall be constructed in such a manner that floors, walls,
closures, and labeling, pending the appropriate sam-
and ceilings may be adequately cleaned and kept clean and
pling, testing, or examination by the quality control unit
kept in good repair; that drips or condensate from fixtures,
before release for manufacturing or packaging.
ducts and pipes does not adulterate raw materials, in-pro-
2. An area for the storage of released components, product
cess, or finished dietary product, or contaminate product
containers, closures, and labeling.
containers, utensils, or packaging materials; and that aisles
3. An area for storage of in-process materials.
or working spaces are provided between equipment and
4. An area for manufacturing and processing operations.
walls and are adequately unobstructed and of adequate
5. An area for packaging and labeling operations.
width to permit employees to perform their duties and to
protect against adulterating in-process or finished product, 6. An area for control and laboratory operations.AasW(f
Any building uood in the manufaoturo of a nutritional product shall
or contaminating processing equipment with clothing or bo maintained in a good stato of repair.
personal contact.AVSP26
It should have adequate space for the orderly placement of equip-
ment and materials to prevent mixups between different oompo
A
raw materials,AUS.W(J
Pharmacopeial Forum
A
Any building used in the manufacture of a dietary product the potential for adulterating raw materials, in-process, or
shall permit the taking of proper precautions to protect diet- finished dietary products, or contaminating processing
ary ingredients or dietary supplements in outdoor bulk fer- equipment, utensils, or packaging materials. AUSP26
mentation vessels by any effective means, including:
(i) Using protective coverings

Plumbing
(ii) Controlling areas over and around the vessels to elim- Potable water
inate harborages for pests. A
at a suitable temperature, and under pressure as need-
(iii) Checking on a regular basis for pests and pest infesta- AUSP26
should be supplied in a plumbing system free of defects that could
tion. contribute contamination to any nutritional
(iv) Skimming the fermentation vessels, as necessary. AUSP26 yAt^
product. Potable water should meet the standards prescribed in the
Environmental Protection Agency's Primary Drinking Water Reg-
ulations (40 CFR Part 141). Water not meeting such standards
should not be permitted in the potable water system for Purified
Lighting Water. If potable water is to be used as a component,
A
raw material,. USP26
Adequate lighting should it should be further purified to satisfy compendial requirements.
Drains should be of adequate size and, where connected directly
be provided in all areas and should not expose bulk orfinishedpro- to a sewer, should have an air break or other mechanical device to
duct to adulteration or contamination. prevent back-siphonage.
A
Adequate lighting should be provided in hand-washing
areas, dressing and locker rooms, and toilet rooms, and in Sewage and Refuse
all areas where product is examined, processed, or stored Sewage, trash, and other refuse in and from the building and im-
mediate premises should
and where equipment or utensils are cleaned; and should
provide safety-type light bulbs, fixtures, sky-lights, or other be disposed of in a safe and sanitary manner.
glass suspended over exposed product in any step of pre-

paration or otherwise protect against product adulteration Washing and Toilet Facilities
in case of glass breakage.AVSP26 Adequate washing facilities should
shall AJJSP26
be provided, including hot and cold water, soap or detergent, air

driers or single-service towels, and clean toilet facilities easily ac-
cessible to working areas.
Ventilation, Air Filtration, Air Heating and Cooling
Adequate ventilation should
^General Maintenance and SanitationAJJSP26
be provided, as well as equipment for adequate control over micro-
organisms, dust, humidity, and temperature when appropriato for Sanitation
A
used inAUSP26 Any building used in the manufacture of a nutritional
the manufacture of a nutritional product. dietaryf[/^5
A
product should be maintained in a clean and sanitary condition
dietary product to minimize odors and vapors (including A
and shall be kept in repair sufficient to prevent raw materi-
steam and noxious fumes) in areas where they may adulte-
als, in-process, or finished dietary products from becoming
rate dietary products; and to locate and operate fans and
adulterated. AVSP26
other air-blowing equipment in a manner that minimizes XL TJiWTtjTv*™
shall
hall AUSP26
Pharmacopeial Forum
be free of infestation by rodents, birds, insects, and other vermin. adulteration of raw materials, in-process, or finished pro-
Trash and organic waste matter shall be held and disposed of in a
timely and sanitary manner. duct, or contamination of processing equipment, utensils
A or packaging materials.AUSP26
Cleaning compounds and sanitizing agents used in clean-
Written procedures are also neooasary
ing and sanitizing procedures shall be free from undesirable
q A U s p 2 6
microorganisms and shall be safe and adequate under the for use of suitable rodenticides, insecticides, fungicides, fumigat-
ing agents, and cleaning and sanitizing agents. These procedures
conditions of use. Compliance with this requirement may should be designed to prevent the contamination of equipment,
components,
be verified by any effective means including purchase of A
raw ûs/^
these substances under a supplier's guarantee or certifica- product containers, closures, packaging, labeling materials, or pro-
ducts. Rodenticides, insecticides, and fungicides should be regis-
tion, or examination of these substances for contamination. tered and used in accordance with the Federal Insecticide,
Fungicide, and Rodenticide Act.
Only the following toxic materials may be used or stored in Sanitation procedures should
a plant were product is processed or exposed: sha.\\AUSp26
apply to work performed by contractors or temporary employees as
well as work performed by full-time employees during the ordinary
course of operations.
(i) Those required to maintain clean and sanitary condi-
Change to read:
tions;
(ii) Those necessary for use in laboratory testing proce-
dures; EQUIPMENT
(iii) Those necessary for plant and equipment maintenance Equipment used in the manufacture of a nutritional product
and operation; and A

dietary supplement shallAas/>2<j
be of appropriate design, adequate size, and suitably located to fa-
(iv) Those necessary for use in the plant's operations. AVSP26 cilitate operations for its intended use and for its cleaning and
Written procedures assigning responsibility for sanitation and maintenance.
describing in sufficient detail the cleaning schedules, methods,
equipment, and materials to be used in cleaning the building and
facilities are nooossary.
A
shall be required.AUSP26 Construction
All equipment should
A
Toxic cleaning compounds, sanitizing agents, and pesti-
sha\[AUSP26
cide chemicals shall be identified, used, held, and stored in a be constructed so that surfaces that contact components;
A
raw materials,AUSP26
manner that protects against adulteration of raw materials, in-process materials, or finished products are not reactive, additive,
or absorptive so as to alter the safety, identity, strength, quality, or
in-process, or finished product, or contamination of proces- purity of the product beyond the established requirements.
Any aubotanooa required for operations such as lubricants or
sing equipment or packaging materials. All relevant regula- ooolant3 ahould not oomo into oontaot with components, product
container, olosurca, in process materials, or finished products that
tions promulgated by other Federal, state, and local would alter the safety, identity^ strongthy quality, or purity of the
product beyond the established requirements.
government agencies for the application, use or holding of A
The design, construction, and use of equipment and uten-
these products should be followed.
sils shall preclude the adulteration of raw materials, packa-
No pests shall be allowed in any area of a dietary product
ging materials, in-process materials, or finished product
manufacturing plant. Effective measures shall be taken to
with any substances required for operation such as lubri-
exclude pests from the processing areas and to protect
cants, fuel, or any other contaminants such as metal frag-
against the adulteration of product on the premises by pests.
ments, contaminated water, etc.AUSP26
The use of insecticides or rodenticides is permitted only un-
der precautions and restrictions that will protect against the
Pharmacopeial Forum
product containers, and closures at all times should be handled and

Cleaning and Maintenance stored in a manner to prevent contamination.
Equipment and utensils ohould
A
Raw agricultural materials that contain soil or other con-
AUSp26
be cleaned, maintained, and sanitized at appropriate taminants shall be washed or cleaned as necessary. Water
q
intervals used for washing, rinsing, or conveying raw agricultural ma-
A terials shall be safe and of adequate sanitary quality. Not-
, between the manufacture of different batches of the same
product and between the manufacture of different prod- withstanding the general requirement for potable water,
water may be reused for washing, rinsing, or conveying
to prevent malfunctions or contamination that would alter the
safety, identity, strength, quality, or purity of the product beyond raw agricultural materials if it does not increase the level
the established requirements.
Written procedures for cleaning and maintaining equipment, in- of contamination of such materials.AU5/>2(5
cluding utensils, used in the manufacture of a product should be
established and followed. These procedures should include, but Bagged or boxed oomponento
are not necessarily limited to, the following: A
— Assignment of responsibility for cleaning and maintaining raw materialsAUS-W(5
equipment. of product containers or closures should be stored off the floor and
— Maintenance and cleaning schedules, including, where appro suitably spaced to permit cleaning and inspection.
Each lot should be appropriately identified as to its status (i.e.,
quarantined, approved, or rejected).
^ 9 A llSPzn
sanitizing schedules.
— A description in sufficient detail of the methods, equipment,
and materials used in cleaning and maintenance operations, Receipt and Storage of Untested Components,
and the methods of disassembling and reassembling equip-
ment, as necessary, to assure proper cleaning and mainte- A
nance. Raw A
— Removal or obliteration of previous batch identification. Product Containers, and Closures
— Identification and protection of clean equipment from con-
tamination prior to use. A
Written procedures shall be established and followed de-
— Inspection of equipment for cleanliness immediately before
use.
scribing the receipt, identification, examination, handling,
A
A written record of major equipment cleaning and use shall and sampling of raw materials.AUSP26
Upon receipt and before acceptance, each container or grouping of
be maintained in individual equipment logs that show the containers of componentBj
A
date, product and lot number of each batch processed. The raw materials,AUS.w<*
product containers, and closures should be examined visually for
persons performing the cleaning shall record in the log that appropriate labeling as to contents, container damage, or broken
seals, and for contamination. They are then stored under quarantine
the work was performed. Entries in the log should be in until they have been tested or examined, as appropriate, and re-
leased.
chronological order.AVSP26 A
Raw materials shall be held in bulk, or in containers de-
Change to read:
signed and constructed so as to protect against adulteration
and shall be held at such temperature and relative humidity
COMPONENTS, and in such a manner as to prevent a dietary ingredient or
A dietary supplement from becoming adulterated. Frozen
RAW MATERIALS,^™
PRODUCT CONTAINERS, AND CLOSURES
raw materials and other ingredients shall be kept frozen. If
Written procedures describing in sufficient detail the receipt,
identification, storage, handling, sampling, testing, and approval thawing is required prior to use, it shall be done in a manner
or rejection of component^
that prevents the raw materials and other ingredients from
A
raw materials,AUSP26
product containers, and closures should be provided. becoming adulterated within the meaning of the h.cX.AVSP26
Component^
A
Raw
Pharmacopeial Forum
port of analysis may be accepted from the supplier of a com

Testing and Approval or Rejection
Each lot of components, A
raw material, provided that the manufacturer estab-
A
raw materials, AUS p 26 lishes the reliability of the supplier's analyses andAUSP26
product containers, and closures should be sampled, tested, or ex- provided that at least one identity test is conducted on such
amined, as appropriate, and released for use by the quality control
unit. Based upon adequate process validation, oomponont
A U ^ A
in-process controls and statistical confidence, a skip-lot sampling raw materialAUS.p2(5
plan is an alternative to testing every batch. by the manufacturer.
Representative samples should be collected for testing or exam- Containers and closures should be tested for conformance
ination. with all appropriate written procedures. However, a certificate
^Sampling of botanicals should be in compliance with the of testing may be accepted from the supplier, provided that at
least a visual identification is conducted on such containers/
closures by the manufacturer.
p r o v i s i o n s s e t i n A r t i c l e s of B o t a n i c a l O r i g i n ( ) ^ ^ Each lot of a oomponont,
The number of containers sampled, and the amount of material ta-
ken from each container, should be based upon appropriate criteria
such as statistical criteria for component A
raw material, XQwork,AUSP26
A
raw material. USP26 product container, or closure that is liable to contamination
variability, confidence levels, and degree of precision desired, the with filth, insect infestation, or other extraneous adulterant
past quality history of the supplier, and the quantity needed for ana- should be examined against established specifications for
lysis and reserve where required. The following procedures should such contamination
be used to collect the samples:
— The containers of components A
and shall comply with any applicable Food and Drug
A
raw materials.^p^tf Administration regulations and guidelines.AUSP26
selected should be cleaned, where necessary, by appropriato Skip-lot examination should not apply in such cases.
Eaoh lot of a oomponont, product container, or olosuro that i3
liable to miorobiologioal oontamination that ia objootionablo
in viow of ita intondod uoo ohould bo-subjootod to miorobio
means. logical tosta boforo use. Skip lot examination should not ap
The containers should be opened, sampled, and resealed in a ply in such oaooa.
manner designed to prevent contamination of their contents
and contamination of other oomponento, A
Each lot of a raw material that is liable to microbiolo-
A gical contamination that is objectionable in view of its
raw A[iSp2(5
product containers, or closures.
- These containers should be identified so that the following in- intended use shall be subjected to microbiological tests
formation can be determined: name of the material sampled,
the lot number, the container from which the sample was ta- before use. Raw materials shall either not contain levels
ken, the date on which the sample was taken, and the name of
the person who collected the sample. of microorganisms that may produce food poisoning or
Use the following procedure to examine and test the samples:
- At least one test should be conducted to verify the identity of other disease in humans, or they shall be otherwise trea-
each oomponont
ted during manufacturing operations so that they no
A longer contain levels that would cause the product to
raw material. USP26
of a product if skip-lot testing is used. be adulterated within the meaning of the Act. In lieu
A
Such tests may include any appropriate test with suffi- of such testing by the manufacturer, a guarantee or cer-
cient specificity to determine identity, including chemi- tification of analysis may be accepted from the supplier
cal and laboratory tests, gross organoleptic analysis, of a component provided that the manufacturer estab-
microscopic identification, or analysis of constituent lishes the reliability of the supplier's analysis.
markers.^™ Raw materials and other ingredients susceptible to
Each oomponont adulteration with aflatoxin or other natural toxins shall
A
raw materialA[/5p2(5
should be tested for conformity with all appropriate written comply with current Food and Drug Administration
specifications for purity, strength, and quality. However, a re-
regulations, guidelines, and action levels for poisonous
Pharmacopeial Forum
or deleterious substances and the requirements in Arti- Rejected Components,

cles of Botanical Origin (561), before these materials A
Raw ^
or ingredients are incorporated into a finished dietary Product Containers, and Closures
Rejected oompononta,
ingredient or dietary supplement. Compliance with this A
raw materials,At/5/>2<5
requirement may be accomplished by analyzing these product containers, and closures should be identified and con-
trolled under a quarantine system that prevents their use in manu-
materials and ingredients for aflatoxins and other natur- facturing or processing operations for which they are unsuitable.
al toxins or, in lieu of such testing by the manufacturer, Change to read:
a guarantee or certification of analysis may be accepted

from the supplier of a raw material provided that the PRODUCTION AND PROCESS CONTROLS
manufacturer establishes the reliability of the supplier's
Written Procedures
Written procedures should be provided for production and pro-
cess control designed to ensure that the nutritional producta
— Any lot of oomponont; A
dietary supplementsAUSK<j
have the identity, strength, quality, and purity they are represented
to possess. These procedures should be drafted, reviewed, and ap-
raw proved by the appropriate organizational units and reviewed and
product container, or closure that meets the appropriate writ- approved by the quality control unit. These production and process
ten specifications of identity, strength, quality, and purity and control procedures should be followed in the execution of the var-
related tests may be approved and released for use. Any lot of ious production and process control functions and should be docu-
such material that does not meet such specifications should be mented at the time of performance. Any deviation from the written
rejected. procedures should be recorded and justified.
Use of Approved Components, A

(1) A11 operations in the receiving, inspecting, transport-
A
R a w Materisk\s,AUSP26
Product Containers, and Closures ing, segregating, preparing, manufacturing, packaging,
Components,
and storing of dietary products shall be conducted in
A
Raw AC5/2 <j
product containers, and closures approved for use should be rotated accordance with adequate sanitation principles.
so that the oldest approved stock is used first. Deviation from the
requirement is permitted if such deviation is temporary and appro (2) All reasonable precautions shall be taken to assure that
J) licit Or
A production procedures do not contribute adulteration
adequate. A U S / , 2 ( 5
from any source. Chemical, microbial, or extraneous-
material testing procedures shall be used where nec-
Retesting of Approved Components, essary to identify sanitation failures or possible product
A
Raw Materials,Aas/>25 adulteration.
Product Containers, and Closures
Compononto, (3) All product that has become contaminated to the extent
A
Raw materials,Aas/>2<5 that is adulterated within the meaning of the Act shall
product containers, and closures should be retested or reexamined,
as appropriate, for identity, strength, quality, and purity, and ap- be rejected, or if permissible, treated or processed to
proved or rejected by the quality control unit
A
after a specified time in storage OVAUSP26 eliminate the contamination.
as necessary, e.g., after exposure to air, heat, or other conditions
that might adversely affect the oomponont; (4) All product manufacturing, including packaging and
A
raw material,AUS7v>5 storage, shall be conducted under such conditions and
product container, or closure and/or after storage of active and in-
active ingredients and in-process materials for long periods of time. controls as are necessary to minimize the potential for
Pharmacopeia! Forum
the growth of microorganisms, or for the adulteration of dietary products from contact with adulterants. Protec-
raw materials, in-process materials and finished pro- tion may be provided by adequate cleaning and sanitiz-
duct. ing of all processing equipment between each
(5) Measures such as sterilizing, irradiating, pasteurizing, manufacturing step.
freezing, refrigerating, controlling pH, or controlling (10) Heat blanching, when required in the preparation of a
water activity (aw) that are taken to destroy or prevent dietary product, should be effected by heating the pro-
the growth of undesirable microorganisms, particularly duct to the required temperature, holding it at this tem-
those of public health significance, shall be adequate perature for the required time, and then either rapidly
under the conditions of manufacture, handling, and dis- cooling the material or passing it to subsequent manu-
tribution to prevent dietary products from being adult- facturing without delay. Thermophilic growth and con-
erated within the meaning of the Act. tamination in blanchers should be minimized by the use
(6) Work-in-process shall be handled in a manner that proof adequate operating temperatures and by periodic
tects against adulteration. cleaning. Where the blanched product is washed prior
(7) Effective measures shall be taken to protect finished to filling, potable water shall be used.
dietary ingredients and dietary supplements from adul- (11) Intermediate of dehydrated dietary products that rely on
teration by raw materials, in-process materials, or re- the control of water (aw) for preventing the growth of
fuse. When raw materials, in-process materials, or undesirable microorganisms shall be processed to and
refuse are unprotected, they shall not be handled simul- maintained at a safe moisture level. Compliance with
taneously in a receiving, loading, or shipping area if this requirement may be accomplished by any effective
that handling could result in adulterated dietary pro- means, including employment of one or more of the fol-
ducts. Dietary ingredients and dietary supplements lowing practices:
transported by conveyor shall be protected against adul- (i) Monitoring the water activity (aw) of the material,
teration as necessary. (ii) Controlling the soluble solids-water ratio in fin-
(8) Effective measures shall be taken as necessary to pro- ished product.
tect against the inclusion of metal or other extraneous (iii) Protecting finished product from moisture pickup,
material in product. Compliance with this requirement by use of a moisture barrier or by other means, so that
may be accomplished by using sieves, traps, magnets, the water activity (aw) of the product does not increase
electronic metal detectors, or other suitable effective to an unsafe level.
means. (12) Dietary ingredients and dietary supplements that rely
(9) Mechanical manufacturing steps such as cutting, sort- principally on the control of pH for preventing the
ing, inspecting, shredding, drying, grinding, blending, growth of undesirable microorganisms shall be moni-
and sifting shall be performed so as to protect dietary tored and maintained at an appropriate pH. Compliance
ingredients and dietary supplements against adultera- with this requirement may be accomplished by any ef-
tion. Compliance with this requirement may be accom- fective means, including employment of one or more of
plished by providing adequate physical protection of the following practices:
© 2002 The United States Ptiarmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
(i) Monitoring the pH and water activity, if appropriate, Sampling and Testing of In-Process Materials and
Nutritional
of raw materials, in-process material, andfinishedpro-
duct.
Products
(ii) Controlling the amount of acid added to the product. To ensure batch uniformity and integrity of nutritional produots;
A
(13) When ice is used in contact with dietary products, it dietary supplements,. USP26
written procedures should be established and followed that de-
shall be made from potable water, and shall be used scribe the in-process controls and tests or examinations to be con-
ducted on appropriate samples of in-process materials. Based upon
only if it has been manufactured in accordance with process validation,
A
verification, Al/5W6
current good manufacturing practice as outlined in 21 in-process controls and statistical confidence, a skip-lot sampling
plan is an alternative to testing every batch. Control procedures
CFR Part 110. AUSP26 should be established to monitor the output of those manufacturing
processes that may be responsible for causing variability in the
characteristics of in-process material and the finished product.
Such control procedures may include, but are not limited to, the
following, where appropriate:
Charge-in of Components — Friability
A
— Weight variation
Raw — Disintegration time
— Dissolution time
Written production and control procedures should include the — Clarity, completeness, or pH of solutions.
following, which are designed to ensure that the nutritional pro In-process specifications for such characteristics should be con-
sistent with finished product specifications. Examination and test-
A
dietary supplements. USP26 ing of samples should ensure that the in-process material and
have the identity, strength, quality, and purity they are represented nutritional product
to possess: A
dietary supplement. USP26
— The batch should be formulated with the intent to provide not conform to the established specifications.
less than 100 percent of the labeled or established amount of In-process materials should be tested for identity, strength, qual-
UOllViJ ity, and purity as appropriate),
y Ai
ingredient. and approved or rejected by the quality control unit during the pro-
— Compononto duction process, e.g., at commencement or completion of signifi-
cant phases or after storage for long periods.
A Rejected
Raw materials±USP26
for product manufacturing should be weighed, measured, or A
subdivided as appropriate and the appropriate signatures re- or AKS72 tf
corded in the batch record. in-process materials should be identified and controlled under a
— Actual yields and percentages of theoretical yield should be quarantine system designed to prevent their use in manufacturing
determined at appropriate phases of processing. or processing operations for which they are unsuitable
A
and to prevent the adulteration of other products. AUSP26
Material scheduled for rework shall be identified as
Change to read:
LABELING AND PACKAGING
Equipment Identification
Materials Examination and Usage Criteria
All compounding and storage containers, processing lines, and
major equipment used during the production of a batch of a product Written procedures should be provided describing in sufficient
should be properly identified to indicate their contents and, when detail the receipt, identification, storage, handling, sampling, ex-
necessary, the phase of processing of the batch. amination, and/or testing of labeling and packaging materials. La-
beling and packaging materials should be representatively sampled
and examined or tested upon receipt and before use in packaging or
labeling of a product.
Any labeling or packaging materials meeting appropriate written
specifications may be approved and released for use. Those that do
not meet such specifications should be rejected to prevent their use
in operations for which they are unsuitable.
A record should be kept of each shipment received of each dif-
ferent labeling and packaging material, which indicates receipt,
date of examination or testing, and whether accepted or rejected.
Pharmacopeial Forum
Labels and other labeling materials for each different product, Tamper-Resistant Packaging
strength, product type, or quantity of contents should be stored se-
parately with suitable identification. Authorized personnel only
should have access to the storage area. REQUIREMENTS
Gang printing of labeling to be used for different products or
different strengths of the same product (or labeling of the same size Each manufacturer and packer who packages a nutritional pro
and identical or similar format and/or color schemes) should be
minimized. If gang printing is employed, packaging and labeling A
operations should provide for special control procedures, taking dietary supplemen
into consideration sheet layout, stacking, cutting, and handling for retail sale ohould
during and after printing.
Printing devices on, or associated with, manufacturing lines A us/26
package the product in a tamper-resistant package, if this product is
used to imprint labeling upon the product unit label or case should accessible to the public while held for sale. A tamper-resistant
be monitored to ensure that all imprinting conforms to the print package is one having an indicator or barrier to entry which, if
specified in the batch production record. breached or missing, can reasonably be expected to provide visible
Obsolete and outdated labels, labeling, and other packaging ma- evidence to consumers that tampering has occurred. To reduce the
terials should be destroyed and documented. likelihood of substitution of a tamper-resistant feature after tamper-
ing, the indicator or barrier to entry is required to be distinctive by
design or by the use of an identifying characteristic (e.g., a pattern,
name, registered trademark, logo, or picture). For purposes of this
Labeling Issuance section, the term "distinctive by design" means that the packaging
cannot be duplicated with commonly available materials or
Strict control should be exercised over labeling issued for use in through commonly available processes. A tamper-resistant pack-
product labeling operations. The control procedures employed age may involve an immediate-container and closure system, or
should be in writing with sufficient detail. secondary-container or carton system, or any combination of sys-
Labeling materials issued for a batch should be carefully exam- tems intended to provide a visual indication of package integrity.
ined for identity and conformity to the labeling specified in the The tamper-resistant feature should be designed to remain intact
master or batch production records. when handled in a reasonable manner during manufacture, distri-
Procedures should be utilized to reconcile the quantities of label- bution, and retail display.
ing issued, used, and returned, and should require evaluation of
discrepancies found. If discrepancies are found between the quan-
tity of product finished and the quantity of labeling issued and are
outside preset limits based on historical operating data, such discre-
pancies should be investigated. LABELING
Returned labeling should be maintained and sorted in a manner
to prevent mixups and provide proper identification. Each retail package of a nutritional produot
All excess labeling bearing lot or control numbers should be de- ^dietary supplement^ ^.p^
stroyed and documented. covered by this section should
shall AUSP26
bear a statement that is prominently placed so that consumers are
Operations alerted to the specific tamper-resistant feature of the package. The
labeling statement should be so placed that it will be unaffected if
Written procedures designed to ensure that correct labels, label- the tamper-resistant feature of the packaging is breached or miss-
ing, and packaging materials are used for nutritional products ing. If the tamper-resistant feature chosen to meet the requirement
above is one that uses an identifying characteristic, that character-
A
dietary supplements*VSP26 istic should be referred to in the labeling statement. For example,
should incorporate the following features: the labeling statement on a bottle with a shrink band could say
— Prevention of mixups and cross-contamination by physical or "For your protection, this bottle has an imprinted seal around the
spatial separation from operations on other products. neck."
— Identification of the product with a lot or control number.
— Examination of packaging and labeling materials for suitabil-
ity and correctness before packaging operations; and docu-
mentation of such examination in the batch production record. Nutritional Product
— Inspection of the packaging and labeling facilities immedi-
ately before use to ensure that all products have been removed A
from previous operations. Inspection should also be made to Dietary SupplementAaS7,2(J
ensure that packaging and labeling materials not suitable for Inspection
subsequent operations have been removed. Results of the in- Packaged and labeled products should be examined during fin-
spection should be documented in the batch production re- ishing operations to ensure that containers and packages in the lot
cords. have the correct label. A representative sample of units should be
collected at the completion of finishing operations and visually ex-
amined for correct labeling. Results of these examinations should
be recorded in the batch production or control records.
Pharmacopeial Forum
Expiration Dating Change to read:
A
ShelfLife AUSP26
LABORATORY CONTROLS
Nutritional produota
A A
Dietary supplementsAUS.W(S QUALITY CONTROL OPERATIONS
should bear an expiration dato, ^™
A The establishment of any specifications, standards, sampling
a date indicative of their shelf life,Aas.w<j plans, test procedures, or other laboratory control mechanisms re-
determined by appropriate testing, to ensure that they meet applic- quired by this general chapter, including any change in such spe-
able standards of identity, strength, quality, and purity at tho time of cifications, standards, sampling plans, test procedures, or other
laboratory control mechanisms, ohould
A
or before the labeled shelf life date. AUSP26 sna\\.USp26
be drafted by the appropriate organizational unit and reviewed and
Expiration dates) approved by the quality control unit. The requirements in this sec-
A
She\f-MeAUSP26 tion should be followed and documented at the time of perfor-
should be related to any storage conditions stated on the labeling. mance. Any deviation from the written specifications, standards,
sampling plans, test procedures, or other laboratory control me-
Change to read: chanisms ohould
AUSp26
be recorded and justified.
Laboratory control
HOLDING AND DISTRIBUTION A
Quality control o p e r ^ ™
includes the establishment of scientifically sound and appropriate
Warehousing Procedures specifications, standards, sampling plans, and test procedures de-
signed to assure that components,
A A
Storage and transportation of finished product shall be raw materials,A[/iS.p2(i
product containers, closures, in-process materials, labeling, and
under conditions that will protect product against physical, finished products conform to appropriate
adequateAusm
chemical, and microbial adulteration as well as against de- standards of identity, strength, quality and purity. These controls
include the following:
terioration of the product and the containQT.AUSp26 — Determination of conformance to appropriate written specifi-
cations for the acceptance of each lot within each shipment of
Written procedures describing the warehousing of nutritional oompononta,
A
A
dietary p p A K S / ^ raw A[/5P2,5
should be established and followed and should include: product containers, closures, and labeling used in the manu-
— Quarantine of finished products before release facture of nutritional
dietaryAWWd
p A W W ( j
by the quality control unit. products. (The specifications include a description of the sam-
— Storage of finished products under appropriate conditions of pling and testing procedures used. Samples should be repre-
temperature, humidity, and light so that the identity, strength, sentative and adequately identified. Such procedures also
quality, and purity of the products are not affected. require appropriate retesting of any component,
A
raw ^ ™
product container, or closure that is subject to deterioration.)
Based upon adequate process validation,
Distribution Procedures
A
verification,A[/5W(5
Written procedures describing the distribution of nutritional pro in-process controls, and statistical confidence, a skip-lot sam-
duota ohould pling plan is an alternative to testing every batch.
A
dietary supplements shall Al/5K(J Determination of conformance to written specifications and a
be established and followed and should include the following: description of sampling and testing procedures for in-process
— A procedure whereby the oldest approved stock of a product materials. (Such samples should be representative and prop-
is distributed first. (Deviation from this requirement is per- erly identified.)
mitted if such deviation is temporary and appropriate.) Determination of conformance to written descriptions of sam-
A
adequate.) At/5W(J pling procedures and appropriate specifications for finished
products. (Such samples should be representative and prop-
— A system by which the distribution of each lot of product can erly identified.)
be readily determined to facilitate its recall if necessary.
Pharmacopeial Forum
The calibration of instruments, at suitable intervals, in accor- The results of such testing should be used in determining appropri-
dance with an established written program containing specific ate storage conditions and expiration datoo:
directions, schedules, limits for accuracy and precision, and
provisions for remedial action in the event accuracy and/or
precision limits are not met. Instruments not meeting estab-
A
lished specifications should protocolAt/5P25
should include the following:
shall AUSP26 — Sample size and test intervals based on statistical criteria for
not be used until repaired. each attribute should be examined to ensure valid estimates of
stability.
— Storage conditions for samples retained for testing.
— Reliable, meaningful, and specific test methods should be
Testing and Release for Distribution used.
— The nutritional produot
There should be appropriate laboratory determination of satis- A
factory conformance to specifications for the finished product, in- dietary supplementAl/5P2(5
cluding the identity and strength prior to release. Based upon should be tested in the same type of container-closure system as
adequate process validation, that in which the nutritional produot
A
A
verification,At/5/>2(j dietary supplementAC/5p2s
in-process controls, or statistical confidence, a skip-lot or compo- is marketed.
site sampling plan is an alternative to testing every batch. An adequate number of batches of each nutritional produot
There should be appropriate laboratory testing, as necessary, of A
dietary supplementAC/5.p25
each batch of nutritional produot should be tested to determine an appropriate) expiration date,
A
dietary supplement. USP26 A
adequate shelf life, A USP26
required to be free of objectionable microorganisms. The accuracy, and a record of these data should be maintained. Accelerated stu-
linearity, sensitivity, specificity, and reproducibility of test methods dies combined with basic stability information on the oompononto,
employed by the firm, when they differ from compendial methods, nutritional produota,
should be established and documented. A
Written procedures should describe any sampling and testing raw materials, dietary supplements,AUS.W(J
plans, which should include the method of sampling and the num- and container-closure systems may be used to support tentative e*-
ber of units per batch to be tested. piration datoa
Products failing to meet established standards or specifications A
and any other relevant quality control criteria should be rejected? shelf lifeAKSM<j
unloao tho variation ia documented by tho quality oontrol unit as not provided fiill shelf-life studies are not available.
affooting finiahod produot aafoty, identity, strength, quality, and Simplified stability testing procedures may be used where
d a t a from s i m i l a r
Rejected or adulterated dietary products shall be identi- P r o d u c t formulations are available to sup-
port a shelf life estimation of a new product.Al/5W(5
fied, stored and disposed of in a manner that protects against Where data from accelerated studies are used to project a tentative
the adulteration of the other products. AUSP26 expiration
Reprocessing may be performed. Prior to acceptance and use, re-
A[/5Wj5
processed material must meet appropriato
date that is oeyond a date supported by actual shelf-life studies,
A stability studies should be conducted, including nutritional produot
establishedA[/s.P25
A
standards, specifications, and any other relevant criteria. dietary supplernentA[/5p2jj
A testing at appropriate intervals, until the tentative expiration date
Written procedures shall be established and followed pre-
A
shelf lifeA0SP2<t
scribing the method for reprocessing batches or operations is verified or the appropriato expiration dato
A
for start-up materials that do not conform to finished goods adequate shelf lifeAUSP26
is determined.
standards or specifications. Finished goods manufactured
using such materials shall meet all established purity, com-
Reserve Samples
position and quality standards.AaS7>2(j
An appropriately identified reserve sample that is representative
of each lot or batch of nutritional produot
A
dietary supplementA[/iS.P25
should be retained and stored under conditions consistent with pro-
Stability Testing duct labeling until at least one year after the expiration dato
There should be a written protocol designed to assess the stabi- A
end of shelf life
lity characteristics of nutritional produoto.
A
dietary supplements. Al/SP26
Pharmacopeia! Forum
of the product. The reserve sample should be stored in the same A description of the product containers, closures, and packa-
immediate container-closure system in which the finished product ging materials, including a specimen or copy of each label and
is marketed or in one that has essentially the same characteristics. all other labeling signed and dated by the person or persons
The reserve sample consists of at least twice the quantity necessary responsible for approval of such labeling or, in lieu of speci-
to perform all the required tests. mens or copies of each label or other labeling, a positive iden-
tification of all labeling used.
Change to read: Complete manufacturing and control instructions, sampling
and testing procedures, specifications, special notations, and
precautions to be followed.
RECORDS AND REPORTS

Any production, control, or distribution record that is required to Batch Production and Control Records
be maintained and is specifically associated with a batch of a pro-
duct should be retained for at least one year after the expiration dato Batch production and control records should be prepared for
A each batch of product produced and should include complete infor-
shelf life Al/SMtf mation relating to the production and control of each batch.
of the batch.
A
Records should be maintained for all components, These records should be reviewed and signed by a second
A
raw materials,AUS/>2tf person from the quality control unit.AWSM(}
product containers, closures, and labeling for at least one year after These records should include accurate reproduction of the appro-
the expiration dato priate master production or control record and documentation that
A
shelf lifeAKSP2tf each significant step in the manufacture, processing, packing, or
holding of the batch was accomplished, including the following:
of the last lot of product incorporating the component
— Dates.
A
raw materialAUSP26 — Identity of individual major equipment and lines used.
or using the container, closure, or labeling. — Specific identification of each batch of component
A
raw At/5p2(5
or in-process material used.
Master Production and Control Records Weights and measures of components
A
To ensure uniformity from batch to batch, master production and raw At /5p 2( j
control records for each product should be prepared, dated, and used in the course of processing.
signed by one person and independently checked, dated, and In-process and laboratory control results.
signed by a second person Inspection of the packaging and labeling areas before and
A
after use.
from the quality control umt.AUSP26 A statement of the actual yield and a statement of the percen-
Master production and control records should include the fol- tage of theoretical yield at appropriate phases of processing.
lowing:
— The name and strength of the product.
— The name and weight or measure of each aotivo ingrodiont A
Description of product containers and closures
A
dietary ingredient AUSP26 used.>USP26
per unit or portion or per unit of weight or measure of the pro- Complete labeling control records, including specimens or
duct, and a statement of the total weight or measure of any copies of all labeling used or identification of all labeling
dosage unit. used.
— A complete list of oompononta Any sampling performed.
A Identification of the persons performing and directly supervis-
raw materials A.USP26 ing or checking any step in the operation.
designated by names or codes sufficiently specific to indicate Any investigation made.
any special quality characteristic. Results of examinations made.
— An accurate statement of the weight or measure of each oom
A
raw material,AKSK?rf
using the same weight system (metric, avoirdupois, or
apothecary) for each component. Laboratory Records
A
raw material. A i ; i S m Laboratory records should include complete data derived from
all tests necessary to ensure compliance with established specifica-
A statement concerning any calculated excess of component. tions and standards, including examinations and assays, as follows:
— A description of the sample received for testing with identifi-
A
raw cation of source (that is, location from where sample was ob-
tained), quantity, lot number or other distinctive code, and
A statement of theoretical weight or measure at appropriate date sample was taken.
phases of processing. — A statement of each method used in the testing of the sample.
A statement of theoretical yield, including the maximum and — A statement of the weight or measure of sample used for each
minimum percentages of theoretical yield beyond which in- test, where appropriate.
vestigation is required.
Pharmacopeial Forum
— A complete record of all data secured in the course of each Change to read:
test, including all graphs, charts, and spectra from laboratory
instrumentation, properly identified to show the specific eom-
A
RETURNED AND SALVAGED PRODUCTS
r a w material J A W S r e t f
product container, closure, in-process material, or finished
product, and lot tested. Returned Nutritional Products
— A record of all calculations performed in connection with the
test, including units of measure, conversion factors, and
equivalency factors. ^Dietary S u p p l e m e n t s ^ ^
— A statement of the results of tests and how the results compare
with established standards of identity, strength, quality, and Returned products should be identified as such and held. If the
purity for the oomponont, conditions under which returned nutritional
A
A
raw material, Al/SWd dietary USP26
product container, closure, in-process material, or finished products nave been held, stored, or shipped before or during their
product tested. return, or if the condition of the product, its container, carton, or
— The initials or signature of the person who performs each test labeling, as a result of storage or shipping, casts doubt on the
and the date(s) the tests were performed. safety, identity, strength, quality, or purity of the product, the re-
turned product should be destroyed unless examination, testing,
Complete records should be maintained of any modification of or other investigations prove the product meets appropriate stan-
an established method employed in testing. Such records should dards of safety, identity, strength, quality, or purity. A product
include the reason for the modification and data to verify that the may be reprocessed provided the subsequent product meets appro
modification produced results that are at least as accurate and reli-
able for the material being tested as the established method.
Complete records should be maintained of any testing and stan- q A U W ; t f
dardization of laboratory reference standards, reagents, and stan- standards, specifications, and characteristics. Records of returned
dard solutions, the periodic calibration of laboratory instruments, products should be maintained and should include the name and
and all stability testing performed. label potency of the product, lot number (or control number or
A
Any deviation should be reviewed and signed by the man- batch number), reason for the return, quantity returned, date of dis-
position, and ultimate disposition of the returned product. If the
agement of the quality control unit.ALOT>2S reason for a product being returned implicates associated batches,
an appropriate investigation is necessary.
Distribution Records Nutritional Product

Distribution records should contain the name and strength of the A
Dietary SupplementAUsras
product, name and address of the consignee, date and quantity Salvaging
shipped, and lot or control number of the finished product. Products that have been subjected to improper storage condi-
tions including extremes in temperature, humidity, smoke, fumes,
pressure, age, or radiation due to natural disasters, fires, accidents,
or equipment failures should not be salvaged and returned to the
Complaint Files marketplace. Whenever there is a question whether products have
been subjected to such conditions, salvaging operations may be
Written procedures describing the handling of all written and conducted only if there is (a) evidence from laboratory tests and
oral complaints regarding a nutritional produot should assays that the products meet all applicable standards of identity,
A
dietary supplement strength, quality, and purity, and (b) evidence that the products and
AWp^
be established and followed. These procedures should include pro- their associated packaging were not subjected to improper storage
visions for review by the quality control unit of any complaint in- conditions as a result of the disaster or accident. Organoleptic ex-
volving the possible failure of a product to meet any of its aminations should be accepted only as supplemental evidence that
specifications and a determination as to the need for an investiga- the nutritional produot
tion. A
dietary supplementACOT,25
Each complaint should be recorded in a file designed especially meets appropriate standards of identity, strength, quality, and pur-
for nutritional produot ity. Records including name, lot number, and disposition should be
A
dietary supplementA(/iS7>2(5 maintained for salvaged products.
complaints. Written records should be maintained until at least one
year after the expiration dato
A
shelf life AUSP26
of the product, or one year after the date that the complaint was A
received, whichever is longer. Defect Action Levels
The written record should include the following information,
where known: the name and strength of the product, lot number, Some dietary ingredients and dietary supplements, even
name of complainant, nature of complaint, and reply to complai-
nant. when produced under current good manufacturing practice,
If an investigation is necessary, the written record should include
the findings of the investigation and follow-up. contain natural or unavoidable defects that at low levels are
Pharmacopeial Forum
not hazardous to health. The Food and Drug Administration Change to read:
establishes maximum levels for these defects in dietary pro-

ducts produced under current good manufacturing practice GLOSSARY O F T E R M S
and uses these levels in deciding whether to recommend
regulatory action. Âdequate means that which is needed to accomplish the
Defect action levels are established for dietary products intended purpose in keeping with good public health prac-
whenever it is necessary and feasible to do so. These levels
AUSP26
are subject to change upon the development of new technol- Batch is a specific quantity of a finished product or other mate-
rial that is intended to have uniform character and quality, within
ogy or the availability of new information. specified limits, and is produced according to a single manufactur-
ing order during the same cycle of manufacture.
Compliance with defect action levels does not excuse vio-
^Blanching means a prepackaging heat treatment of a
lation of the requirement in section 402(a)(4) of the Act that
dietary product for a sufficient time and at a sufficient tem-
dietary products not be prepared, packed, or held under un-
perature to partially or completely inactivate the naturally
sanitary conditions or the requirements in this part that diet-
occurring enzymes and to effect other physical or biochem-
ary product manufacturers, distributors, and holders shall
ical changes in the product. AasW( f
observe current good manufacturing practice. Evidence in- Component is any ingredient intended for use in the manufaoturo
of a product, including those that may not appear in aueh finiohod
dicating that such a violation exists causes a dietary product
A
to be adulterated within the meaning of the Act, even though Raw material is any ingredient intended for use in the
the amounts of natural or unavoidable defects are lower than manufacture of a dietary ingredient or dietary supplement,
the currently established defect action levels. The manufac- including those that may not appear in such finished pro-
turer, distributor, and holder of a dietary product shall at all duct. (A dietary ingredient is a raw material when consider-
times utilize quality control operations that reduce natural or ing the manufacture of a dietary supplement.)
unavoidable defects to the lowest level currently feasible. Composition is (1) the identity of a dietary ingredient or
The mixing of a dietary ingredient or dietary supplement dietary supplement, and (2) the concentration of a dietary
containing defects above the current defect action level with ingredient (e.g., weight or other unit of use/weight or vol-
another lot of dietary ingredient or dietary supplement is not ume), or the potency or activity of one or more dietary in-
permitted and renders the final product adulterated within gredients, as indicated by appropriate procedures.A[/5/>2<5
the meaning of the Act, regardless of the defect level of Nutritional product ia a finiohod produot, for example, tablet,
oapoule, aolutiony etc., that oontaina an active ingredient in aa3ooia-
the final product. tion with inactive ingredient]. Such a produot ahould poosoaa nu
tritional value:
A compilation of the current defect action levels for nat- ^Dietary product means either a dietary ingredient or
ural or unavoidable defects in dietary products that present dietary supplement as defined in this chapter.AUSp2<5
Active ingi«cdicnt ia any oomponent that furniahoo nutritional
no health hazard may be obtain upon request from the In- value at ita proaoribod potency.
dustry Programs Branch (HFF-326), Center for Food Safety ^Dietary ingredient is an ingredient intended for use or
and Applied Nutrition, U.S. Food and Drug Administration, used in a dietary supplement that is:
200 C St., S.W., Washington, DC 2O2O4.AWSWtf
— a vitamin;
— a mineral;
Pharmacopeial Forum
A
dietary ingredient, dietary supplement,AUSP26
— an herb or other botanical; or other material can be determined.
Manufacture of a nutritional product inoludoo proooaoing,
— an amino acid; packaging and labeling oporationa, testing, quality control and
holding of tho product.
— a dietary substance for use by man to supplement the
^Manufacture or manufacturing includes all operations
diet by increasing the total dietary intake, or a concen-
associated with the production of dietary products, includ-
trate, metabolite, constituent, extract; or
ing packaging and labeling operations, testing, and quality
— a combination of any of the foregoing ingredients.
control of a dietary ingredient or dietary supplement.
Dietary supplement is a product (other than tobacco) that Microorganisms means yeast, molds, bacteria, and
is intended to supplement the diet that bears or contains one viruses and includes, but is not limited to, species having
or more of the following dietary ingredients: a vitamin, a public health significance. The term "undesirable microor-
mineral, an herb or other botanical, an amino acid, a dietary ganisms" includes those microorganisms that are of public
substance for use by man to supplement the diet by increas- health significance, that subject a dietary product to decom-
ing the total daily intake, or a concentrate, metabolite, con- position, that indicate that a dietary ingredient or dietary
stituent, extract, or combination of these ingredients, that is supplement is contaminated with filth, or that otherwise
intended for ingestion in a pill, capsule, tablet, or liquid may cause a dietary product to be adulterated within the
form, that is not represented for use as a conventional food meaning of the act. Occasionally in these regulations, the
or as the sole item of a meal or diet, and that is labeled as a adjective "microbial" is used instead of an adjectival phrase
dietary supplement and includes products such as new drug, containing the word microorganism.
certified antibiotic, or licensed biologic that was marketed as Pest refers to any objectionable animals or insects includ-
a dietary supplement or food before approval, certification, ing, but not limited to, birds, rodents, flies, and larvae.
or license unless a sanitary authority waives this provi- Plant means the building or facility or parts thereof, used
sion).^^ for or in connection with the manufacturing, packaging, la-
Inactive ingredient is any component beling, or holding of a dietary product.
A
raw
JLll<wL
Process evaluation is a set of tests performed on a process
A
a dietary AKSK(f intended to evaluate its capacity to consistently produce the
ingredient.
In-process material is any material fabricated, compounded, e* results that it is intended for.
•
AUSP26 Quality control operation is a planned and systematic pro-
blended
A
, ground, extracted, sifted, sterilized, or processed in any cedure for taking all actions necessary to prevent a dietary
other way A USP26 product from being adulterated.AUSP26

that is produced for, and used in, the preparation of the finiGhed Quality control unit is any person or organizational element de-
TTrTjvITrCTT signated by thefirmto be responsible for the duties relating to qual-
A ity control
dietary supplement.AUSF2(5
p A U f f 2 S
Lot is a batch, or a specific identified portion of a batch, having Strength means the concentration of the active substance
uniform character and quality within specified limits. (weight/weight, weight/volume, or unit of use/volume or weight
Lot number, control number, or batch number is any distinctive basis); and/or the potency, that is, the activity of the product as in-
combination of letters, numbers, or symbols, or any combination of dicated by appropriate laboratory tests.
them from which the complete history of the manufacture, proces- Acceptance criteria is the product specifications and acceptance/
sing, packing, holding, and distribution of a batch or lot of finished rejection criteria, such as acceptable quality level and unacceptable
nutritional produot quality level, with an associated sampling plan, that are necessary
for making a decision to accept or reject a lot or batch (or any other
convenient subgroups of manufactured units).
Pharmacopeial Forum
Representative sample is a sample that consists of a number of

units that are drawn based on rational criteria such as random sam-
pling and is intended to assure that the sample accurately portrays REAGENTS, INDICATORS,
the material being sampled.
AND SOLUTIONS
^Rework is a clean, unadulterated material that has been
removed from processing for reasons other than unsanitary
conditions or that has been successfully reconditioned by re-
processing and that is suitable for use in the manufacture of Reagent Specifications
a dietary product.Aas.W(J
Sanitize is the adequate treatment of surfaces
A
equipment, containers, or utensilsAaSp2<j
by a process that is effective in destroying vegetative cells of
pathogenic- bacteria
A
microorganisrns of public health significance^^*,
and in substantially reducing other BRIEFING
A
undesirableAas7>2fi Bacterial Alkaline Protease Preparation. This new reagent is
microorganisms to an-acceptable- total plate count. Suoh treatment used as a component of Test stock solution 1 in the test for Content
shall not advoraoly affect the produot and shall bo safo for the eon of total carotenoids under Lutein Preparation.
A
but without affecting the product or its safety for the con- (HDQ: M. Marques) RTS—36020-2; 36021-2
sumer.
Shall is used to state requirements that must be met under Add the following:
the provisions of this guideline. A
BacteriaI Alkaline Protease Preparation—Use a
Shelf life is the period of time after manufacturing in suitable grade. U"AUSP26
which the dietary supplement is assured to meet applicable
standards of identity, strength, quality, and purity.
Shelf-life {Use by) date is the date beyond which the diet-
BRIEFING
ary supplement is no longer assured to meet applicable stan-
Bromelain. This new reagent is used as a component of Test
dards of identity, strength, quality, and purity. stock solution 1 in the test for Content of total carotenoids under
Lutein Preparation, which is previewed elsewhere in this number
Should is used to state recommended or advisory proce- ofPF.
dures or identify recommended equipment. A y SP26
(HDQ: M. Marques) RTS—36020-2; 36021-2
Skip-lot sampling is a reduced level of sampling/testing for a
particular specified parameters) based upon one or more of the fol-
lowing:
— Statistical analysis of an adequate quantity of historical test Add the following:
data.
— Statistical confidence in the capability of the manufacturing A
process as determined by suitable validation: Bromelain—A proteolytic enzyme isolated from pine-
apple. Use a suitable grade.AUSP26

A t /5 W 6
— Ongoing monitoring of the process using recognized statisti-
cal process control (SPC) techniques.
A
Water activity (aw) is a measure of the free moisture in a
dietary ingredient or dietary supplement and is the quotient
of the water vapor pressure of the substance divided by the
vapor pressure of pure water at the same temperature. AUSP26
Pharmacopeial Forum
BRIEFING BRIEFING
4-(ButyIamino)benzoic Acid. This new reagent is used in the Reagent Footnotes, USP 25 page 2354, page 1133 of PF 26(4)
test for Chromatographic purity under Tetracaine. [July-Aug. 2000], page 1383 of P F 26(5) [Sept-Oct. 2000], page
3118 of PF 27(5) [Sept-Oct 2001], and page 3373 of PF 27(6)
(HDQ: M. Marques) RTS—35780-1 [Nov.-Dec. 2001]. Footnote 43 is revised to delete the other sup-
plier of the reagent 3-O-Methylestrone used in Internal standard
solution under Assay for Conjugated Estrogens. Footnote 46 is
revised to update the brand name and supplier of the reagent Nick-
el-aluminum catalyst used in the test for Halogenated compounds
Add the following: and halides in Benzyl Alcohol. Footnote 78 is revised to update the
A
supplier of the reagent Sulfatase Enzyme Preparation used in the
4-(Butylamino)benzoic Acid, CnH5NO2—193.25— Assay preparation under Assay for Conjugated Estrogens. Foot-
notes 103 and 104 are added to identify the suppliers of the re-
[4740-24-3]. Use a suitable grade. 104AKSre5 agents Bacterial Alkaline Protease Preparation and 4-
(Butylamino)benzoic Acid, respectively, which appear elsewhere
in this number of PF.
Volumetric Solutions (HDQ: M. Marques) RTS—35780-1 35917-1; 35918-1; 35961-

1; 36020-2; 36021-2
BRIEFING
Reagent Footnotes
Lead Perchlorate, Hundredth Molar (0.01 M). This new vol-
umetric solution is used as a reagent in the Procedure in the Assay Where a particular brand or source of a material or piece of equip-
under Sodium Sulfide Topical Gel. ment, or the name and address of a manufacturer, is mentioned (or-
dinarily in a footnote), this identification is furnished solely for
informational purposes as a matter of convenience, without impli-
(HDQ: M. Marques) RTS—35837-1 cation of approval, endorsement, or certification.
Change to read:
Add the following: 43
- Commercially available
A
A
as catalog number 1883-5A[/iSW(j
Lead Perchlorate, Hundredth Molar (0.01 M) from Research Plus, Inc., P.O. Box 324, Bayonne, NJ 07002 emi
from Storaloido, Ino., P.O. BOK 310, Wilton, NH 03086.
Pb(C104)2 406.10 A
, fax number 908-754-2901, Web site: www.researchplus.
Accurately pipet 100 mL of commercially available 0.1 M
lead perchlorate solution into a 1000-mL volumetric flask,
Change to read:
add a sufficient quantity of water to make 1000 mL, and 46
- A suitable grade is "Raney Nickel, Active Catalyst," avail-
standardize the solution as follows: able S«fflTA4&»k-Qiefflieal-GeTr4W4
lcoo, WI 53233.
Accurately pipet 50 mL of 0.01 M lead perchlorate solu- A
as "aluminum-nickel alloy," catalog number 72240, avail-
tion, as prepared above, into a 250-mL conical flask. Add 3
able form Fluka Chemical Corp., fax 1-800-962-9591, Web
mL of aqueous hexamethylenetetramine solution (2.0 g per
site:
100 mL) and 4 drops of 0.5% xylenol .orange indicator pre-
Change to read:
pared by adding 500 mg of xylenol orange to 10 mL of al- n
- A suitable grade is available commercially aa "Gluaulaao,"
from Endo Laboratory, Garden City, I>IY 11530.
cohol and diluting with water to 100 mL. (Omit the alcohol
A
under catalog number S-9626 form Sigma-Aldrich, Web
if the sodium salt of the indicator is used). Titrate with
site: www. sigma-aldrich.com.AUS./>2(j
0.05 M edetate disodium VS to a yellow endpoint. Calculate
the molarity.AKSretf
Pharmacopeial Forum
Add the following: 2001], page 2601 of PF 27(3) [May-June 2001], page 2839 of P F
AlM 27(4) [July-Aug. 2001], page 3120 of PF 27(5) [Sept-Oct. 2001],
- A suitable grade is commercially available as "Protex page 3374 of P F 27(6) [Nov.-Dec. 2001], and page 116 of PF
28(1) [Jan.-Feb. 2002].
6L" from Genencor, 200 Meridian Centre Blvd., Rochester,
(HDQ) RTS—24017-1; 31970-1; 32474-1; 34378-1; 35018-
NY 14618, or as "Optimase Enzyme" from Solvay En- 1; 35617-1; 36043
zymes Inc., 1003 Industrial Pkwy, Elkhart, IN 46516.AUSP2<s
Add the following:
Al04
Add the following:
- A suitable grade is available from Sigma-Aldrich,
A
Doxazosin Mesylate: White to tan-colored powder.
Inc., P.O. Box 2060, Milwaukee, WI 53201; Web site:
Very slightly soluble in methanol and in water. Freely solu-
ble in formic acid.At/5P^
Add the following:
A
GancicIovir: White to off-white crystalline
BRIEFING

Description and Relative Solubility of USP and NF Articles, Add the following:
USP 25 page 2363, page 3037 of PF18(2) [Mar.-Apr. 1992], page A
6597 of PF 19(6) [Nov.-Dec. 1993], page 1250 of PF 21(5) Mangafodipir Trisodium: Pale yellow crystals or
[Sept.-Oct. 1995], page 4533 of PF 23(4) [July-Aug 1997], page
4874 of P F 23(5) [Sept.-Oct. 1997], page 5310 of PF 23(6) [Nov.- crystalline powder. Freely soluble in water; sparingly solu-
Dec. 1997], page 7017 of PF 24(5) [Sept-Oct. 1998], page 7930
of PF 25(2) [Mar.-Apr. 1999], page 8282 of PF 25(3) [May-June ble in methanol; slightly soluble in chloroform; very slightly
1999], page 8589 of PF 25(4) [July-Aug. 1999], page 8917 of PF
25(5) [Sept.-Oct. 1999], page 9254 of PF 25(6) [Nov.-Dec. 1999], soluble in alcohol and in acetone.A.VSP26
page 250 of PF 26(1) [Jan.-Feb. 2000], page 504 of PF 26(2)
[Mar.-Apr. 2000], page 837 of PF 26(3) [May-June 2000], page Add the following:
1135 ofPF26(4) [July-Aug. 2000], page 1385 of PF26(5) [Sept.-
A
Oct. 2000], page 1623 of P F 26(6) [Nov.-Dec. 2000], page 1907 Norgestimate: [To
of PF 27(1) [Jan.-Feb. 2001], page 2281 of PF 27(2) [Mar.-Apr.
Pharmacopeial Forum
Items from Earlier Numbers of PF that Have Not Yet Acetic Acid Irrigation—See PF Vol. 27, No. 3, page 2501.
Appeared in a Supplement, and are Therefore Candidates Acetic Acid Otic Solution—See PF Vol. 27, No. 3, page 2501.
for Subsequent Supplements. Acetohexamide—See PF Vol. 27, No. 3, page 2501.
Acetohexamide Tablets—See PF Vol. 27, No. 3, page 2501.
Acetohydroxamic Acid—See PF Vol. 27, No. 2, page 2115.
GENERAL NOTICES AND REQUIREMENTS Acetohydroxamic Acid Tablets—See PF Vol. 27, No. 3, page
"Official" and "Official Articles"—See PF Vol. 28, No. 1, page 2502.
32. Acetylcholine Chloride—See PF Vol. 27, No. 3, page 2502.
Preservation, Packaging, Storage, and Labeling—See PF Vol. 26, Acetylcholine Chloride for Ophthalmic Solution—See PF Vol. 27,
No. 3, page 653. No. 3, page 2502.
Acetylcysteine—See PF Vol. 27, No. 3, page 2503.
USP MONOGRAPHS Acetylcysteine Solution—See PF Vol. 27, No. 3, page 2503.
Acetylcysteine and Isoproterenol Hydrochloride Inhalation Solu-
Acebutolol Hydrochloride—See PF Vol. 27, No. 3, page 2493. tion—See PF Vol. 27, No. 3, page 2503.
Acebutolol Hydrochloride Capsules—See PF Vol. 28, No. 1, page Acyclovir—See PF Vol. 27, No. 3, page 2503.
33. Acyclovir Capsules—See PF Vol. 27, No. 3, page 2503.
Acepromazine Maleate—See PF Vol. 27, No. 3, page 2493. Acyclovir for Injection—See PF Vol. 27, No. 3, page 2503.
Acepromazine Maleate Injection—See PF Vol. 27, No. 3, page Acyclovir Ointment—See PF Vol. 27, No. 3, page 2504.
Acepromazine Maleate Tablets—See PF Vol. 27, No. 3, page 2494. Acyclovir Tablets—See PF Vol. 27, No. 3, page 2504.
Acetaminophen—See PF Vol. 27, No. 3, page 2494. Adenine—See PF Vol. 27, No. 3, page 2504.
Acetaminophen Capsules—See PF Vol. 27, No. 3, page 2494. Adenosine—See PF Vol. 27, No. 3, page 2504.
Acetaminophen for Effervescent Oral Solution—See PF Vol. 27, Adenosine Injection—See PF Vol. 27, No. 3, page 2504.
No. 3, page 2495. Medical Air—See PF Vol. 27, No. 5, page 2973.
Acetaminophen Oral Solution—See PF Vol. 27, No. 3, page 2494. Alanine—See PF Vol. 27, No. 5, page 2973.
Acetaminophen Oral Suspension—See PF Vol. 27, No. 3, page Albendazole—See PF Vol. 27, No. 3, page 2505.
2495. Albendazole Oral Suspension—See PF Vol. 27, No. 3, page 2505.
Acetaminophen Suppositories—See PF Vol. 27, No. 3, page 2495. Albendazole Tablets—See PF Vol. 27, No. 3, page 2505.
Acetaminophen Tablets—See PF Vol. 27, No. 3, page 2495. Albumin Encapsulated Octafluoropropane Microspheres for Injec-
Acetaminophen and Aspirin Tablets—See PF Vol. 27, No. 3, page tion—See PF Vol. 27, No. 4, page 2688.
2495. Albumin Human—See PF Vol. 27, No. 3, page 2505.
Acetaminophen, Aspirin, and Caffeine Tablets—See PF Vol. 27, Albuterol—See PF Vol. 27, No. 3, page 2505.
No. 3, page 2495. Albuterol Sulfate—See PF Vol. 27, No. 3, page 2506.
Acetaminophen and Caffeine Tablets—See PF Vol. 27, No. 3, page Albuterol Tablets—See PF Vol. 27, No. 3, page 2506.
2496. Alclometasone Dipropionate—See PF Vol. 27, No. 3, page 2506.
Capsules Containing at Least Three of the Following— Acetami- Alclometasone Dipropionate Cream—See PF Vol. 27, No. 3, page
nophen and Salts of Chlorpheniramine, Dextromethorphan, 2507.
and Pseudoephedrine—See PF Vol. 27, No. 3, page 2496. Alclometasone Dipropionate Ointment—See PF Vol. 27, No. 3,
Oral Powder Containing at Least Three of the Following—Aceta- page 2507.
minophen and Salts of Chlorpheniramine, Dextromethor- Alcohol—See PF Vol. 27, No. 3, page 2507.
phan, and Pseudoephedrine—See PF Vol. 27, No. 3, page Dehydrated Alcohol—See PF Vol. 27, No. 3, page 2507.
2496. Dehydrated Alcohol Injection—See PF Vol. 27, No. 3, page 2507.
Oral Solution Containing at Least Three of the Following—Acet- Rubbing Alcohol—See PF Vol. 27, No. 3, page 2507.
aminophen and Salts of Chlorpheniramine, Dextromethor- Alcohol in Dextrose Injection—See PF Vol. 27, No. 3, page 2508.
phan, and Pseudoephedrine—See PF Vol. 27, No. 6, page Alendronate Sodium—See PF Vol. 27, No. 4, page 2688.
3241. Alendronate Sodium Tablets—See PF Vol. 28, No. 1, page 33.
Tablets Containing at Least Three of the Following—Acetamino- Alfentanil Hydrochloride—See PF Vol. 27, No. 3, page 2508.
phen and Salts of Chlorpheniramine, Dextromethorphan, and Alfentanil Injection—See PF Vol. 27, No. 3, page 2508.
Pseudoephedrine—See PF Vol. 27, No. 3, page 2496. Allantoin—See PF Vol. 27, No. 5, page 2973.
Acetaminophen and Codeine Phosphate Capsules—See PF Vol. Allopurinol—See PF Vol. 27, No. 3, page 2508.
27, No. 3, page 2496. Allopurinol Tablets—See PF Vol. 27, No. 3, page 2508.
Acetaminophen and Codeine Phosphate Oral Solution—See PF Allyl Isothiocyanate—See PF Vol. 27, No. 3, page 2509.
Vol. 27, No. 3, page 2497. Alprazolam—See PF Vol. 27, No. 3, page 2509.
Acetaminophen and Codeine Phosphate Oral Suspension— See PF Alprazolam Tablets—See PF Vol. 27, No. 3, page 2509.
Vol. 27, No. 3, page 2497. Alprostadil—See PF Vol. 27, No. 3, page 2509.
Acetaminophen and Codeine Phosphate Tablets—See PF Vol. 27, Alprostadil Injection—See PF Vol. 27, No. 3, page 2514.
No. 5, page 2973. Alteplase—See PF Vol. 27, No. 3, page 2514.
Acetaminophen, Dextromethorphan Hydrobromide, Doxylamine Alteplase for Injection—See PF Vol. 27, No. 3, page 2514.
Succinate, and Pseudoephedrine Hydrochloride Oral Solu- Altretamine—See PF Vol. 27, No. 3, page 2514.
tion—See PF Vol. 27, No. 3, page 2499. Altretamine Capsules—See PF Vol. 27, No. 3, page 2514.
Acetaminophen and Diphenhydramine Citrate Tablets—See PF Potassium Alum—See PF Vol. 27, No. 3, page 2515.
Acetaminophen, Diphenhydramine Hydrochloride, and Pseudo- page 2515.
ephedrine Hydrochloride Tablets—See PF Vol. 27, No. 3, Alumina and Magnesia Tablets—See PF Vol. 27, No. 3, page
page 2499. 2515.
Acetaminophen and Pseudoephedrine Hydrochloride Tablets— Alumina, Magnesia, and Calcium Carbonate Oral Suspension—
See PF Vol. 27, No. 3, page 2500. See PF Vol. 27, No. 6, page 3241.
Acetazolamide—See PF Vol. 27, No. 3, page 2500. Alumina, Magnesia, and Calcium Carbonate Tablets—See PF Vol.
Acetazolamide for Injection—See PF Vol. 27, No. 3, page 2500. 27, No. 3, page 2515.
Acetazolamide Tablets—See PF Vol. 27, No. 3, page 2501. Alumina, Magnesia, Calcium Carbonate, and Simethicone Ta-
Glacial Acetic Acid—See PF Vol. 27, No. 3, page 2501. blets—See PF Vol. 27, No. 6, page 3241.
Pharmacopeial Forum
Alumina and Magnesium Carbonate Oral Suspension—See PF Azithromycin—See PF Vol. 27, No. 6, page 3245.
Vol. 27, No. 6, page 3242. Barium Sulfate—See PF Vol. 28, No. 1, page 38.
Aluminum Phosphate Gel—See PF Vol. 27, No. 6, page 3242. Barium Sulfate Paste—See PF Vol. 25, No. 4, page 8479.
Aluminum Zirconium Octachlorohydrate—See PF Vol. 27, No. 4, Barium Sulfate Suspension—See PF Vol. 28, No. 1, page 38.
page 2691. Barium Sulfate for Suspension—See PF Vol. 28, No. 1, page 39.
Aluminum Zirconium Octachlorohydrate Solution—See PF Vol. Benazepril Hydrochloride—See PF Vol. 28, No. 1, page 39.
27, No. 4, page 2692. Benazepril Hydrochloride Tablets—See PF Vol. 28, No. 1, page
Aluminum Zirconium Octachlorohydrex Gly—See PF Vol. 27, 39.
No. 4, page 2692. Benazepril Tablets—See PF Vol. 27, No. 6, page 3250.
Aluminum Zirconium Octachlorohydrex Gly Solution—See PF Benzethonium Chloride Concentrate—See PF Vol. 28, No. 1, page
Vol. 27, No. 4, page 2693. 41.
Aluminum Zirconium Pentachlorohydrate—See PF Vol. 27, No. 4, Benzethonium Chloride Topical Solution—See PF Vol. 27, No. 5,
page 2693. page 2979.
Aluminum Zirconium Pentachlorohydrate Solution—See PF Vol. Benzylpenicilloyl Polylysine Concentrate—See PF Vol. 28, No. 1,
27, No. 4, page 2694. page 42.
Aluminum Zirconium Pentachlorohydrex Gly—See PF Vol. 27, Betamethasone Valerate—See PF Vol. 27, No. 5, page 2980.
No. 4, page 2695. Betaxolol Tablets—See PF Vol. 27, No. 4, page 2703.
Aluminum Zirconium Pentachlorohydrex Gly Solution—See PF Bethanechol Chloride Injection—See PF Vol. 27, No. 1, page
Vol. 27, No. 4, page 2695. 1754.
Aluminum Zirconium Tetrachlorohydrate—See PF Vol. 27, No. 4, Bethanechol Chloride Tablets—See PF Vol. 27, No. 1, page 1755.
page 2696. Bismuth Citrate—See PF Vol. 27, No. 2, page 2118.
Aluminum Zirconium Tetrachlorohydrate Solution—See PF Vol. Bismuth Subsalicylate Magma—See PF Vol. 28, No. 1, page 43.
27, No. 4, page 2697. Bisoprolol Fumarate—See PF Vol. 26, No. 4, page 982.
Aluminum Zirconium Tetrachlorohydrex Gly—See PF Vol. 27, Bisoprolol Fumarate Tablets—See PF Vol. 26, No. 4, page 983.
No. 4, page 2697. Bisoprolol Fumarate and Hydrochlorothiazide Tablets—See PF
Aluminum Zirconium Tetrachlorohydrex Gly Solution—See PF Vol. 26, No. 4, page 985.
Vol. 27, No. 4, page 2698. Brinzolamide—See PF Vol. 27, No. 4, page 2703.
Aluminum Zirconium Trichlorohydrate—See PF Vol. 27, No. 4, Brinzolamide Ophthalmic Suspension—See PF Vol. 27, No. 4,
page 2698. page 2705.
Aluminum Zirconium Trichlorohydrate Solution—See PF Vol. 27, Bromocriptine Mesylate—See PF Vol. 27, No. 4, page 2707.
No. 4, page 2699. Bromodiphenhydramine Hydrochloride and Codeine Phosphate
Aluminum Zirconium Trichlorohydrex Gly—See PF Vol. 27, No. Syrup—See PF Vol. 27, No. 5, page 2980.
4, page 2700. Bumetanide—See PF Vol. 27, No. 5, page 2982.
Aluminum Zirconium Trichlorohydrex Gly Solution—See PF Vol. Bupropion Hydrochloride—See PF Vol. 27, No. 4, page 2708.
27, No. 4, page 2700. Bupropion Hydrochloride Tablets—See PF Vol. 27, No. 3, page
Amiloxate—See PF Vol. 27, No. 5, page 2975. 2521.
7-Aminodesacetoxycephalosporanic Acid—See PF Vol. 26, No. 6, Bupropion Hydrochloride Extended-Release Tablets—See PF Vol.
page 1534. 27, No. 5, page 2982.
6-Aminopenicillanic Acid—See PF Vol. 27, No. 1, page 1745. Butabarbital Sodium—See PF Vol. 27, No. 6, page 3253.
Aminopentamide Sulfate—See PF Vol. 27, No. 1, page 1748. Butalbital, Aspirin, and Caffeine Capsules—See PF Vol. 27, No. 6,
1748. Calcium Acetate—See PF Vol. 27, No. 6, page 3254.
Aminopentamide Sulfate Tablets—See PF Vol. 27, No. 1, page Calcium Acetate Tablets—See PF Vol. 27, No. 6, page 3254.
1748. Calcium Ascorbate—See PF Vol. 27, No. 6, page 3255.
Aminophylline Rectal Solution—See PF Vol. 27, No. 1, page Calcium Carbonate—See PF Vol. 27, No. 6, page 3255.
1748. Calcium Carbonate and Magnesia Tablets—See PF Vol. 27, No. 6,
Aminophylline Tablets—See PF Vol. 27, No. 4, page 2701. page 3256.
Ferric Ammonium Citrate—See PF Vol. 27, No. 2, page 2117. Calcium Carbonate Oral Suspension—See PF Vol. 27, No. 6, page
Ferric Ammonium Citrate for Oral Solution—See PF Vol. 27, No. 3255.
2, page 2118. Calcium Carbonate Tablets—See PF Vol. 27, No. 6, page 3255.
Amoxicillin Capsules—See PF Vol. 28, No. 1, page 36. Calcium Chloride—See PF Vol. 27, No. 6, page 3256.
Amoxicillin Tablets—See PF Vol. 28, No. 1, page 36. Calcium Citrate—See PF Vol. 27, No. 6, page 3257.
Amoxicillin and Clavulanate Potassium for Oral Suspension—See Calcium Glubionate Syrup—See PF Vol. 27, No. 6, page 3257.
PF Vol. 28, No. 1, page 36. Calcium Gluceptate—See PF Vol. 27, No. 6, page 3257.
Amoxicillin and Clavulanate Potassium Tablets—See PF Vol. 28, Calcium Gluceptate Injection—See PF Vol. 27, No. 6, page 3257.
No. 1, page 37. Calcium Gluconate—See PF Vol. 27, No. 6, page 3258.
Amoxicillin for Oral Suspension—See PF Vol. 27, No. 6, page Calcium Gluconate Injection—See PF Vol. 27, No. 6, page 3258.
3243. Calcium Gluconate Tablets—See PF Vol. 27, No. 6, page 3258.
Amphetamine Sulfate—See PF Vol. 27, No. 3, page 2518. Calcium Hydroxide—See PF Vol. 27, No. 6, page 3258.
Ampicillin Tablets—See PF Vol. 27, No. 2, page 2118. Calcium Hydroxide Topical Solution—See PF Vol. 27, No. 6, page
Arginine Hydrochloride—See PF Vol. 27, No. 6, page 3244. 3259.
Arginine Hydrochloride Injection—See PF Vol. 27, No. 6, page Calcium Lactate—See PF Vol. 27, No. 6, page 3259.
3244. Calcium Lactate Tablets—See PF Vol. 27, No. 6, page 3259.
Aspartic Acid—See PF Vol. 26, No. 5, page 1269. Calcium Lactobionate—See PF Vol. 27, No. 6, page 3260.
Atenolol Tablets—See PF Vol. 28, No. 1, page 38. Calcium Levulinate—See PF Vol. 27, No. 6, page 3260.
Atenolol and Chlorthalidone Tablets—See PF Vol. 27, No. 6, page Calcium and Magnesium Carbonates Tablets—See PF Vol. 27, No.
3244. 6, page 3256.
Atovaquone—See PF Vol. 26, No. 1, page 134. Calcium Pantothenate—See PF Vol. 27, No. 6, page 3260.
Atovaquone Oral Suspension—See PF Vol. 26, No. 1, page 137. Calcium Pantothenate Tablets—See PF Vol. 27, No. 6, page 3260.
Atracurium Besylate—See PF Vol. 27, No. 5, page 2975. Dibasic Calcium Phosphate—See PF Vol. 27, No. 6, page 3261.
Atracurium Besylate Injection—See PF Vol. 26, No. 2, page 403. Calcium Polycarbophil—See PF Vol. 27, No. 6, page 3261.
Pharmacopeial Forum
Calcium Saccharate—See PF Vol. 27, No. 6, page 3261. Cromolyn Sodium Inhalation Powder—See PF Vol. 27, No. 1,
Carbamazepine Extended-Release Tablets—See PF Vol. 27, No. 6, page 1769.
page 3261. Cycloserine—See PF Vol. 27, No. 5, page 2998.
Carbamazepine Oral Suspension—See PF Vol. 27, No. 4, page Cycloserine Capsules—See PF Vol. 27, No. 5, page 2998.
2711. Cyclosporine Capsules—See PF Vol. 27, No. 4, page 2721.
Carboprost Tromethamine—See PF Vol. 27, No. 5, page 2988. Cyclosporine Oral Solution—See PF Vol. 27, No. 4, page 2727.
Carboprost Tromethamine Injection—See PF Vol. 27, No. 5, page Cysteine Hydrochloride—See PF Vol. 27, No. 4, page 2728.
2990. Danazol—See PF Vol. 27, No. 6, page 3269.
Urea C 13—See PF Vol. 26, No. 2, page 410. Desogestrel—See PF Vol. 27, No. 4, page 2728.
Urea C 13 for Oral Solution—See PF Vol. 26, No. 2, page 412. Desogestrel and Ethinyl Estradiol Tablets—See PF Vol. 27, No. 6,
Urea C 14 Capsules—See PF Vol. 27, No. 2, page 2126. page 3270.
Cefaclor—See PF Vol. 27, No. 3, page 2523. Dextran 40—See PF Vol. 27, No. 3, page 2533.
Cefaclor Extended-Release Tablets—See PF Vol. 27, No. 2, page Dextran 70—See PF Vol. 27, No. 3, page 2533.
2126. Dextroamphetamine Sulfate—See PF Vol. 27, No. 3, page 2533.
Cefazolin Ophthalmic Solution—See PF Vol. 27, No. 6, page Dextroamphetamine Sulfate Tablets—See PF Vol. 27, No. 5, page
3262. 3003.
Cefepime Hydrochloride—See PF Vol. 27, No. 5, page 2991. Dextrose and Sodium Chloride Injection—See PF Vol. 27, No. 3,
Cefepime for Injection—See PF Vol. 27, No. 5, page 2994. page 2534.
Cefixime—See PF Vol. 27, No. 4, page 2711. Diatrizoate Meglumine and Diatrizoate Sodium Solution—See PF
Cefpodoxime Proxetil—See PF Vol. 28, No. 1, page 44. Vol. 27, No. 6, page 3273.
Cefpodoxime Proxetil for Oral Suspension—See PF Vol. 28, No. Diethylcarbamazine Citrate—See PF Vol. 27, No. 1, page 1775.
1, page 48. Diethylcarbamazine Citrate Tablets—See PF Vol. 27, No. 1, page
Cefpodoxime Proxetil Tablets—See PF Vol. 28, No. 1, page 49. 1777.
Cefuroxime Axetil Tablets—See PF Vol. 27, No. 5, page 2996. Diflorasone Diacetate—See PF Vol. 27, No. 5, page 3003.
Cellulose Sodium Phosphate—See PF Vol. 27, No. 6, page 3263. Digoxin—See PF Vol. 28, No. 1, page 55.
Chlordiazepoxide and Amitriptyline Hydrochloride Tablets—See Digoxin Tablets—See PF Vol. 28, No. 1, page 55.
PF Vol. 27, No. 6, page 3263. Dihydroergotamine Mesylate—See PF Vol. 24, No. 1, page 5562.
Chlordiazepoxide Hydrochloride and Clidinium Bromide Cap- Dihydroergotamine Mesylate Injection—See PF Vol. 24, No. 1,
sules—See PF Vol. 27, No. 4, page 2712. page 5564.
Chlorhexidine Gluconate Oral Rinse—See PF Vol. 27, No. 1, page Diloxanide Furoate—See PF Vol. 27, No. 1, page 1778.
1765. Diltiazem Hydrochloride Extended-Release Capsules—See PF
Chlorhexidine Gluconate Solution—See PF Vol. 27, No. 5, page Vol. 27, No. 3, page 2535.
2996. Dinoprost Tromethamine—See PF Vol. 27, No. 3, page 2537.
Chlorothiazide Sodium for Injection—See PF Vol. 28, No. 1, page Dinoprostone—See PF Vol. 28, No. 1, page 56.
51. Divalproex Sodium Delayed-Release Tablets—See PF Vol. 27,
Chloroxylenol—See PF Vol. 27, No. 6, page 3264. No. l,page 1781.
Chlorpheniramine Maleate Tablets—See PF Vol. 27, No. 6, page Dobutamine in Dextrose Injection—See PF Vol. 27, No. 2, page
3265. 2140.
Chlorpheniramine Maleate and Pseudoephedrine Hydrochloride Dolasetron Mesylate—See PF Vol. 26, No. 4, page 1017.
Extended-Release Capsules—See PF Vol. 27, No. 3, page Dolasetron Mesylate Injection—See PF Vol. 25, No. 4, page 8493.
2525. Dolasetron Mesylate Tablets—See PF Vol. 26, No. 1, page 145.
Cholestyramine for Oral Suspension—See PF Vol. 28, No. 1, page Doxazosin Mesylate Tablets—See PF Vol. 27, No. 6, page 3275.
51. Doxepin Hydrochloride—See PF Vol. 27, No. 4, page 2730.
Choline Bitartrate—See PF Vol. 27, No. 4, page 2715. Doxycycline Hyclate Capsules—See PF Vol. 27, No. 4, page 2731.
Choline Chloride—See PF Vol. 27, No. 4, page 2717. Edetate Disodium—See PF Vol. 27, No. 6, page 3277.
Sodium Chromate Cr 51 Injection—See PF Vol. 27, No. 3, page Multiple Electrolytes Injection Type 1—See PF Vol. 27, No. 4,
2526. page 2731.
Cimetidine Tablets—See PF Vol. 28, No. 1, page 52. Emedastine Difumarate—See PF Vol. 27, No. 1, page 1782.
Cinoxate—See PF Vol. 27, No. 3, page 2526. Emedastine Ophthalmic Solution—See PF Vol. 27, No. 1, page
Cinoxate Lotion—See PF Vol. 27, No. 3, page 2527. 1782.
Ciprofloxacin Ophthalmic Ointment—See PF Vol. 27, No. 6, page Enalapril Maleate Tablets—See PF Vol. 27, No. 3, page 2541.
3266. Enalapril Maleate and Hydrochlorothiazide Tablets—See PF Vol.
Citric Acid—See PF Vol. 25, No. 3, page 8114. 27, No. 3, page 2541.
Clidinium Bromide—See PF Vol. 27, No. 4, page 2720. Ergoloid Mesylates Tablets—See PF Vol. 28, No. 1, page 59.
Clindamycin Hydrochloride Capsules—See PF Vol. 27, No. 4, Erythromycin Estolate Oral Suspension—See PF Vol. 27, No. 4,
page 2720. page 2731.
Clindamycin Phosphate—See PF Vol. 27, No. 6, page 3267. Erythromycin Ointment—See PF Vol. 27, No. 6, page 3278.
Clomiphene Citrate—See PF Vol. 27, No. 5, page 2997. Estradiol—See PF Vol. 27, No. 2, page 2141.
Clomipramine Hydrochloride—See PF Vol. 27, No. 3, page 2529. Estropipate Tablets—See PF Vol. 27, No. 6, page 3280.
Clomipramine Hydrochloride Capsules—See PF Vol. 28, No. 1, Ethacrynate Sodium for Injection—See PF Vol. 27, No. 4, page
page 52. 2731.
Clonazepam—See PF Vol. 25, No. 3, page 8120. Ethosuximide Capsules—See PF Vol. 27, No. 4, page 2732.
Clonazepam Tablets—See PF Vol. 28, No. 1, page 54. Etodolac Capsules—See PF Vol. 27, No. 2, page 2143.
Clonidine Transdermal System—See PF Vol. 27, No. 1, page 1766. Etoposide—See PF Vol. 27, No. 5, page 3004.
Clorazepate Dipotassium Tablets—See PF Vol. 28, No. 1, page 54. Etoposide Capsules—See PF Vol. 27, No. 5, page 3004.
Clorsulon—See PF Vol. 28, No. 1, page 55. Felodipine—See PF Vol. 27, No. 2, page 2144.
Clozapine—See PF Vol. 25, No. 6, page 9129. Felodipine Extended-Release Tablets—See PF Vol. 27, No. 1, page
Cocaine and Tetracaine Hydrochlorides and Epinephrine Topical Fenoldopam Mesylate Injection—See PF Vol. 27, No. 1, page
Solution—See PF Vol. 27, No. 6, page 3269. 1785.
Fenoprofen Calcium—See PF Vol. 27, No. 6, page 3280.
Pharmacopeial Forum
Ferric Subsulfate Solution—See PF Vol. 27, No. 3, page 2543. Iodixanol Injection—See PF Vol. 27, No. 6, page 3311.
Ferric Sulfate—See PF Vol. 27, No. 2, page 2144. Iodoform—See PF Vol. 27, No. 2, page 2170.
Ferumoxides Injection—See PF Vol. 27, No. 3, page 2543. Iohexol—See PF Vol. 28, No. 1, page 70.
Ferumoxsil Oral Suspension—See PF Vol. 27, No. 6, page 3281. Iopromide Injection—See PF Vol. 27, No. 2, page 2170.
Finasteride—See PF Vol. 27, No. 2, page 2144. Ioxaglic Acid—See PF Vol. 27, No. 6, page 3312.
Finasteride Tablets—See PF Vol. 27, No. 2, page 2144. Iron Sucrose Injection—See PF Vol. 27, No. 5, page 3012.
Fluorodopa F 18 Injection—See PF Vol. 26, No. 1, page 155. Isoamyl Methoxycinnamate—See PF Vol. 27, No. 5, page 3017.
Fluoxetine Capsules—See PF Vol. 27, No. 2, page 2150. Isoflupredone Acetate—See PF Vol. 27, No. 4, page 2749.
Fluoxetine Tablets—See PF Vol. 27, No. 6, page 3283. Isoflupredone Acetate Injectable Suspension—See PF Vol. 27, No.
Flurandrenolide Cream—See PF Vol. 27, No. 2, page 2152. 4, page 2751.
Flurandrenolide Ointment—See PF Vol. 27, No. 2, page 2154. Isoflurane—See PF Vol. 26, No. 1, page 172.
Fluoxymesterone—See PF Vol. 28, No. 1, page 59. Isosorbide Concentrate—See PF Vol. 28, No. 1, page 71.
Fosphenytoin Sodium—See PF Vol. 27, No. 6, page 3285. Diluted Isosorbide Dinitrate—See PF Vol. 27, No. 3, page 2564.
Fosphenytoin Sodium Injection—See PF Vol. 27, No. 6, page Isotretinoin Capsules—See PF Vol. 27, No. 1, page 1790.
3287. Ivermectin—See PF Vol. 27, No. 1, page 1790.
Furosemide Oral Solution—See PF Vol. 28, No. 1, page 59. Kanamycin Sulfate—See PF Vol. 27, No. 6, page 3312.
Gabapentin—See PF Vol. 27, No. 5, page 3004. Ketamine Hydrochloride—See PF Vol. 27, No. 4, page 2752.
Gabapentin Capsules—See PF Vol. 27, No. 2, page 2160. Ketoconazole Oral Suspension—See PF Vol. 27, No. 6, page 3313.
Gadodiamide—See PF Vol. 27, No. 2, page 2163. Ketorolac Tromethamine—See PF Vol. 27, No. 6, page 3313.
Gadodiamide Injection—See PF Vol. 27, No. 2, page 2163. Lactulose Concentrate—See PF Vol. 28, No. 1, page 71.
Gadoteridol—See PF Vol. 27, No. 2, page 2163. Lansoprazole—See PF Vol. 26, No. 5, page 1293.
Gadoteridol Injection—See PF Vol. 27, No. 2, page 2164. Lansoprazole Delayed-Release Capsules—See PF Vol. 26, No. 5,
Ganciclovir for Injection—See PF Vol. 27, No. 5, page 3009. page 1295.
Gemfibrozil—See PF Vol. 27, No. 6, page 3289. Lamivudine—See PF Vol. 27, No. 1, page 1796.
Glutaral Concentrate—See PF Vol. 28, No. 1, page 60. Letrozole—See PF Vol. 27, No. 6, page 3313.
Glyburide Tablets—See PF Vol. 28, No. 1, page 60. Letrozole Tablets—See PF Vol. 28, No. 1, page 71.
Glycerin—See PF Vol. 27, No. 5, page 3010. Levocarnitine—See PF Vol. 28, No. 1, page 71.
Gonadorelin Hydrochloride—See PF Vol. 27, No. 3, page 2552. Levodopa—See PF Vol. 27, No. 4, page 2753.
Graftskin—See PF Vol. 27, No. 6, page 3290. Levodopa Capsules—See PF Vol. 27, No. 4, page 2754.
Guaifenesin—See PF Vol. 27, No. 4, page 2735. Levodopa Tablets—See PF Vol. 27, No. 4, page 2754.
Guanfacine Tablets—See PF Vol. 27, No. 4, page 2736. Levonorgestrel—See PF Vol. 27, No. 3, page 2565.
Haloperidol—See PF Vol. 27, No. 6, page 3300. Levothyroxine Sodium Oral Powder—See PF Vol. 27, No. 6, page
Heparin Sodium—See PF Vol. 25, No. 6, page 9153. 3313.
Hydralazine Hydrochloride Oral Solution—See PF Vol. 27, No. 6, Lincomycin Hydrochloride Soluble Powder—See PF Vol. 28, No.
page 3301. 1, page 73.
Hydrochlorothiazide—See PF Vol. 28, No. 1, page 60. Lorazepam Oral Concentrate—See PF Vol. 27, No. 4, page 2754.
Hydrochlorothiazide Tablets—See PF Vol. 27, No. 4, page 2739. Lorazepam Tablets—See PF Vol. 27, No. 4, page 2756.
Hydrocodone Bitartrate—See PF Vol. 28, No. 1, page 63. Lovastatin—See PF Vol. 27, No. 3, page 2566.
Hydrocodone Bitartrate and Acetaminophen Tablets—See PF Vol. Mafenide Acetate for Topical Solution—See PF Vol. 27, No. 1
27, No. 6, page 3301. page 1800.
Hydrocortisone Acetate Ophthalmic Suspension—See PF Vol. 27, Magnesium Carbonate, Citric Acid, and Potassium Citrate for Oral
No. 6, page 3302. Solution—See PF Vol. 26, No. 4, page 1050.
Hydrocortisone Valerate Ointment—See PF Vol. 27, No. 2, page Magnesium Sulfate—See PF Vol. 27, No. 4, page 2758.
2165. Manganese Chloride for Oral Solution—See PF Vol. 27, No. 2,
Hydrogen Peroxide Concentrate—See PF Vol. 28, No. 1, page 65. page 2171.
Hydromorphone Hydrochloride Tablets—See PF Vol. 26, No. 5, Mannitol—See PF Vol. 27, No. 5, page 3017.
page 1291. Mannitol Injection—See PF Vol. 28, No. 1, page 73.
Hydroxyzine Hydrochloride Tablets—See PF Vol. 27, No. 6, page Medroxyprogesterone Acetate—See PF Vol. 27, No. 2, page 2172.
3302. Megestrol Acetate Oral Suspension—See PF Vol. 27, No. 6, page
Ibuprofen—See PF Vol. 27, No. 4, page 2740. 3314.
Idarubicin Hydrochloride—See PF Vol. 27, No. 6, page 3302. Menthyl Anthranilate—See PF Vol. 27, No. 5, page 3021.
Indinavir Sulfate—See PF Vol. 27, No. 2, page 2165. Mephenytoin—See PF Vol. 27, No. 2, page 2174.
Insulin—See PF Vol. 27, No. 3, page 2553. Mephenytoin Tablets—See PF Vol. 27, No. 2, page 2174.
Insulin Injection—See PF Vol. 27, No. 2, page 2168. Mephobarbital Tablets—See PF Vol. 26, No. 1, page 178.
Isophane Insulin Suspension—See PF Vol. 27, No. 2, page 2169. Meradimate—See PF Vol. 27, No. 5, page 3021.
Insulin Human—See PF Vol. 28, No. 1, page 65. Meropenem—See PF Vol. 27, No. 1, page 1801.
Insulin Lispro—See PF Vol. 28, No. 1, page 66. Meropenem for Injection—See PF Vol. 27, No. 1, page 1801.
Insulin Lispro Injection—See PF Vol. 28, No. 1, page 69. Mesalamine Rectal Suspension—See PF Vol. 27, No. 6, page
Isophane Insulin Human Suspension—See PF Vol. 27, No. 2, page 3315.
2169. Methadone Hydrochloride Oral Solution—See PF Vol. 28, No. 1,
Insulin Zinc Suspension—See PF Vol. 27, No. 2, page 2169. page 74.
Extended Insulin Zinc Suspension—See PF Vol. 27, No. 2, page Methohexital Sodium for Injection—See PF Vol. 27, No. 1, page
2169. 1801.
Prompt Insulin Zinc Suspension—See PF Vol. 27, No. 2, page Methylprednisolone Acetate for Rectal Suspension—See PF Vol.
2170. 27, No. 5, page 3022.
Insulin Human Zinc Suspension—See PF Vol. 27, No. 2, page Methyltestosterone—See PF Vol. 28, No. 1, page 74.
2170. Metoprolol Succinate—See PF Vol. 27, No. 6, page 3316.
Extended Insulin Human Zinc Suspension—See PF Vol. 27, No. 2, Metoprolol Succinate Extended-Release Tablets—See PF Vol. 27,
page 2170. No. l,page 1803.
Inulin—See PF Vol. 27, No. 6, page 3303. Miconazole Nitrate—See PF Vol. 25, No. 2, page 7838.
Iodixanol—See PF Vol. 27, No. 6, page 3303. Miconazole Nitrate Cream—See PF Vol. 26, No. 5, page 1302.
Pharmacopeial Forum
Milrinone—See PF Vol. 27, No. 2, page 2175. Potassium Chloride Extended-Release Tablets—See PF Vol. 27,
Minocycline Hydrochloride—See PF Vol. 27, No. 5, page 3022. No. 3, page 2575.
Misoprostol—See PF Vol. 26, No. 5, page 1304. Povidone—See PF Vol. 22, No. 6, page 3163.
Misoprostol Dispersion—See PF Vol. 28, No. 1, page 76. Praziquantel—See PF Vol. 28, No. 1, page 84.
Misoprostol Tablets—See PF Vol. 26, No. 5, page 1310. Prednisolone—See PF Vol. 27, No. 5, page 3036.
Morphine Sulfate Suppositories—See PF Vol. 27, No. 6, page Prednisolone Acetate—See PF Vol. 27, No. 5, page 3037.
3318. Primidone—See PF Vol. 27, No. 4, page 2774.
Myrrh—See PF Vol. 28, No. 1, page 78. Progesterone Injection—See PF Vol. 27, No. 5, page 3038.
Nabumetone—See PF Vol. 27, No. 5, page 3024. Progesterone Vaginal Suppositories—See PF Vol. 27, No. 6, page
Nabumetone Tablets—See PF Vol. 26, No. 5, page 1315. 3323.
Neomycin Sulfate, Isoflupredone Acetate, and Tetracaine Hydro- Propofol—See PF Vol. 27, No. 4, page 2774.
chloride Ointment—See PF Vol. 27, No. 4, page 2758. Pseudoephedrine Hydrochloride Extended-Release Capsules—See
Neomycin Sulfate, Isoflupredone Acetate, and Tetracaine Hydro- PF Vol. 27, No. 6, page 3323.
chloride Topical Powder—See PF Vol. 27, No. 4, page 2760. Pseudoephedrine Hydrochloride Extended-Release Tablets—See
Nifedipine—See PF Vol. 27, No. 3, page 2569. PF Vol. 28, No. 1, page 85.
Nifedipine Capsules—See PF Vol. 28, No. 1, page 78. Pseudoephedrine Hydrochloride, Carbinoxamine Maleate, and
Nifedipine Extended-Release Tablets—See PF Vol. 27, No. 3, page Dextromethorphan Hydrobromide Oral Solution—See PF
2570. Vol. 27, No. 2, page 2196.
Nizatidine—See PF Vol. 27, No. 6, page 3319. Pyrantel Pamoate—See PF Vol. 27, No. 3, page 2576.
Norethindrone Acetate—See PF Vol. 27, No. 4, page 2762. Pyrantel Pamoate Oral Suspension—See PF Vol. 27, No. 6, page
Norethindrone Acetate and Ethinyl Estradiol Tablets—See PF Vol. 3325.
27, No. 6, page 3320. Pyrethrum Extract—See PF Vol. 26, No. 1, page 202.
Norgestimate and Ethinyl Estradiol Tablets—See PF Vol. 28, No. Ramipril—See PF Vol. 27, No. 5, page 3039.
1, page 79. Repaglinide—See PF Vol. 27, No. 6, page 3325.
Octisalate—See PF Vol. 27, No. 5, page 3027. Repaglinide Tablets—See PF Vol. 26, No. 5, page 1333.
Octocrylene—See PF Vol. 27, No. 5, page 3028. Ribavirin—See PF Vol. 27, No. 3, page 2577.
Octyl Salicylate—See PF Vol. 27, No. 5, page 3028. Rifampin Oral Suspension—See PF Vol. 27, No. 6, page 3327.
Ofloxacin—See PF Vol. 27, No. 4, page 2763. Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Hydrochlor-
Oxybenzone—See PF Vol. 27, No. 3, page 2572. ide Tablets—See PF Vol. 27, No. 5, page 3041.
Oxybutynin Chloride—See PF Vol. 26, No. 6, page 1561. Rimantadine Hydrochloride—See PF Vol. 24, No. 2, page 5927.
Oxycodone Hydrochloride—See PF Vol. 28, No. 1, page 84. Rimantadine Hydrochloride Tablets—See PF Vol. 24, No. 2, page
Oxycodone Hydrochloride Oral Solution—See PF Vol. 27, No. 4, 5929.
page 2763. Ringer's Injection—See PF Vol. 27, No. 4, page 2777.
Oxycodone and Acetaminophen Capsules—See PF Vol. 27, No. 6, Saquinavir Capsules—See PF Vol. 27, No. 2, page 2197.
Water O 15 Injection—See PF Vol. 27, No. 2, page 2182. Saw Palmetto Capsules—See PF Vol. 26, No. 6, page 1571.
Paclitaxel—See PF Vol. 27, No. 2, page 2183. Saw Palmetto Extract—See PF Vol. 26, No. 6, page 1567.
Paclitaxel Injection—See PF Vol. 27, No. 3, page 2572. Scopolamine Hydrobromide Injection—See PF Vol. 27, No. 6,
Paroxetine Hydrochloride—See PF Vol. 27, No. 4, page 2763. page 3328.
Paroxetine Tablets—See PF Vol. 27, No. 5, page 3029. Sevoflurane—See PF Vol. 27, No. 3, page 2577.
Penicillamine Capsules—See PF Vol. 27, No. 5, page 3031. Shark Liver Oil—See PF Vol. 26, No. 6, page 1643.
Penicillin G Sodium for Injection—See PF Vol. 27, No. 3, page Sodium Acetate—See PF Vol. 27, No. 6, page 3328.
2574. Sodium Butyrate—See PF Vol. 27, No. 2, page 2197.
Pentazocine and Naloxone Hydrochlorides Tablets—See PF Vol. Sodium Chloride—See PF Vol. 27, No. 4, page 2777.
28, No. l,page 84. Sodium Chloride Injection—See PF Vol. 27, No. 4, page 2777.
Pentoxifylline—See PF Vol. 26, No. 2, page 432. Sodium Chloride Ophthalmic Ointment—See PF Vol. 27, No. 6,
Pentoxifylline Extended-Release Tablets—See PF Vol. 27, No. 2, page 3329.
page 2188. Sodium Hypochlorite Topical Solution—See PF Vol. 27, No. 6,
Perflutren Protein-Type A Microspheres for Injection—See PF page 3329.
Vol. 27, No. 4, page 2769. Sodium Phosphates Rectal Solution—See PF Vol. 27, No. 1, page
Pergolide Mesylate—See PF Vol. 26, No. 4, page 1060. 1816.
Pergolide Tablets—See PF Vol. 25, No. 2, page 7845. Sodium Sulfide—See PF Vol. 27, No. 1, page 1816.
Phenylpropanolamine Hydrochloride—See PF Vol. 26, No. 6, Sodium Sulfide Topical Gel—See PF Vol. 27, No. 1, page 1816.
page 1562. Somatropin—See PF Vol. 25, No. 4, page 8540.
Phenyltoloxamine Dihydrogen Citrate—See PF Vol. 27, No. 6, Somatropin for Injection—See PF Vol. 25, No. 4, page 8551.
page 3321. Sorbitol Solution—See PF Vol. 27, No. 6, page 3329.
Phenytoin Sodium—See PF Vol. 27, No. 5, page 3031. Sotalol Hydrochloride—See PF Vol. 26, No. 4, page 1068.
Extended Phenytoin Sodium Capsules—See PF Vol. 27, No. 5, Sotalol Hydrochloride Tablets—See PF Vol. 27, No. 1, page 1816.
page 3034. Spironolactone—See PF Vol. 27, No. 3, page 2581.
Chromic Phosphate P 32 Suspension—See PF Vol. 27, No. 6, page Stanozolol Tablets—See PF Vol. 27, No. 6, page 3331.
3323. Streptomycin Injection—See PF Vol. 28, No. 1, page 86.
Polymyxin B Sulfate and Trimethoprim Ophthalmic Solution— Streptomycin for Injection—See PF Vol. 28, No. 1, page 86.
See PF Vol. 27, No. 2, page 2196. Streptomycin Sulfate—See PF Vol. 28, No. 1, page 87.
Potassium Chloride—See PF Vol. 27, No. 4, page 2773. Sulfadimethoxine—See PF Vol. 27, No. 4, page 2778.
Potassium Chloride in Dextrose Injection—See PF Vol. 27, No. 4, Sulfadimethoxine Oral Suspension—See PF Vol. 27, No. 2, page
page 2774. 2198.
Potassium Chloride in Dextrose and Sodium Chloride Injection— Sulfadimethoxine Sodium—See PF Vol. 27, No. 4, page 2778.
See PF Vol. 27, No. 4, page 2774. Sulfadimethoxine Soluble Powder—See PF Vol. 27, No. 2, page
Potassium Chloride in Sodium Chloride Injection—See PF Vol. 2198.
27, No. 4, page 2774. Sulfadimethoxine Tablets—See PF Vol. 27, No. 2, page 2198.
Sulindac—See PF Vol. 25, No. 5, page 8879.
Pharmacopeial Forum
Sulindac Tablets—See PF Vol. 25, No. 5, page EXCIPIENTS

Sulisobenzone—See PF Vol. 27, No. 5, page 3044. USP and NF Excipients, Listed by Category—See PF Vol. 26, No.
Sunflower Oil—See PF Vol. 27, No. 4, page 2779. 2, page 447.
Sutilains—See PF Vol. 27, No. 2, page 2199.
Sutilains Ointment—See PF Vol. 27, No. 2, page 2201.
Tacrine Capsules—See PF Vol. 26, No. 2, page 444. GENERAL CHAPTERS
Tacrine Hydrochloride—See PF Vol. 26, No. 5, page 1337.
Tamoxifen Citrate Tablets—See PF Vol. 27, No. 4, page 2779. General Tests and Assays
Taurine—See PF Vol. 27, No. 6, page 3331.
Technetium Tc 99m Arcitumomab Injection—See PF Vol. 27, No. General Requirements for Tests and Assays
2, page 2202. I) Injections—See PF Vol. 27, No. 5, page 3068.
Technetium Tc 99m Depreotide Injection—See PF Vol. 27, No. 3, I1) USP Reference Standards—See PF Vol. 22, No. 6, page 3212;
page 2583. PF Vol. 23, No. 4, page 4500; PF Vol. 24, No. 2, page 5965;
Terazosin Hydrochloride—See PF Vol. 27, No. 2, page 2202. PF Vol. 24, No. 5, page 6925; PF Vol. 25, No. 2, page 7876;
Terbutaline Sulfate—See PF Vol. 26, No. 3, page 752. PF Vol. 25, No. 3, page 8222; PF Vol. 25, No. 4, page 8561;
Terbutaline Sulfate Inhalation Aerosol—See PF Vol. 26, No. 3, PF Vol. 25, No. 5, page 8893; PF Vol. 25, No. 6, page 9222;
page 753. PF Vol. 26, No. 1, page 218; PF Vol. 26, No. 2, page 471; PF
Terbutaline Sulfate Injection—See PF Vol. 26, No. 3, page 756. Vol. 26, No. 3, page 793; PF Vol. 26, No. 4, page 1101; PF
Terbutaline Sulfate Tablets—See PF Vol. 26, No. 3, page 757. Vol. 26, No. 5, page 1369; PF Vol. 26, No. 6, page 1606; PF
Testolactone Tablets—See PF Vol. 27, No. 6, page 3332. Vol. 27, No. 1, page 1832; PF Vol. 27, No. 2, page 2268; PF
Tetracycline Hydrochloride Oral Suspension—See PF Vol. 27, No. Vol. 27, No. 3, page 2594; PF Vol. 27, No. 4, page 2806; PF
6, page 3333. Vol. 27, No. 5, page 3071; PF Vol. 27, No. 6, page 3348; and
Thalidomide—See PF Vol. 27, No. 1, page 1818. PFVol. 28, No. l,page 111.
Thalidomide Capsules—See PF Vol. 27, No. 1, page 1818. (13) Concordance of Foreign Pharmacopeial Tests and Assays—
Theophylline Oral Solution—See PF Vol. 27, No. 5, page 3044. See PF Vol. 24, No. 1, page 5612.
Theophylline Syrup—See PF Vol. 27, No. 1, page 1819.
Thyroid Tablets—See PF Vol. 28, No. 1, page 88. Apparatus for Tests and Assays
Tiagabine Hydrochloride—See PF Vol. 26, No. 4, page 1076.
Tinidazole—See PF Vol. 27, No. 1, page 1820. (41) Weights and Balances—See PF Vol. 26, No. 6, page 1607.
Tobramycin Inhalation Solution—See PF Vol. 26, No. 5, page
1340. Microbiological Tests
Tolazamide—See PF Vol. 27, No. 6, page 3333.
Tolnaftate Topical Aerosol—See PF Vol. 27, No. 1, page 1821. (55) Biological Indicators—Resistance Performance Tests— See
Torsemide—See PF Vol. 27, No. 1, page 1821. PF Vol. 27, No. 4, page 2807.
Triamterene and Hydrochlorothiazide Tablets—See PF Vol. 27, 61) Microbial Limit Tests—See PF Vol. 27, No. 2, page 2269.
No. 3, page 2584. 62) Microbiological Procedures for Absence of Objectionable
Trichlorfon—See PF Vol. 26, No. 6, page 1576. Microorganisms—See PF Vol. 27, No. 2, page 2269.
Tripelennamine Hydrochloride Injection—See PF Vol. 27, No. 1, (71) Sterility Tests—See PF Vol. 26, No. 4, page 1102.
page 1824.
Trolamine Salicylate—See PF Vol. 27, No. 4, page 2780.
Crystallized Trypsin for Inhalation Solution—See PF Vol. 27, No. Chemical Tests and Assays
l,page 1824.
Tylosin—See PF Vol. 27, No. 4, page 2780. LIMIT TESTS
Urofollitropin—See PF Vol. 27, No. 2, page 2207.
Urofollitropin for Injection—See PF Vol. 27, No. 5, page 3045. (191) Identification Tests—General—See PF Vol. 27, No. 6, page
Valrubicin—See PF Vol. 26, No. 5, page 1346. 3349.
Valrubicin Intravesical Solution—See PF Vol. 26, No. 1, page 211. (281) Residue on Ignition—See PF Vol. 28, No. 1, page 112.
Valsartan Capsules—See PF Vol. 27, No. 5, page 3050.
Valsartan and Hydrochlorothiazide Tablets—See PF Vol. 27, No. OTHER TESTS AND ASSAYS
4, page 2780. (381) Elastomeric Closures for Injections—See PF Vol. 26, No. 4,
Vancomycin—See PF Vol. 27, No. 4, page 2783. page 1108.
Vancomycin Hydrochloride—See PF Vol. 27, No. 4, page 2784. (561) Articles of Botanical Origin—See PF Vol. 27, No. 5, page
Vancomycin Injection—See PF Vol. 27, No. 4, page 2784. 3072.
Vancomycin for Injection—See PF Vol. 27, No. 4, page 2785. (581) Vitamin D Assay—See PF Vol. 26, No. 4, page 1111.
Vancomycin Hydrochloride for Injection—See PF Vol. 27, No. 4,
page 2786.
Sterile Vancomycin Hydrochloride—See PF Vol. 27, No. 4, page Physical Tests and Determinations
2786. (621) Chromatography—See PF Vol. 27, No. 6, page 3352.
Vecuronium Bromide—See PF Vol. 27, No. 5, page 3053. (625) Clarity and Degree of Opalescence of Liquids—See PF Vol.
Verteporfin—See PF Vol. 27, No. 3, page 2585. 26, No. 6, page 1616.
Verteporfin for Injection—See PF Vol. 27, No. 3, page 2587. (627) Degree of Color of Liquids—See PF Vol. 26, No. 6, page
Vinorelbine Tartrate—See PF Vol. 27, No. 5, page 3054. 1617.
Sterile Water for Injection—See PF Vol. 27, No. 4, page 2787. 643 Total Organic Carbon—See PF Vol. 27, No. 6, page 3356.
Purified Water—See PF Vol. 27, No. 5, page 3057. 645 Water Conductivity—See PF Vol. 27, No. 5, page 3076.
Xylazine—See PF Vol. 27, No. 5, page 3057. 661 Containers—See PF Vol. 27, No. 4, page 2817.
Yohimbine Hydrochloride—See PF Vol. 27, No. 2, page 2218. 671) Containers—Permeation—See PF Vol. 27, No. 6, page
Yohimbine Injection—See PF Vol. 27, No. 2, page 2219. 3357.
Zidovudine Capsules—See PF Vol. 27, No. 5, page 3058. 724 Drug Release—See PF Vol. 27, No. 6, page 3358.
Zileuton—See PF Vol. 27, No. 6, page 3335. 776 Optical Microscopy—See PF Vol. 26, No. 1, page 229.
781 Optical Rotation—See PF Vol. 27, No. 4, page 2819.
Pharmacopeial Forum
(795) Pharmacy Compounding—See PF Vol. 27, No. 5, page Dicyclohexyl Phthalate—See PF Vol. 26, No. 2, page 504.
3078. Diethylpyrocarbonate—See PF Vol. 27, No. 6, page 3365.
(905) Uniformity of Dosage Units—See PF Vol. 27, No. 3, page 2,7-Dihydroxynapthalene—See PF Vol. 21, No. 3, page 823.
2595. N,N-Dimethyldodecylamine-N-oxide—See PF Vol. 27, No. 4,
page 2837.
General Information 2,5-Dimethylphenol—See PF Vol. 27, No. 6, page 3364.
3,5-Dimethylphenol—See PF Vol. 27, No. 3, page 2596.
(1010) Analytical Data—Interpretation and Treatment—See PF 1,4-Dimethylpiperazine—See PF Vol. 27, No. 1, page 1903.
Vol. 27, No. 5, page 3086. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl Tetrazolium Bro-
(1035) Biological Indicators for Sterilization—See PF Vol. 27, No. mide—See PF Vol. 27, No. 6, page 3365.
4, page 2820. Dimethyltin Dibromide—See PF Vol. 25, No. 3, page 8280.
(1046) Gene and Cell Therapy Products—See PF Vol. 27, No. 1, Dioleoylglycerol—See PF Vol. 26, No. 6, page 1622.
page 1835. Racemic Epinephrine—See PF Vol. 23, No. 4, page 4529.
(1047) Biotechnology-Derived Articles—Tests—See PF Vol. 27, oc-Ergocryptine—See PF Vol. 27, No. 4, page 2837.
No. 2, page 2277. Escin—See PF Vol. 27, No. 4, page 2837.
(1116) Microbiological Evaluation of Clean Rooms and Other 17oc-Estradiol—See PF Vol. 27, No. 2, page 2278.
Controlled Environments—See PF Vol. 25, No. 3, page 8264. Ether, Peroxide-Free—See PF Vol. 27, No. 6, page 3365.
(1118) Monitoring Devices—Time, Temperature, and Humidity— Ethidium Bromide—See PF Vol. 27, No. 6, page 3366.
See PF Vol. 26, No. 2, page 481. 4'-Ethoxyacetophenone—See PF Vol. 26, No. 5, page 1382.
(1119) Near-Infrared Spectrophotometry— See PF Vol. 27, No. 5, Ethylbenzene—See PF Vol. 25, No. 1, page 7582.
page 3101. Fast Green FCF—See PF Vol. 27, No. 2, page 2278.
(1141) Packaging, Storage, and Distribution of Pharmacopeial Ar- FD&C Blue No. 1—See PF Vol. 28, No. 1, page 115.
ticles—See PF Vol. 26, No. 2, page 493. 9-Fluorenylmethyl Chloroformate—See PF Vol. 25, No. 5, page
(1146) Packaging Practice—Repackaging a Single Solid Oral 8916.
Drug Product into a Unit-Dose Container—See PF Vol. 27, Formamide, Anhydrous—See PF Vol. 27, No. 5, page 3115.
No. 4, page 2827. L-Glutamic Acid—See PF Vol. 27, No. 6, page 3366.
(1151) Pharmaceutical Dosage Forms—See PF Vol. 26, No. 2, L-Glutamine—See PF Vol. 27, No. 6, page 3366.
page 499. Guanidine Isothiocyanate—See PF Vol. 27, No. 6, page 3366.
(1186) Shipping and Storage of Labile Preparations—See PF Vol. Heptafluorobutyric Acid—See PF Vol. 26, No. 4, page 1132.
25, No. 6, page 9248. L-Histidine Hydrochloride Monohydrate—See PF Vol. 27, No. 6,
(1191) Stability Considerations in Dispensing Practice—See PF page 3366.
Vol. 28, No. l,page 112. Hydrazine Sulfate—See PF Vol. 27, No. 4, page 2837.
(1206) Sterile Drug Products for Home Use—See PF Vol. 26, No. Hydroxy Naphthol Blue—See PF Vol. 27, No. 6, page 3366.
3, page 812. Hypoxanthine—See PF Vol. 27, No. 6, page 3367.
(1207) Sterile Product Packaging—Integrity Evaluation—See PF Indole—See PF Vol. 25, No. 4, page 8586.
Vol. 27, No. 5, page 3111. Indole-3-carboxylic Acid—See PF Vol. 25, No. 4, page 8586.
Iodoethane—See PF Vol. 24, No. 6, page 7327.
REAGENTS, INDICATORS, AND SOLUTIONS Isoferulic Acid—See PF Vol. 27, No. 4, page 2837.
Isopropyl Acetate—See PF Vol. 26, No. 4, page 1132.
Reagent Specifications 2-Isopropylphenol—See PF Vol. 27, No. 4, page 2838.
Isorhamnetin—See PF Vol. 27, No. 2, page 2279.
Agarose—See PF Vol. 27, No. 6, page 3363. Kaempferol—See PF Vol. 27, No. 2, page 2279.
Ammonia Water, Stronger—See PF Vol. 27, No. 6, page 3363. Linoleic Acid—See PF Vol. 27, No. 6, page 3367.
Ammonium Formate—See PF Vol. 25, No. 4, page 8586. oc-Lipoic Acid—See PF Vol. 27, No. 6, page 3367.
Ammonium Pyrrolidinedithiocarbamate—See PF Vol. 27, No. 5, Manganese Dioxide—See PF Vol. 27, No. 6, page 3367.
page 3115. Manganese Dioxide, Activated—See PF Vol. 27, No. 6, page
Aniline Sulfate—See PF Vol. 27, No. 2, page 2277. 3367.
Antifoam Reagent—See PF Vol. 26, No. 6, page 1621. Mercurous Nitrate—See PF Vol. 27, No. 6, page 3368.
L-Aspartic Acid—See PF Vol. 27, No. 6, page 3363. Methyl Benzenesulfonate—See PF Vol. 24, No. 4, page 6591.
Azure A—See PF Vol. 27, No. 5, page 3115. 3-Methyl-2-benzothiazolinone Hydrazone Hydrochloride— See
Biuret—See PF Vol. 26, No. 2, page 503. PF Vol. 25, No. 3, page 8280.
Branched Polymeric Sucrose—See PF Vol. 27, No. 6, page 3363. Methyl Green—See PF Vol. 27, No. 2, page 2279.
Butyrolactone—See PF Vol. 22, No. 6, page 3248. 1-Methylpiperazine—See PF Vol. 27, No. 1, page 1903.
Canada Balsam—See PF Vol. 27, No. 2, page 2278. N-Methylpyrrolidine—See PF Vol. 27, No. 5, page 3116.
Carmine—See PF Vol. 27, No. 2, page 2278. Monooleoylglycerol—See PF Vol. 26, No. 6, page 1622.
m-Chlorobenzoic Acid—See PF Vol. 26, No. 4, page 1132. Morin—See PF Vol. 25, No. 3, page 8280.
1-Chloronaphthalene—See PF Vol. 27, No. 6, page 3364. 1-Naphthylamine—See PF Vol. 27, No. 5, page 3116.
Compactin—See PF Vol. 27, No. 3, page 2595. Nickel Chloride Hexahydrate—See PF Vol. 26, No. 5, page 1382.
0.5 M Copper Sulfate Solution—See PF Vol. 26, No. 5, page 1382. Nickel(II) Sulfate Heptahydrate—See PF Vol. 27, No. 5, page
Cupric Nitrate—See PF Vol. 27, No. 6, page 3364. 3116.
Cyclohexylmethanol—See PF Vol. 25, No. 1, page 7582. Nicotinamide Adenine Dinucleotide—See PF Vol. 27, No. 3, page
Deoxyadenosine Triphosphate—See PF Vol. 27, No. 6, page 3364. 2596.
Deoxycytidine Triphosphate—See PF Vol. 27, No. 6, page 3364. /3-Nicotinamide Adenine Dinucleotide—See PF Vol. 27, No. 3,
Deoxyguanosine Triphosphate—See PF Vol. 27, No. 6, page 3364. page 2596.
Deoxyribonucleic Acid Polymerase—See PF Vol. 27, No. 6, page n-Nonylamine—See PF Vol. 27, No. 6, page 3368.
3365. Nonylphenol Polyoxyethylene Ether—See PF Vol. 27, No. 6, page
Deoxythymidine Triphosphate—See PF Vol. 27, No. 6, page 3365. 3368.
Dextran, High Molecular Weight—See PF Vol. 27, No. 5, page Oligo-deoxythymidine—See PF Vol. 27, No. 6, page 3368.
3115. Pentadecanoic Acid Methyl Ester—See PF Vol. 26, No. 6, page
Dibutylammonium Phosphate—See PF Vol. 26, No. 4, page 1132. 1622.
Dicyclohexyl—See PF Vol. 25, No. 1, page 7582. 2-Pentanone—See PF Vol. 26, No. 4, page 1132.
Pharmacopeial Forum
o-Phenanthroline Monohydrochloride Monohydrate—See PF Vol. Volumetric Solutions

27, No. l.page 1904.
Phenol Red, Sodium—See PF Vol. 27, No. 6, page 3368. Edetate Disodium, Twentieth-Molar (0.05 M)—See PF Vol. 27,
Phenoxyacetic Acid—See PF Vol. 27, No. 1, page 1904. No. 6, page 3373.
3-Phenoxybenzoic Acid—See PF Vol. 27, No. 3, page 2596.
Phenylacetic Acid—See PF Vol. 27, No. 1, page 1904. Reagent Footnotes
Polyoxyethylene (20) Sorbitan Monolaurate—See PF Vol. 27, No.
Footnote 43—See PF Vol. 27, No. 6, page 1133.
6, page 3368. Footnote 85—See PF Vol. 26, No. 4, page 1133.
Polysaccharide Molecular Weight Standards—See PF Vol. 27, No. Footnote 87—See PF Vol. 26, No. 5, page 1383.
Propionaldehyde—See PF Vol. 24, No. 6, page 7328. Footnote 89—See PF Vol. 26, No. 6, page 1623.
Protein Standard Solution (8 g/dL)—See PF Vol. 26, No. 6, page Footnote 92—See PF Vol. 27, No. 3, page 2597.
1622. Footnote 93—See PF Vol. 27, No. 3, page 2597.
(-)-Pseudoephedrine—See PF Vol. 23, No. 5, page 4872. Footnote 94—See PF Vol. 27, No. 3, page 2597.
Putrescine Dihydrochloride—See PF Vol. 27, No. 6, page 3369. Footnote 95—See PF Vol. 27, No. 3, page 2597.
Reverse Transcriptase—See PF Vol. 27, No. 6, page 3369. Footnote 96—See PF Vol. 27, No. 5, page 3118.
Ribonuclease Inhibitor—See PF Vol. 27, No. 6, page 3369. Footnote 97—See PF Vol. 27, No. 5, page 3118.
Silver Chloride, Granular Reagent—See PF Vol. 26, No. 5, page Footnote 98—See PF Vol. 27, No. 5, page 3118.
1383. Footnote 99—See PF Vol. 27, No. 6, page 3374.
/3-Sitosterol—See PF Vol. 26, No. 3, page 835. Footnote 100—See PF Vol. 27, No. 6, page 3374.
Soda Lime—See PF Vol. 27, No. 4, page 2838. Footnote 101—See PF Vol. 27, No. 6, page 3374.
Sodium Iodate—See PF Vol. 27, No. 6, page 3369. Footnote 102—See PF Vol. 27, No. 6, page 3374.
Tetrahydrofuran, Peroxide-Free—See PF Vol. 27, No. 6, page
3369.
1,1,4,4-Tetraphenyl-1,3-butadiene—See PF Vol. 26, No. 6, page REFERENCE TABLES
1623.
Thionine Acetate—See PF Vol. 27, No. 2, page 2279. Container Specifications for Capsules and Tablets—See PF Vol.
Thymidine—See PF Vol. 27, No. 6, page 3369. 28, No. l.page 115.
Toluidine Blue—See PF Vol. 27, No. 2, page 2280. Description and Relative Solubility of USP and NF Articles—See
Toluidine Blue O—See PF Vol. 27, No. 2, page 2280. PF Vol. 23, No. 4, page 4533; PF Vol. 23, No. 5, page 4874;
a,a,oc-Trifluoro-p-cresol—See PF Vol. 27, No. 3, page 2596. PF Vol. 23, No. 6, page 5310; PF Vol. 24, No. 5, page 7017;
Trimethyltin Bromide—See PF Vol. 25, No. 3, page 8281. PF Vol. 25, No. 2, page 7930; PF Vol. 25, No. 3, page 8282;
Trioleoylglycerol—See PF Vol. 26, No. 6, page 1623. PF Vol. 25, No. 4, page 8589; PF Vol. 25, No. 5, page 8917;
Tris(hydroxymethyl)aminomethane Acetate—See PF Vol. 27, No. PF Vol. 25, No. 6, page 9254; PF Vol. 26, No. 1, page 251; PF
5, page 3117. Vol. 26, No. 2, page 504; PF Vol. 26, No. 2, page 505; PF Vol.
Tris(hydroxymethyl)aminomethane Hydrochloride—See PF Vol. 26, No. 3, page 837; PF Vol. 26, No. 4, page 1135; PF Vol. 26,
27, No. 6, page 3370. No. 5, page 1385; PF Vol. 26, No. 6, page 1623; PF Vol. 27,
N-Tris(hydroxymethyl)methylglycine—See PF Vol. 27, No. 5, No. 1, page 1907; PF Vol. 27, No. 2, page 2281; PF Vol. 27,
page 3117. No. 3, page 2601; PF Vol. 27, No. 4, page 2839; PF Vol. 27,
L-Tyrosine Disodium—See PF Vol. 27, No. 6, page 3370. No. 5, page 3120; PF Vol. 27, No. 6, page 3374; and PF Vol.
Uridine—See PF Vol. 27, No. 3, page 2597. 28, No. l.page 116.
Water, HPLC Grade—See PF Vol. 28, No. 1, page 115.
Vinyl Acetate—See PF Vol. 21, No. 2, page 466.
2-Vinylpyridine—See PF Vol. 26, No. 2, page 504. GENERAL NOTICES AND REQUIREMENTS
l-Vinyl-2-pyrrolidone—See PF Vol. 22, No. 6, page 3249. "Official" and "Official Articles"—See PF Vol. 28, No. 1, page
Zinc Sulfate Heptahydrate—See PF Vol. 26, No. 2, page 504.
Indicator and Test Papers NF MONOGRAPHS

Hydroxy Naphthol Blue Indicator—See PF Vol. 27, No. 6, page Acacia Syrup—See PF Vol. 27, No. 4, page 2787.
3370. Diluted Acetic Acid—See PF Vol. 27, No. 4, page 2788.
Hydroxy Naphthol Blue Trituration—See PF Vol. 27, No. 6, page Acetyltributyl Citrate—See PF Vol. 27, No. 5, page 3058.
3370. Acetyltriethyl Citrate—See PF Vol. 27, No. 5, page 3058.
Thiazole Yellow Paper—See PF Vol. 27, No. 5, page 3117. Myristyl Alcohol—See PF Vol. 27, No. 3, page 2589.
Anise Oil—See PF Vol. 27, No. 4, page 2789.
Test Solutions Benzalkonium Chloride—See PF Vol. 27, No. 4, page 2789.
Benzalkonium Chloride Solution—See PF Vol. 27, No. 5, page
Buffer Solutions—See PF Vol. 27, No. 6, page 3371. 3059.
Cupric Citrate TS—See PF Vol. 27, No. 5, page 3117. Benzyl Alcohol—See PF Vol. 27, No. 4, page 2790.
Ferroin TS—See PF Vol. 27 No. 1, page 1905. Butylated Hydroxyanisole—See PF Vol. 27, No. 3, page 2590.
Iodine, Diluted TS—See PF Vol. 27, No. 6, page 3372. Calcium Silicate—See PF Vol. 27, No. 6, page 3337.
Mercuric-Potassium Iodide TS, Alkaline—See PF Vol. 27, No. 6, Calcium Sulfate—See PF Vol. 27, No. 6, page 3337.
page 3372. Caprylocaproyl Macrogolglycerides—See PF Vol. 26, No. 2, page
Nickel Standard Solution TS—See PF Vol. 27, No. 5, page 3117. 448.
Perchloric Acid TS—See PF Vol. 27 No. 1, page 1905. Caraway—See PF Vol. 27, No. 4, page 2790.
Potassium Iodide and Starch TS—See PF Vol. 27, No. 6, page Caraway Oil—See PF Vol. 27, No. 4, page 2791.
3373. Carbomer 941—See PF Vol. 27, No. 6, page 3338.
Potassium Thiocyanate TS—See PF Vol. 27, No. 5, page 3118. Carbomer Copolymer—See PF Vol. 27, No. 2, page 2219.
Carbomer Interpolymer—See PF Vol. 27, No. 2, page 2222.
Pharmacopeia! Forum
Carboxymethylcellulose Sodium 12—See PF Vol. 26, No. 6, page Kava—See PF Vol. 28, No. 1, page 100.
1577. Powdered Kava—See PF Vol. 28, No. 1, page 104.
Cardamom Oil—See PF Vol. 27, No. 4, page 2791. Powdered Kava Extract—See PF Vol. 26, No. 3, page 783.
Cardamom Seed—See PF Vol. 27, No. 4, page 2792. Semisolid Kava Extract—See PF Vol. 26, No. 3, page 784.
Compound Cardamom Tincture—See PF Vol. 27, No. 4, page Kava Capsules—See PF Vol. 26, No. 3, page 785.
2793. Kava Tablets—See PF Vol. 26, No. 3, page 787.
Cellulose Acetate Butyrate—See PF Vol. 25, No. 2, page 7861. Lauroyl Macrogolglycerides—See PF Vol. 26, No. 2, page 456.
Cetostearyl Alcohol—See PF Vol. 26, No. 6, page 1350. Lemon Oil—See PF Vol. 27, No. 4, page 2798.
Cetyl Palmitate—See PF Vol. 27, No. 1, page 1825. Licorice—See PF Vol. 26, No. 5, page 1363.
Chamomile—See PF Vol. 27, No. 5, page 3059. Licorice Fluidextract—See PF Vol. 27, No. 4, page 2799.
Cherry Juice—See PF Vol. 27, No. 4, page 2793. Linoleoyl Macrogolglycerides—See PF Vol. 26, No. 2, page 457.
Cherry Syrup—See PF Vol. 27, No. 4, page 2795. a-Lipoic Acid—See PF Vol. 27, No. 6, page 3338.
Chocolate—See PF Vol. 27, No. 4, page 2795. Magnesium Aluminometasilicate—See PF Vol. 27, No. 3, page
Chocolate Syrup—See PF Vol. 27, No. 4, page 2796. 2590.
Chondroitin Sulfate Sodium—See PF Vol. 27, No. 5, page 3059. Magnesium Aluminosilicate—See PF Vol. 27, No. 3, page 2593.
Chondroitin Sulfate Tablets—See PF Vol. 27, No. 5, page 3063. Maltitol Solution—See PF Vol. 27, No. 6, page 3340.
Clove Oil—See PF Vol. 27, No. 4, page 2796. Methacrylic Acid Copolymer—See PF Vol. 27, No. 4, page 2800.
Copovidone—See PF Vol. 24, No. 5, page 6891. Powdered Milk Thistle Extract—See PF Vol. 27, No. 2, page 2259.
Purified Cotton Filler—See PF Vol. 26, No. 1, page 213. Milk Thistle Capsules—See PF Vol. 27, No. 2, page 2261.
Crospovidone—See PF Vol. 27, No. 5, page 3065. Milk Thistle Tablets—See PF Vol. 27, No. 2, page 2263.
Dimethicone—See PF Vol. 27, No. 6, page 3338. Mono- and Di-glycerides—See PF Vol. 27, No. 5, page 3065.
Echinacea angustifolia—See PF Vol. 26, No. 6, page 1578. Nettle—See PF Vol. 28, No. 1, page 105.
Powdered Echinacea angustifolia—See PF Vol. 26, No. 6, page Powdered Nettle—See PF Vol. 28, No. 1, page 108.
1583. Powdered Nettle Extract—See PF Vol. 28, No. 1, page 109.
Powdered Echinacea angustifolia Extract—See PF Vol. 26, No. 6, Oleic Acid—See PF Vol. 26, No. 5, page 1366.
page 1583. Oleoyl Macrogolglycerides—See PF Vol. 26, No. 2, page 459.
Echinacea pallida—See PF Vol. 26, No. 6, page 1585. Orange Oil—See PF Vol. 27, No. 4, page 2800.
Powdered Echinacea pallida—See PF Vol. 26, No. 6, page 1588. Orange Syrup—See PF Vol. 27, No. 4, page 2801.
Powdered Echinacea pallida Extract—See PF Vol. 26, No. 6, page Sweet Orange Peel Tincture—See PF Vol. 27, No. 4, page 2802.
1588. Poloxamer—See PF Vol. 27, No. 4, page 2802.
Echinacea purpurea Root—See PF Vol. 26, No. 6, page 1590. Polyethylene Glycol—See PF Vol. 27, No. 5, page 3067.
Powdered Echinacea purpurea—See PF Vol. 26, No. 6, page 1593. Purified Rayon Filler—See PF Vol. 26, No. 1, page 216.
Powdered Echinacea purpurea Extract—See PF Vol. 26, No. 6, St. John's Wort—See PF Vol. 26, No. 2, page 460.
page 1594. Powdered St. John's Wort—See PF Vol. 25, No. 2, page 7876.
Eleuthero—See PF Vol. 26, No. 6, page 1596. Powdered St. John's Wort Extract—See PF Vol. 26, No. 2, page
Powdered Eleuthero—See PF Vol. 26, No. 6, page 1598. 463.
Powdered Eleuthero Extract—See PF Vol. 26, No. 6, page 1599. Sodium Starch Glycolate—See PF Vol. 22, No. 6, page 3202.
Ethyl Acetate—See PF Vol. 27, No. 4, page 2797. Sorbitol—See PF Vol. 27, No. 6, page 3342.
Ethylcellulose—See PF Vol. 25, No. 2, page 7866. Noncrystallizing Sorbitol Solution—See PF Vol. 27, No. 6, page
Fennel Oil—See PF Vol. 27, No. 4, page 2797. 3344.
Garlic Delayed-Release Tablets—See PF Vol. 28, No. 1, page 89. Stearoyl Macrogolglycerides—See PF Vol. 26, No. 2, page 467.
Ginger Capsules—See PF Vol. 27, No. 2, page 2227. Sucrose—See PF Vol. 22, No. 6, page 3206.
Ginkgo—See PF Vol. 27, No. 2, page 2229. Sunflower Oil—See PF Vol. 27, No. 4, page 2803.
Powdered Ginkgo Extract—See PF Vol. 27, No. 2, page 2233. Suspension Structured Vehicle—See PF Vol. 27, No. 6, page 3346.
Ginkgo Capsules—See PF Vol. 27, No. 2, page 2238. Sugar-Free Suspension Structured Vehicle—See PF Vol. 27, No. 6,
Ginkgo Tablets—See PF Vol. 27, No. 2, page 2240. page 3346.
American Ginseng—See PF Vol. 27, No. 2, page 2243. Tributyl Citrate—See PF Vol. 27, No. 5, page 3067.
Powdered American Ginseng—See PF Vol. 27, No. 2, page 2247. Triethyl Citrate—See PF Vol. 27, No. 5, page 3068.
Powdered American Ginseng Extract—See PF Vol. 27, No. 2, page Ubidecarenone—See PF Vol. 26, No. 6, page 1601.
2247. Ubidecarenone Capsules—See PF Vol. 27, No. 2, page 2265.
Asian Ginseng Capsules—See PF Vol. 26, No. 3, page 775. Ubidecarenone Tablets—See PF Vol. 27, No. 2, page 2267.
Asian Ginseng Tablets—See PF Vol. 27, No. 2, page 2254. Valerian Capsules—See PF Vol. 27, No. 1, page 1825.
Goldenseal—See PF Vol. 27, No. 2, page 2255. Vanilla—See PF Vol. 27, No. 4, page 2804.
Powdered Goldenseal—See PF Vol. 27, No. 2, page 2257. Vanilla Tincture—See PF Vol. 27, No. 4, page 2805.
Powdered Goldenseal Extract—See PF Vol. 27, No. 2, page 2258. Xanthan Gum Solution—See PF Vol. 27, No. 6, page 3347.
Hawthorn Leaf with Flower—See PF Vol. 26, No. 5, page 1357.
Powdered Hawthorn Leaf with Flower—See PF Vol. 26, No. 5,
NUTRITIONAL SUPPLEMENTS
page 1362.
Glucosamine Hydrochloride—See PF Vol. 28, No. 1, page 92. USP MONOGRAPHS
Glucosamine Potassium Sulfate—See PF Vol. 28, No. 1, page 94.
Glucosamine Sodium Sulfate—See PF Vol. 28, No. 1, page 95. Calcium and Vitamin D with Minerals Tablets—See PF Vol. 27,
Glucosamine Tablets—See PF Vol. 28, No. 1, page 97. No. 2, page 2283.
Glucosamine and Chondroitin Sulfate Tablets—See PF Vol. 28,
No. 1, page 98. GENERAL CHAPTERS
Hydroxypropyl Beta Cyclodextrin—See PF Vol. 24, No. 6, page
7284. (2040) Disintegration and Dissolution of Nutritional Supple-
Isopropyl Myristate—See PF Vol. 26, No. 5, page 1362. ments—See PF Vol. 26, No. 3, page 838.
Pharmacopeial Forum
(Canceled proposals may be republished at any time in a future number of Pharmacopeial Forum.)
[PF28(1)-PF28(6)]
Title and Proposal Vol No. Page(s)
USP Monographs
fAlcohol 22 3021
fDehydrated Alcohol 22 3024
7-Aminodesacetoxycephalosporanic Acid (new) 26 1534
6-Aminopenicillanic Acid (new) 27 1745
Citric Acid (new) 25 8114
Delavirdine Mesylate (new) 24 7143
Delavirdine Mesylate Tablets (new) 24 7145
Diethylcarbamazine Citrate—Limit of 1-meihylpiperazine and 27 1775
/, 4-dimeihylpiperazine
Diethylcarbamazine Citrate Tablets—Limit of1-methylpiperazine 27 1777
and 1,4-dimeihylpiperazine
Estradiol—Assay 25 9140
fFluorodopa F 18 Injection—Specific activity; 26 155
pH;
USP Reference Standards;
Radiochemical purity;
Chemical purity;
Enantiomeric purity
Glipizide—Ordinary impurities 27 1786
Heparin Sodium—Identification 25 9153
Hydroxizine Hydrochloride Tablets—Dissolution 27 2553
(subsections Medium and Apparatus)
fPaclitaxel (new) 27 2183
Rimantidine Hydrochloride (new) 24 5927
Rimantidine Hydrochloride Tablets (new) 24 5929
Ritonavir (new) 24 7176
Ritonavir Capsules (new) 24 7178
Trichlorfon—Labeling 26 1576
USP and NF Excipients, Listed by Category 26 447
f(l) Injections—Packaging 27 3068
(subsection Content variation of single-dose injections
containing 30 mL or less)
(11) USP Reference Standards
USP 6-Aminopenicillanic Acid RS 27 1832
ÛSP 6-Fluoro-D,L-dopa RS 25 8222
fUSP Tinidazole RS 27 2268
\USP Tinidazole Related Compound A RS 27 2268
ÛSP Saquinavir Related Compound A RS 27 2268
f (13) Concordance of Foreign Pharmacopeial Tests 24 5612
and Assays (new)
f(281) Residue on Ignition 27 2325
t(381) Elastomeric Closures for Injections— 26 1108
Physicochemical Tests
(1151) Pharmaceutical Dosage Forms—Bioavailability 24 5828
1,4-Dimethylpiperazine (new) 27 1403

f Dimethyltin Dibromide (new) 25 8280
1-Methylpiperazine (new) 27 1903
1-Methylpyrrolidone (new) 24 7199
f Morin (new) 25 8280
•fNickel Chloride Hexahydrate (new) 26 1382
Phenoxyacetic Acid (new) 27 1904
Phenylacetic Acid (new) 27 1904
(-)Pseudoephedrine (new) 23 4872
tTrimethyltin Bromide (new) 25 8281
Pharmacopeial Forum

Title and Proposal VoL No. Page(s)
Reagent Footnotes
|Footnote43 27 6 3373
Reference Tables
Description and Relative Solubility—6-Aminopenicillanic Acid, 27 1 1907
^Piperazine Adipate
NF Monographs
Purified Cotton Filler (new) 26 1 213
fEthylcellulose 25 2 7866
Purified Rayon Filler (new) 26 1 216
fNew cancellations in 28(2).
HARMONIZATION
This section contains monographs or chapters undergoing harmonization by the Pharmacopeial Discussion Group (PDG).
The PDG consists of the United States Pharmacopeia (USP), the European Pharmacopoeia (EP), and the Japanese Pharma-
copoeia (JP). The process of harmonization is composed of several steps (Stages).
item. The PDG distributes the work by consensus among the three participating pharmacopeias. Harmonization may be car-
ried out retrospectively for existing monographs or chapters, or prospectively for new monographs or chapters.
experts, and staff.
Stage 5: Consensus
A. Provisional
B. Final
Adopted items are published by the three pharmacopeias in their Supplements or, where applicable, in a new edition of their
Pharmacopeias.
region.
Pharmacopeial Forum
568 HARMONIZATION Vol. 28(2) [Mar.-Apr. 2002]
HARMONIZATION 567
Petrolatum 569
White Petrolatum 570
MONOGRAPHS (NF) 572
Butylparaben 572
Ethylparaben 574
Methylparaben 575
Polyethylene Glycol 577
Propylparaben 581
Stearic Acid 583
(601) Aerosols, Metered-Dose Inhalers, and Dry Powder Inhalers 584
(699) Density of Solids 603
(776) Optical Microscopy 606
(811) Powder Fineness 611
(846) Specific Surface Area 612
(1174) Powder Flow 618
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] HARMONIZATION 569
(12) Organic acids—Deleted based on comments that the test is

MONOGRAPHS (USP) unnecessary since bleaching is done by a nonoxidative pro-
cess.
(13) Fixed oils, fats, and rosin—Deleted based on comments that
these compounds will not be present in petrolatum, since the
oleum process is no longer used to produce petrolatum.
(14) Limit of sulfur-containing compounds—Deleted based on
comments that the test was not suitable for petrolatum.
(15) Polycyclic aromatic hydrocarbons—Deleted based on com-
BRIEFING ments that this test is unnecessary.
(16) Readily carbonizable substances (271)—Deleted based on
Petrolatum, USP 25 page 1346 and page 4561 of PF 23(4) comments that this test is unnecessary.
[July-Aug. 1997]. This proposal reflects the Council of Experts'
efforts to develop a harmonized monograph for Yellow Petrolatum
Jelly. The United States Pharmacopeia is the coordinating pharma- (EMC: J. Lane) RTS—36202-3
copeia for the international harmonization of compendial standards
for the subject article. The revisions presented in this proposal re-
present the OFFICIAL INQUIRY STAGE 4 draft in the harmoni-
zation process. The proposed draft also incorporates comments and
suggestions made by EP and JP. The harmonized monograph sec- Change to read:
tions proposed for the USP monograph have been editorially A
styled. Readers are therefore urged to review these late-stage In- Yellow Petrolatum Jelly
Process Revision proposals carefully and to respond to USP no la-
ter than May 15,2002.
Major changes proposed include the following: » Petrolatum is a purified mixture of saturated
(1) A change of the monograph title from Petrolatum to Yellow
Petrolatum Jelly. semisolid and bleached hydrocarbons obtained
(2) In the opening paragraph (the definition)—No change.
(3) Packaging and storage—Added the statement, " . . . protected from petroleum. It may contain a suitable stabili-
from light." This proposal to specify protection from light is
based on comments received. zer.
(4) Labeling—Added the statement, "Where the labeling indi-
cates the consistency, determine compliance using Consis-
tency." The Consistency test, which measures a Packaging and storage—Preserve in well-closed
functionality parameter of the article, is not intended to be a
required test in this harmonized monograph; therefore, the containers, protected from light.
proposed Labeling wording regarding consistency is intended
to indicate that the Consistency test procedure in the harmo-
nized monograph is to be used to determine consistence va- Labeling—The labeling indicates the name and
lues if such values are reported in the labeling for the article.
(5) Color—No change. concentration of any added stabilizer. Where the labeling
(6) Identification—This section was added and employs an IR
test, which is based on the corresponding EP test. indicates the consistency, determine compliance using
(7) Specific gravity—Deleted based on comments that the wide
test limits are not suitable to characterize the article. Consistency.
(8) Melting range—No change.
(9) Consistency—The USP monograph specifies a consistency Color—Melt about 10 g on a steam bath, and pour 5 mL of
value between 100 and 300. Comments were received indicat-
ing that these limits are too wide to provide relevant informa- the liquid into a clear-glass 16- x 150-mm bacteriological
tion. Also, consistency is a functionality property of this
article. For these reasons, a Consistency test procedure with- test tube: the warm, melted liquid is not darker than a
out limits is proposed in this draft harmonized monograph.
The Consistency test is not a required monograph test, but solution made by mixing 3.8 mL of ferric chloride CS and
is provided in the monograph as the designated test method
for determining consistency values if such values are reported 1.2 mL of cobaltous chloride CS in a similar tube, the
in the labeling for the article.
(10) Acidity or alkalinity—This test replaces the USP tests for comparison of the two being made in reflected light
Acidity and Alkalinity. The proposed test procedure is based
on the corresponding test from EP. The proposed test provides against a white background, the tubes being held directly
stricter limits for alkalinity and acidity than do the USP or JP
tests. against the background at such an angle that there is no
(11) Residue on ignition—The USP monograph contains the re-
quirement that the test specimen "volatilizes without emitting fluorescence.
an acid odor." It is proposed to delete this requirement for
safety reasons, to avoid requiring an analyst to smell the va-
por. The USP monograph also contains a 0.1% limit, while the
JP and the EP monographs contain a 0.05% limit. The 0.05%
limit is proposed in this draft harmonized monograph.
Pharmacopeial Forum
Identification—Its infrared absorption spectrum, obtained Without disturbing the surface of the substance under test,
by spreading a thin film of melted test specimen between place the container on the penetrometer table, and lower the
sodium chloride plates, exhibits high-intensity bands cone until the tip just touches the top surface of the test sub-
between 3000 cm"1 and 2800 cm"1, medium intensity stance at a spot 25 mm to 38 mm from the edge of the con-
1 1
bands between 1500 cm" and 1300 cm" , and low tainer. Adjust the zero setting and quickly release the
intensity bands between 750 cm"1 and 700 cm"1. plunger, then hold it free for 5 seconds. Secure the plunger,
Melting range, Class III (741): between 38° and 60°. and read the total penetration from the scale. Make three or
Consistency— more trials, each so spaced that there is no overlapping of
the areas of penetration. Where the penetration exceeds 20
Apparatus—Determine the consistency of Yellow
mm, use a separate container of the test substance for each
Petrolatum Jelly by means of a penetrometer fitted with a
trial. Read the penetration to the nearest 0.1 mm. Calculate
polished cone-shaped metal plunger weighing 150 g,
the average of the three or more readings, and conduct
having a detachable steel tip of the following dimensions:
further trials to a total of 10 if the individual results differ
the tip of the cone has an angle of 30°, the point being
from the average by more than + 3%: each mm of penetra-
truncated to a diameter of 0.381 + 0.025 mm, the base of
tion corresponds to a consistency value of 10.
the tip is 8.38 + 0.05 mm in diameter, and the length of the
tip is 14.94 + 0.05 mm. The remaining portion of the cone Acidity or alkalinity—To 10 g add 20 mL of boiling water,
has an angle of 90°, is about 28 mm in height, and has a and shake vigorously for 1 minute. Allow to cool, and
maximum diameter at the base of about 65 mm. The decant. To 10 mL of the aqueous layer add 0.1 mL of a 1
containers for the test are flat-bottom metal cylinders that in 10 solution in alcohol of phenolphthalein TS. The
are 100 + 6 mm in diameter and not less than 65 mm in solution is colorless. Not more than 0.5 mL of 0.01 N
sodium hydroxide is required to change the color of the
height. They are constructed of at least 1.6-mm (16-
indicator to red.
gauge) metal, and are provided with well-fitting, water-
tight covers. Residue on ignition (281)—Heat 10 g in an open porcelain
Procedure—Place the required number of containers in an or platinum dish over a Bunsen flame: on ignition it yields
oven, and bring them and a quantity of Yellow Petrolatum not more than 0.05% of residue.At/5.W(5
Jelly to a temperature of 82 + 2.5°. Pour the Yellow

Petrolatum Jelly into one or more of the containers, filling
to within 6 mm of the rim. Cool to 25 ± 2.5° over a period
of not less than 16 hours, protected from drafts. Two hours
before the test, place the containers in a water bath at 25 +
BRIEFING
0.5°. If the room temperature is below 23.5° or above 26.5°,
adjust the temperature of the cone to 25 ± 0.5° by placing it White Petrolatum, USP 25 page 1346 and page 4561 of PF
23(4) [July-Aug. 1997]. This proposal reflects the Council of Ex-
in the water bath. perts' efforts to develop a harmonized monograph for White Pet-
rolatum Jelly. The United States Pharmacopeia is the coordinating
pharmacopeia for the international harmonization of compendial
standards for the subject article. The revisions presented in this
proposal represent the OFFICIAL INQUIRY STAGE 4 draft in
the harmonization process. The proposed draft also incorporates
Pharmacopeial Forum
comments and suggestions made by EP and JP. The harmonized Change to read:
monograph sections proposed for the USP monograph have been
editorially styled. Readers are therefore urged to review these late- A
stage In-Process Revision proposals carefully and to respond to White Petrolatum Jelly
USP no later than May 15, 2002.
Major changes proposed include the following:
(1) A change of the monograph title from White Petrolatum to » White Petrolatum is a purified and wholly or
White Petrolatum Jelly.
(2) In the opening paragraph (the definition)—No change. nearly decolorized mixture of semisolid hydrocar-
(3) Packaging and storage—Added the statement, " . . . protected
from light." This proposal to specify protection from light is bons obtained from petroleum. It may contain a
based on comments received.
(4) Labeling—Added the statement, "Where the labeling indi-
cates the consistency, determine compliance using Consis- suitable stabilizer.
tency.'''' The Consistency test, which measures a
functionality parameter of the article, is not intended to be a
required test in this harmonized monograph; therefore, the Packaging and storage—Preserve in well-closed
proposed Labeling wording regarding consistency is intended
to indicate that the Consistency test procedure in the harmo- containers, protected from light.
nized monograph is to be used to determine consistence va-
lues if such values are reported in the labeling for the article. Labeling—The labeling indicates the name and
(5) Color—No change.
(6) Identification—This section was added and employs an IR concentration of any added stabilizer. Where the labeling
test, which is based on the corresponding EP test.
(7) Specific gravity—Deleted based on comments that the wide indicates the consistency, determine compliance using
test limits are not suitable to characterize the article.
(8) Melting range—No change. Consistency.
(9) Consistency—The USP monograph specifies a consistency
value between 100 and 300. Comments were received indicat- Color—Melt about 10 g on a steam bath, and pour 5 mL of
ing that these limits are too wide to provide relevant informa-
tion. Also, consistency is a functionality property of this the liquid into a clear-glass, 16- x 150-mm bacteriological
article. For these reasons, a Consistency test procedure with-
out limits is proposed in this draft harmonized monograph. test tube: the warm, melted liquid is not darker than a
The Consistency test is not a required monograph test, but
is provided in the monograph as the designated test method solution made by mixing 1.6 mL of ferric chloride CS and
for determining consistency values if such values are reported
in the labeling for the article. 3.4 mL of water in a similar tube, the comparison of the two
(10) Acidity or alkalinity—This test replaces the USP tests for
Acidity and Alkalinity. The proposed test procedure is based being made in reflected light against a white background,
on the corresponding test from EP. The proposed test provides
stricter limits for alkalinity and acidity than do the USP or JP the tubes being held directly against the background at
tests.
(11) Residue on ignition—The USP monograph contains the re- such an angle that there is no fluorescence.
quirement that the test specimen "volatilizes without emitting
an acid odor." It is proposed to delete this requirement for Identification—Its infrared absorption spectrum, obtained
safety reasons, to avoid requiring an analyst to smell the va-
por. The USP monograph also contains a 0.1% limit, while the by spreading a thin film of melted test specimen between
JP and the EP monographs contain a 0.05% limit. The 0.05%
limit is proposed in this draft harmonized monograph. sodium chloride plates, exhibits high-intensity bands
(12) Organic acids—Deleted based on comments that the test is
unnecessary since bleaching is done by a nonoxidative pro- between 3000 cm"1 and 2800 cm"1, medium intensity
cess.
(13) Fixed oils, fats, and rosin—Deleted based on comments that bands between 1500 cm"1 and 1300 cm"1, and low
these compounds will not be present in petrolatum, since the
oleum process is no longer used to produce petrolatum. intensity bands between 750 cm"1 and 700 cm"1.
(14) Limit of sulfur-containing compounds—Deleted based on
comments that the test was not suitable for petrolatum. Melting range, Class III (741): between 38° and 60°.
(15) Polycyclic aromatic hydrocarbons—Deleted based on com-
ments that this test is unnecessary. Consistency—
(16) Readily carbonizable substances (271)—Deleted based on
comments that this test is unnecessary.
Apparatus—Determine the consistency of White
Petrolatum Jelly by means of a penetrometer fitted with a

(EMC: J. Lane) RTS—36202-2
polished cone-shaped metal plunger weighing 150 g,
having a detachable steel tip of the following dimensions:
the tip of the cone has an angle of 30°, the point being
Pharmacopeial Forum
truncated to a diameter of 0.381 + 0.025 mm, the base of Acidity or alkalinity—To 10 g add 20 mL of boiling water,
the tip is 8.38 + 0.05 mm in diameter, and the length of the and shake vigorously for 1 minute. Allow to cool, and
tip is 14.94 + 0.05 mm. The remaining portion of the cone decant. To 10 mL of the aqueous layer add 0.1 mL of a 1
has an angle of 90°, is about 28 mm in height, and has a in 10 solution in alcohol of phenolphthalein TS. The
maximum diameter at the base of about 65 mm. The solution is colorless. Not more than 0.5 mL of 0.01 N
containers for the test are flat-bottom metal cylinders that sodium hydroxide is required to change the color of the
are 100 + 6 mm in diameter and not less than 65 mm in indicator to red.
height. They are constructed of at least 1.6-mm (16- Residue on ignition (281)—Heat 10 g in an open porcelain
gauge) metal, and are provided with well-fitting, water- or platinum dish over a Bunsen flame: on ignition it yields
tight covers. not more than 0.05% of residue. A.USP26
Procedure—Place the required number of containers in an
oven, and bring them and a quantity of White Petrolatum
Jelly to a temperature of 82 ± 2.5°. Pour the White MONOGRAPHS (NF)
Petrolatum Jelly into one or more of the containers, filling
to within 6 mm of the rim. Cool to 25 ± 2.5° over a period
of not less than 16 hours, protected from drafts. Two hours
before the test, place the containers in a water bath at
25 + 0.5°. If the room temperature is below 23.5° or
above 26.5°, adjust the temperature of the cone to
BRIEFING
25 + 0.5° by placing it in the water bath.
Butylparaben, NF 20 page 2517. The European Pharmaco-
Without disturbing the surface of the substance under test, poeia, a member of the Pharmacopeial Discussion Group, is the
coordinating pharmacopeia in the efforts toward the international
place the container on the penetrometer table, and lower the harmonization of compendial standards for this monograph. The
presented text represents the PROPOSAL STAGE 3 draft in the
cone until the tip just touches the top surface of the test sub- harmonization process. This draft is similar to the current USP
monograph. The current proposals are being previewed and are re-
stance at a spot 25 mm to 38 mm from the edge of the con- produced according to the style and format of the European Phar-
macopoeia. Readers are therefore urged to review these proposals
tainer. Adjust the zero setting and quickly release the carefully and respond to USP no later than May 15, 2002.
plunger, then hold it free for 5 seconds. Secure the plunger,
and read the total penetration from the scale. Make three or
more trials, each so spaced that there is no overlapping of
the areas of penetration. Where the penetration exceeds 20
Butyl Parahydroxybenzoate
Butylis parahydroxybenzoas
mm, use a separate container of the test substance for each CnH14O3 Mr 194.2
trial. Read the penetration to the nearest 0.1 mm. Calculate

the average of the three or more readings, and conduct DEFINITION
further trials to a total of 10 if the individual results differ Butyl parahydroxybenzoate contains not less
from the average by more than + 3%: each mm of penetra- than 99.0 per cent and not more than the equiva-
tion corresponds to a consistency value of 10. lent of 100.5 per cent of butyl 4-hydroxybenzoate.
Pharmacopeial Forum
CHARACTERS Acidity. To 2 ml of solution S add 3 ml of alcohol R, 5 ml

A white or almost white, crystalline powder or colourless of carbon dioxide-free water R and 0.1 ml of bromocresol
crystals, very slightly soluble in water, freely soluble in al- green solution R. Not more than 0.1 ml of 0.1 M sodium
cohol and in methanol. hydroxide is required to change the colour of the indicator
IDENTIFICATION to blue.
First identification: A, B. Related substances. Examine by thin-layer chroma-
Second identification: A, C, D. tography (2.2.27), using as the coating substance a
A. Melting point (2.2.14): 68°C to 71°C. suitable octadecylsilyl silica gel with a fluorescent
B. Examine by infrared absorption spectrophotometry indicator having an optimal intensity at 254 nm.
(2.2.24), comparing with the spectrum obtained with butyl Test solution (a). Dissolve 0.10 g of the substance to be
parahydroxybenzoate CRS. examined in acetone R and dilute to 10 ml with the same
C. Examine the chromatograms obtained in the test for solvent.
r e l a t e d s u b s t a n c e s . The p r i n c i p a l spot in the Test solution (b). Dilute 1 ml of test solution (a) to 10 ml
chromatogram obtained with test solution (b) is similar in with acetone R.
p o s i t i o n and size to the p r i n c i p a l spot in the Reference solution (a). Dilute 0.5 ml of test solution (a) to
chromatogram obtained with reference solution (b). 100 ml with acetone R.
D. To about 10 mg in a test-tube add 1 ml of sodium Reference solution (b). Dissolve 10 mg of butyl

carbonate solution R, heat to boiling for 30 s and cool parahydroxybenzoate CRS in acetone R and dilute to 10
(solution A). To about 10 mg in a similar test-tube add 1 ml with the same solvent.
ml of sodium carbonate solution R; the substance partly Reference solution (c). Dissolve 10 mg of propyl
dissolves (solution B). Add at the same time to solutions parahydroxybenzoate R in 1 ml of test solution (a) and
A and B 5 ml of aminopyrazolone solution R and 1 ml of dilute to 10 ml with acetone R.
potassium ferricyanide solution R and mix. Solution B is Apply to the plate 2 ul of each solution. Develop over a
yellow or orange-brown. Solution A is orange or red, the path of 15 cm using a mixture of 1 volume of glacial acetic
colour being clearly more intense than any similar colour acid R, 30 volumes of water R and 70 volumes of methanol
that may be obtained with solution B. R. Allow the plate to dry in air and examine in ultraviolet
light at 254 nm. Any spot in the chromatogram obtained
TESTS
with test solution (a), apart from the principal spot, is not
Solution S. Dissolve 1.0 g in alcohol R and dilute to 10
more intense than the spot in the chromatogram obtained
ml with the same solvent.
with reference solution (a) (0.5 per cent). The test is not va-
Appearance of solution. Solution S is clear (2.2.1) and
lid unless the chromatogram obtained with reference solu-
not more intensely coloured than reference solution BY6
tion (c) shows two clearly separated principal spots.
(Method II, 2.2.2).
Sulphated ash (2.4.14). Not more than 0.1 per cent,
determined on 1.0 g.
Pharmacopeial Forum
ASSAY DEFINITION
Place 2.000 g in a ground glass-stoppered flask and add Ethyl parahydroxybenzoate contains not less
40.0 ml of / M sodium hydroxide. Boil under a reflux con- than 99.0 per cent and not more than the equiva-
denser for 1 h. Allow to cool and rinse the condenser with lent of 100.5 per cent of ethyl 4-hydroxybenzoate.
water R. Titrate the excess sodium hydroxide with 0.5 M CHARACTERS
sulphuric acid, continuing the titration until the second A white or almost white, crystalline powder or colourless
point of inflexion and determining the end-point potentio- crystals, very slightly soluble in water, freely soluble in al-
metrically (2.2,20). Carry out a blank titration. 1 ml of 1 cohol and in methanol.
Msodium hydroxide is equivalent to 0.1942 g of C H H 14 O 3 . IDENTIFICATION
First identification: A, B.
IMPURITIES
Second identification: A, C, D.
A. R = H : 4-hydroxybenzoic acid,
A. Melting point (2.2.14): 115°C to 118°C.
B. R = CH3 : methyl 4-hydroxybenzoate,
B. Examine by infrared absorption spectrophotometry
C. R = CH2-CH3 : ethyl 4-hydroxybenzoate
(2.2.24), comparing with the spectrum obtained with ethyl
D. R = CH2-CH2-CH3 : propyl 4-hydroxybenzoate.
parahydroxybenzoate CRS.
C. Examine the chromatograms obtained in the test for
related s u b s t a n c e s . The p r i n c i p a l spot in the
chromatogram obtained with test solution (b) is similar in
position and size to the principal spot in the
BRIEFING chromatogram obtained with reference solution (b).

D. To about 10 mg in a test-tube add 1 ml of sodium
Ethylparaben, NF 20 page 2546. The European Pharmaco-
poeia, a member of the Pharmacopeial Discussion Group, is the carbonate solution R, heat to boiling for 30 s and cool
harmonization of compendial standards for this monograph. The (solution A). To about 10 mg in a similar test-tube add 1
harmonization process. This draft is similar to the current USP ml of sodium carbonate solution R; the substance partly
produced according to the style and format of the European Phar- dissolves (solution B). Add at the same time to solutions
carefully and respond to USP no later than May 15, 2002. A and B 5 ml of aminopyrazolone solution R and 1 ml of
(EMC: J. Lane) RTS—36202-12 potassium ferricyanide solution R and mix. Solution B is
yellow or orange-brown. Solution A is orange or red, the
colour being clearly more intense than any similar colour
Ethyl Parahydroxybenzoate
Ethylis parahydroxybenzoas that may be obtained with solution B.
C 9 H 10 O 3 Mr166.2
TESTS

Pharmacopeia! Forum
Appearance of solution. Solution S is clear (2.2.1) and Sulphated ash (2.4.14). Not more than 0.1 per cent,
not more intensely coloured than reference solution BY6 determined on 1.0 g.
(Method II, 2.2.2). ASSAY
Acidity. To 2 ml of solution S add 3 ml of alcohol R, 5 ml Place 2.000 g in a ground glass-stoppered flask and add
of carbon dioxide-free water R and 0.1 ml of bromocresol 40.0 ml of 1 M sodium hydroxide. Boil under a reflux con-
green solution R. Not more than 0.1 ml of 0.1 M sodium denser for 1 h. Allow to cool and rinse the condenser with
hydroxide is required to change the colour of the indicator water R. Titrate the excess sodium hydroxide with 0.5 M
to blue. sulphuric acid, continuing the titration until the second
Related substances. Examine by thin-layer chroma- point of inflexion and determining the end-point potentio-
tography (2.2.27), using a suitable octadecylsilyl silica gel metrically (2.2.20). Carry out a blank titration. 1 ml of /
with a fluorescent indicator having an optimal intensity at Msodium hydroxide is equivalent to 0.1662 g of C9H10O3.
254 nm as the coating substance. IMPURITIES
Test solution (a). Dissolve 0.10 g of the substance to be A. R = H : 4-hydroxybenzoic acid,
examined in acetone R and dilute to 10 ml with the same B. R = CH3 : methyl 4-hydroxybenzoate,
solvent. C. R = CH2-CH2-CH3 : propyl 4-hydroxybenzoate
Test solution (b). Dilute 1 ml of test solution (a) to 10 ml D. R = CH2-CH2-CH2-CH3 : butyl 4-hydroxybenzoate.
with acetone R.
Reference solution (a). Dilute 0.5 ml of test solution (a) to
100 ml with acetone R.
Reference solution (b). Dissolve 10 mg of ethyl
parahydroxybenzoate CRS in acetone R and dilute to 10
ml with the same solvent. BRIEFING
Reference solution (c). Dissolve 10 mg of methyl Methylparaben, NF 20 page 2581 and page 3200 of PF 22(6)
[Nov.-Dec. 1996]. The European Pharmacopoeia, a member of the
parahydroxybenzoate R in 1 ml of test solution (a) and Pharmacopeial Discussion Group, is the coordinating pharmaco-
peia in the efforts toward the international harmonization of com-
dilute to 10 ml with acetone R. pendial standards for this monograph. The presented text
represents the OFFICIAL INQUIRY STAGE 4 draft in the harmo-
Apply to the plate 2 ul of each solution. Develop over a nization process based in part on comments received in response to
the CONSENSUS STAGE 5B draft. Because of significant
path of 15 cm using a mixture of 1 volume of glacial acetic changes in the Assay, the draft has been reverted back to the OF-
FICIAL INQUIRY STAGE 4. It is proposed to widen the content
acid R, 30 volumes of water R and 70 volumes of methanol limits and slightly change the operating conditions for the Assay,
following comments from users and experimental work to check
R. Allow the plate to dry in air and examine in ultraviolet the precision of the Assay. The current proposals are reproduced
according to the style and format of the European Pharmacopoeia.
light at 254 nm. Any spot in the chromatogram obtained Readers are therefore urged to review these late-stage In-Process
Revision proposals carefully and to respond to USP no later than
with test solution (a), apart from the principal spot, is not May 15, 2002.
more intense than the spot in the chromatogram obtained (EMC: J. Lane) RTS—36202-11
with reference solution (a) (0.5 per cent). The test is not va-
lid unless the chromatogram obtained with reference solu-
tion (c) shows two clearly separated principal spots.
Pharmacopeial Forum
Solution (b) is yellow to orange-brown. Solution (a) is

Methyl Parahydroxybenzoate
orange to red, the colour being clearly more intense than
Methylis parahydroxybenzoas
any similar colour which may be obtained with solution (b).
(Graphic formula to come)
C8H8O3 Mr\52.\
TESTS
DEFINITION Appearance of solution. Solution S is clear (2.2.1) and
Methyl 4-hydroxybenzoate. not more intensely coloured than reference solution BY6
Content 98.0 per cent to 102.0 per cent. (2.2.2, Method II).
CHARACTERS Acidity. To 2 ml of solution S add 3 ml of alcohol R, 5 ml
Appearance: white, crystalline powder or colourless of carbon dioxide-free water R and 0.1 ml of bromocresol
crystals. green solution R. Not more than 0.1 ml of 0.1 M sodium
Solubility: very slightly soluble in water, freely soluble in hydroxide is required to change the colour of the indicator
alcohol and in methanol. to blue.
IDENTIFICATION Related substances. Thin-layer chromatography

. First identification: A, B. (2.2.27).
Second identification: A, C, D. Test solution (a). Dissolve 0.10 g of the substance to be
A. Melting point (2.2.14): 125°C to 128°C. examined in acetone R and dilute to 10 ml with the same
B. Infrared absorption spectrophotometry (2.2.24). solvent.
Comparison: methyl parahydroxybenzoate CRS. Test solution (b). Dilute 1 ml of test solution (a) to 10 ml
C. Examine the chromatograrns obtained in the test for with acetone R.
related substances. Reference solution (a). Dilute 0.5 ml of test solution (a) to
Results: the principal spot in the chromatogram obtained 100 ml with acetone R.
with test solution (b) is similar in position and size to the Reference solution (b). Dissolve 10 mg of methyl
principal spot in the chromatogram obtained with parahydroxybenzoate CRS in acetone R and dilute to 10
reference solution (b). ml with the same solvent.
D. To about 10 mg in a test-tube add 1 ml of sodium Reference solution (c). Dissolve 10 mg of ethyl

carbonate solution R, boil for 30 s and cool (solution a). parahydroxybenzoate CRS in 1 ml of test solution (a) and
To a further 10 mg in a similar test-tube add 1 ml of dilute to 10 ml with acetone R.
sodium carbonate solution R; the substance partly Plate: suitable octadecylsilyl silica gel with a fluorescent
dissolves (solution b). Add at the same time to solution indicator having an optimal intensity at 254 nm as the
(a) and solution (b) 5 ml of aminopyrazolone solution R coating substance.
and 1 ml of potassium ferricyanide solution R and mix.
Pharmacopeia! Forum
Mobile phase: glacial acetic acid R, water R, methanol R

(1:30:70 V/V/V). BRIEFING
Application: 2 ul. Polyethylene Glycol, NF 20 page 2595. This proposal reflects

the Council of Experts' efforts to develop a harmonized mono-
Development: over a path of 15 cm. graph for Polyethylene Glycol. The United States Pharmacopeia
is the coordinating pharmacopeia for the international harmoniza-
Drying: in air. tion of compendial standards for the subject article. The revisions
presented in this proposal, which represents the OFFICIAL IN-
Detection: examine in ultraviolet light at 254 ran. QUIRY STAGE 4 draft in the harmonization process, reflect those
changes suggested by the PEG Working Group of the International
System suitability: the chromatogram obtained with Pharmaceutical Excipients Council of The Americas in the Stimuli
to the Revision Process article, "Proposed Harmonized Mono-
reference solution (c) shows 2 clearly separated principal graph for Polyethylene Glycol (Macrogol) with Average Molecular
Weight of 300 to 8000," published elsewhere in PF. The proposed
spots. draft also incorporates comments and suggestions made by EP and
JP. The harmonized monograph sections proposed for the NF
Limits: monograph have been editorially styled. Readers are therefore
urged to review these late-stage In-Process Revision proposals
—any impurity: any spot in the chromatogram obtained carefully and to respond to USP no later than May 15, 2002.
Major changes proposed include the following:
with test solution (a), apart from the principal spot, is not (1) The deletion of polyethylene glycol 200 (PEG 200) from this
family monograph since PEG 200 that meets the monograph
more intense than the spot in the chromatogram obtained requirements for Limit ofethylene glycol and diethylene gly-
col is reportedly not commercially available.
with reference solution (a) (0.5 per cent). (2) In the opening paragraph (the Definition)—The use of stabi-
lizers was deleted from the monograph, because the stabili-
Sulphated ash (2.4.14): maximum 0.1 percent, zers added may affect the quality of drug products. The
limits for the average molecular weight have been deleted
determined on 1.0 g. from the monograph. Those limits were considered redun-
dant, because viscosity is tested and limited.
ASSAY (3) Packaging and storage—Well-closed containers has been
changed to tight containers, because of the potential volatility
To 1.000 g add 20.0 ml of 1Msodium hydroxide. Heat at of some low molecular weight polyethylene glycols that are in
liquid form.
about 70°C for 1 h. Cool rapidly in an ice bath. Prepare a (4) Labeling—No change.
(5) USP Reference standards—Two new Reference Standards
blank in the same manner. Carry out the titration on the so- have replaced the previous Reference Standard to comply
with the proposed IR test.
lutions at room temperature. Titrate the excess sodium hy- (6) Completeness and color of solution—A numerical limit spe-
cification for color has been added to reduce the subjectivity
droxide with 0.5 M sulphuric acid, continuing the titration of the current Completeness and color of solution test.
(7) Identification—A new, definitive Identification test based on
until the second point of inflexion and determining the end- IR spectroscopy performed by comparison with two reference
substances has been added: one of low molecular weight
point potentiometrically (2.2.20). (300) and one of high molecular weight (8000). The test for
Viscosity was also moved to the Identification section, be-
1 ml of 7 M sodium hydroxide is equivalent to 152.1 mg cause it can be used to distinguish between the various types
of materials.
ofCoHoO,. (8) Viscosity—The EP method for Viscosity has been adopted, as
o o J it is easier to perform and complies to the range of 300 to
35,000 molecular weight. The test for Viscosity has been
IMPURITIES moved under Identification.
(9) pH—No change.
A. R = H: 4-hydroxybenzoic acid, (10) Average molecular weight—This test has been deleted, based
on the viscosity-molecular weight relationship among the
B. R = CH2-CH3 : ethyl 4-hydroxybenzoate, polyethylene glycols.
(11) Residue on ignition—A sample weight of 10 g, which is suf-
C. R = CH2-CH2-CH3: propyl 4-hydroxybenzoate, ficent for a limit of not more than 0.1%, is proposed.
(12) Limit of free ethylene oxide and 1,4-dioxane—A modification
D. R = CH2-CH2-CH2-CH3: butyl 4-hydroxybenzoate. of the current USP gas chromatographic method, having a
simplified method for preparing the Standard preparation,
and a revised ethylene oxide limit based on the current PhEur
limit are proposed.
(13) Limit of ethylene glycol and diethylene glycol—A capillary
gas chromatographic method for the Limit ofethylene glycol
and diethylene glycol test and a reduced limit based on the
current limit in the U.S. Code of Federal Regulations are pro-
Pharmacopeial Forum
posed. The limit was changed to not more than 620 ppm for Labeling—Polyethylene Glycols must be labeled to state,
ethylene glycol to comply with current International Confer-
ence on Harmonization (ICH) guidelines. as part of the official title, the nominal average molecular
(14) Water—A new test for Water, with a limit corresponding to
that in the JP monograph test, has been added. weight. Blends of two or more discrete Polyethylene
(15) Organic volatile impurities—This test has been deleted be-
cause it is unnecessary for this compound. Glycols must be labeled to state, as part of the official
(16) Heavy metals—This test has been deleted because Polyethy-
lene glycol is totally organic and not derived from any mate- title, the word "BLEND".
rials that usually contain heavy metals.
USP Reference standards < 11)—USP Polyethylene Gly-
col 300 RS. USP Polyethylene Glycol 8000 RS.
Completeness and color of solution—Dissolve 5 g of
Change to read:
Polyethylene Glycol in 50 mL of water. The color of the
A
Polyethylene Glycol solution is not greater than 25 Pt-Co, and at 25 ± 5° the
Pharmacy Equivalent Name: PEG solution is clear for nominal molecular weights less than
or equal to 1000 and not more than slightly hazy for
nominal molecular weights greater than 1000.
Poly(oxy-1,2-ethanediyl), a-hydro-w-hydroxy-. Identification—

Polyethylene glycol [25322-68-3]
Synonym: Macrogol A: Infrared Absorption (197F), use a thin film of test
specimen, melt if necessary, on undried specimen, in the
range from 4000 cm"1 to 600 cm"1.
» Polyethylene Glycol is an addition polymer of
B: It complies with the test for Viscosity.
ethylene oxide and water, represented by the for-
Viscosity (911)—The viscosity is calculated using the
mula:
accompanying table. The viscosity is within the limits
H(OCH2CH2)flOH,
specified in the accompanying table. For Polyethylene
in which n represents the average number ofoxy- gycols having a relative molecular weight greater than
ethylene groups. 400, determine the viscosity on a 50% w/w solution of the
substance to be examined. For a Polyethylene Glycol not
The nominal average molecular weight is from
listed in the table, calculate the limits by interpolation.
300 to 35000.
Nominal Average Viscosity Range, Density
For blends of two or more discrete Polyethylene Molecular Weight Centistokes (mm2 • s"1) (g/mL)
300 71-94 1.120
Glycols, each Polyethylene Glycol component of
400 94-116 1.120
the blend must meet the monograph requirements 600 13.9-18.5 1.080
1000 20.4-27.7 1.080
for its nominal average molecular weight, and the 1500 31-46 1.080
blend must meet all other monograph require- 3000 69-93 1.080
3350 76-110 1.080
ments except for viscosity. 4000 102-158 1.080
6000 185-250 1.080
Packaging and storage—Preserve in tight containers away 8000 240^72 1.080
20000 2500-3200 1.080
from direct sunlight.
35000 10000-13000 1.080
Pharmacopeia! Forum
pH (791): Dissolve 5.0 g of Polyethylene Glycol in 100 mL pressure headspace vial that can be sealed. Add 48 uL of
of water with an unadjusted pH of 5.0 or greater, stirring in a 1,4-dioxane, equivalent to 50 mg of 1,4-dioxane, from a
sealed bottle, if necessary. To this solution, add 0.30 mL of a syringe, seal, and cap the vial. Using the special handling
saturated solution of potassium chloride. The test solution described in the following, complete the preparation.
should be maintained at 25 ± 2° during the measurement. Ethylene oxide is a gas at room temperature. It is usually
The measured pH is between 4.0 and 7.5. stored in a lecture-type gas cylinder or small metal
Residue on ignition (281): not more than 0.1%, a 10 g pressure bomb. Chill the cylinder in a refrigerator before
specimen and a tared platinum dish being used, and the use. Transfer about 5 mL of the liquid ethylene oxide to a
residue being moistened with 2 mL of sulfuric acid. 100-mL beaker chilled in wet ice. Using a gas-tight syringe
Limit of free ethylene oxide and 1,4-dioxane— that has been chilled in a refrigerator, transfer 57 uL of the
liquid ethylene oxide, equivalent to 50 mg of ethylene
Stripped polyethylene glycol 400—Into a 5000-mL 3-
oxide, to the mixture contained in the headspace vial, and
neck, round-bottom flask equipped with a stirrer, a gas
mix. With the aid of a syringe, transfer about 2 mL of this
dispersion tube, and a vacuum outlet, place 3000 g of
solution to a 5-mL beaker. Transfer 1.0 mL of this solution
Polyethylene Glycol 400. At room temperature, evacuate
to a 100-mL volumetric flask, dilute with Stripped
the flask carefully to a pressure of less than 1 mm of
polyethylene glycol 400 to volume, and mix. Transfer 10
mercury, applying the vacuum slowly while observing for
mL of this solution to a 100-mL volumetric flask, dilute
excessive foaming due to entrapped gases. After any
with Stripped polyethylene glycol 400 to volume, and mix
foaming has subsided and while stirring continuously,
to obtain a Standard preparation having known
sparge with nitrogen, allowing the pressure to rise to 10
concentrations of 10 ug per g for both ethylene oxide and
mm of mercury. [NOTE—The 10-mm value is a guideline.
1,4-dioxane. Transfer 1.0 mL of the Standard preparation
Deviations from this value only affect the total time
to a 22-mL pressure headspace vial, seal with a silicone
required to strip the Polyethylene Glycol 400.] Continue
septum with or without a pressure relief star spring and a
stripping for a minimum of 1 hour. [NOTE—Completeness
pressure relief safety aluminum sealing cap, and crimp the
of the stripping procedure should be verified by making a
cap closed with a cap-sealing tool.
headspace injection of the stripped Polyethylene Glycol
Resolution solution—Transfer 4.90 g of Stripped
400.] Shut off the vacuum pump, and bring the flask
polyethylene glycol 400 to a 22-mL pressure headspace
pressure back to atmospheric pressure while maintaining
vial. Pipet 50 uL of acetaldehyde into the vial. Using the
nitrogen sparging. Remove the gas dispersion tube with
special handling described under Standard preparation,
the gas still flowing, and then turn off the gas flow.
transfer about 50.0 uL of liquid ethylene oxide into the
Transfer the Stripped polyethylene glycol 400 to a suitable
vial. Immediately seal the vial, and shake. Transfer 1.0
nitrogen-filled container.
mL of this solution to a 100-mL volumetric flask, dilute
Standard preparation—[Caution—Ethylene oxide and
with Stripped polyethylene glycol 400 to volume, and mix.
1,4-dioxane are toxic and flammable. Prepare these
solutions in a well-ventilated fume hood.] Transfer 4.90 g
of Stripped polyethylene glycol 400 to a tared 22-mL
Pharmacopeial Forum
Transfer 10.0 mL of this solution to a 100-mL volumetric chromatogram of the Test preparation are not greater than
flask, dilute with Stripped polyethylene glycol 400 to vol- those of the corresponding peaks in the chromatogram of
ume, and mix. Transfer 1.0 mL of this Resolution solution the Standard preparation, corresponding to not more than
to a 22-mL pressure headspace vial; and seal, cap, and crimp 10 ug per g of ethylene oxide and not more than 10 ng
as directed for the Standard preparation. per g of 1,4-dioxane.
Test preparation—Transfer 1.0 g of Polyethylene Glycol Limit of ethylene glycol and diethylene glycol—
to a 22-mL pressure headspace vial; and seal, cap, and crimp [NOTE—Applies to Polyethylene Glycol having a nom-
as directed for the Standard preparation. inal molecular weight of 300 or above but not more than
Chromatographic system (see Chromatography (621))— 1000; testing not required for nominal molecular weights
The gas chromatograph is equipped with a balanced greater than 1000.]
pressure automatic headspace sampler and a flame- Internal standard solution—Prepare a solution in water
ionization detector and contains a 0.32-mm x 50-m containing about 1000 |ig of 1,4-butanediol in each mL.
fused-silica capillary column containing bonded phase Standard solution—Prepare a solution in water containing
G27 in a 5-um film thickness. The column temperature is about 500 ug of ethylene glycol, about 500 ug of diethylene
programmed from 70° to 250° at 10° per minute, with the glycol, and about 500 |ig of 1,4-butanediol in each mL.
injection port at 85° and the detector at 250°. The carrier Test solution—Transfer about 4 g of Polyethylene Glycol,
gas is helium at a flow rate of about 2.9 mL per minute. accurately weighed, to a small bottle. Pipet 5 mL of Internal
Chromatograph the Resolution solution, and record the standard solution and 1 mL of water into the bottle. Cap the
peak responses as directed for Procedure: the relative bottle, and shake to mix.
retention times are about 0.9 for acetaldehyde and 1.0 for Chromatographic system (see Chromatography (621))—
ethylene oxide; and the resolution, R, between the The gas chromatograph is equipped with a flame-ionization
acetaldehyde peak and the ethylene oxide peak is not less detector, a split injection system, and a 0.53-mm x 30-m
than 1.3. fused-silica analytical column coated with 1.2-um film of
Procedure—Place the vials containing the Standard phase G16 (or, preferably, its bonded equivalent). The
preparation and the Test preparation into the automated carrier gas is helium, flowing at a rate of about 40 cm per
sampler, and heat the vials at a temperature of 80° for 30 second, and the split vent flow is about 100 mL per
minutes. Using a 2-mL gas syringe preheated in an oven minute. The injection port and detector temperatures are
at 90°, separately inject 1.0 mL of the headspace from maintained at 250° and 260°, respectively. The column
each vial into the c h r o m a t o g r a p h , r e c o r d the temperature is programmed to increase from 180° to 260°
chromatogram, and measure the areas for the major peaks. at a rate of 10° per minute, and then it is maintained at
[NOTE—A headspace apparatus that automatically transfers 260° for at least 22 minutes.
the measured amount of headspace may be used to perform Procedure—Inject 1 uL of the Standard solution into the
the injection.] The relative retention times for ethylene chromatograph, record the chromatogram, and record the
oxide and 1,4-dioxane are about 1.0 and 3.4, respectively. areas of the first (ethylene glycol), the second (internal
The peak areas for ethylene oxide and 1,4-dioxane in the standard), and third (diethylene glycol) peaks as rSE, rSh
Pharmacopeial Forum
and rSD, respectively. Inject 1 uL of the Test solution into the

BRIEFING
chromatograph, and record the chromatogram as directed
Propylparaben, NF 20 page 2609. The European Pharmaco-
for Standard solution. Use the retention times observed in poeia, a member of the Pharmacopeial Discussion Group, is the
the chromatogram of the Standard solution to identify the harmonization of compendial standards for this monograph. The
peaks in the chromatogram of the Test solution harmonization process. This draft is similar to the current USP
corresponding to ethylene glycol, the internal standard, produced according to the style and format of the European Phar-
and diethylene glycol. Record the areas of the ethylene carefully and respond to USP no later than May 15, 2002.
glycol, the internal standard, and diethylene glycol peaks
as rE, rh and rD, respectively. Calculate the response
factors, FN, of ethylene glycol and diethylene glycol by
the formula:
Propyl Parahydroxybenzoate
(CNrSI) / (CslrSN), Propylis parahydroxybenzoas
in which CN is the concentration, in ug per mL, of the ana- C

10 H 12°3 Mr 180.2
lyte of interest in the Standard solution; rSI is the peak area

for the internal standard obtained from the Standard solu-
tion; CS1 is the concentration, in jig per mL, of the internal
DEFINITION
standard in the Standard solution; and rSN is the peak area Propyl parahydroxybenzoate contains not less
for the analyte of interest obtained from the Standard solu- than 99.0 per cent and not more than the equiva-
tion. Calculate the percentages, by weight, of ethylene gly- lent of 100.5 per cent of propyl 4-hydroxybenzo-
col and diethylene glycol in the portion of Polyethylene ate.
Glycol taken by the formula: CHARACTERS
{FNC,rN) / (2000/v 00,
A white, crystalline powder, very slightly soluble in water,
in which FN is as obtained above; Q is the concentration, in freely soluble in alcohol and in methanol.
ug per mL, of the internal standard in the Internal standard IDENTIFICATION
solution; rând r, are the peak areas of the analyte of inter- First identification: A, B.
est and the internal standard, respectively, obtained from the Second identification: A, C, D.
Test solution; and W is the weight, in g, of Polyethylene A. Melting point (2.2.14): 96°C to 99°C.
Glycol in the Test solution: not more than 620 ppm ethylene B. Examine by infrared absorption spectrophotometry
glycol and not more than 0.2% of ethylene glycol and (2.2.24), comparing with the spectrum obtained with
diethylene glycol combined is found. propyl parahydroxybenzoate CRS.
Water, Method la (921): not more than 1.0%.ANF2] C. Examine the chromatograms obtained in the test for
r e l a t e d s u b s t a n c e s . The p r i n c i p a l spot in the
chromatogram obtained with test solution (b) is similar in
p o s i t i o n and size to the p r i n c i p a l spot in the
chromatogram obtained with reference solution (b).
Pharmacopeial Forum
D. To about 10 mg in a test-tube add 1 ml of sodium Reference solution (c). Dissolve 10 mg of ethyl

carbonate solution R, boil for 30 s and cool (solution A). parahydroxybenzoate R in 1 ml of test solution (a) and
To about 10 mg in a similar test-tube add 1 ml of sodium dilute to 10 ml with acetone R.
carbonate solution R; the substance partly dissolves Apply to the plate 2 ul of each solution. Develop over a
(solution B). Add at the same time to solution A and path of 15 cm using a mixture of 1 volume of glacial acetic
solution B 5 ml of aminopyrazolone solution R and 1 ml acid R, 30 volumes of water R and 70 volumes of methanol
of potassium ferricyanide solution R and mix. Solution B R. Allow the plate to dry in air and examine in ultraviolet
is yellow to orange-brown. Solution A is orange to red, light at 254 nm. Any spot in the chromatogram obtained
the colour being clearly more intense than any similar with test solution (a), apart from the principal spot, is not
colour that may be obtained with solution B. more intense than the spot in the chromatogram obtained
TESTS with reference solution (a) (0.5 per cent). The test is not va-
Solution S. Dissolve 1.0 g in alcohol R and dilute to 10 lid unless the chromatogram obtained with reference solu-
ml with the same solvent. tion (c) shows two clearly separated principal spots.
Appearance of solution. Solution S is clear (2.2.1) and Sulphated ash (2.4.14). Not more than 0.1 per cent,
not more intensely coloured than reference solution BY6 determined on 1.0 g.
(Method II, 2.2.2). ASSAY
Acidity. To 2 ml of solution S add 3 ml of alcohol R, 5 ml Place 2.000 g in a ground glass-stoppered flask and add
of carbon dioxide-free water R and 0.1 ml of bromocresol 40.0 ml of 1Msodium hydroxide. Heat gently under a reflux
green solution R. Not more than 0.1 ml of 0.1 M sodium condenser for 1 h. Cool to room temperature and rinse the
hydroxide is required to change the colour of the indicator condenser with water R. Titrate the excess sodium hydrox-
to blue. ide with 0.5 M sulphuric acid, continuing the titration until
Related substances. Examine by thin-layer chro- the second point of inflexion and determining the end-point
matography (2.2.27), using as the coating substance a potentiometrically (2.2.20). Carry out a blank titration. 1 ml
suitable octadecylsilyl silica gel with a fluorescent of 1 M sodium hydroxide is equivalent to 0.1802 g of
indicator having an optimal intensity at 254 run. C
10 H 12°3-
Test solution (a). Dissolve 0.10 g of the substance to be IMPURITIES
examined in acetone R and dilute to 10 ml with the same A. R = H : 4-hydroxybenzoic acid,
solvent. B. R = CH3 : methyl 4-hydroxybenzoate,
Test solution (b). Dilute 1 ml of test solution (a) to 10 ml C. R = CH 2 -CH 3 : ethyl 4-hydroxybenzoate
with acetone R. D. R = CH2-CH2-CH2-CH3 : butyl 4-hydroxybenzoate.
Reference solution (a). Dilute 0.5 ml of test solution (a) to
100 ml with acetone R.
Reference solution (b). Dissolve 10 mg of propyl
parahydroxybenzoate CRS in acetone R and dilute to 10
Pharmacopeia! Forum
Solubility: practically insoluble in water, soluble in

BRIEFING alcohol and in light petroleum (50-70°C).
Stearic Acid, NF 20 page 2627 and page 6763 of PF 24(5) IDENTIFICATION

[Sept.-Oct. 1998]. The European Pharmacopoeia, a member of
the Pharmacopeial Discussion Group, is the coordinating pharma-
copeia in the efforts toward the international harmonization of A. It complies with the test for freezing point (see Tests).
compendial standards for this monograph. The presented text re-
presents the OFFICIAL INQUIRY STAGE 4 draft in the harmoni-
zation process. There are only editorial changes from the STAGE 3 B. Acid value (2.5.7): 194 to 212, determined on 0.1 g.
draft. The current proposals are reproduced according to the style
and format of the European Pharmacopoeia. Readers are therefore
urged to review these late-stage In-Process Revision proposals C. Examine the chromatograms obtained in the assay.
carefully and to respond to USP. Readers are asked to respond
no later than May 15, 2002.
Results: the retention times of the principal peaks in the
chromatogram obtained with the test solution are
approximately the same as those of the principal peaks in
Stearic Acid the chromatogram obtained with the reference solution.
Acidum stearicum
TESTS
Appearance. Heat the substance to be examined to about

75°C. The resulting liquid is not more intensely coloured
DEFINITION
than reference solution Y7 or BY7 (2.2.2, Method I).
Mixture consisting mainly of stearic acid
( C 1 8 H 3 6 O 2 ; M r 2 8 4 . 5 ) and p a l m i t i c acid Acidity. Melt 5.0 g, shake for 2 min with 10 ml of hot
(C16H32O2;Mr256.4) obtained from fats or oils of carbon dioxide-free water R, cool slowly and filter. To the
vegetable or animal origin. filtrate add 0.05 ml of methyl orange solution R. No red
Content: colour develops.

Stearic acid 50 Stearic acid: 40.0 per cent to
60.0 per cent Iodine value (2.5.4). See Table 1474.-1.
Sum of the contents of stearic
and palmitic
acids: minimum 90.0 per cent Freezing point (2.2.18). See Table 1474.-1.
Stearic acid 70 Stearic acid: 60.0 per cent to Table 1474.-1.
80.0 per cent
Sum of the contents of stearic Type Iodine value Freezing point (°C)
and palmitic Stearic acid maximum 4.0 53-59
acids: minimum 90.0 per cent 50
Stearic acid 95 Stearic acid: minimum 90.0 per Stearic acid maximum 4.0 57-64
cent 70
Sum of the contents of stearic Stearic acid maximum 1.5 64-69
and palmitic 95
acids: minimum 96.0 per cent
Nickel (2.4.27): maximum 1 ppm.

CHARACTERS
ASSAY
Appearance: white, waxy, flaky crystals, white hard Gas chromatography (2.2.28): use the normalisation
masses or white or yellowish-white powder procedure.
Pharmacopeial Forum
Test solution. In a conical flask fitted with a reflux LABELLING

condenser, dissolve 0.100 g of the substance to be The label states the type of stearic acid (50, 70, 95).
examined in 5 ml of boron trifluoride-methanol solution
R. Boil under reflux for 10 min. Add 4.0 ml of heptane R
through the condenser and boil again under reflux for 10 GENERAL CHAPTERS
min. Allow to cool. Add 20 ml of a saturated solution of
sodium chloride R. Shake and allow the layers to separate.
Remove about 2 ml of the organic layer and dry it over 0.2 g General Tests and Assays
of anhydrous sodium sulphate R. Dilute 1.0 ml of this
solution to 10.0 ml with heptane R. General Requirements for Tests and
Reference solution. Prepare the reference solution in the Assays
same manner as the test solution using 50 mg of palmitic
acid R and 50 mg of stearic acid R instead of the
substance to be examined.
Column: BRIEFING
- material: fused silica,
Aerosols, Metered-Dose Inhalers, and Dry Powder Inhalers
- size: I = 30 m, O = 0.32 mm, (EP). USP 25 page 1964. The European Pharmacopoeia is the co-
ordinating pharmacopeia for this topic. This text represents the
- stationary phase: macrogol 20 000 R (film thickness: PROPOSAL STAGE 3 (first inquiry) draft according to the Inter-
0.5 urn). - national Harmonization procedure. It is based on the text currently
in force in Europe, but several modifications are proposed:
Carrier gas: helium for chromatography R. — Apparatus A: use restricted to pressurized inhalers, and to
powder inhalers in special circumstances.
Flow rate: 2.4 ml/min. — Apparatus B: deleted.
— Apparatus D: introduction of data on the modified configura-
Temperature: tion of this apparatus.
The current proposals are being previewed and are reproduced
Time (min) Temperature (°C) according to the style and format of the European Pharmacopoeia.
Readers are therefore urged to review these proposals carefully and
Column 0-2 70 respond to USP no later than May 15, 2002.
2-36 70-* 240
36-41 240
Injection 220 (AER: K. Zaidi) RTS—34848-1
port
Detector 260
Detection: flame ionisation

2.9.18. PREPARATIONS FOR
Injection: 1 ul.
INHALATION: AERODYNAMIC
ASSESSMENT OF FINE
Relative retention with reference to methyl stearate:
PARTICLES
methyl palmitate = about 0.88.
System suitability: reference solution: This test is used to determine the fine particle character-
- resolution: minimum 5.0 between the peaks due to istics of the aerosol clouds generated by preparations for in-
methyl stearate and methyl palmitate. halation.

Unless otherwise justified and authorised, one of the fol-
lowing apparatus and test procedures is used.
Pharmacopeial Forum
APPARATUS A (GLASS IMPINGER) The use of apparatus A is restricted to the assessment of

The apparatus is shown in Figure 2.9.18.-1 (see also Table pressurised inhalers. Apparatus A is not used for the assess-
2 9 ig _n ment of powder inhalers unless it has been demonstrated
that an air flow rate of 55-65 litres per minute is suitable.
Figure 2.9.18.-1.—Apparatus Afar the aerodynamic assessment of fine particles. Dimensions in millimetres (tolerances ± 1 mm unless
otherwise prescribed)
Pharmacopeial Forum
Ta-
ble 2.9.18.-1.—Component specification for Figure 2.9.18.-1
Code Item Description Dimensions

Mouthpiece Moulded rubber adapter for actuator mouthpiece
adaptor
B Throat Modified round-bottomed flask 50 ml

ground-glass inlet socket 29/32
ground-glass outlet cone 24/29
Neck Modified glass adapter

ground-glass inlet socket 24/29
ground-glass outlet cone 24/29
Lower outlet section of precision-bore glass tubing
bore diameter 14
Selected bore light-wall glass tubing
external diameter 17
D Upper Modified round-bottomed flask 100 ml

impingement ground-glass inlet socket 24/29
chamber ground-glass outlet cone 24/29
Pharmacopeial Forum
Table 2.9.18.-1.—Component specification for Figure 2.9.18.-1 (Continued)
Coupling Medium-wall glass tubing

tube ground-glass cone 14/23
Bent section and upper vertical section 13
external diameter
Lower vertical section
external diameter
Screwthread, Plastic screw cap 28/13

side-arm Silicone rubber ring 28/11
adaptor PTFE washer 28/11
Glass screwthread, thread size 28
Side-arm outlet to vacuum pump,
minimum bore diameter
Pharmacopeial Forum
Table 2.9.18.-1.—Component specification for Figure 2.9.18.-1 (Continued)
Lower jet Modified polypropylene filter holder connected to lower see Figure 2.9.18.-1
assembly vertical section of coupling tube by PTFE tubing
Acetal circular disc with the centres of four jets arranged 10
on a projected circle of diameter 5.3 mm with an

integral jet spacer peg
peg diameter
peg protrusion
H
Lower Conical flask 250 ml
impingement ground-glass inlet socket 24/29
chamber
Dimensions in millimetres, unless otherwise stated.
Procedure for pressurised inhalers the bottom of the lower impingement chamber. Connect a
Place the actuator adapter in position at the end of the suitable pump to the outlet of the apparatus and adjust the
throat so that the mouthpiece end of the actuator, when in- airflowthrough the apparatus, as measured at the inlet to the
serted to a depth of about 10 mm, lines up along the hori- throat, to 60 + 5 litres per minute.
zontal axis of the throat and the open end of the actuator, Prime the metering valve by shaking for 5 s and dischar-
which accepts the pressurised container, is uppermost and ging once to waste; after not less than 5 s, shake and dis-
in the same vertical plane as the rest of the apparatus. charge again to waste. Repeat a further three times.
Introduce 7 ml and 30 ml of a suitable solvent into the Shake for about 5 s, switch on the pump to the apparatus
upper and lower impingement chambers, respectively. and locate the mouthpiece end of the actuator in the adapter,
Connect all the component parts and ensure that the as- discharge once immediately. Remove the assembled inhaler
sembly is vertical and adequately supported and that the from the adapter, shake for not less than 5 s, relocate the
lower jet-spacer peg of the lower jet assembly just touches mouthpiece end of the actuator in the adapter and discharge
Pharmacopeia! Forum
again. Repeat the discharge sequence for a further eight Fine particle dose and particle size distribution
times, shaking between actuations. After discharging the APPARATUS C. MULTI-STAGE LIQUID IMPINGER
tenth delivery, wait for not less than 5 s and then switch The Multi-stage Liquid Impinger consists of impaction
off the pump. Dismantle the apparatus. stages 1 (pre-separator), 2, 3 and 4 and an integral filter
Wash the inner surface of the inlet tube to the lower im- stage (stage 5), see Figures 2.9.18.-4/6. An impaction stage
pingement chamber and its outer surface that projects into comprises an upper horizontal metal partition wall (B)
the chamber with a suitable solvent collecting the washings through which a metal inlet jet tube (A) with its impaction
in the lower impingement chamber. Determine the content plate (D) is protruding, a glass cylinder (E) with sampling
of active ingredient in this solution. Calculate the amount port (F) forming the vertical wall of the stage, and a lower
of active ingredient collected in the lower impingement horizontal metal partition wall (G) through which the tube
chamber per actuation of the valve and express the results (H) connects to the next lower stage. The tube into stage 4
as a percentage of the dose stated on the label. (U) ends in a multi-jet arrangement. The impaction plate (D)
Procedure for powder inhalers is secured in a metal frame (J) which is fastened by two
Introduce 7 ml and 30 ml of a suitable solvent into the wires (K) to a sleeve (L) secured on the jet tube (C). The
upper and lower impingement chambers, respectively. horizontal face of the collection plate is perpendicular to
Connect all the component parts and ensure that the as- the axis of the jet tube and centrally aligned.
sembly is vertical and adequately supported and that the The upper surface of the impaction plate is slightly raised
jet spacer peg of the lower jet assembly just touches the bot- above the edge of the metal frame. A recess around the peri-
tom of the lower impingement chamber. Without the inhaler meter of the horizontal partition wall guides the position of
in place, connect a suitable pump to the outlet of the appa- the glass cylinder. The glass cylinders are sealed against the
ratus and adjust the air flow through the apparatus, as mea- horizontal partition walls with gaskets (M) and clamped to-
sured at the inlet to the throat, to 60 + 5 litres per minute. gether by six bolts (N). The sampling ports are sealed by
Prepare the inhaler for use and locate the mouthpiece in stoppers. The bottom-side of the lower partition wall of
the apparatus by means of a suitable adapter. Switch on the stage 4 has a concentrical protrusion fitted with a rubber
pump for 5 s. Switch off the pump and remove the inhaler. O-ring (P) which seals against the edge of a filter placed
Repeat for a further nine discharges. Dismantle the appara- in the filter holder. The filter holder (R) is constructed as a
tus. basin with a concentrical recess in which a perforated filter
Wash the inner surface of the inlet tube to the lower im- support (S) is flush-fitted. The filter holder is dimensioned
pingement chamber and its outer surface that projects into for 76 mm diameter filters. The assembly of impaction
the chamber with a suitable solvent, collecting the washings stages is clamped onto the filter holder by two snap-locks
in the lower impingement chamber. Determine the content (T). Connect a right angle bend metal tube induction
of active ingredient in this solution. Calculate the amount
of active ingredient collected in the lower impingement
chamber per discharge and express the results as a percen-
tage of the dose stated on the label.
Pharmacopeial Forum
port according to Figure 2.9.18.-7 onto the stage 1 inlet jet seal between the inhaler and the induction port. The front
tube of the impinger. A rubber O-ring on the jet tube pro- face of the inhaler mouthpiece must be flush with the front
vides an airtight connection to the induction port. A suitable face of the induction port,
mouthpiece adapter should be used to provide an airtight
Table 2.9.18.-3.—Dimensions*' of jet tube with impaction plate
Type Code ( 2 ) Stage 1 Stage 2 Stage 3 Stage 4 Filter (stage 5)
Distance 1 9.5 5.5 4.0 6.0 n.a

(-.0+.5) (-.0+.5) (-.0+.5) (-.0+.5)
0
Distance 2 26 31 33 30.5
Distance 3 8 5 5 5 5
Distance 4 3 3 3 3 n.a.
Distance 5 0 3 3 3 3
Distance 6(3) 20 25 25 25 25
Distance 7 n.a. n.a. n.a. 8.5 n.a.
Diameter c 25 14 8.0(± .1) 21 14

Diameter d 50 30 20 30 n.a.
Diameter e 27.9 16.5 10.5 23.9 n.a.
Diameter f 31.75 22 14 31 22
(-.0+.5)
Diameter g 25.4 21 13 30 21
Diameter h n.a. n.a. n.a. 2.70 (± .5) n.a.
Diameter j n.a. n.a. n.a. 6.3 n.a.
Diameter k n.a. n.a. n.a. 12.6 n.a.
Radius(4) r 16 22 27 28.5 0
Radius s 46 46 46 46 n.a.
Radius t n.a. 50 50 50 50
Angle w 10° 53° 53° 53° 53°
Angle u n.a. n.a. n.a. 45° n.a.
Angle V n.a. n.a. n.a. 60° n.a.
*-}\ Measures in mm with tolerances according to ISO 2768-m unless otherwise stated
f Refer to Figure 2.9.18.-5
y/
(
Including gasket
' Relative centreline of stage compartment
n.a. = not applicable
Pharmacopeial Forum
Stage 5 (filter)
Outlet
Figure 2.9.18.-4.—The Multi-stage Liquid Impinger
Pharmacopeial Forum
stage center^
Figure 2.9.18.-5.—Details of jet tube and impaction plate. Inserts show end of multi-jet tube U leading to stage 4 (numbers
and lowercase letters refer to Table 2.0.18.-3 and uppercase letters refer to Figure 2.9.18.-4).
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081
Figure 2.9.18.-6.—Details of the filter stage (stage 5). Numbers refer to dimensions (0 = diameter). Uppercase letters refer to Table
2.9.18.-2.
Pharmacopeial Forum
Drill, counter-bore
and lap for an M4 or
U-32n cap screw (2)
Note: use minimum clearance for
screw in the lower part to aid
in precise alignement
Isometric view of induction port

Note
(1) Material may be aluminium or stainless steel.
(2) Machine from 33 mm (L5*) bar stock.
(3) Bore 19 mm hole through bar.
(4) Cut tube to exact 45° as shown.
{5} The Inner bores and tapers should be smooth - approximate 0.40 Jim (16 p n ) finish.
(6) Mil! joining cads of stock to provide a liquid tight leak-free seal.
(7) Set up a holding fixture for aligning the inner 19 mm bore and for drilling and tapping
M4 x 0.7 or 8-32 threads. There must be virtually no mismatch of the inner bores in the miter joint
Figure 2.9.18.-7.—Induction port. Dimensions in mm unless otherwise stated
Procedure for pressurised metered-dose preparations let of the apparatus and adjust the air flow through the
for inhalation. Dispense 20 ml of a solvent, capable of dis- apparatus, as measured at the inlet to the induction port,
solving the active ingredient into each of stages 1 to 4 and to 30 ± 1.5 litres per minute. Switch off the air flow.
replace the stoppers. Tilt the apparatus to wet the stoppers, Unless otherwise prescribed in the patient instructions,
thereby neutralising electrostatic charge. Place a suitable fil- shake the inhaler for 5 s and discharge one delivery to waste.
ter capable of quantitatively collecting the active ingredient Switch on the pump to the apparatus, locate the mouthpiece
in stage 5 and assemble the apparatus. Place a suitable end of the actuator in the adapter and discharge the inhaler
mouthpiece adapter in position at the end of the induction into the apparatus, depressing the valve for a sufficient time
port so that the mouthpiece end of the actuator, when in- to ensure complete discharge. Remove the assembled inha-
serted, lines up along the horizontal axis of the induction ler from the adapter. Repeat the procedure.
port and the inhaler is positioned in the same orientation in-
tended for use. Connect a suitable vacuum pump to the out-
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The number of discharges should be minimised and ty- tion in the respective stage by carefully tilting and rotating
pically would not be greater than ten. The number of dis- the apparatus, observing that no liquid transfer occurs be-
charges should be sufficient to ensure an accurate and tween the stages.
precise determination of the fine particle dose. After the fi- Using a suitable method of analysis, determine the quan-
nal discharge, wait for 5 s and then switch off the pump. tity of active ingredient contained in each of the six volumes
Dismantle the filter stage of the apparatus. Carefully re- of solvent.
move the filter and extract the active ingredient into an ali- Calculate the fine particle dose (see below).
quot of the solvent. Remove the induction port and Procedure for powder inhalers. Place a suitable low resis-
mouthpiece adapter from the apparatus and extract the ac- tance filter capable of quantitatively collecting the drug in
tive ingredient into an aliquot of the solvent. If necessary, stage 5 and assemble the apparatus. Connect the apparatus
rinse the inside of the inlet jet tube to stage 1 with solvent, to a flow system according to the scheme specified in Figure
allowing the solvent to flow into the stage. Extract the active 2.9.18.-8. Unless otherwise defined, conduct the test at the
ingredient from the inner walls and the collection plate of flow rate, Q, used in the test for uniformity of delivered
each of the four upper stages of the apparatus into the solu- dose, drawing 4 litres of air through the apparatus.
E
| Timer |
r Impactor
D 1 P3 P2
Vacuum HUM
Pump k
Two-way Row
Solenoid Control
Valve Valve
r» F
Connector Vacuum Tubing
A B
Figure 2.9.18.-8.—Experimental set-up for testing powders for inhalation
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Table 2.9.18.-4.—Component specification for Figure 2.9.18.-8

Item
Code Description
Connector ID> 8 mm, e.g., short metal coupling, with low-diameter branch
toP3
B Vacuum tubing 8 + 0.5 mm ID x 50 + 10 cm length, e.g., silicon tubing with an OD

of 14 mm and an ID of 8 mm.
Two-way Minimum airflow resistance orifice having an internal diameter of

solenoid valve > 8 mm and a maximum response time 100 milliseconds (e.g.
type 256-A08, Biirkert GmbH, D-74653 Ingelfmgen), or equivalent.
D Vacuum Pump must be capable of drawing the required flow rate through the
pump assembled apparatus with the dry powder inhaler in the mouthpiece
adapter (e.g. product type 1023, 1423 or 2565, Gast Manufacturing
Inc., Benton Harbor, MI 49022), or equivalent. Connect the pump to
the solenoid valve using short and/or wide (> 10 mm ID) vacuum
tubing and connectors to minimise pump capacity requirements.
Timer Timer capable to drive the solenoid valve for the required duration
(e.g type 6814, RS Components International, Corby, NN17 9RS,
UK), or equivalent.
P2P3 Pressure Determine under steady-state flow condition with an absolute,

measurements measurements pressure transducer.
Flow control Adjustable regulating valve with maximum Cn > 1, (e.g. type
valve 8FV12LNSS, Parker Hannifin pic, Barnstaple, EX31 1NP, UK),
or equivalent.
Pharmacopeia! Forum
Connect a flow meter, calibrated for the volumetric flow should be minimised and typically would not be greater than
leaving the meter, to the induction port. Adjust the flow con- ten. The number of discharges should be sufficient to ensure
trol valve to achieve steady flow through the system at the an accurate and precise determination of fine particle dose.
required rate, Q ( + 5 per cent). Switch off the flow. After the final discharge, wait for 5 s and then switch off the
Ensure that critical flow occurs in the flow control valve pump.
by the following procedure. With the inhaler in place and Dismantle the filter stage of the apparatus. Carefully re-
the test flow rate established, measure the absolute pressure move the filter and extract the active ingredient into an ali-
on both sides of the control valve (pressure reading points quot of the solvent. Remove the induction port and
P2 and P3 in Figure 2.9.18.-8). A ratio P3/P2 < 0.5 indi- mouthpiece adapter from the apparatus and extract the ac-
cates critical flow. Switch to a more powerful pump and tive ingredient into an aliquot of the solvent. If necessary,
re-measure the test flow rate if critical flow is not indicated, rinse the inside of the inlet jet tube to stage 1 with solvent,
Dispense 20 ml of a solvent, capable of dissolving the ac- allowing the solvent to flow into the stage. Extract the active
tive ingredient into each of the four upper stages of the ap- ingredient from the inner walls and the collection plate of
paratus and replace the stoppers. Tilt the apparatus to wet each of the four upper stages of the apparatus into the solu-
the stoppers, thereby neutralising electrostatic charge. Place tion in the respective stage by carefully tilting and rotating
a suitable mouthpiece adapter in position at the end of the the apparatus, observing that no liquid transfer occurs be-
induction port. tween the stages.
Prepare the dry-powder inhaler for use according to pa- Using a suitable method of analysis, determine the
tient instructions. With the pump running and the two-way amount of active ingredient contained in each of the six vo-
valve closed, locate the mouthpiece of the inhaler in the lumes of solvent.
mouthpiece adapter. Discharge the powder into the appara- Calculate the fine particle dose (see below).
tus by opening the valve for the required time, T ( + 5 per
cent). Repeat the procedure. The number of discharges
Pharmacopeial Forum
Table 2.9.18.-5.—Calculations for Apparatus C.
Use
.where Q is the flow rate in litres per minute

Cut-off Mass of active ingredient Cumulative mass of Cumulative fraction
diameter deposited per discharge active ingredient of active ingredient
(um) deposited per discharge (per cent)
d4=1.7-q1 mass from stage 5, m5* cA = m, f4 = (c4/c)-100

mass from stage 4, m4 c, = c, + m. f3 = (c3/c)-100
=
6.8 • mass from stage 3, m3 = c, + m. f2 = (c2/c)-100
mass from stage 2, m2 c = c + m2 100
stage 5 is the filter stage
APPARATUS D—"ANDERSEN" SIZING SAMPLER tion port. The front face of the inhaler mouthpiece must be
The "Andersen" 1 ACFM non-viable ambient sizing flush with the front face of the induction port. In the config-
sampler consists of 8 aluminum stages together with a final uration for powder inhalers, a pre-separator is placed above
filter. The stages are clamped together and sealed with O- the top stage to collect large masses of non-respirable pow-
rings. In the configuration used for pressurised inhalers, Fig- der. It is connected to the induction port as shown in Figure
ure 2.9.18.-9, the entry cone of the sampler is connected to a 2.9.18.-10. To accommodate high flow rates through the
right-angle bend metal induction port defined in Figure sampler, the outlet nipple, used to connect the sampler to
2.9.18.-7. A suitable mouthpiece adapter should be used the vacuum system is enlarged to have an internal diameter
to provide an airtight seal between the inhaler and the induc- > 8 mm.
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^ft<afRSpSpi^SSS^KSt^^
Figure 2.9.18.-9.— "Andersen "sizing sampler adapted for pressurised inhalers
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Cross-section
R12.7—4
R15
05
Top view R14.4
Groove for O-ring
R10
R44
R38.3t|
R6.70±0.03
Do not break edge
45° ±3°.
94
Material: aluminium (may be nickel plated for
chemical Inertness).
Side view
Except where noted, aH edges to be broken
and buns removed
Surface to be dean machine tooled finish.
Interior bore to be polished to Ra 0.40 \im.
Oring: nominal dimensions: ID 29 mm,
OD 32 mm, width 1.8 mm
Do not break edge
Figure 2.9.18.-10.—Connection of the induction port to the preseparator of the Andersen sizing sampler
Procedure for pressurised inhalers. Assemble the "An- ler unit is positioned in the same orientation as the intended
dersen" Sampler with a suitable filter in place and ensure use. Connect a suitable pump to the outlet of the apparatus
that the system is airtight. Place a suitable mouthpiece adap- and adjust the airflowthrough the apparatus, as measured at
ter in position at the end of the induction port so that the the inlet to the induction port, to 28.3 ± 1 . 5 litres per min-
mouthpiece end of the actuator, when inserted, lines up ute. Switch off the air flow.
along the horizontal axis of the induction port and the inha-
Pharmacopeia! Forum
Unless otherwise prescribed in the patient instructions, 28.3 litres per minute are applied. Reduced discrimination
shake the inhaler for 5 s and discharge one delivery to waste. between the cut points will occur as the flow rate is in-
Switch on the pump to the apparatus, locate the mouthpiece creased.

end of the actuator in the adapter and discharge into the ap- Modified configuration
paratus, depressing the valve for a sufficient time to ensure In order to overcome the issue of cut point change (from
complete discharge. Remove the assembled inhaler from the the standard values) and reduced discrimination between the
adapter. Repeat the procedure. The number of discharges cut points at a higher flow rate modified versions may be
should be minimised and typically would not be greater than used. Modified configurations are available for use at 60 li-
ten. The number of discharges should be sufficient to ensure tres per minute and 90 litres per minute. These are described
an accurate and precise determination of the fine particle in Pharmeuropa 12.4 p. 584-588 with calibration data. The
dose. After the final discharge, wait for 5 s and then switch modification requires that two stages are exchanged for two
off the pump. modified stages.
Dismantle the apparatus. Carefully remove the filter For use at 60 litres per minute stage 7 is removed and
and extract the drug into an aliquot of the solvent. Remove stage 0 is replaced with stage " - 0 " , additionally stage " -
the induction port and mouthpiece adapter from the appara- 1" is place on top of stage " - 0 " to provide the 8 stage im-
tus and extract the drug into an aliquot of the solvent. Ex- pactor.
tract the drug from the inner walls and the collection plate of For use at 90 litres per minute stages 6 and 7 are re-
each of the stages of the apparatus into aliquots of solvent. moved. Then stage " - 1 " is placed on top of stage 0 and
Using a suitable method of analysis, determine the quan- stage " - 2 " is placed on top of stage " - 1 " to provide the
tity of drug contained in each of the nine volumes of solvent. 8 stage impactor.
Calculate the fine particle dose (see below). For the standard configuration and the modified config-
Procedure for powder inhalers. uration the experimental procedure is identical and is de-
In order to assess powder inhalers, the "Andersen" scribed below.
Sampler may be used in the standard configuration or in a Assemble the "Andersen" Sampler with the pre-se-
modified configuration. parator and a suitable filter in place and ensure that the sys-
Standard configuration tem is airtight. To ensure efficient particle capture, coat each
The Andersen Sampler in the standard configuration plate with glycerol or similar high viscosity liquid deposited
(with stages 0 to 7 in place) can be used at 28.3 litres per from a volatile solvent. The pre-separator should be coated
minute and at other flow rates. Calibration data over a range in the same way or should contain 10 ml of a suitable sol-
of flow rates has been published in Pharmeuropa 12.4 p. vent. Connect the apparatus to a flow system according to
584-588. The data showed that an empirical equation can the scheme specified in Figure 2.9.18.-8.
be used to calculate cut points over the range of 28 litres Unless otherwise defined conduct the test at the flow rate
per minute to 90 litres per minute (see alsoTable 2.9.18.- used in the test for uniformity of delivered dose drawing 4
6). By using the Andersen sampler in the standard config- litres of air through the apparatus. At high flow rates it may
uration the cut points will change when other flow rates than be necessary to remove the lowest stages from the stack.
Pharmacopeial Forum
Connect a flow meter, calibrated for the volumetric flow Using a suitable method of analysis, determine the quan-
leaving the meter, to the induction port. Adjust the flow con- tity of active ingredient contained in each of the nine vo-
trol valve to achieve steady flow through the system at the lumes of solvent.
required rate, Q ( ± 5 per cent). Ensure that critical flow oc- Calculate the fine particle dose (see below).
curs in the flow control valve by the procedure described for Calculations
Apparatus C. Switch off the airflow. From the analyses of the solutions, calculate the mass of
Prepare the dry-powder inhaler for use according to the active ingredient deposited on each stage per discharge and
patient instructions. With the pump running and the two- the mass of active ingredient per discharge deposited in the
way valve closed, locate the mouthpiece of the inhaler in induction port, mouthpiece adapter and where used the pre-
the mouthpiece adapter. Discharge the powder into the ap- separator. The total mass of the active ingredient is not less
paratus by opening the valve for the required time, T ( + 5 than 75 per cent and not more than 125 per cent of the aver-
per cent). Repeat the discharge sequence. The number of age delivered dose determined during testing for uniformity
discharges should be minimised and typically would not of delivered dose. If the total mass is outside this range the
be greater than ten. The number of discharges should be suf- test must be repeated.
ficient to ensure an accurate and precise determination of Starting at the filter, derive a cumulative mass vs. cut-off
fine particle dose. After the final discharge, wait for 5 s diameter of the respective stages (see Table 2.9.18.-5 for
and then switch off the pump. Apparatus C or Table 2.9.18.-6 for Apparatus D). Calculate
Dismantle the apparatus. Carefully remove the filter and by interpolation the mass of active ingredient less than 5
extract the active ingredient into an aliquot of the solvent. um. This is the Fine Particle Dose (FPD).
Remove the pre-separator, induction port and mouthpiece When using the modified Andersen Sampler the calcula-
adapter from the apparatus and extract the drug into an ali- tions are made in an identical manner except that the stage
quot of the solvent. Extract the active ingredient from the numbers now reflect the presence of the modified stages (see
inner walls and the collection plate of each of the stages Table 2.9.18.-7).
of the apparatus into aliquots of solvent. If necessary, and where appropriate, plot the cumulative
fraction of active ingredient versus cut-off diameter (seeTa-
bles 2.9.18.-5/6) on log probability paper, and use this plot
Table 2.9.18.-6.—Calculations for Apparatus D, standard configuration
Use qj = (28.3/Q)1/2, where Q is the flow rate in litres per minute

Cut-off Mass of active Cumulative mass of active Cumulative fraction
diameter substance deposited substance deposited per of active substance
(urn) per discharge discharge (per cent)
d 7 «0.4-q 1 mass from stage 8, m8 = ms f7 = (c7/c) • 100
mass from stage 7, m7 c 6 = c7 m7 f6 = (c6/c)-100
l.l-q, mass from stage 6, m6 c5 = c6 + m6 f5 = (c5/c) • 100
Pharmacopeial Forum
Table 2.9.18.-6.—Calculations for Apparatus D, standard configuration (Continued)
Use q{ = (28.3/Q)1/2, where Q is the flow rate in litres per minute
d3 = 3.3 •<li mass from stage 4, m4 c 3 = c 4 + m4 f3 = (c3/c)-100

d2 = 4.7 mass from stage 3, m3 c 2 = c 3 + m3 f2 = (c2/c)-100
dj = 5.8 •qi mass from stage 2, m2 Cj = C 2 + m2
d0 = 9.0 •qi mass from stage 1, « i c 0 = c{ + m
i fo = (co/c)-lOO
mass from stage 0, m0 c = c o + m0 100
to determine values for the Mass Median Aerodynamic Dia- harmonization of compendial standards for this article. This propo-
sal represents the PROPOSAL STAGE 3 draft. The current propo-
meter (MMAD) and the Geometric Standard Deviation sals are being previewed and are reproduced according to the style
and format of theEuropean Pharmacopoeia. Readers are therefore
(GSD), as appropriate. Appropriate computational methods urged to review these proposals carefully and respond to USP no
later than May 15, 2002.
may also be used.
(ETM: J. Lane RTS—36202-13)
Table 2.9.18.-7.—Cut-off diameters for Apparatus D,
modified configuration
Stage No. Cut-off diameter Cut-off diameter
(um) (um) 2.2.42. DENSITY OF SOLIDS
60 litres per minute 90 litres per minute
7 — — TERMS AND DEFINITIONS

6 d7 = 0.4 — If the principle of operation of the instrument requires the
5 d6 = 0.7 d7 = 0.4 determination of the void volume in the sample tube, for ex-
4 d 5 = 1.1 d6 = 0.7 ample, by the admission of a non-adsorbed gas, such as he-
3 d4 = 2.1 d5 = 1.1 lium, this procedure is carried out at this point, followed by
2 d3 = 3.3 d4 = 2.1 evacuation of the sample. The adsorption of nitrogen gas is
1 d2 = 4.7 d3 = 3.3 then measured as described below.
0 — d2 = 4.7 Raise a Dewar vessel containing liquid nitrogen at
-0 d! = 5.8 — -196°C up to a defined point on the sample cell. Admit a
-1 d0 = 9.0 dj = 5.8 sufficient volume of nitrogen gas to give a relative pressure,
-2 — d0 = 9.0 PIP0, equal to 0.10 ± 0.02. Measure the volume adsorbed,
Va. Repeat the measurement of Va at PIP0 values of 0.10 ±
0.02 and 0.30 ± 0.02.
A minimum of three data points is required. Additional
measurements may be carried out, especially on those rare
BRIEFING
occasions when non-linearity is obtained at a PIP0 value
Density of Solids (EP). USP 25 page 2009. The revisions pre-
sented in this proposal were submitted by the European Pharmaco- close to 0.3. Since non-linearity is often obtained at PIP0
poeia, the coordinating pharmacopeia for the international
or below 0.05, values in this region are not recommended.
Pharmacopeial Forum
or below 0.05, values in this region are not recommended. — the bulk density which further includes the interparticu-
The test for linearity, the treatment of the data, and the cal- late void volume formed in the powder bed; the bulk
culation of the specific surface area of the sample are de- density is also called apparent density.
scribed above. CRYSTAL DENSITY
REFERENCE MATERIALS The crystal density of a substance is the average mass per
Periodically verify the functioning of the apparatus using unit volume, exclusive of all voids that are not a fundamen-
appropriate reference materials of known surface area which tal part of the molecular packing arrangement. It is an intrin-
should have a specific surface area similar to that of the sam- sic property of the substance, and hence should be
ple to be examined. independent of the method of determination. The crystal
The density of solids corresponds to their average mass density can be determined either by calculation or by simple
per unit volume and typically is expressed in grams per cu- measurement.
3
bic centimetre (g/cm ) although the international unit is the A. The calculated crystal density is obtained using:
kilogram per cubic meter (1 g/cm3 = 1000 kg/m3). Unlike 1) crystallographic data (volume and composition of
gases and liquids whose density depends only on tempera- the unit cell) of a perfect crystal, from for example X-ray
ture and pressure, the density of a solid particle also depends diffraction data—single crystal or by indexation of powder
on its molecular assembly and therefore varies with the crys- X-ray diffraction data,
tal structure and degree of crystallinity. When a solid parti-
2) the molecular mass of the substance.
cle is amorphous or partially amorphous, its density may
further depend upon the history of preparation and treat- B. The measured crystal density is the mass to vol-
ment. ume ratio after measuring the single crystal mass and vol-
Therefore, unlike fluids, the densities of two chemically ume.
equivalent solids may be different, and this difference re- PARTICLE DENSITY
flects a difference in solid-state structure. The density of The particle density takes into account both the crystal
constituent particles is an important physical characteristic density and the intraparticulate porosity (sealed and/or ex-
of pharmaceutical powders. perimentally non-accessible open pores). Thus, particle den-
The density of a solid particle can assume different values sity depends on the value of the volume determined which
depending on the method used to measure the volume of the in turn depends on the method of measurement. The particle
particle. It is useful to distinguish three levels of expression density can be determined using one of the two following
of density: methods.
— the crystal density which includes only the solid frac- A. The pycnometric density is determined by measur-
tion of the material; the crystal density is also called ing the volume occupied by a known mass of powder which
true density, is equivalent to the volume of gas displaced by the powder
— the particle density which also includes the volume due using a gas displacement pycnometer (2.9.23). In pycno-
to intraparticulate pores, metric density measurements, the volume determined in-
cludes the volume occupied by open pores; however, it
Pharmacopeia! Forum
excludes the volume occupied by sealed pores or pores in- B. The tapped density is achieved by mechanically
accessible to the gas. Due to the high diffusivity of helium, tapping a measuring cylinder containing a powder sample.
which is the preferred choice of gas, most open pores are After observing the initial volume, the cylinder is mechani-
accessible to the gas. Therefore, the pycnometric density cally tapped, and volume readings are taken until little
of a finely milled powder is generally not very different further volume change is observed (2.9.15).
from the crystal density. Hence, this density is the best esti-
mate of the true density of an amorphous or partially crystal- 2.9.23. PYCNOMETRIC DENSITY OF SOLIDS
line sample and is therefore widely applicable for processed The test for pycnometric density of solids is intended to
pharmaceutical powder samples. determine the volume occupied by a known mass of powder
by measuring the volume of gas displaced under defined
B. The mercury porosimeter density is also called
conditions. Hence, its pycnometric density is calculated.
granular density. With this method the volume determined
APPARATUS
also excludes contributions from sealed pores; however, it
includes the volume only from open pores larger than some The apparatus (see Figure 2.9.23.-1) consists of the fol-
size limit. This pore size limit or minimal access diameter lowing:
depends on the maximal mercury intrusion pressure applied — a sealed test cell, with an empty cell volume (Vc), con-
during the measurement and under normal operating pres- nected through a valve to a reference cell, with a refer-
sures the mercury does not penetrate the finest pores acces- ence volume (Vr),
sible to helium. Various granular densities can be obtained — a system capable of pressurising the test cell with the
from one sample since, for each applied mercury intrusion measurement gas until a defined pressure (P) indicated
pressure, a density can be determined that corresponds to the by a manometer,
pore size limit at that pressure. — the system is connected to a source of measurement
BULK AND TAPPED DENSITY gas, which is preferably helium, unless another gas is
specified(1).
The bulk density of a powder includes the contribution of
The temperature of the gas pycnometer is between 15°C
interparticulate void volume. Hence, the bulk density de-
and 30°C and must not vary by more than 2°C during the
pends on both the density of powder panicles and the space
course of measurement.
arrangement of particles in the powder bed.
The apparatus is calibrated which means that the volumes
The bulk density of a powder is often very difficult to
(Vc) and (Vr) are determined, using calibrated, polished steel
measure with good reproducibility since the slightest distur-
balls having a total volume (around 6 cm3) known to the
bance of the bed may result in a new density. Thus, it is es-
nearest 0.001 cm3. The procedure described below is fol-
sential in reporting bulk density to specify how the
lowed in two runs. Firstly, with an empty test cell and sec-
determination was made.
ondly with the steel balls placed in the test cell. The volumes
A. The bulk density is determined by measuring the
(I)
volume of a known mass of powder, that has been passed If gases other than helium are used, it would not be surprising to obtain
values different from those obtained with helium, since the penetration of
through a screen, into a graduated cylinder (2.9.15). the gas is dependent on the size of the pore as well as the cross-sectional
area of the penetrating molecule. For example, the pycnometric density of
porous materials will be overestimated by a measure using nitrogen by
comparison with helium.
Pharmacopeial Forum
(Vc) and (Vr) are calculated using the equation for the sample Record the final pressure (P,). Repeat the measurement
volume taking into account that the volume is zero in the sequence for the same powder sample until consecutive
first run. measurements of the sample volume (Vs) agree to within
0.5 per cent. The sample volume is expressed in cm3. Un-
load the test cell and measure the final powder mass (m) ex-
pressed in grams.
EXPRESSION OF THE RESULTS
The sample volume (Vs) is given by the expression:
V =V —
Pi-Pr
-1
Vt - reference volume The density (r) is given by the equation:

Vc " cell volume
Vt - sample volume m
P=
M - manometer F
Figure 2.9.23.-1.—Schematic diagram of a gas pycnometer
METHOD
Weigh the test cell of the pycnometer and record the mass.
Fill the test cell with a given mass of powder of the sub-
stance to be examined. Seal the test cell in the pycnometer. BRIEFING
Remove volatile contaminants in the powder by degassing (776) Optical Microscopy, USP 25 page 2040 and page 7456
of PF 25(1) [Jan.-Feb. 1999]. The United States Pharmacopeia is
the powder under a constant purge of gas; occasionally, the coordinating pharmacopoeia for the international harmoniza-
tion of test methods as provided in this general test chapter. The
powders may initially have to be degassed under vacuum. presented text represents the PROPOSAL STAGE 4 draft in the
harmonization process. The proposal corresponds to the current
Record the system reference pressure (Pr) as indicated by USP 25 text for the general chapter Optical Microscopy (776) with
the addition of a new section, Limit Test of Particle Size by Micro-
the manometer while the valve that connects the reference scopy. This new section is based on the corresponding European
Pharmacopoeia test, 2.9.13, having the same title. Readers are
cell with the test cell is open. Close the valve to separate therefore urged to review these late-stage In-Process Revision pro-
posals carefully and to respond to USP no later than May 15,2002.
the reference cell from the test cell. Pressurise the test cell Other revisions include:
(1) In the opening paragraph a change was made to include par-
with the gas to an initial pressure (P,) and record the value ticles above 1 urn, instead of a range.
(2) Number of particles to characterize—changed to read "For a
obtained. Open the valve to connect the reference cell with sufficiently large homogeneous population...."
the test cell.
Pharmacopeial Forum
(3) Particle Shape Characterization—the following sentence has achromatic objectives and are preferable with apochromats
been added to the text. "The homogeneity of the powder
should be checked using appropriate magnification." This and are required for appropriate color rendition in photomi-
has been added by suggestion of EP.
crography. Condensers corrected for at least spherical aber-
(ETM: J. Lane) RTS—36202-10
ration should be used in the microscope substage and with
the lamp. The numerical aperture of the substage condenser
Change to read:
should match that of the objective under the conditions of
use; this is affected by the actual aperture of the condenser
A
(776) OPTICAL MICROSCOPY diaphragm and the presence of immersion oils.
Adjustment—The precise alignment of all elements of the

Optical microscopy for particle characterization can gen-
optical system and proper focusing are essential. The focus-
erally be applied to particles 1 um and greater. The lower
ing of the elements should be done in accordance with the
limit is imposed by the resolving power of the microscope.
recommendations of the microscope manufacturer. Critical
The characterization of smaller particles can often be ac-
axial alignment is recommended.
complished by means of electron optical imaging techni-
Illumination—A requirement for good illumination is a
ques such as those described under Scanning Electron
uniform and adjustable intensity of light over the entire field
Microscopy (1181) where practical image resolution ap-
proaches 0.01 um. The upper limit is less definite and is de- of view; Kohler illumination is preferred. With colored par-
termined by the increased difficulty associated with the ticles, choose the color of the filters used so as to control the
characterization of larger particles compared with sieve ana- contrast and detail of the image.
lysis. For particles in excess of 75 um, the preferred method Visual Characterization—The magnification and numeri-
of particle size analysis is by use of sieve analysis. Often cal aperture should be sufficiently high to allow adequate
stereo-microscopy can be a useful aid with larger particles, resolution of the edges of the images of the particles to be
yet it is not as definitive. Optical microscopy is particularly characterized. Determine the actual magnification using a
useful for characterizing particles that are not spherical. This calibrated stage micrometer to calibrate an ocular micro-
method may also serve as a base for the calibration of faster meter. Errors can be minimized if the magnification is suffi-
and more routine methods that may be developed. cient that the image of the particle is at least 10 ocular
divisions. Each objective must be calibrated separately. To
Apparatus—Use a microscope that is stable and protected
calibrate the ocular scale, the stage micrometer scale and the
from vibration. The microscope magnification (product of
ocular scale should be aligned. In this way, a precise deter-
the objective magnification, ocular magnification, and addi-
mination of the distance between ocular stage divisions can
tional magnifying components) must be sufficient to allow
be made. Several different magnifications may be necessary
adequate characterization of the smallest particles to be clas-
to characterize materials having a wide particle size distribu-
sified in the test specimen. The greatest numerical aperture
tion.
of the objective should be sought for each magnification
(1)
range. Polarized light may be used in conjunction with suit- If gases other than helium are used, it would not be surprising to obtain
values different from those obtained with helium, since the penetration of
able analyzers and retardation plates. Color filters of rela- the gas is dependent on the size of the pore as well as the cross-sectional
area of the penetrating molecule. For example, the pycnometric density of
tively narrow spectral transmission should be used with porous materials will be overestimated by a measure using nitrogen by
comparison with helium.
Pharmacopeial Forum
Photographic Characterization—If particle size is to be de- examined (for example, 10 to 100 mg) and suspend it in
termined by photographic methods, take care to ensure that 10.0 mL of a suitable medium in which the powder does
the object is sharply focused at the plane of the photographic not dissolve, adding, if necessary, a wetting agent. Introduce
emulsion. Determine the actual magnification by photo- a portion of the homogeneous suspension into a suitable
graphing a calibrated stage micrometer, using photographic counting cell and scan under a microscope an area corre-
film of sufficient speed, resolving power, and contrast. Ex- sponding to not less than 10 |ig of the powder to be exam-
posure and processing should be identical for photographs ined. Count all the particles having a maximum dimension
of both the test specimen and the determination of magnifi- greater than the prescribed size limit. The size limit and the
cation. The apparent size of a photographic image is influ- permitted number of particles exceeding the limit are stated
enced by the exposure, development, and printing processes in the monograph.
as well as by the resolving power of the microscope. Number of Particles to Characterize—The number of par-
Preparation of the Mount—The mounting medium will ticles characterized must be sufficient to ensure an accepta-
vary according to the physical properties of the test speci- ble level of uncertainty in the measured parameter.
men. Sufficient, but not excessive, contrast between the spe- Successively higher magnification may be necessary to en-
cimen and the mounting medium is required to ensure sure proper dispersion of the specimen. An estimate of the
adequate detail of the specimen edge. The particles should number of particles, n, to be measured that will provide an
rest in one plane and be adequately dispersed to distinguish acceptable level of uncertainty in the mean particle diameter
individual particles of interest. Furthermore, the particles can be obtained from the statistical theory of normal popu-
must be representative of the distribution of sizes in the ma- lations. For a sufficiently large homogeneous population
terial and must not be altered during preparation of the (n > 30), the uncertainty in the estimate for the mean par-
mount. Care should be taken to ensure that this important ticle diameter, d, is given in the formula:
requirement is met. Selection of the mounting medium must
include a consideration of the analyte solubility.
Crystallinity Characterization—The crystallinity of a ma-

terial may be characterized to determine compliance with
in which zc corresponds to the desired confidence coefficient and s
the crystallinity requirement where stated in the individual is the standard deviation of the test specimen. For n > 30, zc is about
1.96 at the 95% confidence level. Other confidence coefficients can
monograph of a drug substance. Unless otherwise specified be obtained from reference books on statistics, and, if necessary,
small population statistics can be similarly applied. From this equa-
in the individual monograph, mount a few particles of the tion, it can be seen that the uncertainty in the measured diameter
decreases as the number of particles increases. As an example, to
specimen in mineral oil on a clean glass slide. Examine obtain an uncertainty of + 5 um in a specimen that has a standard
deviation of 20 um would require that 61 particles be accurately
the mixture using a polarizing microscope: the particles measured.
show birefringence (interference colors) and extinction po- An estimate of the uncertainty in the standard deviation of
sitions when the microscope stage is revolved. a specimen can be obtained in a similar fashion. The stan-
Limit Test of Particle Size by Microscopy—Unless other- dard deviation of the population, a, is estimated to lie in the
wise specified in the individual monograph, use the follow- interval:
ing method. Weigh a suitable quantity of the powder to be
Pharmacopeia! Forum
particles would have to be measured to obtain a similar con-

fidence of ± 10% in the standard deviation (e.g., 18.3 < s <
22.3).
For a material that conforms more closely to a log nor-
anc
where s is the standard deviation of the specimen, and \a ^ Xb mal distribution, the logarithm of the individual particle dia-
are the confidence
2can
coefficients obtained from the x2 distribution.
Xa and Xb be obtained from standard statistics references or meters can be computed, and the mean and the standard
approximated byanthe following expressions at the 95% confidence
level where Xa ^ Xb represent the 97.5 and 2.5 percentile va- deviation of the log particle diameter directly substituted
lues, respectively:
in the above equations. The anti-logs correspond to the geo-
metric mean and geometric standard deviation, respectively.
2
- +1.96 + Win - 3
Additional information on particle size measurement, sam-
ple size, and data analysis is available, for example, in
and
ASTM E20-85.
Particle Size Characterization—The measurement of parti-

cle size varies in complexity depending on the shape of the
particle. The homogeneity of the powder should be checked
In general, a larger sample must be acquired to obtain a using appropriate magnification. For spherical particles, size
good estimate of the standard deviation or distribution of the is defined by the diameter. For irregular particles, a variety
population. For the example population described above, if of definitions of particle size exist. In general, for irregularly
the mean particle diameter was 50 um, only 61 particles shaped particles, characterization of particle size must also
would have to be measured to obtain an uncertainty of include information on the type of diameter measured as
10% in the diameter (e.g., d = 50 ± 5 urn), but about 200 well as information on particle shape. Several commonly
used measurements of particle size are defined below (see
Figure 1):
Pharmacopeia! Forum
Ferets diameter
Martin s diameter
Projected area diameter
Maximum horizontal intercept
Fig. 1. Commonly used measurements of particle size.
Length—The longest dimension from edge to edge of a

Feret'sDiameter—The distance between imaginary parallel particle oriented parallel to the ocular scale.
lines tangent to a randomly oriented particle and perpendi-
Width—The longest dimension of the particle measured at
cular to the ocular scale.
right angles to the length.
Martin s Diameter—The diameter of the particle at the point Particle Shape Characterization—For irregularly shaped
that divides a randomly oriented particle into two equal pro- particles, characterization of particle size must also include
jected areas. information on particle shape. The following defines some
commonly used descriptors of particle shape (see Figure 2):
Projected area Diameter—The diameter of a circle that has
the same projected area as the particle.
Columnar
Lath
Fig. 2. Commonly used descriptions of particle shape.
Pharmacopeial Forum
Acicular—Slender, needle-like particle of similar width Optical— Color (using proper color balancing filters),
and thickness. transparent, translucent, opaque.
Columnar—Long, thin particle with a width and thickness Defects—Occlusions, inclusions.

that are greater than those of an acicular particle.
Surface characteristics may be described as:
Flake—Thin,flatparticle of similar length and width.

Cracked—Partial split, break, or fissure.
Plate—Flat particles of similar length and width but with

Smooth—Free of irregularities, roughness, or projections.
greater thickness than flakes.
Porous—Having openings or passageways.
Lath—Long, thin, and blade-like particle.
Rough—Bumpy, uneven, not smooth.
Equant—Particles of similar length, width, and thickness;
Pitted—Small indentations.A.VSP26
both cubical and spherical particles are included.
General Observations—A particle is generally considered

BRIEFING
to be the smallest discrete unit. A particle may be a liquid or
(811) Powder Fineness, USP 25 page 2060 and page 7462 of
semisolid droplet; a single crystal or polycrystalline; amor- PF'25(1) [Jan.-Feb. 1999]. The United States Pharmacopeia is the
phous or an agglomerate. Particles may be associated. This test methods as provided in this general test chapter. The presented
text represents the OFFICIAL INQUIRY STAGE 4 draft in the har-
degree of association may be described by the following monization process. The proposal corresponds to the current USP
25 text for general chapter (811) Powder Fineness with the addi-
terms: tion of new text in the section Classification of Powder Fineness.
This new text is based in part on the corresponding European
Pharmacopoeia test 2.9.12. Sieve Test. However, instead of speci-
Lamellar—Stacked plates. fying "not more than 40 per cent passes" as in the European Phar-
macopoeia text, the corresponding value at which "not more than
10 percent passes" is specified. This proposed text is not consid-
Aggregate—Mass of adhered particles. ered to result in a significant change in the particle size distribution
values, assuming that the material under test has a log normal par-
ticle size distribution. The proposed text offers the advantage of
more clearly describing the upper and lower ends of the particle
Agglomerate—Fused or cemented particles. size distribution, i.e., the not less than 95 percent and not more than
10 per cent fractions. The proposed text also provides the alterna-
tive of reporting the particle size distribution on the basis of the
Conglomerate—Mixture of two or more types of particles. percent passing a specified sieve, i.e., not more than x percent
passes through a y urn sieve. Readers are therefore urged to review
these late-stage In-Process Revision proposals carefully and to re-
Spherulite—Radial cluster. spond to USP no later than May 15, 2002.
Other revisions include the following:
(1) The term "very coarse" has been deleted from the draft based
Drusy—Particle covered with tiny particles. on comments that it is not used in EP or JP.
(2) Powdered Vegetable and Animal Drugs has been deleted
Particle condition may be described by the following based on comments that it is irrelevant for harmonization.
terms:
Edges—Angular, rounded, smooth, sharp, fractured.
Pharmacopeial Forum
(3) The air permeation method has been deleted based on com- d
90 = smallest sieve opening through which 90% or
ments that it would be better to describe this method sepa-
rately. This paragraph is no longer referenced in a USP more of the material passes
monograph.
d
50 = smallest sieve opening through which 50% or
(ETM: J. Lane) RTS—36202-4
more of the material passes
d
io = smallest sieve opening through which 10% or
Change to read:
more of the material passes.
A The upper and lower limit of the sieve opening values

(811) POWDER FINENESS may be reported when results of two or more test lots are
Test procedures for sieving powder materials are de- combined, e.g., "Lot A has a d50 value of 1000 um with a
scribed under Particle Size Distribution Estimation by Ana- range of 850-1180 um."
lytical Sieving (786), and, where practical, the particle size An alternative but less informative method of classifying
distribution should be estimated by this procedure. The clas- powder fineness is by use of the terms in the following table.
sification of powder fineness in this Pharmacopeia, ex-
pressed in descriptive terms, is provided in the table. For Classification of Powders by Fineness
practical reasons, sieves are the preferred means of measur-
Descriptive Term d50Sieve Opening (um)
ing powder fineness for most pharmaceutical purposes.
355-1000
Sieving is most suitable where a majority of the particles Coarse
are larger than about 75 urn, although it can be used for Moderately Fine 180-355
some powders having smaller particle sizes where the meth- Fine 125-180
od can be validated. Avoid processing conditions that would Very Fine 90-125 AUSP26
alter the true particle size distribution of the powder being

tested. In determining powder fineness, no portion of the
material may be rejected unless specifically permitted in
the individual monograph.
BRIEFING
Sieves for Pharmacopeial Testing—
Sieves for Pharmacopeial testing are described under Specific Surface Area (EP). USP 25 page 2072. The revisions
presented in this proposal were submitted by the European Phar-
macopoeia, the coordinating pharmacopeia for the international
Particle Size Distribution Estimation by Analytical Sieving harmonization of compendial standards for this article. This propo-
sal represents the PROPOSAL STAGE 3 draft. The current propo-
(786). sals are being previewed and are reproduced according to the style
and format of the European Pharmacopoeia. Readers are therefore
Classification of Powder Fineness— urged to review these proposals carefully and respond to USP no
later than May 15, 2002.
Powder fineness may be classified by determining the smal-
lest sieve opening through which a specified quantity of ma- (ETM: J. Lane) RTS—36202-7
terial passes. Results are typically reported as
Pharmacopeial Forum
2.9.26. SPECIFIC SURFACE AREA A value of Va is measured at each of not less than three
BY GAS ADSORPTION values of PIP0.
Then the BET value
INTRODUCTION
The specific surface area of a powder is determined by l
physical adsorption of a gas on the surface of the solid

and by measuring the amount of adsorbate gas correspond-
H
ing to a monomolecular layer on the surface. Physical ad-
is plotted against PIP0, according to equation (1). This plot
sorption results from relatively weak forces (van der
should yield a straight line usually in the approximate rela-
Waals forces) between the adsorbate gas molecules and
tive pressure range 0.05 to 0.3. The data are considered ac-
the adsorbent surface of the test powder. The amount of
ceptable if the correlation coefficient, r, of the linear
gas adsorbed can be measured by a gravimetric, volumetric
regression is not less than 0.9975; that is, r2 is not less than
or continuous flow procedure.
0.995. From the resulting linear plot, the slope, which is
BRUNAUER, EMMETT AND TELLER (BET) THEORY
AND SPECIFIC SURFACE AREA DETERMINATION equal to (C-l)/VmC, and the intercept, which is equal to
MULTI-POINT MEASUREMENT l/VmC, are evaluated by linear regression analysis. From
The data are treated according to the Brunauer, Emmett these values, Vm is calculated as \l(slope + intercept), while
and Teller (BET) adsorption isotherm equation: C is calculated as (slope/intercept) + 1. From the value of Vm
so determined, the specific surface area, S, in m2 • g"1, is cal-
1 C-l P 1 culated by the equation:
(1)
VC P V_C
ri V_Na
(2)
mx 22400
P = partial vapour pressure of adsorbate gas in equi-

librium with the surface at-196°C (b.p. of liquid
N Avogadro constant (6.023 x 1023 mol"1),
nitrogen), in pascals,
effective cross-sectional area of one adsor-
Po = saturated pressure of adsorbate gas, in pascals,
bate molecule, in square metres (0.162 nm2
Va = volume of gas adsorbed at standard temperature
for nitrogen and 0.195 nm2 for krypton),
and pressure (STP) [273.15 K and atmospheric
m mass of test powder, in grams,
pressure (1.013 x 105 Pa)], in millilitres,
22400 volume, in millilitres, occupied by the adsor-
Vm - volume of gas adsorbed at STP to produce an ap-
bate gas at STP allowing for minor depar-
paraent monolayer on the sample surface, in
tures from the ideal.
millilitres,
C = dimensionless constant that is related to the en-
thalpy of adsorption of the adsorbate gas on the
powder sample.
Pharmacopeial Forum
SINGLE-POINT MEASUREMENT
Normally, at least three measurements of Va each at differ-
ent values of PIPO are required for the determination of spe- (4)
cific surface area by the dynamic flow gas adsorption

technique {Method I) or by volumetric gas adsorption
{Method II). However, under certain circumstances de- The specific surface area is calculated from Vm by equa-
scribed below, it may be acceptable to determine the specific tion (2) given above.
surface area of a powder from a single value of Va measured EXPERIMENTAL TECHNIQUES
at a single value of PIP0 such as 0.300 (corresponding to This section describes the methods to be used for the sam-
0.300 mole of nitrogen or 0.001038 mole fraction of kryp- ple preparation, the dynamic flow gas adsorption technique
ton), using the following equation for calculating Vm: {Method I) and the volumetric gas adsorption technique
{Method II).
V..V.U-- (3) SAMPLE PREPARATION

Outgassing
Before the specific surface area of the sample can be de-
The specific surface area is then calculated from the value termined, it is necessary to remove gases and vapours that
of Vm by equation (2) given above. may have become physically adsorbed onto the surface after
The single-point method may be employed directly for a manufacture and during treatment, handling and storage. If
series of powder samples of a given material for which the outgassing is not achieved, the specific surface area may be
material constant C is much greater than unity. These cir- reduced or may be variable because an intermediate area of
cumstances may be verified by comparing values of specific the surface is covered with molecules of the previously ad-
surface area determined by the single-point method with sorbed gases or vapours. The outgassing conditions are cri-
that determined by the multiple-point method for the series tical for obtaining the required precision and accuracy of
of powder samples. Close similarity between the single- specific surface area measurements on Pharmaceuticals be-
point values and multiple-point values suggests that 1/C ap- cause of the sensitivity of the surface of the materials.
proaches zero.
Conditions. The outgassing conditions must be demon-
The single-point method may be employed indirectly for
strated to yield reproducible BET plots, a constant weight of
a series of very similar powder samples of a given material
test powder, and no detectable physical or chemical changes
for which the material constant C is not infinite but may be
in the test powder.
assumed to be invariant. Under these circumstances, the er-
The outgassing conditions defined by the temperature,
ror associated with the single-point method can be reduced
pressure and time should be so chosen that the original sur-
or eliminated by, using the multiple-point method to evalu-
face of the solid is reproduced as closely as possible. Out-
ate C for one of the samples of the series from the BET plot,
gassing of many substances is often achieved by applying a
from which C is calculated as (1 + slope/intercept). Then Vm
vacuum or by purging the sample in a flowing stream of a
is calculated from the single value of Va measured at a single
non-reactive, dry gas. In either case, elevated temperatures
value of PIP0, by the equation:
Pharmacopeia! Forum
are sometimes applied to increase the rate at which the con- MEASUREMENTS
taminants leave the surface. Outgassing by heating the pow- Since the amount of gas adsorbed under a given pressure
der sample may change the nature of the surface and should tends to increase on decreasing the temperature, adsorption
be avoided, unless specifically indicated. measurements are usually made at a low temperature. Mea-
If heating is employed, the recommended temperature and surement is performed at -196°C, the boiling point of liquid
time of outgassing are as low as possible so as to achieve nitrogen.
reproducibly high measures of specific surface area within Method I: the dynamicflowmethod
an acceptable time span. For outgassing sensitive samples, Principle of the method
other outgassing methods such as the desorption-adsorption In the dynamic flow method (see Figure 2.9.26.-1), the
cycling method may be employed. recommended adsorbate gas is dry nitrogen or krypton,
while helium is employed as a diluent gas, which is not ad-
Adsorbate
sorbed under the recommended conditions.
The standard technique is the adsorption of nitrogen at li-
A minimum of three mixtures of the appropriate adsorbate
quid nitrogen temperature.
gas with helium are required within the PIPO range 0.05 to
For powders of low specific surface area (<1 m2 • g"1) the
0.30.
proportion adsorbed is low, the use of krypton at liquid ni-
The gas detector-integrator should provide a signal that is
trogen temperature is preferred in such cases since the low
approximately proportional to the volume of the gas passing
vapour pressure exerted by this gas greatly reduces the error.
through it under defined conditions of temperature and pres-
All gases used must be free from moisture.
sure. For this purpose, a thermal conductivity detector with
Quantity of sample an electronic integrator is one among various suitable types.
Accurately weigh a quantity of the test powder such that A minimum of three data points within the recommended
2
the total surface of the sample is at least 1 m when adsor- range of 0.05 to 0.30 for PIP0 is to be determined.
bate is nitrogen and 0.5 m2 when the adsorbate is krypton.
Pharrnacopeial Forum
Self seals quick connection

_ . , Calibrating _ -.
Ftow
Onngseals septum P Path
selection meter
Flow valve I Diffusion
control , baffle
valve
Outgassing
Differential station
flow
controller
Vent
Gas inlet Detector
Detector
Figure 2.9.26.-1.—Schematic diagram of the dynamic flow method apparatus.
Use a nitrogen/helium mixture for a single-point determi-

Procedure
nation and several such mixtures or premixing two streams
A known mixture of the gases, usually nitrogen and he-
of gas for a multiple-point determination.
lium, is passed through a thermal conductivity cell, through
Calculation is essentially the same as for the volumetric
the sample again through the thermal conductivity cell and
method.
then to a recording potentiometer.
Method II: the volumetric method
Immerse the sample cell in liquid nitrogen, then the sam-
Principle of the method
ple adsorbs nitrogen from the mobile phase. This unba-
In the volumetric method (see Figure 2.9.26.-2), the re-
lances the thermal conductivity cell, and a pulse is
commended adsorbate gas is nitrogen which is admitted into
generated on a recorder chart.
the evacuated space above the previously outgassed powder
Remove from the coolant; this gives a desorption peak
sample to give a defined equilibrium pressure, P, of the gas.
equal in area and in the opposite direction to the adsorption
The use of a diluent gas, such as helium, is therefore unne-
peak. Since this is better defined than the adsorption peak, it
cessary, although helium may be employed for other pur-
is the one used for the determination.
poses, such as to measure the void volume.
To effect the calibration, inject sufficient air into the sys-
Since only pure adsorbate gas, instead of a gas mixture, is
tem to give a peak of similar magnitude to the desorption
employed, interfering effects of thermal diffusion are
peak and obtain the proportion of gas adsorbed per unit peak
avoided in this method.
area (air can be used instead of nitrogen since it has the same
thermal conductivity).
© 2002 The United States Pharrnacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
»
To cold traps and
vacuum pumps
Vapour Vacuum
pressure Air
manometer
Figure 2.9.26.-2.—Schematic diagram of the volumetric method apparatus.
Raise a Dewar vessel containing liquid nitrogen at

-196°C up to a defined point on the sample cell. Admit a
Procedure
sufficient volume of nitrogen gas to give a relative pressure,
Admit a small amount of dry nitrogen into the sample
PIP0 equal to 0.10 + 0.02. Measure the volume adsorbed,
tube to prevent contamination of the clean surface, remove
Va. Repeat the measurement of Va zXPIP0 values of 0.20 +
the sample tube, insert the stopper, and weigh it. Calculate
0.02 and 0.30 ± 0.02.
the weight of the sample. Attach the sample tube to the vol-
A minimum of three data points is required. Additional
umetric apparatus. Cautiously evacuate the sample down to
measurements may be carried out, especially on those rare
the specified pressure (e.g. 2.66 Pa or less). Alternately,
occasions when non-linearity is obtained at a PIPO, value
some instruments operate by evacuating to a specified rate
close to 0.3. Since non-linearity is often obtained at PIP0
of pressure change (e.g. less than 13 Pa/30 s) and holding
or below 0.05, values in this region are not recommended.
for a specified period of time before commencing the next
The test for linearity, the treatment of the data, and the cal-
step.
culation of the specific surface area of the sample are de-
If the principle of operation of the instrument requires the
scribed above.
determination of the void volume in the sample tube, for ex-
REFERENCE MATERIALS
ample, by the admission of a non-adsorbed gas, such as he-
Periodically verify the functioning of the apparatus using
lium, this procedure is carried out at this point, followed by
appropriate reference materials of known surface area which
evacuation of the sample. The adsorption of nitrogen gas is
should have a specific surface area similar to that of the sam-
then measured as described below.
ple to be examined.
Pharmacopeial Forum
maceutical literature. In addition, while it is clear that no sin-

BRIEFING
gle and simple test method can adequately characterize the
(1174) Powder Flow. The United States Pharmacopeia is the
coordinating pharmacopeia for the international harmonization of flow properties of pharmaceutical powders, this chapter pro-
test methods as provided in this proposed new general information
chapter. The presented text represents the OFFICIAL INQUIRY poses the standardization of test methods that may be valu-
STAGE 4 draft in the harmonization process. The proposal corre-
sponds to the Stimuli article text as published on page 8298 of PF able during pharmaceutical development.
25(3) [May-June 1999] and to the PROPOSAL STAGE 3 draft as
published on page 954 of PF 26(4) [July-Aug. 2000]. Readers are Four commonly reported methods for testing powder flow
therefore urged to review these late-stage In-Process Revision pro-
posals carefully and to respond to USP no later than May 15,2002. are (1) angle of repose, (2) compressibility index or Hausner
Major changes include the following:
(1) Basic Methods for Compressibility Index and Hausner Ra- ratio, (3) flow rate through an orifice, and (4) shear cell. In
tio—For clarification, the sentence has been modified to state,
"...the basic procedure is to measure (1) the unsettled appar- addition, numerous variations of each of these basic meth-
ent volume, Vo, and (2) the final tapped volume, Vp of the
powder after tapping the material until no further volume ods are available. Given the number of test methods and var-
changes occur in accordance with Bulk Density and Tapped
Density (616)." iations, standardizing the test methodology, where possible,
(2) Flow through an Orifice—Clarifying sentences were added to
the section. would be advantageous.
(3) Basic Methods for Angle of Repose—The phrase, "such that
the diameter of the pile is known," was eliminated based on With this goal in mind, the most frequently used methods
comments received. The resulting sentence will read, "The
base upon which the pile forms may be of fixed diameter or are discussed below. Important experimental considerations
the diameter of the powder cone may be allowed to vary as the
pile forms." are identified and recommendations are made regarding
(4) Angle of Repose General Scale of Flow ability—Editorial
changes were made to the section. standardization of the methods. In general, any method of
(5) Table 2. Scale of Flowability—Performance descriptions
were deleted based on comments that these terms did not ap- measuring powder flow should be practical, useful, reprodu-
ply to pharmaceutical products.
(6) Basic Methods for Flow through an Orifice—Modifications cible, sensitive, and yield meaningful results. It bears repeat-
of the quantity of powder from 50 g to 100 g and the measure
of time in seconds and tenths of seconds are proposed, to be ing that no one simple powder flow method will adequately
consistent with EP.
or completely characterize the wide range of flow properties
(ETM: J. Lane) RTS—36202 experienced in the pharmaceutical industry. An appropriate
strategy may well be the use of multiple standardized test
Add the following: methods to characterize the various aspects of powder flow
as needed by the pharmaceutical scientist.
(1174) POWDER FLOW
Angle of Repose
The widespread use of powders in the pharmaceutical in- The angle of repose has been used in several branches of
dustry has generated a variety of methods for characterizing science to characterize the flow properties of solids. Angle
powder flow. Not surprisingly, scores of references appear of repose is a measure of mterparticulate friction, or resis-
in the pharmaceutical literature, attempting to correlate the tance to movement between particles. Angle of repose test
various measures of powder flow to manufacturing proper- results are reported to be very dependent upon the method
ties. The development of such a variety of test methods was used. Experimental difficulties arise due to segregation of
inevitable; powder behavior is multifaceted and thus com- material and consolidation or aeration of the powder as
plicates the effort to characterize powder flow. The purpose the cone is formed. Despite its difficulties, the method con-
of this chapter is to review the methods for characterizing
powder flow that have appeared most frequently in the phar-
Pharmacopeial Forum
tinues to be used in the pharmaceutical industry, and a num- VARIATIONS IN ANGLE OF REPOSE METHODS
ber of examples demonstrating its value in predicting man-
In addition to the above methods, variations of them have
ufacturing problems appear in the literature.
been used to some extent in the pharmaceutical literature:
The angle of repose is the constant, three-dimensional an-
• Drained angle of repose. This is determined by allow-
gle (relative to the horizontal base) assumed by a cone-like
ing an excess quantity of material positioned above a
pile of material formed by any of several different methods
fixed diameter base to "drain" from the container. For-
(described briefly below). It has been severely criticized for
mation of a cone of powder on the fixed diameter base
its lack of reproducibility and because it does not always
allows determination of the drained angle of repose.
correlate with manufacturing properties or other measures
• Dynamic angle of repose. This is determined by filling
of powder flow.
a cylinder (with a clear, flat cover on one end) and ro-
tating it at a specified speed. The dynamic angle of re-
BASIC M E T H O D S FOR A N G L E OF REPOSE pose is the angle (relative to the horizontal) formed by
the flowing powder. The internal angle of kinetic fric-
A variety of angle of repose test methods are described in
tion is defined by the plane separating those particles
the literature. The most common methods for determining
sliding down the top layer of the powder and those par-
the static angle of repose can be classified on the basis of
ticles that are rotating with the drum (with roughened
the following two important experimental variables:
surface).
(1) The height of the "funnel" through which the powder
passes may be fixed relative to the base, or the height
may be varied as the pile forms. ANGLE OF REPOSE GENERAL SCALE OF FLOWABILITY
(2) The base upon which the pile forms may be of fixed
While there is some variation in the qualitative descrip-
diameter or the diameter of the powder cone may be al-
tion of powder flow using the angle of repose, much of
lowed to vary as the pile forms.
the pharmaceutical literature appears to be consistent with
the classification by Carr , which is shown in Table 1. There
are examples in the literature of formulations with an angle
* Carr, R.L. Evaluating Flow Properties of Solids. Chem.

Eng. 1965, 72, 163-168.
Pharmacopeial Forum
of repose in the range of 40° to 50° that manufactured satis- powder on a layer of powder. This can be done by using a
factorily. When the angle of repose exceeds 50°, the flow is base of fixed diameter with a protruding outer edge to retain
rarely acceptable for manufacturing purposes. a layer of powder upon which the cone is formed.
Table 1. Flow Properties and Corresponding Angles of RECOMMENDED PROCEDURE FOR ANGLE OF REPOSE
Repose*
Form the angle of repose on a fixed base with a retaining
Flow Property Angle of Repose (degrees) lip to retain a layer of powder on the base. The base should
be free of vibration. Vary the height of the funnel to care-
Excellent 25-30
fully build up a symmetrical cone of powder. Care should
Good 31-35
be taken to prevent vibration as the funnel is moved. The
Fair—aid not needed 36-40
funnel height should be maintained approximately 2-4 cm
Passable—may hang up 41-45
from the top of the powder pile as it is being formed in order
Poor—must agitate, vibrate 46-55
to minimize the impact of falling powder on the tip of the
Very poor 56-65
cone. If a symmetrical cone of powder cannot be success-
Very, very poor >66
fully or reproducibly prepared, this method is not appropri-
ate. Determine the angle of repose by measuring the height
EXPERIMENTAL CONSIDERATIONS FOR ANGLE OF
REPOSE of the cone of powder and calculating the angle of repose, a,
from the following equation:
Angle of repose is not an intrinsic property of the powder,
that is to say, it is very much dependent upon the method , , N height
used to form the cone of powder. On this subject, the exist- tan(a) = -—
0.5 base
ing literature raises these important considerations:
• The peak of the cone of powder can be distorted by the
impact of powder from above. By carefully building the
Compressibility Index and Hausner Ratio
powder cone, the distortion caused by impact can be
minimized. In recent years the compressibility index and the closely
• The nature of the base upon which the powder cone is related Hausner ratio have become the simple, fast, and pop-
formed influences the angle of repose. It is recom- ular methods of predicting powder flow characteristics. The
mended that the powder cone be formed on a "common compressibility index has been proposed as an indirect mea-
base," which can be achieved by forming the cone of sure of bulk density, size and shape, surface area, moisture
content, and cohesiveness of materials because all of these
can influence the observed compressibility index. The com-
pressibility index and the Hausner ratio are determined by
measuring both the bulk volume and tapped volume of a
powder.
Pharmacopeia! Forum
BASIC METHODS FOR COMPRESSIBILITY INDEX AND

HAUSNER RATIO Compressibility Hausner Ratio
Index (%) Flow Character
While there are some variations in the method of deter-
>38 Very, verv poor >1.60
mining the compressibility index and Hausner ratio, the ba-
sic procedure is to measure (1) the unsettled apparent
volume, Vo, and (2) the final tapped volume, Vf, of the pow- EXPERIMENTAL CONSIDERATIONS FOR THE
COMPRESSIBILITY INDEX AND HAUSNER RATIO
der after tapping the material until no further volume
changes occur in accordance with Bulk Density and Tapped Compressibility index and Hausner ratio are not intrinsic
Density (616). The compressibility index and the Hausner properties of the powder, that is to say, they are dependent
ratio are calculated as follows: upon the methodology used. The existing literature points
out several important considerations affecting these meth-
ods:
y _j7
Compressibility Index = 100 x | — — - • The diameter of the cylinder used
• The number of times the powder is tapped to achieve
Hausner Ratio = — the tapped density
v/ • The mass of material used in the test
• Rotation of the sample during tapping
In a variation of these methods, the rate of consolidation

is sometimes measured rather than, or in addition to, the
RECOMMENDED PROCEDURE FOR COMPRESSIBILITY
change in volume that occurs on tapping. For the compres- INDEX AND HAUSNER RATIO
sibility index and the Hausner ratio, the generally accepted

USP general test chapter Bulk Density and Tapped
scale of flowability is given in Table 2*.
Density (616) provides well-documented methods for de-
termination. Use a 250-mL volumetric cylinder with a test
Table 2. Scale of Flowability* sample weight of 100 g. Smaller weights and volumes may
be used, but variations in the method should be described
Compressibility Hausner Ratio
with the results. An average of three determinations is re-
Index (%) Flow Character
commended.
1-10 Excellent 1.00-1.11
11-15 Good 1.12-1.18 Flow through an Orifice
16-20 Fair 1.19-1.25 The flow rate of a material depends upon many factors,
21-25 Passable 1.26-1.34 some of which are particle-related and some related to the
26-31 Poor 1.35-1.45 process. Monitoring the rate of flow of material through
32-37 Verv poor 1.46-1.59 an orifice has been proposed as a better measure of powder
* Carr, R.L. Evaluating Flow Properties of Solids. Chem. flowability. Of particular significance is the utility of mon-
Eng. 1965, 72, 163-168.
Pharmacopeial Forum
itoring flow continuously since pulsating flow patterns have VARIATIONS IN METHODS FOR FLOW THROUGH AN
ORIFICE
been observed even for free flowing materials. Changes in
flow rate as the container empties can also be observed. Em- Either mass flow rate or volume flow rate can be deter-
pirical equations relating flow rate to the diameter of the mined. Mass flow rate is the easier of the methods, but it
opening, particle size, and particle density have been deter- biases the results in favor of high-density materials. Since
mined. However, determining the flow rate through an ori- die fill is volumetric, determining volume flow rate may
fice is useful only with free-flowing materials. be preferable. A vibrator is occasionally attached to facilitate
The flow rate through an orifice is generally measured as flow from the container, however, this appears to complicate
the mass per time flowing from any of a number of types of interpretation of results. A moving orifice device has been
containers (cylinders, funnels, hoppers). Measurement of proposed to more closely simulate rotary press conditions.
the flow rate can be in discrete increments or continuous. The minimum diameter orifice through which powder flows
can also be identified.
BASIC METHODS FOR FLOW THROUGH AN ORIFICE
GENERAL SCALE OF FLOWABILITY FOR FLOW

There are a variety of methods described in the literature. THROUGH AN ORIFICE
The most common for determining the flow rate through an
No general scale is available because flow rate is critically
orifice can be classified based on three important experi-
dependent on the method used to measure it. Comparison
mental variables:
between published results is difficult.
(1) The type of container used to contain the powder. Com-
mon containers are cylinders, funnels, and hoppers
from production equipment.
EXPERIMENTAL CONSIDERATIONS FOR FLOW
(2) The size and shape of the orifice used. The orifice dia- THROUGH AN ORIFICE
meter and shape are critical factors in determining pow-

Flow rate through an orifice is not an intrinsic property of
der flow rate.
the powder. It is very much dependent upon the methodol-
(3) The method of measuring powder flow rate. Flow rate
ogy used. The existing literature points out several impor-
can be measured continuously using an electronic bal-
tant considerations affecting these methods:
ance with some sort of recording device (strip chart re-
• The diameter and shape of the orifice
corder, computer). It can also be measured in discrete
• The type of container material (metal, glass, plastic)
samples (for example, the time it takes for 100 grams
• The diameter and height of the powder bed.
of powder to pass through the orifice to the nearest tenth
of a second or the amount of powder passing through
RECOMMENDED PROCEDURE FOR FLOW THROUGH AN
the orifice in 10 seconds to the nearest tenth of a gram). ORIFICE
Flow rate through an orifice can be used only for materials

that have some capacity to flow. It is not useful for cohesive
materials. Provided that the height of the powder bed (the
Pharmacopeial Forum
'head' of powder) is much greater than the diameter of the defined assessment of powder flow properties have been de-
orifice, the flow rate is virtually independent of the powder veloped. Shear cell methodology has been used extensively
head. Use a cylinder as the container because the cylinder in the study of pharmaceutical materials. From these meth-
material should have little effect on flow. This configuration ods, a wide variety of parameters can be obtained, including
results in flow rate being determined by the movement of the yield loci representing the shear stress-shear strain rela-
powder over powder rather than powder along the wall of tionship, the angle of internal friction, the unconfmed yield
the container. Powder flow rate often increases when the strength, the tensile strength, and a variety of derived para-
height of the powder column is less than two times the diameters such as the flow factor and other flowability indices.
meter of the column. The orifice should be circular and the Because of the ability to more precisely control experimen-
cylinder should be free of vibration. General guidelines for tal parameters, flow properties can also be determined as a
dimensions of the cylinder are as follows: function of consolidation load, time, and other environmen-
• Diameter of opening > 6 times the diameter of the par- tal conditions. The methods have been successfully used to
ticles determine critical hopper and bin parameters.
• Diameter of the cylinder > 2 times the diameter of the
opening
BASIC METHODS FOR SHEAR CELL
Use of a hopper as the container may be appropriate and
representative of flow in a production situation. It is not ad- One type of shear cell is the cylindrical shear cell which is
visable to use a funnel, particularly one with a stem, because split horizontally, forming a shear plane between the lower
flow rate will be determined by the size and length of the stationary base and the upper moveable portion of the shear
stem as well as the friction between the stem and the pow- cell ring. After powder bed consolidation in the shear cell
der. A truncated cone may be appropriate, but flow will be (using a well-defined procedure), the force necessary to
influenced by the powder-wall friction coefficient, thus, se- shear the powder bed by moving the upper ring is deter-
lection of an appropriate construction material is important. mined. Annular shear cell designs offer some advantages
For the opening in the cylinder, use a flat-faced bottom over the cylindrical shear cell design, including the need
plate with the option to vary orifice diameter to provide for less material. A disadvantage, however, is that because
maximum flexibility and better ensure a powder-over-pow- of its design, the powder bed is not sheared as uniformly
der flow pattern. Rate measurement can be either discrete or because material on the outside of the annulus is sheared
continuous. Continuous measurement using an electronic more than material in the inner region. A third type of shear
balance can more effectively detect momentary flow rate cell (plate-type) consists of a thin sandwich of powder be-
variations. tween a lower stationary rough surface and an upper rough
surface that is moveable.
Shear Cell Methods
All of the shear cell methods have their advantages and
In an effort to put powder flow studies and hopper design disadvantages, but a detailed review is beyond the scope
on a more fundamental basis, a variety of powder shear tes- of this chapter. As with the other methods for characterizing
ters and methods that permit more thorough and precisely powder flow, many variations are described in the literature.
Pharmacopeial Forum
A significant advantage of shear cell methodology in gener- Conclusions

al is a greater degree of experimental control. The methodol-
No single, simple measurement of powder flow can di-
ogy generally is rather time-consuming and requires
rectly or indirectly assess all of the parameters that affect
significant amounts of material and a well-trained operator.
flow. Generally speaking, shear cell methods offer the most
control and provide the most information. However, the
RECOMMENDATIONS FOR S H E A R C E L L widespread use of angle of repose, compressibility index,

and flow rate through an orifice indicates that each has a
The many existing shear cell configurations and test
place in the characterization of powder flow. Because of
methods provide a wealth of data and can be used very ef-
the multivariable nature of powder flow, rapid characteriza-
fectively to characterize powder flow. They are also helpful
tion of powder flow during development when time and ma-
in the design of equipment such as hoppers and bins. Be-
terial are limited is challenging but important, and these
cause of the diversity of available equipment and experi-
commonly used methods appear to be of value in this con-
mental procedures, no specific recommendations regarding
methodology are presented in this chapter. It is recom-
mended that the results of powder flow characterization
using shear cell methodology include a complete descrip-
tion of equipment and methodology used.
PHARMACOPEIAL PREVIEWS
This section contains potential revisions not yet targeted for official adoption. These may include drafts for new monographs
or chapters; drafts for standards that would require new or unusual technology; drafts for which more data are required; or
changes that would affect numerous monographs, thus having a broad impact on individual products. Readers should review
the drafts in this section and provide comments to the appropriate staff liaison whose name is cited in the Briefing (use the
Staff Directory to find the contact information).
Briefings Each Preview is preceded by a Briefing in the following format:
BRIEFING
the revision. Other relevant information. (For example, if a chromatographic method is being used, column
specifications and retention times for compounds of interest.) Finally, the Committee designation (see How
To Use PF), the name of the scientific staff liaison who handled this item, and USP tracking correspondence
number, as shown in the example below:
Symbols No symbols are used in this section, as Previews are not yet targeted for official adoption.
Pharmacopeial Forum
626 PHARMACOPEIAL PREVIEWS Vol. 28(2) [Mar.-Apr. 2002]

MONOGRAPHS (US?) 627
Bismuth Subsalicylate Oral Suspension [new] 627
MONOGRAPHS (NF) 628
Ammonio Methacrylate Copolymer Dispersion [new] 628
Coriander Oil [new] 629
Corn Syrup Solids [new] 630
Lemon Tincture [new] 631
Lutein [new] 632
Lutein Preparation [new] 634
Compound Orange Spirit [new] 637
Tolu Balsam Syrup [new] 637
Tolu Balsam Tincture [new] 638
(661) Containers 639
(1075) Good Compounding Practices [new] 640
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] PHARMACOPEIAL PREVIEWS 627
Assay—
MONOGRAPHS (USP)
Standard preparation—Transfer about 500 mg of bismuth
metal, accurately weighed, into a 200-mL volumetric flask,
dissolve in 12 mL of nitric acid, and dilute with 0.01 N nitric
BRIEFING acid to volume. Transfer 10.0 mL of this solution into a 500-

mL volumetric flask, and dilute with 1 N nitric acid to
Bismuth Subsalicylate Oral Suspension. Because there is no
existing USP monograph for this dosage form, a new monograph, volume to obtain solution having a concentration of 50 ug
based on NDA-approved methods of analysis, is being previewed.
The analytical method is based upon UV/VIS Spectrophotometric of bismuth per mL.
measurements at a wavelength of 463 nm.
(PA2: J. Kelly) RTS—31672-1; 32910-2
quantity of about 10 g of Oral Suspension, previously
well-shaken in its original container to ensure homo-
Add the following:
geneity, to a 200-mL volumetric flask. Add about 100 mL
Bismuth Subsalicylate Oral Suspension of 1 N nitric acid, mix, and dilute with 1 N nitric acid to
volume. Mix well without shaking, and transfer 10.0 mL
» Bismuth Subsalicylate Oral Suspension is a sus- of this mixture into a 100-mL volumetric flask, and dilute
pension that contains not less than 90.0 percent with 1 N nitric acid to volume. Centrifuge about 20 mL at
and not more than 110.0 percent of the labeled 4500 rpm for at least 10 minutes.
Procedure—Transfer an accurately measured volume of
amount of CyHsBiO^ It may contain one or more
the Assay preparation that contains about 0.9 mg of
suitable buffers, coloring agents, flavors, preser-
bismuth subsalicylate and 10 mL of the Standard
vatives, stabilizers, sweeteners and suspending
preparation to separate 50-mL volumetric flasks. Add
agents. 10.0 mL of 10% ascorbic acid solution and 25.0 mL of
Packaging and storage—Preserve in tight containers and 20% potassium iodide solution into each volumetric flask,
avoid freezing. dilute with water to volume, and mix well. Concomitantly
Identification— determine the absorbances of both solutions in 1.0-cm
A: It responds to the tests for Bismuth (191). cells at a wavelength of 463-nm with a suitable
B: It meets the requirements of the tests for Salicylate spectrophotometer using the reagent blank to set the
spectrophotometer. Calculate the quantity, in mg, of
(191), after acidifying with nitric acid.
C7H5B1O4 in the portion of Oral Suspension taken by the
formula:
Microbial limits (61)—The total aerobic microbial count
does not exceed 100 per g, the combined yeast and mold (362.1 l/208.98)20(C/P%V^),
count does not exceed 50 cfu per g, and it meets the in which 362.11 and 208.98 are the molecular weights of
requirements of the tests for absence of Escherichia coli bismuth subsalicylate and bismuth, respectively, C is the
and of Salmonella species. concentration, in (ig per mL, of bismuth in the Standard pre-
Pharmacopeial Forum
628 PHARMACOPEIA!. PREVIEWS Vol. 28(2) [Mar.-Apr. 2002]
paration, Fis the volume, in mL, of the Assay preparation

Ammoniomethacrylate units
taken, and Av and As are the absorbances of the Assay pre- dried basis (%)
paration and the Standard preparation, respectively. Type Min Max
A 10.18 13.73
B 6.11 8.26
MONOGRAPHS (NF)
temperature not exceeding 25° for Type A, and not
exceeding 30° for Type B. Protect from freezing.
Labeling—Label it to state whether it is Type A or Type B.
USP Reference standards (11)—USP Ammonio Metha-
crylate Copolymer Type A RS. USP Ammonio Methacrylate
BRIEFING
Copolymer Type B RS.
Ammonio Methacrylate Copolymer Dispersion. Because
there is no existing iVF monograph for this excipient, a new mono- Identification—
graph is being previewed.
A: Infrared Absorption (197K). Proceed as directed,
except to use the residue obtained in the Loss on drying
test as the test specimen.
Add the following:
B: It meets the requirements for Viscosity and Assay
Ammonio Methacrylate Copolymer tests.
Dispersion Viscosity (911)—Use a viscosimeter equipped with a
spindle having a cylinder 1.88 cm in diameter and 6.51
» Ammonio Methacrylate Copolymer Dispersion cm high, attached to a shaft 0.32 cm in diameter. The
is an aqueous dispersion of Ammonio Methacry- distance from the top of the cylinder to the lower tip of
late Copolymer Type A or B in water. It may con- the shaft is 0.75 cm, and the immersion depth is 8.15 cm.
tain surface-active agents. The assay requirements Adjust the temperature to 20° + 0.10. With the spindle
rotating at 30 rpm, immediately record the scale reading.
differ for the two types, as set forth in the accom-
Multiply the scale reading by the constant for the
panying table.
viscosimeter spindle and speed employed to obtain the
viscosity in centipoises. The viscosity is not more than
100 centipoises.

between 68.5% and 71.5% of its weight.
Pharmacopeia! Forum
Residue on ignition (281)—Using mild heating conditions Methacrylate Copolymer Dispersion Type A dissolves
(e.g., steam bath, sand bath, etc.) to avoid loss of material, completely, and Ammonio Methacrylate Copolymer
evaporate the dispersion to dryness prior to ignition: not Dispersion Type B dissolves only partially.
more than 0.5% residue is obtained, calculated on the
undried dispersion basis.
Limit of monomers—Proceed as directed in the test for
Limit of monomers under Ammonio Methacrylate
Copolymer: not more than 0.002% of methyl methacrylate
BRIEFING
and not more than 0.008% of ethyl acrylate are found.
Coagulum content—Accurately weigh a stainless steel Coriander Oil. Because there is no existing NF monograph for
this compounding vehicle, a new monograph is being previewed.
sieve having 125-um openings, and filter 100 g of This monograph, which previously appeared in NF, was omitted
after 1990. It is proposed that this monograph be reinstated to pro-
Dispersion through it. Wash the sieve with distilled water vide standards for pharmaceutical vehicles and flavors that are
used, as provided for in Pharmaceutical Compounding—Non Ster-
until a clear filtrate is obtained, and dry the sieve to ile Preparations (795). Changes have been made to the mono-
graph to adapt to standardized nomenclature and labeling
constant weight at 105°: the weight of the residue does requirements, and to conform to updated nomenclature and abbre-
viations appearing in the 2000 edition of Herbs of Commerce. Re-
not exceed 1000 mg (1%). viewers are encouraged to submit comments.
Assay—Dry under vacuum 2 g of Ammonio Methacrylate (CRX: C. Okeke) RTS—35456-01
Copolymer Dispersion Type A, or 4 g of Ammonio

Methacrylate Copolymer Dispersion Type B at 90° for 30 Add the following:
minutes. Dissolve in 75 mL of glacial acetic acid. After Coriander Oil

the solution has cooled down, add 25 mL of 0.6% cupric
acetate solution and titrate with 0.1 N perchloric acid VS,
» Coriander Oil is the volatile oil obtained by
determining the end point potentiometrically. Perform a
steam distillation from the dried ripe fruit of Cor-
blank titration and make any necessary correction. Each
iandrum sativum L. (Fam. Apiaceae).
mL of 0.1 N perchloric acid is equivalent to 20.772 mg of
ammonio methacrylate (C9H18C1NO2) units. Packaging and storage—Preserve in tight, light-resistant
containers, protect from light and store at controlled room
Description and solubility:
temperature. Avoid exposure to excessive heat.
Add the following: Labeling—The label states the Latin binomial name and,
Ammonio Methacrylate Copolymer Dispersion: Milky following the official name, the part of the plant source
white liquids of low viscosity with a faint characteristic from which the article was derived.
odor. Miscible with water in any proportion; the milky Solubility in 70 percent alcohol—One volume dissolves in
white appearance being retained. A clear or slightly 3 volumes of 70% alcohol.
cloudy solution is obtained on mixing one part with five Specific gravity (841): between 0.863 and 0.875.
parts of acetone, alcohol, or isopropyl alcohol. When
mixed with methanol in a ratio of 1:5, Ammonio
Pharmacopeial Forum
Angular rotation (781 A): between +8° and +15°. Identification—Add a few drops of a solution (1 in 20) to 5
mL of hot, alkaline cupric tartrate TS: a copious, red
Refractive index (831): between 1.462 and 1.472 at 20°.
precipitate of cuprous oxide is formed (distinction from
Heavy metals, MethodII (231): 0.004%.
sucrose).
does not exceed 1000 per g, and the total combined molds
and yeast count does not exceed 100 per g.
BRIEFING Heavy metals, Method II (231): 5 ug per g, an ignition
Corn Syrup Solids. Because there is no existing NF mono- temperature of 500° being used.
graph for this excipient, a new monograph, based in part on the
corresponding Food Chemicals Codex monograph for 'Glucose Starch—Dissolve 1 g in 10 mL of water, and add 1 drop of
Syrup, Dried' is being previewed. The test for Total solids is mea-
sured using the Karl Fisher titrimetric method rather than by the iodine TS: a yellow color indicates the absence of soluble
refractive index method used in the Corn Syrup monograph.
starch.
Total solids—To determine the water content, proceed as
directed for Water, Method la (921), except to use an
Add the following:
accurately weighed amount of Corn Syrup Solids (Wv) for
Corn Syrup Solids the Test Preparation; under Standardization of the Reagent*
to proceed as directed, except to use the formula for
» Corn Syrup Solids (Dried Glucose Syrup) is a significant amounts of water (1% or more); and under the
dried mixture of saccharides obtained by partial Procedure to calculate the water content in the Test
hydrolysis of edible corn starch by food grade Preparation as Ww — SF. Calculate the percentage of total
solids in the portion of Test Preparation taken by the
acids and/or enzymes. It contains not less than
formula:
20.0 percent reducing sugar content (dextrose
equivalent) expressed as D-glucose, calculated
on the dried basis. in which Wu is the weight, in mg, of the Corn Syrup Solids
obtained for the Test Preparation, and Ww is the weight, in
Packaging and storage—Preserve in tightly closed con-
mg, of water determined: The total solids is not less than
tainers, and store in a dry place.
90.0%, when the reducing sugar content is 88.0% or greater;
Labeling—Label it to indicate its nominal dextrose
and not less than 93.0%, when the reducing sugar content is
equivalent. Label it also to indicate the presence of sulfur
between 20.0% and 88.0%.
dioxide if the residual concentration is greater than 10 mg
per kg. * Pure methanol can make the detector overly sensitive, par-
ticularly at low ppm levels of water, causing it to deflect to
USP Reference standards {11 )—USP Dextrose RS. dryness and slowly recover with each addition of reagent.
This slows down the titration and may allow the system to
actually pick up ambient moisture during the resulting long
titration. Adding chloroform or a similar nonconducting sol-
vent will retard this sensitivity and can improve the analysis.
Pharmacopeial Forum
Limit of sulfur dioxide—Transfer about 78 g of Corn Assay for reducing sugars (dextrose equivalent)—
Syrup Solids, accurately weighed, to a 250-mL conical Apparatus and Standard preparation—Proceed as
flask, dilute with 122 mL of water, and mix to dissolve. directed for Assay for reducing sugars (dextrose
Proceed as directed for Limit of sulfur dioxide under Corn equivalent) under Corn Syrup.
Syrup, beginning with "Cool to between 5° and 10°." Assay preparation—Transfer about 4 g of Corn Syrup
Each mL of 0.005 N iodine is equivalent to 0.16 mg of Solids, accurately weighed, to a 500-mL volumetric flask,
SO2: not more than 40 jag per g is found. dilute with water to volume, and mix.
Limit of lead—[NOTE—For the preparation of all aqueous Procedure—Proceed as directed for Assay for reducing
solutions and for the rinsing of glassware before use, sugars (dextrose equivalent) under Corn Syrup beginning
employ water that has been passed through a strong-acid, with "Transfer 25-mL portions of alkaline cupric tartrate
strong-base, mixed-bed ion-exchange resin before use. For TS..." Calculate the percentage of reducing sugars as D-
digestion, use acid-cleaned, high-density polyethylene, glucose, calculated on the dried basis, in the portion of
polypropylene, polytef or quartz tubes. Select all reagents Corn Syrup Solids taken by the formula:
to have as low a content of lead as practicable, and store
all reagent solutions in borosilicate glass containers.
Cleanse glassware before use by soaking in warm 8 N in which A is the percentage of dry solids in the Corn Syrup
nitric acid for 30 minutes and rinsing with deionized Solids as determined in the test for Total solids; Cs is the
water. Store final diluted solutions in acid-cleaned plastic concentration, in mg per mL, of USP Dextrose RS in the
or polytef tubes or bottles.] Standard preparation; Cv is the concentration, in mg per

mL, of Corn Syrup Solids taken to prepare the Assay pre-
Modifier solution, Standard solutions, Standard blank,
paration; and Vs and Vv are the titrated volumes, in mL,
and Test blank—Proceed as directed for Limit of lead
of the Standard preparation and the Assay preparation, re-
under Corn Syrup.
spectively.
Test solution—[NOTE—Perform this procedure in a fume
hood.] Transfer about 1.2 g of Corn Syrup Solids, accurately Description and Solubility
weighed, and proceed as directed for Limit of lead under
Add the following:
Corn Syrup beginning with "Warm both solutions..."
Procedure—Proceed as directed for Limit of lead under Corn Syrup Solids: It is a sweet, white to light yellow pow-
Corn Syrup. Calculate the concentration, in fig per g, of der or granules soluble in water. NF category: [To come.]
lead in the portion of Corn Syrup Solids taken by the

formula:
0.0l(C/W),
in which C is the concentration, in ng per mL, of lead in the

Test solution, as determined from the calibration curve; and BRIEFING
Wis the weight, in g, of Com Syrup Solids taken to prepare Lemon Tincture. Because there is no existing NF monograph
for this compounding article, a new monograph is being pre-
the Test solution: the limit is 0.5 ug per g. viewed. This monograph provides standards for a pharmaceutical
Pharmacopeial Forum
vehicle and flavor as provided for in Pharmaceutical Compound- Labeling—The label states the Latin binomial name and,
ing—Nonsterile Preparations (795). Changes have been made to
the monograph to adapt to standardized nomenclature and labeling following the official name, the part of the plant source
requirements, and to conform to updated nomenclature and abbre-
viations appearing in the 2000 edition of Herbs of Commerce. Re- from which the article was derived.
viewers are encouraged to submit comments.
Heavy metals, Method II (231): not more than 0.004%.
Alcohol content, Method I (611): between 62% and 72% of
the labeled amount of C2H5OH is found.

Add the following:
Lemon Tincture
» Lemon Tincture is prepared from lemon peel,

which is the outer yellow rind of the fresh, ripe
BRIEFING
fruit of Citrus x Limon Osbeck (Fam. Rutaceae).
Lutein; Lutein Preparation. Because there are no existing NF
monographs for these articles that are used in the manufacture of
dietary supplements, new monographs are being previewed for
Lemon peel 500 g adoption as public standards. The commercial article that is cov-
90QmL ered by this monograph, contains predominantly the carotenoids,
Alcohol lutein, and zeaxanthin, but also may contain a minor amount of
waxes. The rubric limits are proposed to take into account an ac-
Alcohol, sufficient quantity to ceptable level of waxes. A method for the determination of waxes
is not yet available such that interested parties are encouraged to
make 1000 mL submit comments and possible methods of analysis. The UV test
for Content of total carotenoids is not specific to distinguish be-
tween lutein and zeaxanthin such that a separate HPLC procedure
Prepare peel as directed for Process M, in Tinc- is used to determine the amounts of lutein and zeaxanthin. The li-
quid chromatographic procedures in the tests for Content of lutein
tures under Pharmaceutical Dosage Forms and Zeaxanthin and other related compounds are based on ana-
lyses performed with the Hypersil brand of L3 column, 3-um par-
ticle size. The typical retention times for lutein and zeaxanthin are
(1151). Macerate 500 g of the lemon peel in 11.9 and 12.5 minutes, respectively.
900 mL of alcohol in a closed container, and store
(DSN: J. Esker; NL: C. Barnstein) RTS—36020-1; 36021-1
in a warm place. Agitate the container frequently
for 3 days or until the soluble matter is dissolved. Add the following:
Transfer the mixture to a filter, using talc as the
Lutein
filtering medium, and when most of the liquid
has drained away, wash the residue on the filter
with a sufficient amount of alcohol, and combine C
40H56°2 568.87
/?-e-carotene-3,3'-diol (3R, 3'R, 6'R) [127-40-2].
the filtrates so that the preparation is brought to a
final volume of 1000 mL.
» Lutein is the purified fraction obtained from sa-
Packaging and storage—Preserve Lemon Tincture in
ponification of the oleoresin of Tagetes erecta L. It
tight, light-resistant containers, and avoid exposure to
direct sunlight and to excessive heat. Store at controlled
contains not less than 80.0 percent of total carote-
room temperature. noids calculated as lutein (C40H56O2). It contains
Pharmacopeial Forum
not more than 8.0 percent of zeaxanthin, both cal- peaks: not less than 75.0 % of lutein is found; and not more
culated as lutein (C40H56O2), on the anhydrous ba- than 8.0 % of zeaxanthin is found. Calculate the percentage
of other related compounds in the portion of Lutein taken by
sis.
the formula:
lOOfo/r,),
containers, in a cold place.
USP Reference standards (11)—USP Lutein RS. in which, r, is the individual peak response of any other peak
Identification— in the chromatogram (excluding zeaxanthin and lutein), and
A: Ultraviolet-Visible Absorption (197U)— rs is the sum of the responses of all the peaks: not more than
Spectral range: 300 to 700 nm. 0.1 percent of any single other impurity is found.
Solution: Prepare as directed below for the Test solution in Organic volatile impurities, Method IV (467): meets the
the test for Content of total carotenoids. requirements.
Ratio: A446/A414, between 1.09 and 1.11. Solvent: dimethylformamide or dimethylsulfoxide.
B: The retention time for the major peak in the Content of lutein
chromatogram of the Test solution corresponds to that in Solvent: a mixture of hexanes, acetone, toluene,
the chromatogram of the Standard solution, as obtained in dehydrated alcohol, (10:7:7:6).
the test for Content of lutein. Mobile phase—;Prepare a filtered and degassed mixture of
hexane and ethyl acetate (75:25). Make adjustments if
Water, Method I (921): not more than 1.0 %.
Residue on ignition (281): not more than 1.0 %.
(621)).
Lead (251): not more than 1 jj.g per g.
Standard solution—Dissolve a suitable quantity of USP
Heavy metals, Method II (231): not more than 5 [ig per g.
Lutein RS in Mobile phase to obtain a solution containing
Zeaxanthin and other related compounds—
Solvent, Mobile phase, Standard solution, Test solution,
Test solution—Transfer about 1 mL of Test stock
and Chromatographic system—Proceed as directed under
preparation from the test for Content of total carotenoids,
Content of lutein.
and evaporate to dryness with a stream of nitrogen. Add 1
mL of Mobile phase, and sonicate to dissolve.
matogram, and measure the peak responses. Calculate the
percentage of zeaxanthin in the portion of lutein taken by
the formula:
um packing L3. The flow rate is about 1.5 mL per minute.
in which Tc is the content, in percentage, of total carotenoids responses as directed for Procedure: the relative retention
as determined below; rt is the individual peak response of times are about 1.05 for zeaxanthin, and 1.0 for lutein; the
zeaxanthin; and rs is the sum of the responses of all the resolution, R, between lutein and zeaxanthin is not less than
Pharmacopeial Forum
1.0; the tailing factor is not more than 2; and the relative (11) USP Reference Standards
Add the following:
2.0%.
USP Lutein RS—Do not dry. Keep tightly closed, and
store under nitrogen in a cool place. Protect from light.
Description and Solubility
percentage of lutein taken by the formula: Add the following:
Tc(rt/rX Lutein: Red crystalline powder, soluble in ethanol, ethyl

acetate, and methylene chloride. Partially soluble in hexane.
in which Tc is the content, in percentage, of total carotenoids
as determined below; rt is the individual peak response of
lutein; and rs is the sum of the responses of all the peaks:
BRIEFING
not less than 75.0 % of lutein is found.
Content of total carotenoids— Lutein Preparation—See briefing under Lutein. A monograph
for Lutein Preparation is being previewed for commercial materials
Solvent: a mixture of hexanes, acetone, toluene, and containing lutein that is combined with one or more inert sub-
stances to increase the stability of the lutein and to facilitate the
dehydrated alcohol (10:7:7:6). manufacture of dietary supplements containing lutein. To deter-
mine the Content of total carotenoids in Lutein Preparation, differ-
Test stock solution—Transfer about 15 mg of lutein to a ent test preparations are required and are dependent on the type of
Preparation. For products as a gelatin matrix or beadlet, an enzy-
matic hydrolysis is needed to release the carotenoids from a gelatin
100-mL volumetric flask, and dissolve in and dilute with matrix. Other procedures are needed for other, non-gelatin, solid
lutein preparations or lutein suspensions in oil. The UV test for
Solvent to volume. Content of total carotenoids is not specific to distinguish between
lutein and zeaxanthin such that a separate HPLC procedure is used
Test solution—Quantitatively dilute the Test stock solution to determine the ratio of lutein and zeaxanthin.
(1 in 100) with dehydrated alcohol to obtain a solution with
(DSN: J. Esker; NL: C. Barnstein) RTS—36020-2; 36021-2
a final concentration of about 1.5 jig per mL.
Procedure—Determine the absorbance of the Test
Add the following:
solution at the wavelength of maximum absorbance at
about 446 nm, with a suitable spectrophotometer, using
Lutein Preparation
dehydrated alcohol as a blank. Calculate the percentage of
total carotenoids as lutein (C40H56O2) by the formula: » Lutein Preparation is a combination of lutein
1000,4/ 2 5 5 ^
with one or more inert substances. It may be in
a solid or a liquid form. It contains not less than
in which A is the absorbance of the Test solution; Wis the
weight, in g, of Lutein taken to prepare the Test stock solu-
tion; and 255 is the absorptivity of the pure lutein.
the labeled amount of total carotenoids, calculated
as lutein (C40H56O2) on the anhydrous basis. The
lutein content of total carotenoids is not less than
93.5 percent and the zeaxanthin content is not
more than 10.0 percent.
Pharmacopeial Forum
Packaging and storage—Preserve in tight, light-resistant in which rt is the individual peak response of zeaxanthin,
containers, in a cold place. and rs is the sum of the responses of all the peaks. Calculate
Labeling—The label states that this article is not intended the percentage of other related compounds relative to total
for direct administration to humans or animals. carotenoids in the Preparation taken by the formula:
USP Reference standards (11 )—USP Lutein RS. 100(r,/r,),

Identification—
in which r, is the individual peak response of any other peak
A: Ultraviolet-Visible Absorption (197U)—
in the chromatogram (excluding zeaxanthin and lutein), and
Spectral range: 300 to 700 nm
rs is the sum of the responses of all the peaks: not more than
Solution: Prepare as directed below for the Test solution in
0.1 percent of any other impurity is found.
the test for Content of total carotenoids.
Content of lutein—
Ratio: A 446 /A 474 , between 1.09 and 1.11.
Solvent: a mixture of hexanes, acetone, toluene, and
dehydrated alcohol (10:7:7:6).
the chromatogram of the Standard solution, as obtained in hexane and ethyl acetate (75:25). Make adjustments if
the test for Content of lutein. necessary (see System Suitability under Chromatography
Water, Method I (921): not more than 1.0 %. (621)).
Residue on ignition (281): not more than 1.0 %. Standard solution—Dissolve a suitable quantity of USP
Lead (251): not more than 1 jj.g per g. Lutein RS in Mobile phase to obtain a solution containing
Heavy metals, Method II (231): not more than 5 jag per g. about 150 ug per mL.
Organic volatile impurities, Method IV (467): meets the Test solution—Transfer 1.0 mL of the Test stock solution
requirements. 1, or 1.0 mL of Test stock solution 2, or 2.0 mL of the Test
Solvent: dimethylformamide or dimethylsulfoxide. stock solution 3 from the test for the Content of total
carotenoids into a suitable vial. Evaporate the solvent to
Zeaxanthin and other related compounds—
dryness under a stream of nitrogen. Add about 1.0 mL of
Solvent, Mobile phase, Standard solution, Test solution,
Mobile phase, and sonicate to dissolve.
and Chromatographic system—Proceed as directed under
Content of lutein.
um packing L3. The flow rate is about 1.5 mL per minute.
percentage of zeaxanthin relative to total carotenoids in
responses as directed for Procedure: the relative retention
the Preparation taken by the formula:
times are about 1.05 for zeaxanthin, and 1.0 for lutein; the
lOOfa/r,),
resolution, R, between lutein and zeaxanthin is not less than
Pharmacopeial Forum
1.0; the tailing factor is not more than 2; and the relative Add about 20 mL of warm water, stopper the flask, and
standard deviation for replicate injections is not more than sonicate for 30 minutes with occasional swirling. Cool to
2.0%. room temperature, and add 30.0 mL of methylene
Procedure—Inject a volume (about 10 uL) of the Test chloride. Shake the flask for 1 minute, and place in the
solution into the chromatograph, record the chro- dark for 30 minutes to allow separation of the layers.
matogram, and measure the peak responses. Calculate the Transfer about 10 mL of the red lower layer to a test tube
percentage of lutein relative to total carotenoids in the containing 2 to 3 g of anhydrous sodium sulfate. Stopper
Preparation taken by the formula: the tube, and shake gently.
Test stock solution 3 (for liquid lutein suspensions in
100(r,/r,),
oil)—Transfer an accurately weighed amount of Lutein
in which r, is the individual peak response of lutein, and rs is
Preparation equivalent to about 6 mg of lutein to a 100-
the sum of the responses of all the peaks: not less than 93.5
mL volumetric flask, and dilute with Solvent to volume.
percent of lutein is found.
Add a magnetic bar, and stir for 30 minutes.
Content of total carotenoids— Test solution—Transfer 1.0 mL of Test stock solution 1, or
Solvent: a mixture of hexanes, acetone, toluene, and 1.0 mL of Test stock solution 2, or 2 mL of Test stock
dehydrated alcohol (10:7:7:6). solution 3 into a 100-mL volumetric flask, and dilute with
Test stock solution 1 (for solid lutein preparations labeled dehydrated alcohol to volume.
as containing gelatin)—Transfer the amount of Lutein Procedure—Determine the absorbance of the Test
Preparation equivalent to about 4.5 mg of lutein to a 100- solution at the wavelength of maximum absorbance at
mL flask. Add about 20 mL of warm water, about 60 about 446 nm, with a suitable spectrophotometer, using
Units of a bacterial alkaline protease preparation, and 1 dehydrated alcohol as a blank. Calculate the percentage of
mg of bromelain. Stopper the flask, and sonicate for 30 total carotenoids as lutein (C40H56O2) by the formula:
minutes with occasional swirling. Cool to room tem-
100VDA/225W,
perature, and add 30.0 mL of methylene chloride. Shake
the flask for 1 minute, and place in the dark for 30 in which V is the volume of organic solvent, (30.0 mL for
minutes to allow separation of the layers . Transfer about Test stock solution 1, 30.0 mL for Test stock solution 2, and
10 mL of the red lower layer to a test tube containing 2 to 100.0 mL for Test stock solution 3) used in preparing the
3 g of anhydrous sodium sulfate. Stopper the tube, and Test stock solution; D is the dilution factor used in preparing
shake gently. the Test solution; A is the absorbance of the Test solution; W
Test stock solution 2 (for other solid lutein prep- is the weight, in mg, of Lutein Preparation taken to prepare
arations)—Transfer the amount of Lutein Preparation the Test stock solution; and 255 is the absorptivity of the
equivalent to about 4.5 mg of lutein to a 100-mL flask. pure lutein.
Pharmacopeial Forum
Assay—Transfer 2.0 mL of Compound Orange Spirit and

1.0 mL of kerosene to a Babcock bottle, graduated to 8%,
BRIEFING
and mix. Add sufficient saturated calcium chloride solution,
Compound Orange Spirit, Tolu Balsam Syrup, Tolu Balsam
Tincture. Because there are no existing NF monographs for these acidified with hydrochloric acid, to almost fill the bulb of the
compounding articles, new monographs are being previewed.
These monographs, which appear in this number of PF, were pre- bottle. Rotate the bottle vigorously to ensure mixing, then
viously official in a past NF, but were discontinued after 1990.
These monographs have only minimal changes, as necessary, to add a sufficient quantity of the calcium chloride solution
reflect current editorial style and general requirements. They are
intended to provide standards for pharmaceutical vehicles and fla- to bring the separated oil into the neck of the bottle.
vors that are used as provided for in the general test chapter Phar-
maceutical Compounding—Nonsterile Preparations (795). Centrifuge for 5 minutes at about 1500 rpm, and read the
Changes have been made to the monographs to adapt to standar-
dized nomenclature and labeling requirements and to conform to volume of oil in the stem. Subtract five divisions on the
updated nomenclature and abbreviations appearing in the current
2000 edition of Herbs and Commerce. Reviewers of PF are en- volumetric flask for the kerosene added, and multiply the
couraged to examine these Previews and submit comments.
remaining number of divisions by 10.5 to obtain the
volume, in mL, of mixed oils in 100 mL of the Com-
pound Orange Spirit.
Add the following:
Compound Orange Spirit
» Compound Orange Spirit contains, in each 100

mL, not less than 25 mL and not more than 30 mL
BRIEFING
of the mixed oils. See Pharmaceutical Com-
Tolu Balsam Syrup—See briefing under Compound Orange
pounding—Nonsterile Preparations (795). Spirit.

Orange Oil 200 mL
Lemon Oil 50 mL Add the following:
Coriander Oil 20 mL Tolu Balsam Syrup

5
Anise Oil "^
Alcohol, a sufficient quantity, » Prepare Tolu Balsam Syrup as follows (see
to make 1000 mL Pharmaceutical Compounding—Nonsterile Pre-
Mix the oils with sufficient Alcohol to make the parations (795)).
product measure 1000 mL.

Tolu Balsam Tincture 50 mL
Packaging and storage—Preserve in tight containers,
Magnesium Carbonate 10 g
protected from light, and store in a cold place.
82
Sucrose ° g
Purified Water, a sufficient quantity,
70.0%ofC 2 H 5 OH.
to make 1000 mL
Pharmacopeial Forum
Add the Tincture all at once to the Magnesium

BRIEFING
Carbonate and 60 g of the Sucrose in a mortar, and
mix. Gradually add 430 mL of Purified Water with Tolu Balsam Tincture—See briefing under Compound Orange
Spirit.
trituration, and filter. Dissolve the remainder of
the Sucrose in the clear filtrate with gentle heating,
strain the syrup while warm, and add sufficient Add the following:
Purified Water through the strainer to make the
Tolu Balsam Tincture
product measure 1000 mL. Mix.
NOTE—Tolu Balsam Syrup may be prepared » Tolu Balsam Tincture is prepared from Tolu Bal-
also as follows. Place 760 g of the Sucrose in a sam obtained from Myroxylon balsamum (L.)
suitable percolator, the neck of which is nearly Harms van balsamum (Fam. Fabaceae). Prepare
filled with loosely packed cotton, moistened after Tolu Balsam Tincture as follows (see Pharmaceu-
packing with a few drops of water. Pour the fil- tical Compounding—Nonsterile Preparations
trate, obtained as directed in the preceding instruc- (795)).
tions, upon the Sucrose, and regulate the outflow
2Q0
to a steady drip of percolate. When all of the liquid Tolu Balsam g
has run through, return portions of the percolate, if To make 1000 mL
necessary, to dissolve all the Sucrose. Then pass Prepare Tolu Balsam tincture as directed for
enough Purified Water through the cotton to make Process M under Tinctures (see Pharmaceutical
the product measure 1000 mL. Mix. Dosage Forms (1151)), using alcohol as the men-
Packaging and storage—Preserve in tight containers, and struum.
store at controlled room temperature.
Labeling—The label states the Latin binomial name and, containers, and store at controlled room temperature.
following the official name, the part of plant source from Avoid exposure to direct sunlight and to excessive heat.
which the article was derived. Labeling—The Label states the Latin binomial name and,
Acid value—Take 2% of solution, add phenolphthalein TS, following the official name, the part of the plant source from
and titrate with 0.5 N alcoholic potassium hydroxide VS: which the article was derived.
the acid value is between 112 and 168.
Alcohol content, MethodII (611): between 3.0% and 5.0% 83.0%ofC 2 H 5 OH.
ofC 2H5OH.
Pharmacopeial Forum
with a drug product (e.g., many topical products), migration

GENERAL CHAPTERS of ingredients may be a concern. Proceed as directed for
these closure resins in the section Biological Tests—Plastics
and Other Polymers. Also, all ingredients in pharmaceutical
General Tests and Assays
containers meet the requirements of 21 CFR175-177 for In-
direct Food Additives.
Physical Tests and Determinations Specifically, both torque retention and stress resistance
studies are carried out at room and stability temperature con-
ditions and compared to the control container-closure sys-
tem. For torque, the results are as good as—within limits—
BRIEFING the original closure system after a minimum of one week's

storage. Stress cracking studies are carried out for a mini-
(661) Containers, USP 25 page 1999 and page 2817 of PF
27(4) (July-Aug. 2001]. Based on discussions and comments re- mum of one month's duration to confirm satisfactory perfor-
ceived during a USP Packaging, Storage, and Distribution Open
Conference in August of 1999, The Expert Committee published mance.
an article in Stimuli to the Revision Process (see page 517 of P F
26(2) [Mar.-Apr. 2000] concerning the inclusion in this chapter of
methods for the interchangeability testing of closure resins and The container-closure system proposed complies with
other molded components. The Expert Committee is proposing
to add this new section, Test Methods and Acceptance Criteria previously established limits for permeation under Contain-
for Polyethylene and Polypropylene Closure Resins and Molded
Components, in the Pharmacopeial Previews in this number of ers—Permeation (671). The ability to resist stress cracking
PF. See also the proposal to include a section in this chapter for
Polypropylene Containers under In-Process Revision in this num- is established in the presence of the finished product at con-
ber of PF.
trol and stability temperatures.
(PSD: C. Okeke) RTS—36046-1 Prescription Vials—Prescription vials used by pharma-
cists to repackage and dispense drug products are also
Add the following: molded of polypropylene, usually with an added amber col-
TEST METHODS AND ACCEPTANCE orant. The pharmaceutical product may spend one year in
CRITERIA FOR POLYETHYLENE AND this vial, but standards for its chemical composition have
POLYPROPYLENE CLOSURE RESINS not been generated. Prescription vials are required to under-
AND MOLDED COMPONENTS go the same degree of scrutiny as the market container sys-
Closures—For most liquid and solid oral dosage forms, tem.
the closure is fitted with a liner and, in many cases, an inner Multiple Internal Reflectance—Proceed as directed in
seal. The function of the enclosure in these cases is to pro- the section for Apparatus and Procedure under Polypropy-
tect the integrity of the inner seal or to achieve a suitable lene Containers.
contact seal of the closure liner with the lip of the bottle. Preparation of Specimen—Proceed as directed in the sec-
In many cases, the closure does not come in contact tion for Polypropylene Containers, except that closure sec-
with the drug product, and migration of ingredients is not tions only may be compressed to a thin, uniform film by
a concern. In cases where the closure does come in contact exposing them to temperatures of about 177° underpressure
(15,000 psi or more).
Pharmacopeial Forum
Specification—Determine the IR spectrum from 3500 to Add the following:

600 cm-1. The spectrum of the specimen exhibits major ab-
(1075) GOOD COMPOUNDING
sorption bands only at the same wavelengths as the spec- PRACTICES
trum of the appropriate USP Reference Standard, similarly
determined. The purpose of this chapter is to provide compounders with
Thermal Analysis—Cut a section of the article, weigh- guidance on applying good compounding practices for the
ing about 6 to 10 mg, and place it in the test-specimen preparation of compounded formulations for dispensing
pan. Heat the specimen from room temperature to 200° at and/or administration to humans or animals. It is expected
a rate of 10° per minute, then cool it at a rate of 10° per min- that pharmacists or compounders engaged in the compound-
ute. Reheat as before, using equipment capable of performing of drugs will compound in conformance with applicable
ing the determinations described under Thermal Analysis state and federal compounding laws, regulations, or guide-
(891). The thermogram of the specimen is similar to the lines.
thermogram of the polypropylene house standard, similarly
determined, and the endotherms and exotherms in the ther- APPLICABLE DEFINITIONS
mogram of the specimen do not differ from those of USP Compounding—(See Pharmaceutical Compounding—
Polypropylene RS by more than 6.0°. Nonsterile Preparations (795).) Compounding involves
Extractables—Proceed as directed in the section Physi- the preparation, mixing, assembling, packaging, and label-
cochemical Tests—Plastics. Where the closure or compo- ing of a drug or device in accordance with a licensed prac-
nent is to come in contact with a drug product intended titioner's prescription under an initiative based on the
for use with visceral or mucosal tissues, perform the test de- practitioner/patient/pharmacist/compounder relationship in
scribed in the section Biological Tests—Plastics and Other the course of professional practice. Compounding includes
Polymers. the following:
a. Preparation of drugs or devices in anticipation of pre-
scription drug orders based on routine, regularly ob-
served prescribing patterns.
BRIEFING
b. Reconstitution of commercial products that may re-
(1075) Good Compounding Practices. This new general
chapter is intended to provide compounders with guidance on ap- quire the addition of two or more ingredients as a result
plying good compounding practice for the preparation of com-
pounded formulations for dispensing or administration to of a licensed practitioner's prescription drug order.
humans or animals. The chapter was drafted from currently avail-
able state laws on good compounding practices and was reviewed c. Manipulation of commercial products that may require
by the Expert Committee on Compounding Pharmacy, the Expert
Committee on Parenteral Products—Compounding and Prepara- the addition of one or more ingredients as a result of a
tion, and the Compounding Pharmacy Project Team.
Comments on this chapter should be addressed to Dr. Claudia licensed practitioner's prescription drug order.
Okeke.
d. Preparation of drugs or devices for the purposes of, or
as an incident to, research, teaching, or chemical analy-
sis.
Pharmacopeial Forum
Levels of Compounding—
Level 8 Other sterile injections and patches
Level 1 Nonsterile (topical) Preparation of chemotherapeutic injections
Mixing of one or two creams or implants
Mixing of creams with alcohol, water, etc Preparation of transdermal patches
(as per manufacturer's Level 9 Sterile (radiopharmaceuticals)
labeling instruction) Preparation of radiopharmaceuticals
Level 2 Nonsterile (topical)
Manufacturing—Manufacturing involves the produc-
Preparation of nonsterile topical ointment,
tion, propagation, conversion, or processing of a drug or de-
cream
vice, either directly or indirectly, by extraction of the drug
Preparations with no dosage limitation
from substances of natural origin or by means of chemical or
Level 3 Nonsterile (reconstituting or flavoring)
biological synthesis. Manufacturing also includes (1) any
Reconstitution according to manufacturer's
packaging or repackaging of the substance(s) or labeling
labeling instruction
or relabeling of containers for the promotion and marketing
Addition of flavoring
of such drugs or devices; (2) any preparation of a drag or
Level 4 Sterile (simple injections, e.g., reconsti-
device that is given or sold for resale by pharmacies, practi-
tuted for immediate administration)
tioners, or other persons; (3) the distribution of inordinate
Preparation of injections for immediate ad-
amounts of compounded preparations or the copying of
ministration
commercially available drug products; and (4) the prepara-
Level 5 Nonsterile (dosage forms)
tion of any quantity of a drug product without a licensed
Preparation of solid oral dosage forms (ta-
prescriber/patient/licensed pharmacist/compounder rela-
blets, capsules)
tionship.
Preparation of liquid oral dosage forms
Component—A component is any ingredient used in the
(emulsion, solutions, suspensions, etc)
compounding of a drag product, including any that are used
Preparation of suppositories, lozenges
in its preparation, but may not appear on the labeling of such
Level 6 Sterile (ophthalmics/otics)
a product. (See Pharmaceutical Compounding—Nonsterile
Preparation of ophthalmic and otic suspen-
Preparations (795) for additional definitions.)
sions, solutions
Pharmacy Generated Product (PGP)—A pharmacy
Level 7 Sterile (complex injections)
generated product (PGP) is a product that is prepared, pack-
Preparation of injections for many patients
aged, and labeled in a pharmacy and can be sold by the phar-
Preparation of injection not for immediate
macy without a prescription. PGPs are clearly different from
administration
drags defined in section 201 (g) of the Federal Food, Drag,
Preparation of total parenteral nutritions
and Cosmetic Act.
(TPNs)
Preparation of multi-component injection
Pharmacopeial Forum
Compounder—A compounder is a pharmacist or a phy- c. The compounder shall ensure that personnel engaged in
sician who is engaged in the act of compounding pursuant to compounding wear clean clothing appropriate to the
a precription order by a licensed prescriber. type of compounding performed, e.g., coats, gowns,
gloves, masks, shoes, aprons, or other items as needed
RESPONSIBILITIES OF THE COMPOUNDER
for protection of personnel from chemical exposures
and for prevention of drag contamination.
a. Compounders who are engaged in drug compounding
d. The compounder shall implement procedures to pre-
or nutriceutical compounding shall be proficient in
vent cross-contamination when compounding with
compounding and should continually expand their
drags (e.g., penicillins) that require special precaution
compounding knowledge by participating in seminars
to prevent cross-contamination.
and/or studying appropriate literature.
b. A compounder shall be familiar with all of the details of TRAINING
Pharmaceutical Compounding—Nonsterile Prep- All personnel involved in the compounding, evaluation,
arations (795), Pharmaceutical Compounding—Ster- packaging, and dispensing of compounded preparations
ile Preparations {797), and other applicable state or shall be properly trained for the type of com-pounding con-
federal compounding guidelines or laws. In addition, ducted. All training activities will be covered by appropriate
the compounder shall be responsible for the following: standard operating procedures (SOPs) and documentation.
• certifying all prescription orders; All compounders and all personnel involved in com-
• approving or rejecting all components, drag pro- pounding must be well trained and must participate in cur-
duct containers, closures, in-process materials, rent, relevant training programs. It is the responsibility of
and labeling; the pharmacist to ensure that a training program has been
• preparing and reviewing all compounding records implemented and that it is ongoing. Standards of pharmacy
to assure that errors have not occurred in the com- practice require that all employees be adequately trained in
pounding process; their job functions and that all of the training is properly
• assuring the proper maintenance, cleanliness, and documented. Steps in the training procedure will include
use of all equipment used in a prescription com- the following:
pounding practice; a. All employees involved in pharmaceutical compound-
• assuring that only personnel authorized by the ing shall read and become familiar with Pharmaceuti-
compounding supervisor shall be in the immediate cal Compounding—Nonsterile Preparations (795),
vicinity of the drug compounding operations; Pharmaceutical Compounding—Sterile Preparations
assuring that the drag product and components of (797), and Pharmaceutical Calculations in Prescrip-
drag products are not on the list of federally recog- tion Compounding (1160).
nized drag products that have been withdrawn or
removed from the market for public health reasons.
Pharmacopeial Forum
b. All employees shall read and become familiar with each Documentation enables a pharmacy, whenever necessary,
of the procedures related to compounding, including to systematically trace, evaluate, and replicate the steps in-
those involving the facility, equipment, personnel, ac- cluded throughout the preparation process of a compounded
tual compounding, evaluation, packaging, storage, product.
and dispensing.
DRUG COMPOUNDING FACILITIES
c. The compounder shall meet with employees to review
their work and answer any questions the employees
a. Compounding facilities shall have an adequate space
may have concerning SOPs.
that is specifically designated for compounding of pre-
d. The compounder shall demonstrate the procedures for
scriptions. This area may include a space for the storage
the employee, and will observe and guide the employee
of equipment and materials.
throughout the procedure. The employee will then re-
b. Sterile compounded preparations shall be compounded
peat the procedure without any assistance from, but un-
in accordance with the provisions in Pharmaceutical
der the supervision of, the pharmacist.
Compounding—Sterile Preparations (797), and asep-
e. When the employee has demonstrated to the compoun-
tic processes shall be conducted in an area separate and
der a verbal and functional knowledge of the procedure,
distinct from the area used for the compounding of non-
then and only then, will the employee be permitted to
sterile products.
perform the procedure without supervision.
c. The areas used for compounding shall be maintained in
f. When the compounder is satisfied with the employee's
clean, orderly, and sanitary conditions.
knowledge and proficiency, the compounder will sign
d. The areas for drug compounding shall be maintained in
off on the documentation records to show that both
a good state of repair. The plumbing system shall be
the employee and the compounder agree.
free of defects that could contribute to contamination
g. The compounder shall continually monitor the work of
of any compounded product. Adequate washing facil-
the employee and answer any questions the employee
ities shall be easily accessible to the compounding
may have concerning the SOPs.
areas. Such facilities shall include, but not be limited
PROCEDURES AND DOCUMENTATION to, hot and cold water, soap or detergent, and an air-
All significant procedures performed in the compounding drier or single-use towels.
area will be covered by SOPs and will be documented. e. Potable water shall be supplied under continuous posi-
Procedures should be developed for the facility, equip- tive pressure.
ment, personnel, preparation, packaging, and storage of f. The area for compounding shall have adequate lighting
compounded preparations to ensure accountability, accu- and ventilation.
racy, quality, safety (including access to Material Safety g. The area for compounding shall be free of infestation
Data Sheets) and uniformity in a compounding practice. by insects, rodents, and other vermin. Trash shall be
More importantly, implementing SOPs establishes proce- held and disposed of in a sanitary and timely manner.
dural consistency and also provides a reference for orienta- h. Sewage and other refuse in the area of compounding
tion and training of personnel. shall be disposed of in a safe and sanitary manner.
Pharmacopeial Forum
i. Bulk drags and other chemicals or materials used in the e. Immediately prior to initiation of compounding opera-
compounding of drags must be stored as directed by the tions, the equipment shall be inspected by the com-
manufacturer, or according to USP monograph require- pounder to determine its suitability for use.
ments, in a clean, dry area (defined temperature condi- f. The equipment shall be cleaned appropriately using
tion), or in a refrigerator or freezer as specified. The special instructions when cross-contaminating products
bulk chemicals shall be stored in a manner such that or products requiring special precaution, e.g., antibio-
they are protected from contamination. All containers tics, cytotoxins, cancer drags, and other hazardous ma-
shall be properly labeled. terials, are used with the equipment. If possible, special
j. If parenteral products are compounded, the compoun- equipment may be dedicated for such use or if the same
der shall refer to Pharmaceutical Compounding—Ster- equipment is being used for all drag products, appropri-
ile Preparations {191), and Injections (1) for ate procedures must be in place to allow meticulous
compounding technique applications. cleaning of equipment prior to use with other drags.
DRUG COMPOUNDING EQUIPMENT COMPONENT SELECTION REQUIREMENTS

(See also Pharmaceutical Compounding—Nonsterile
a. The compounder shall first attempt to use USP-NF
Compounding (795).)
drag substances manufactured in an FDA-registered fa-
a. The equipment or utensils used for compounding of a cility.
drag product shall be of appropriate design and ca- b. The compounder shall also first attempt to use inactive
pacity. The equipment shall be stored in such a manner components manufactured in an FDA-registered facil-
as to protect it from contamination, and shall be located ity.
in such a place as to facilitate operations for its use, c. If components are not obtainable from an FDA-regis-
maintenance, and cleaning. tered facility or if the FDA and/or the providing com-
b. The equipment shall be cleaned and sanitized prior to pany cannot document FDA registration, compounders
use to prevent contamination that may affect the safety shall use their professional judgment in first receiving,
or quality of compounded preparations. storing, or using the components that meet official com-
c. The equipment shall be of suitable composition such pendial requirements or are provided by another high
that the surfaces that contact components are neither re- quality source.
active, additive, nor absorptive and therefore will not d. If components of compendial quality are not obtain-
affect or alter the purity of the compounded prepara- able, components of high quality such as those that
tions. are chemically pure, analytical reagent grade, American
d. Automated, mechanical, electronic, and other types of Chemical Society-certified, or Food Chemical Codex
equipment used in compounding shall be routinely in- grade may be used.
spected, calibrated as necessary, and checked to ensure
proper performance.
Pharmacopeial Forum
e. When a component is not obtained from an official c. The containers and closures shall be stored off the floor,
compendial source or is not obtainable from the sources handled and stored to prevent contamination, and ro-
mentioned above, the component may be obtained from tated so that the oldest approved stock is used first.
a source deemed acceptable and reliable in the profes- d. The containers and container closures shall be stored in
sional judgment of the compounder. such a way as to permit inspection and cleaning of the
f. When a component is derived from ruminant animals work area.
(e.g., bovine, caprine, ovine) the supplier shall provide e. The containers and container closures shall be made of
written assurance that these animals were born, raised, clean materials that are neither reactive, additive, nor
or slaughtered in countries where bovine spongiform absorptive.
encephalopathy (BSE) and scrapie are known not to ex- f. The containers and closures shall be of suitable material
ist. so as not to alter the quality, strength, or purity of the
g. The compounder shall not use components that are compounded drug.
listed by FDA to be withdrawn from the market for g. The compounder shall ensure that the containers and
public health reasons. container closures selected to dispense the finished
h. Components shall be stored off the floor, handled and compounded prescription, whether sterile or nonsterile
stored to prevent contamination, and rotated so that the or radiopharmaceutical, meet the criteria in sections
oldest stock is used first. (a)-(f) above.
PACKAGING AND DRUG PRODUCT CONTAINERS COMPOUNDING CONTROLS
a. The compounder shall ensure that the containers and a. The compounder shall ensure that there are written pro-
container closures used in packaging the compounded cedures for the compounding of drug products to assure
preparations meet the requirements under Containers that the finished products have the identity, strength,
(661) and Containers—Permeation (671). The com- quality, and purity that they purport to have.
pounder shall obtain written records from the supplier b. The compounder shall establish procedures for listing
to show that the containers meet USP requirements. components, their amounts (weight or volume), the or-
b. Containers and container closures intended for com- der of component mixing, and a description of the com-
pounding of sterile preparations and nonsterile prepara- pounding process.
tions must be handled, sterilized (if appropriate), and c. The compounder shall list all equipment, utensils, and
stored as described in Pharmaceutical Compound- container closure systems relevant to the sterility, stabi-
ing—Sterile Preparations (797) and Pharmaceutical lity, and intended use of a drug.
Compounding—Nonsterile Preparations (795). The d. The written procedures described above shall be fol-
use of commercially available presterilized containers lowed in execution of the compounding process.
may be considered. e. The compounder shall accurately weigh, measure, and
subdivide as appropriate.
Pharmacopeial Forum
dures shall be followed. Such procedures shall include

f. The compounder shall check and recheck each proce-
validation of sterilization processes (see Pharmaceuti-
dure at each stage of the process to ensure that each
cal Compounding—Sterile Preparations (797)).
weight or measure is correct as stated in the written
m. The compounder shall establish appropriate beyond-
compounding procedures.
use dates determined either from available USP-NF
g. If a component is transferred from the original contain-
monographs, appropriate testing, or from peer-re-
er to another container (e.g., a powder is taken from the
viewed literature.
original container, weighed, placed in a container, and
n. The compounder shall adopt appropriate storage re-
stored in that other container), the new container shall
quirements as provided in Preservation, Packaging,
be identified with the component name, weight or mea-
Storage, and Labeling under General Notices and Re-
sure, the lot or control number, the expiration or be-
quirements.
yond-use date, and the transfer date.
h. The compounder shall have drug compounding proce- LABELING
dures available in either written form or electronically
1. Products prepared in anticipation of a prescription prior
stored with printable documentation.
to receiving a valid prescription should not be prepared
i. The procedures shall include a description of (1) the
in an inordinate amount. A regularly used amount
components, their amounts, the order of component ad-
should be prepared on the basis of a history of prescrip-
ditives, and the compounding process; (2) the required
tions filled by the pharmacy. These products shall be
equipment and utensils; and (3) the drug product con-
labeled or documentation referenced with the follow-
tainer and closure system.
ing:
j. The compounder shall have established written proce-
a. A complete list of ingredients or preparation name
dures that will describe the tests or examinations to be
and reference or established name or distinct com-
conducted on the product compounded (e.g., the degree
mon name
of weight variation among capsules) to assure unifor-
b. Dosage form
mity and integrity of compounded drug products.
c. Strength
k. Appropriate control procedures shall be established to
d. Preparation date
monitor the output and to validate the performance of
e. Name and address of compounder
those compounding processes that may be responsible
f. Inactive ingredients
for causing variability in the final compounded prepara-
g. Batch or lot number
tions. Factors that may cause variability include (1)
h. Assigned beyond-use date, based on published
capsule weight variation; (2) adequacy of mixing to as-
data, or appropriate testing, or USP-NF standards.
sure uniformity and homogeneity; and (3) clarity, com-
Storage conditions for these products shall be dictated
pleteness, or pH of solutions.
by their composition and sterility, e.g., stored in a clean,
1. Appropriate written procedures shall be designed to
dry place (defined temperature condition), in a refrig-
prevent microbiological contamination of compounded
erator, or at controlled room temperature.
drug products purporting to be sterile, and these proce-
Pharmacopeia! Forum
2. The compounder shall examine the product for correct c. All records of all compounded products shall be kept
labeling after completion of the compounding process. for a period of time as set forth in the state laws or reg-
3. The compounder's prescription label shall contain the ulations. Such records shall be readily available for
following: authorized inspection.
a. Patient's name
COMPOUNDING FOR A PRESCRIBER'S OFFICE
b. Prescriber's name
USE
c. Name and address of compounder
d. Prescription number a. Compounders may prepare compounded drug products
e. Established name or distinct common name (can- for a prescriber's office use pursuant to federal and state
not use trademarked name of a manufactured pro- requirements.
duct) b. An order by the prescriber indicating the formula and
f. Strength quantity ordered may be filled in the compounder's fa-
g. Statement of quantity cility.
h. Directions for use c. The compounder shall compound the product for the
i. Date filled purpose of administration by or for the prescriber.
j. Beyond-use date/storage, etc. d. A record of the compounding process shall be main-
k. An appropriate designation that this is a com- tained.
pounded prescription e. A label may be generated and a number may be as-
1. Any other federal or state requirements signed.
NOTE—The compounder shall not use an NDC number COMPOUNDING VETERINARIAN PRODUCTS
assigned to another product.
a. Compounders shall compound prescriptions for ani-
4. The compounder shall label any excess compounded
mals on the basis of prescription orders.
products so as to reference them to the formula used,
b. These prescriptions shall be handled and filled as are
the assigned control number, and beyond-use date
human prescriptions.
based on the compounder's appropriate testing, pub-
lished data, or USP-NF standards. COMPOUNDING PHARMACY GENERATED
PRODUCTS
RECORDS AND REPORTS
a. Compounders may prepare compounded drug products
a. The compounder shall maintain records, including but
that can be sold without a prescription.
not limited to, the hard copy of the prescription to indi-
b. Pharmacy generated products (PGP) shall be com-
cate that the prescription is compounded.
pounded using the same procedures as those for pre-
b. The compounder shall keep adequate records of con-
scription drug products detailed in this chapter.
trolled drug substances (scheduled drugs) used in com-
pounding.
© 2002 The United States Pharrnacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
c. Additional labeling sufficient for patient use will be re- ferent from drags defined in section 201 (g) of the Federal
quired to meet the individual State Board of Pharmacy Food, Drag, and Cosmetic Act.]
and federal requirements. [NOTE—PGPs are clearly dif-
STIMULI TO THE
REVISION PROCESS
This section may contain the following:
• reports or statements of authoritative committees
• original research reports
• evaluations of new and existing pharmacopeial methods
• commentaries
• articles relevant to compendial issues
These items are published to stimulate discussion and continual review of pharmacopeial standards. Generally, if a Subcom-
mittee publishes an article on which they are specifically seeking comment, this will be clearly stated in the article. Readers
may submit comments on issues raised in this section, but comment is not as critical as that for In-Process Revision and
Pharmacopeial Previews sections. Readers interested in submitting should see Instructions to Authors.
650 of the USPC or the USP Council of Experts Vol. 28(2) [Mar.-Apr. 2002]

Defining Column Equivalence 652
Polypropylene Containers: Status and Comments Received 656
Review of Pharmaceutical Calculations in Prescription Compounding (1160) 661
V o l . 28(2) [ M a r . - A p r . 2002] of the USPC or the USP Council of Experts 651
Instructions to Authors
Contributions in the form of original research reports, evaluations of new and existing cornpendial methods, and other
commentaries and articles relevant to drug standards or to USP-NF revision will be considered for publication in the Phar-
macopeial Forum under the section Stimuli to the Revision Process. Manuscripts are received with the explicit understanding
that they have not been published previously and that they are not simultaneously under consideration by any other publica-
tion.
All manuscripts are subject to review by USP headquarters staff, Committee members, or qualified outside referees, and if
accepted for publication will be subject to editing by USP staff. Accepted manuscripts become the property of the USP
Convention, Inc., (USPC) and may not be published else where without written permission from the USPC. Authors are
also responsible for obtaining permission for reprinting any illustrations that have been published elsewhere.
Abstract—Include an abstract of not more than 250 words stating the purpose and the results or conclusions of the article.
References—Consult a current copy of the Pharmacopeial Forum and the ACS Style Guide for assistance with reference
style.
Copyright—Copyright transfer documents will be sent to authors after manuscripts have been accepted for publication.
Contact Person—When submitting a manuscript, designate one author of the article as correspondent and include that
author's full address, telephone number, FAX number, and e-mail address.
Submission Instructions—Manuscripts must be submitted both as an electronic file and as a printed copy of the electronic
file. Submit the text in Microsoft® Word or another current word-processing application. The preferred format for graphics
submitted electronically is tagged image file format (TIFF). Graphics that cannot be submitted electronically must be camera-
ready, of easily reproducible quality and size, and clearly labeled. Photocopies are not acceptable. Manuscripts submitted for
publication should be addressed to:
Pharmacopeial Forum
Executive Secretariat, USP
12601 Twinbrook Pkwy.
Rockville, MD 20852
Defining Column Equivalence

Preston Poulter,* Column Engineering Inc.
ABSTRACT With each new chromatographic method that specifies the use of a given column "or equivalent," it becomes
increasingly important to establish an industrial standard for exactly what an equivalent column is. This article addresses the
issue of defining column equivalence for liquid chromatography. Recent approaches are discussed, and recommendations are
made to provide a quantitative yet flexible method to determine equivalency.
INTRODUCTION Further problems are presented by columns that offer un-

ique chemistries, such as YMC Basic®, Phenomenex Sy-
Most LC methods validated today specify the use of a gi- nergi Max-RP®, and Zorbax Bonus-RP®, to name a few.
ven column "or equivalent." In addition, ICH Guidance re- Specifying what an equivalent to a totally unique chemistry
commends that liquid chromatographers test more than one would be is difficult and would presumably have to be done
"column type" to ensure robustness (7). However, there re- based on performance rather than on column chemistry.
mains a great deal of confusion among liquid chromatogra-
Contemporary methods for how a chromatographer
phers and even regulatory agencies about what the
would demonstrate a given column's equivalence to the
definition of an equivalent is.
brand that was used in the initial validation study vary
In the article, HPLC Packings Used in the USP-NF, Dr. widely from chromatographer to chromatographer and from
Margareth Marques gives an extensive list of chromatogra- company to company. Common practices used to demon-
phy media, which represent given L designations (i.e., LI, strate equivalence could be organized along the following
L7, etc.), with the caveat that "all columns that meet the continuum:
same specifications are not necessarily alike." That caveat,
• Using the column manufacturer's data and recommen-
and the fact that such an article had to be published in the
dations as indicative that a given column is equivalent.
first place, suggest that there is some confusion among chro-
• Performing the method's system suitability test. Any
matographers about exactly what brand names constitute a
column that passed system suitability would be deemed
given L designation and whether two columns that share the
appropriate for the method.
same L designation should be considered equivalent for a
• Reconducting the specificity part of a validation.
given method (2). The issue only becomes murkier in a fol-
• Conducting a battery of tests similar to completely re-
low-up article where Dr. Marques states (3):
validating the method—which attempts to answer the
"The USP description of LI packing 'octadecyl silane equivalency question by simply not asking it.
chemically bonded to porous silica or ceramic micro-parti- All of these practices are in use from lab to lab. In some
culates, 3 to 10 um in diameter' is not very specific. At the cases, different departments of the same company will have
time of publication for this article there were approximately dramatically different definitions of column equivalence. In
220 different brand names that could match this description. the absence of an industry standard method for determining
It is well known that not all of them are interchangeable or column equivalence, none of these options can be said to be
equivalent." the preferred method. Adding to the complexity of the situa-
Dr. Marques recommended that chromatographers use tion is that the above methods vary widely in terms of the
the selectivity charts published by various manufacturers time investments they require to complete them.
and scientists in determining what columns are equivalent. Many labs seem to have erred on the side of caution and
That all Cl 8 columns do not perform similarly under sim- have adopted a policy of never altering the brand of chroma-
ilar conditions is not new to chromatographers (4). The rea- tographic media once a method becomes validated. Whether
son for this is that columns that share the same L designation these companies are technically running a regulatory risk by
can have large differences in the not testing other "column types" as recommended by ICH
• surface area of the base silica, Guidance is debatable, but this practice clearly does go
• bonding density of the ligand, against the spirit of the robustness recommendation (/). If
• modification to the ligand (such as incorporation of a company's policy is that equivalency can only be demon-
"embedded polar groups", etc.), and strated by doing parallel validation, then that company
• extent of end-capping and reagents used. would have to do twice as much work to demonstrate
equivalence as a company that defined column equivalence
• Correspondence should be addressed to Preston Poulter, Column Engi-
neering, Inc., 1930 S. Bon View Ave., Suite 20, Ontario, CA 91761; e-mail to be demonstrated by acceptable system suitability tests.
ppoulter@mediaone.net.
Vol. 28(2) [Mar.-Apr. 2002] of the USPC or the USP Council of Experts 653
This commonly held view that equivalency can only be 3. Hydrophobicity, as measured by a for amylbenzene
demonstrated through revalidation essentially makes equiv- and for butylbenzene
alency a non-issue since revalidation is for many companies 4. Steric selectivity, as measured by the retention factor of
prohibitively expensive. Furthermore, this approach seems triphenlyene and o-terphenyl
unnecessary. The chromatography column provides a given 5. Hydrogen-bonding capacity, as measured by a for caf-
separation with a given selectivity. If another column de- feine and for phenol
monstrates similar selectivity to the column used in the gi- 6. Ion-exchange capacity at pH 7, as measured by a for
ven method, and can pass system suitability for that method, benzylamine and for phenol
then that column should be deemed equivalent. Not to take 7. Ion-exchange capacity at pH 3, as measured by a for
this approach leads to a number of challenging issues for benzylamine and for phenol
those who are trouble-shooting a method postvalidation,
such as the following: The resulting radar plots gave a graphical reference with
• Should a company whose QC department is no longer which to compare different materials for equivalence.
able to meet system suitability requirements, due to re- RECOMMENDATIONS
producibility issues with the chromatographic material,
recommend revalidation to its management even if the Before an industry standard can hope to be established for
method could be shown to work as written on a compet- column equivalence, a quantitative way to figure similarities
ing brand? If a given chromatographic material be- or differences among materials is essential. This method
comes unavailable because of a back order or because must allow for the comparison of novel chemistries to more
it was discontinued, should the company be made to re- traditional ones. Furthermore, special consideration should
validate an otherwise perfectly acceptable method? be given to determine whether any measured differences for
• Stated another way, should a company be made to re- a specific separation are significant or not.
validate the entire method if only a slight modification When the radar plots of the materials listed in the Table
to the method was necessary? below are compared to the various polarity/hydrophobicity
This article seeks to stimulate discussion in the hopes of parameters, it is important to note that the majority of col-
reaching some commonly agreed upon benchmark for what umns that share the same hydrophobicity and polarity have
exactly constitutes a demonstration of "column equiva- similar radar plots. There are exceptions, however, such as
lence." Previous discussions on this topic compared col- Ultrasphere ODS and Waters Spherisorb ODS(B), which are
umns based upon capacity factor for each component in a ranked in the same category but have dramatically different
mixture of compounds and whether they were classified as radar plots. This exception demonstrates the difficulty of de-
tailing (5). veloping hard and fast rules with regard to column equiva-
lence. Consequentially, it is hard to imagine a method of
demonstrating column equivalence that does not involve
RECENT ATTEMPTS TO DEFINE COLUMN EQUIVALENCE
the system suitability parameters for a given method. One
Recent promotional literature by Mac-Mod Analytical must keep in mind, however, that in practice even chroma-
ranked columns by the retention factor for toluene and used tography columns from a reputable vendor manufactured
these rankings to classify them into columns having high, from the same lot of silica have been shown to have some
medium, or low hydrophobicity. It then ranked these col- differences (8).
umns by their a-value for pyridine/phenol and used these With all the above points in mind, it is the recommenda-
rankings to classify the columns as having high, moderate, tion of this author that columns that have values for hydro-
or low polarity. Mac-Mod Analytical used other parameters phobicity, for hydrogen-bonding capacity, and for steric
to rank columns, but hydrophobicity and polarity were used selectivity that differ by no less than 20% and that pass
to construct a 3 x 3 matrix in order to define equivalent col- the system suitability test for a given method should be
umns (see the Table below) (6). deemed equivalent for a given method.
One limitation of the recommendations in this approach is
that it does not differentiate columns that have shape selec- COMMENTS SOLICITED
tivity from those that do not. Shape selectivity is a common
separation factor for biomolecules and polyaromatic hydro- As this work is an attempt to find a commonly agreed
carbons and should be considered for some methods as ad- upon definition for column equivalence that will offer the
ditional equivalency criteria. best compromise of method flexibility and regulatory rigor,
Another recent work comparing chromatography col- the comments and discussions of other parties are critical.
umns created "radar plots" for different chromatographic
materials (7). The radar plots used the following seven axes REFERENCES
to compare materials:
1. Plate count, as measured for amylbenzene 1. ICH Guidance, Q2B Validation of Analytical Proce-
2. Amount of alkyl chains, as measured by the retention dures: Methodology plO.
factor (k) for amylbenzene 2. Marques, M. HPLC Packings Used in the USP-NF. PF
26(1) 2000, 273-288.
3. Marques, M. Chromatographic Reagents Used in the Mac-Mod Analytical Brochure. Comparison Guide to
USP-NF. PF 27(4), 2001, 2882-2905. C18 Reversed Phase HPLC Columns, 2001.
4. Claessens, H.A.; Vermeer, E.A.; Cramers, C.A. A Cruz, E.; Euerby, M.R.; Johnson CM.; Hackett, C.A.
Comparison of Reversed-Phase Performance for Some Chromatographic Classifications of Commercially
Commercially Available C18 HPLC Columns. LC-GC Available Reverse-Phase HPLC Columns. Chromato-
1994,12(2), 114-121. graphia 1997, 44 (3-4), 151-161.
5. Steffeck, R.; Woo, S.; Weigand, R.; Anderson, J. A Kele, M; Guiochon G. Repeatability and Reproducibil-
Comparison of Silica-Based C18 and C8 HPLC Col- ity of Retention Data and Band Profiles on Reverse-
umns to Aid Column Selection. LC-GC 1995, 13 (9), Phase Liquid Chromatography Columns. Submitted
720-726. for publication to J. Chromatogr., 2000.
Column Recommendations Using Various Polanty/Hydrophobicity Parameters

High Polarity/ High Polarity/ High Polarity/
Low Hydrophobicity Moderate Hydrophobicity High Hydrophobicity
Exsil ODS(l) CosmosilC18-AR LiChrosorbRP-18
Hypersil ODS Exsil ODS LiChrospherRP-18
NovapakC18 Hypersil BDS C18
Partisil ODS Resolve Cl8
Vydac 218MS TSK ODS-80TM
Vydac 218TP jxBondapak C18
Vydac Selectaport 300P Waters Spherisorb ODS(l)
Waters Spherisorb ODS(2)
Zorbax ODS
Moderate Polarity/ Moderate Polarity/ Moderate Polarity/
Synchropak CR101 CapcellPakAGC18 Nucleosil C18
Vydac Selectapore 300M CapcellPakSGC18 Partisil ODS(2)
Vydac Selectapore 90M Genesis C18 Symmetry C18
XterraMSC18 Inertsil ODS YMC J'Sphere ODS H80
Inertsil ODS(2)
NucleosilC18-AR
Partisil ODS(3)
Prodigy ODS(3)
PurospherRP-18e
TSK ODS-120T
Ultrasphere ODS
Waters Spherisorb ODS(B)
YMC J'Sphere ODS M80
YMC ODS A
YMC ODS AM
Zorbax Extend Cl8
Zorbax Rx-C 18
Zorbax SB-C18
Low Polarity/ Low Polarity/ Low Polarity/
Exsil ODS(B) Ace C18 Develosil ODS-MG
CapcellpakUGC18 Inertsil ODS(3)
Develosil ODS-HG Kromasil C18
Develosil ODS-UG
Hichrom C18
Hichrom RPB
Hypersil HyPURITY C18
Luna Cl8(2)
Nucleosil C18 HD
Prodigy ODS(2)
YMC Pro C18
Zorbax XDB-C18
Polypropylene Containers: Status and Comments Received1

Thomas Medwick, Rutgers University College of Pharmacy; Leonard Bailey, Rutgers University College of Pharmacy; Thomas Ambrosio,
Schering Plough Research Institute 2 Claudia C. Okeke, Ph.D., USP Staff Liaison
ABSTRACT This article provides background information on USP's collaborative study on polypropylene containers, a
result of which was the proposed addition to the USP general test chapter Containers (661) of a section entitled Polypro-
pylene Containers. Tables at the end of the article provide the results of the collaborative study. Comments were received
from the latest publication in PF(see page 2817 of the July-August issue) of this new section and are given along with the
Expert Committee's responses.
INTRODUCTION other studies conducted by the Society of Plastic Industry

Inc. (SPI). The results of the study from the test procedures
The Expert Committee on Packaging, Storage, and Dis- by Clyde Erskine are shown in Tables 2 and 3 below. The
tribution's consideration of adding a section for polypropy- recommended requirements were designed to be similar to
lene (PP) containers was based on the fact that the PP resins those for High-Density Polyethylene and Low-Density Poly-
are used in increasing quantity for manufacturing containers ethylene in Containers (661). The PP containers tested were
for solid and liquid dosage forms. PP containers are known 5 mL and 40 mL in volume. Each column is headed with a
to have an advantage when packaging sterile products be- letter (A thru E) representing the company that performed
cause of their ability to withstand certain sterilizing proce- the test or USP for the USP lab.
dures. The PSD Expert Committee believed that a procedure
allowing interchangeability of containers should be devel-
oped and added to the USP general test chapter Containers DISCUSSION
(661). The ingredients used to manufacture polypropylene Based on these results, the addition of a proposed section
containers comply with the sections applicable to food on Polypropylene Containers was published in PF 26(4)
packaging material in Title 21 of the Code of Federal Reg- [July-Aug. 2000](2). Comments were received, and the re-
ulations and FDA's requirement for food-contact PP (7). sponse by the PSD Expert Committee to these comments are
PP homopolymers and copopolymers are long-chain listed below:
polymers synthesized under controlled conditions of heat Comment 1: It was suggested to limit polypropylene use
and pressure by catalytic polymerization of propylene from to "solid and aqueous oral dosage forms" due to expressed
not less than 65% propylene and not less than 95% total ole- concerns that "cosolvents will enhance the extraction poten-
fins (7). tial...since the proposal does not address the safety issues
PP is known to have distinctive infrared absorption and to resulting from differences in extraction profiles resulting
possess characteristic thermal properties. The properties of from variation of drug product formulation and polymer
PP may be altered when reground polymer is incorporated composition, we believe it is necessary to limit the proposal
during the manufacture of containers. Based on some of to those drug products where the safety issues are at a mini-
these considerations, the Expert Committee conducted a mum for the polymer".
collaborative study in which five pharmaceutical companies Response: In response the PSD Expert Committee felt
and the USP lab participated. Most of the proposed test pro- that, since PP has few additives and is generally non-reac-
cedures in the collaborative study were published in PF tive, there is a very low potential for extraction. Also,
24(6) as a stimuli article by Clyde Erskine (7) and include although hexane is used in the testing, solvents such as hex-
Multiple Internal Reflectance, Thermal Analysis, Water Va- anes, or solvents of their polarity, are not likely to be cosol-
por Permeation, Heavy Metal and Nonvolatile Residue, vents in dosage forms. The data from the USP collaborative
Buffering Capacity, Residue on Ignition, and Biological Re- study confirmed low extractability.
activity, In Vitro. Table 1 compares the available test proce-
dures for plastic with those proposed in this study, as well as
Comment 2. It was suggested to include a test for Water
Vapor Permeation.
1
Correspondence should be addressed to Claudia C. Okeke, Ph.D., Scien- Response: The Expert Committee's response is that this
tist, U.S. Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852; test is already included.
e-mail cco@usp.org.
2
Thomas Medwick, Ph.D., is chairman of the USP Expert Committee on
Packaging, Storage, and Distribution (PSD); Leonard Bailey, Ph.D., and
Thomas Ambrosio, Ph.D., are members of the PSD Expert Committee.
Comment 3. There was a comment that the following Response: The PSD Expert Committee responded that
phrase from the section on Containers for Ophthalmics— tight is defined (but not well-closed) in the section for Poly-
Plastics should also be included in the proposed new section ethylene Terephthalate Bottles and Polyethylene Terephtha-
on Polypropylene Containers: "Factors such as plastics late G Bottles. The Expert Committee does not want to
composition, processing and cleaning procedures, contact- make any changes until the definitions of tight and well-
ing media, inks, adhesives, absorption, adsorption, and per- closed are resolved in the general chapter Containers—Per-
meability of preservatives, and conditions of storage may meation (671).
also affect the suitability of a plastic for a specific use."
Response: The PSD Expert Committee responded that it
Comment 7. The comment suggesting that a method for
is publishing under In-Process Revision in this number of
gas transmission be included was reviewed by the PSD Ex-
PF a new section Polypropylene Containers for Ophthal-
mics to accommodate these comments. pert Committee.
Response: The Expert Committee responded that no spe-
cific types of gas or gases of concern were mentioned; and
Comment 4. There were recommendations to specify the they decided not to make any changes until this is clarified
types of packaging components in which polypropylene and shown to be a major concern. Also, there is already a
containers could be used. There was some confusion about requirement for water vapor permeation.
the phrase "primary container" mentioned in the earlier
proposal. CONCLUSION
Response: The Expert Committee eliminated its mention
from the final draft. The section on Polypropylene Containers is scheduled to
appear in this issue of PF under In-Process Revision. This
proposal was deferred from the First Supplement to USP
Comment 5. There were comments about the use of the 25-NF 20 due to the unavailability of the polypropylene
terms "equivalent" and "protocol" that were mentioned in homopolymer and copolymer reference standards. The
the earlier proposal. PSD Expert Committee welcomes additional comments re-
Response: The Expert Committee eliminated these terms garding any of the proposed changes to Containers (661).
from the final draft.
REFERENCE
Comment 6. There was a comment that suggested a mul-

tiple-class system, such as tight and well-closed, be included 1. Erskine, C. Recommended Procedure to Allow the In-
similar to the one in the current section for Polyethylene Ter- terchangeability of Polypropylene Containers for
ephthalate Bottles and Polyethylene Terephthalate G Bot- Packaging Solid and Liquid Dosage Forms. PF
tles. 24(6), 1998, 7341-7342.
2. (661) Containers. In-Process Revision, PF 26(4), 2000,
1117-1119.
Table 1. Plastics Tests
i 2 3 4 5 6 7 8 9
Polyethylene Polyethylene Polyethylene Polypropylene Polypropylene
Physicochcmical Polyethylene Polyethylene Containers LDPE Terephthalate (PET) Terephthalate G Erskine Study PF Recommendation
Bottles (PETG)
TEST Tests—Plastics Containers HDPE Containers LDPE SPI Study Bottles 26(4) SPI Study
H 2 O,70° = H 2 O,70° = H 2 O,70° = H 2 0,70° = H 2 0,70° =
nmt 12.0 mg; nmt 12.0 mg; nmt 12.0 mg; nmt 10.0 mg; nmt 12.0 mg;
ale, 70° = ale, 70° = ale, 70° = ale, 70° = ale, 70° =
Not>l5mg nmt 75.0 mg; nmt 75.0 mg; nmt 75.0 mg; nmt 60.0 mg; nmt 75.0 mg;
NONVOLATILE (120cm 2 ,H 2 O, hexanes, 50° = hexanes, 50° = hexanes, 50° = hexanes, 50° = hexanes, 50° =
RESIDUE (NVR) 70°,24hrs) nmt 100 mg nmt 350 mg nmt 350 mg N/A N/A nmt 225 mg nmt 350 mg
RESIDUE ON (ifNVR>5mg)
IGNITION 5mg N/A N/A 5 mg proposed N/A N/A N/A 5 mg proposed
20mLH 2 O,70° 20mLH 2 O,70° 20mLH 2 O,70° 20mLH 2 O, 70° 20 mL H 2 0,70° 20mLH 2 O ( 70° 20mLH 2 O,70° 20 mL H 2 0,70°
extract extract extract extract extract extract extract extract
HEAVY METALS lppm lppm lppm lppm 1 ppm lppm 1 ppm 1 ppm
BUFFERING 20 mL extract 20 mL extract 20 mL extract 20 mL extract
CAPACITY not > 10 mL N/A N/A not > 10 mL N/A N/A not > 10 mL not > 10 mL
3500-600 cm 1 ,
all spectra
MULTIPLE 3500-600 cm 1 , similar,
INTERNAL 3500-600001', 3500-600 cm"1, 3500-600 cm 1 , 4000-400 cm 1 , 4000-400 cm 1 , USP homo- or co- no standard
REFLECTANCE N/A. USPHDPEStd USPLDPE Std USP LDPE Std USP PET std USP PETG std polymer Ref Std available
differ from std, recommended,
THERMAL differ from std, differ from std, differ from std, differ from std, differ from std, homo- nmt 12°, differ from std
ANALYSIS N/A HDPE nmt 6.0° LDPE nmt 8.0° LDPE nmt 8.0° PET nmt 4.0° PETG nmt 6.0° co- nmt 6° nmt 20°
LIGHT see Light see light see Light see Light see Light
TRANSMISSION N/A Transmission Transmission Transmission Transmission Transmission
tight container tight container
HDPE-nmt 1 of 10 LDPE-nmt 1 of 10 LDPE-nmt 1 of 10 if: > 100 mg/day/L if: >100 mg/day/L nmt 1 of 10 > nmt 1 of 10 >
WATER VAPOR >I0 mg/day/L, >20 mg/day/L, >50 mg/day/L, in nmt 1 of 10; in nmt 1 of 10; 15 mg/day/L; 20mg/day/L;
PERMEATION N/A none >25 mg none >30 mg none >60 mg none > 200 mg none > 200 mg none > 25 mg none > 30 mg
50% ale for 25% ale for
10 days at 49°; 10 days at 49°;
COLORANT abs <.0l, 350- abs<.01,350-
EXTRACTION N/A N/A N/A N/A 700 nm 700 nm N/A N/A
TOTAL
ERPHTHALOYL
MOIETIES N/A N/A N/A N/A 1 ppm lppm N/A N/A
ETHYLENE
GLYCOL N/A N/A N/A N/A 1 ppm lppm N/A N/A
Table 2. Polypropylene Test Results Using a 5-mL Container
TEST PARTICIPANTS
A B C D USP E A D USP
WATER 0.54 1 0.1 0.1 0 0.8 0.62 0.3 0.9 0.2 1 0
NONVOLATILE RESIDUE (mg) ALCOHOL 29.6 3.2 8.3 10.9 7 5.4 0.2 2.1 14.7 15 1.4 1
HEXANF. 22.6 97.4 162 103.4 126 61.5 42.09 65.8 204.5 295 170.6 219
HEAVY METALS (PPM) <1 <1 <1 <1 <I <1 <1 | <1 <1 | <l | <1 <1
WATER VAPOR TRANSMISSION 6.3 7.1 14.5 128 11.2 3.7 2.6 12.1 14.5 15.5 60.8*
7.5 11.9 14.5
r o.o
0.0 12.2 14 6.3 9.7 11.4 13 11.5 8.2
MG/DAY/LITER 6 7.1 12.3 0.0 11.5 13.3 7.1 3.9 10.7 13.8 9.1 12.7
*NOTES RROKE.VSEAL 8.9 7.9 13 0.0 16.3 10.5 6.2 9.1 11.4 14.5 10.7 11.3
7 8.7 11.6 18.0 10.8 12.6 6.4 0 10 14.5 9.9 12
6.5 8.7 10.9 0.0 14.9 11.9 6.4 7.8 11.4 13 5.9 106
5.5 9.5 11.6 0.0 11.5 i 11.9 6.1 8.4 10.7 13.8 10.7 675.5*
7.1 7.1 12.3 0.0 10.8 13.3 6.7 7.8 11.7 15.2 12.3 10.6
5.7 10.3 14.5 0.0 12.2 9.8 6.6 5.8 12.1 13 13.1 12
6.4 7.9 11.6 0.0 12.2 11.2 7.5 17.5 12.1 14.5 10.7 10.6
THERMAL ANALYSIS
BNDOTKERM 153 136.9 129.4 128.3 129.6 131.6
ONSET 166.1 167.0 151.9 152.8 152.5 149.9 148.5 150.3 149.9 151.7 149.0 149.6
PEAK
EXOTHERM 131.5 106.0 108.6 107.8 104.5 124.2
ONSET 127.2 135.0 102.1 102.3 105.7 104.7 103 1008 120.3 116.9 115.0 119.7
PEAK
B UFFERING CAPACITY 0.15 <l <0.1 0.05 n/r <0.1 0.25 0.05 <0.1 | <.0l | <1 N/T
N/T = NOT TESTED
MULTIPLE INTERNAL REFLECTANCE RESULTS CONFORM | N/T RESULTS CONFORM N/T
N / T = NOT TESTED
RESIDUE ON IGNITION N/R <1 N/R <0.I | N/T <0.1 N/R 0.3 <0.1 N/R | <1 N/T
N/T = NOT TESTED N/R = NOT REQUIRED
BIOLOGICAL REACTIVITY TESTS, PASS PASS N/T N/T 1 N/T PASS PASS N/T PASS N/T | PASS N/T
IN VITRO
N/T = NOT TESTED
ssaoojd uoisjAay aq) oj iinmiig
Table 3. Polypropylene Test Results Using a 40-mL Container
TEST TEST PARTICIPANTS
E C USP D B A C E USP B
NONVOLATILE RESIDUE (mg) WATER 11 0.5 0 0.1 0.2 1.07 0.2 0.8 1 0.8 0.4 <0.1
ALCOHOL 41.4 53 7 li 1.2 3.2 2.3 5.4 1 3 5.6 19.9
HEXANE 172.4 66 126 112.3 84 81.9 66 53.1 63 163.4 154.2 220.9
HEAVY METALS (PPM)
WATER VAPOR TRANSMISSION 4.5 3.9 4.7 8.5 6.1 5.5 5.4 6.7 6.4 7 4.9 0.1
MG/DAY/LITER 4.5 5 4.6 4.9 6.4 6 4.7 6.7 6.6 7.2 4.5 0.8
*NOTES BROKEN SEAL 4.5 4.2 4.6 3.5 6.1 5.6 5.5 5.6 6.6 6.6 5.3 1.2
4.5 3.9 207.4 14.9 5.9 5.3 5 5.6 6.4 7.3 6.6 2.8
5.7 3.2 228 7.4 6.3 5.5 5.1 5.6 6.2 7.7 8.4 1.6
4.5 4.4 4.7 16.8 6.3 5.2 4.9 5.6 6.7 7.6 5.4 1.1
4.5 3.9 4.5 6.8 6.3 5.9 5.1 6.7 6.5 7.2 8.4 0.1
4.5 3.9 361.2 3.9 6.3 6.2 4.8 5.6 6.6 7.3 7.3 0
5.7 4.1 4.8 6.6 6.5 6.1 5.4 6.7 6.5 7 7.1 7.1
5.7 4.1 5.3 14.3 6.1 5.1 5 6.7 9.5 7.2 5.8 0.3
THERMAL ANALYSIS
ENDOTHERM
ONSET 154.7 137.1 142.1 134.6 134.9 132.4
PEAK 166.5 167.9 168.2 152.8 120 150 147.8 149.9 148.4 150 150.5 150
EXOTHERM
ONSET 132.6 106.1 108.6 109 108 120.6
PEAK 128.8 125.8 126.3 102.3 112.6 104.2 102.1 105.2 102.8 115 104.5 116.6
BUFFERING CAPACITY 0.1 <0.1 | 0.05 <1 | 0.15 <.01 <0.1 <1 0.15 0.1
MULTIPLE INTERNAL REFLECTANCE RESULTS CONFORM NtT | RESULTS CONFORM N/t RESULTS CONFORM
N/T = NOT TESTED
RESIDUE ON IGNITION <0.1 N/A | N/A <1 | N/A N/A <1 N/A N/A
N/T= NOT TESTED
BIOLOGICAL REACTIVITY TESTS PASS N/t N/T N/T PASS 1 PASS N/t PASS NAT N/T PASS N/T
IN VITRO
N7t=NOTTESTED
Review of Pharmaceutical Calculations in Prescription Compounding (1160)

Claudia C. Okeke*, United States Pharmacopeia; Mary Ann F. Kirkpatrick and J. Graham Nairn, Expert Committee on Compounding
Pharmacy
ABSTRACT Pharmaceutical Calculations in Prescription Compounding (1160), which was previewed in Pharmacopeial
Forum 26(6) [Nov.-Dec. 2000], provides guidelines for calculations commonly used in pharmacy compounding. It is de-
signed to be a companion chapter to Pharmaceutical Compounding—Nonsterile Preparations (795) (/), Pharmaceutical
Compounding—Sterile Preparations (797) (formerly Sterile Drug Products for Home Use (1206)), and Good Compounding
Practices (1075) (2) and is intended to serve as an informational chapter. Pharmaceutical Compounding—Nonsterile Pre-
parations (795), on the other hand, is a general test chapter, and the provisions of that chapter are implemented via the First
Supplement to USP 24-NF19.
This draft chapter review and revision was generated as a result of consideration of the following: (a) the original document
published on page 1658 of PF 26(6) and comments received in response to that document, subsequent to the meeting of the
Expert Committee on Compounding Pharmacy; (b) comments from meetings of the Expert Committee on Pharmacy
Compounding held on May, 14, 2001 and August 22, 2001; (c) comments received by J. Graham Nairn subsequent to the
August meeting; and (d) review by the Expert Committee on Pharmacy Compounding of a revised draft that was submitted
by the co-authors. Public comments are encouraged and should be addressed to Dr. Claudia C. Okeke.
INTRODUCTION checking is by estimation. This involves rounding off the

quantities involved in the calculation, and comparing the es-
The purpose of this chapter is to provide general informa- timated result with the calculated value.
tion to guide and assist pharmacists in performing the nec-
Finally, the following steps should be taken: the dosage of
essary calculations when preparing or compounding any
each active ingredient in the prescription should be checked;
pharmaceutical article (see Pharmaceutical Compound-
all calculations should be doubly checked, preferably by an-
ing—Nonsterile Preparations (795) [1], Pharmaceutical
other pharmacist; and where instruments are used in com-
Compounding—Sterile Preparations (797), and Good
pounding, they should be carefully checked to ascertain
Compounding Practices (1075) [2]) or when simply dispen-
that they will function properly. See Aerosols, Metered-
sing prescriptions (see Stability Considerations in Dispen-
sing Practice (1191) [3]).
Dose Inhalers, and Dry Powder Inhalers (601) and
Water-Solid Interactions in Pharmaceutical Systems
Correct pharmaceutical calculations can be accomplished (1241) for information on specific instruments (3).
by using, for example, proper conversions from one mea-
surement system to another and properly placed decimal
points, by understanding the arithmetical concepts, and by BASIC MATHEMATICAL CONCEPTS
paying close attention to the details of the calculations. Be-
SIGNIFICANT FIGURES
fore proceeding with any calculation, pharmacists should do
the following: (a) read the entire formula or prescription Expressed values are considered significant to the last di-
carefully; (b) determine which materials are needed; and git shown (see Significant Figures and Tolerances in the
then (c) select the appropriate methods of preparation and General Notices) (3). Significant figures are digits with
the appropriate calculation. practical meaning. The accuracy of the determination is im-
There are often several ways to solve a given problem. plied by the number of figures used in its expression. In
Logical methods that require as few steps as possible should some calculations zeros may not be significant. For exam-
be selected in order to ensure that calculations are done cor- ple, for a measured weight of 0.0298 g, the zeros are not
rectly. The best approach is the one that yields results that significant; they are used merely to locate the decimal point.
are accurate and free of error. The pharmacist must double- In the example, 2980 g, the zero may also be used to indicate
check each calculation before proceeding with the prepara- the decimal point, in which case the zero is not significant.
tion of the article or prescription order. One way of double- Alternately, however, the zero may indicate that the weight
is closer to 2981 g or 2979 g, in which case the zero is sig-
nificant. In such a case, knowledge of the method of mea-
Correspondence should be addressed to Dr. Claudia C. Okeke, 12601 surement would be required in order to indicate whether the
Twinbrook Parkway, Rockville MD 20852; E-mail cco@usp.org. Claudia
C. Okeke, Ph.D., is staff liaison to the Expert Committee on Compounding zero is or is not significant. In the case of a volume measure-
Pharmacy and the Expert Committee on Parenteral Products—Compound- ment of 298 mL, all of the digits are significant. In a given
ing and Preparation.
result, the last significant figure written is approximate but Products and Quotients
all preceding figures are accurate. For example, a volume of When multiplying or dividing, the result shall have no
29.8 mL implies that 8 is approximate. The true volume falls more significant figures than the measurement with the
between 29.75 and 29.85. Thus, 29.8 mL is accurate to the smallest number of significant figures entering into the cal-
nearest 0.1 mL, which means that the measurement has been culation.
made within ± 0.05 mL. Likewise, a value of 298 mL is
accurate to the nearest 1 mL and implies a measurement fall- EXAMPLE—
ing between 297.5 and 298.5, which means that the mea-
surement has been made within ± 0.5 mL and is subject 4.266 x 21 = 90
to a maximum error calculated as follows:
0.5mL Rounding Off—For rules on rounding off measurements
x 100% = 0.17% or calculated results, see Interpretation of Requirements un-
298 mL der Significant Figures and Tolerances in the General No-
tices (3). Note, however, that in the example above, if 21 is
an absolute number, e.g., the number of doses, then the an-
A zero in a quantity such as 298.0 mL is a significant fig- swer, 89.586, is rounded off to 89.59 which has 4 significant
ure and implies that the measurement has been made within figures (4).
the limits of 297.95 and 298.05 with a possible error calcu-
lated as follows: LOGARITHMS
The logarithm of a number is the exponent or the power
0.05 mL
xl00% = 0.017% to which a given base must be raised in order to equal that
298.0 mL number.
Definitions—
EXAMPLES—
1. 29.8 mL = 29.8 ± 0.05 mL (accurate to the nearest 0.1
mL)
2. 29.80 mL = 29.80 ± 0.005 mL (accurate to the nearest pKa = -log Ka,
0.01 mL) where [H+] is the hydrogen ion concentration in an aqueous
3. 29.800 mL = 29.800 ± 0.0005 mL (accurate to the solution and Ka is the ionization constant of the acid in an
nearest 0.001 mL) aqueous solution. The [H+] = the antilogarithm of (-pH),
The degree of accuracy in the last example is greatest. and the Ka = the antilogarithm of (-pKa).
Thus, the number of significant figures provides an estimate The pH of an aqueous solution containing a weak acid
both of true value and of accuracy. may be calculated using the Henderson-Hasselbalch equa-
tion:
EXAMPLES OF SlGNFICANT FIGURES—
pH = pKa + log [salt]/[acid]
Measurement Number of Significant Figures
2.98
2.980 EXAMPLE—
0.0298 A solution contains 0.020 moles per liter of sodium
0.0029 acetate and 0.010 mole per liter of acetic acid, which has
a pKa value of 4.76. Calculate the pH and the [H+] of the
Calculations—All figures should be retained until the solution. Substituting into the above equation, pH = 4.76
calculations have been completed. Only the appropriate + log (0.020/0.010) = 5.06, and the [H+] = antilogarithm
number of significant figures, however, should be retained of (-5.06) = 8.69 x 10-6.
in the final result.
Determining the number of significant figures— BASIC PHARMACEUTICAL CALCULATIONS
Sums and Differences
When adding or subtracting, the number of decimal The remainder of this chapter will focus on basic pharma-
places in the result shall be the same as the number of dec- ceutical calculations. It is important to recognize the rules
imal places in the component with the fewest decimal involved when adding, subtracting, dividing, and multiply-
places. ing values. The interrelationships between various units
within the different weighing andmeasuring systems are
EXAMPLE— also important and have to be understood.
11.5 + 11.65 + 9.90 = 33.1
CALCULATIONS IN COMPOUNDING Example 1: Triturate Morphine Sulfate USP and Lactose

The pharmacist must be able to calculate the amount or NF to obtain 10 g in which there are 30 mg of Morphine
concentration of drug substances in each unit or dosage por- Sulfate USP for each 200 mg of the morphine-lactose mix-
tion of a compounded preparation at the time it is dispensed. ture. [NOTE—Clinical dosages of morphine mean Morphine
Pharmacists must perform calculations and measurements Sulfate USP, which is the pentahydrate.]
to obtain, theoretically, 100% of the amount of each ingre- Equation Factor Numerical Value
dient in compounded formulations. Calculations must ac-
count for the active ingredient, or active moiety, and water W weight, in g, of Morphine Sulfate
content of drug substances, which includes that in the che- USP
mical formulas of hydrates. Official drug substances and a 1.5 g of morphine sulfate pentahy-
added substances must meet the requirements under Loss drate in the prescription
on Drying (731), which must be included in the calculations b 759 g/mole
of amounts and concentrations of ingredients. The pharma- d 1.0
cist should consider the effect of ambient humidity on the e 759 g/mole
gain or loss of water from drugs and added substances in
containers subjected to intermittent opening over prolonged 1.5g(759g/mole)
storage. Each container should be opened for the shortest 1.0(759g/mole) ' 6'
duration necessary and then closed tightly immediately after
use.
The nature of the drug substance that is to be weighed and Example 2: Accurately weigh an amount of Aminophyl-
used in compounding a prescription must be known exactly. line USP to obtain 250 mg of anhydrous theophylline.
If the substance is a hydrate, its anhydrous equivalent [NOTE—The powdered aminophylline dihydrate weighed
weight may need to be calculated. On the other hand, if there contains 0.4% w/w adsorbed moisture as stated in the Cer-
is adsorbed moisture present that is either specified on a certificate of Analysis.]
tificate of analysis or that is determined in the pharmacy im-
mediately before the drug substance is used by the Equation Factor Numerical Value
procedure under Loss on Drying (731), this information W weight, in mg, of Aminophylline
must be used when calculating the amount of drug sub- USP (dihydrate)
stance that is to be weighed in order to determine the exact a 250 mg of theophylline
amount of anhydrous drug substance required.
b 456 g/mole
There are cases in which the required amount of a dose is d 0.996
specified in terms of a cation [e.g., Li(+), netilmicin (n+)], e 360 g/mole
an anion [e.g., F(-)], or a molecule (e.g., theophylline in
aminophylline). In these instances, the drug substance
weighed is a salt or complex, a portion of which represents W
_250mg (456g/mole) ...
the pharmacologically active moiety. Thus, the exact 0.996 (360g/mole)
amount of such substances weighed must be calculated on
the basis of the required quantity of the pharmacological
moiety. Example 3: Accurately weigh an amount of Lithium Ci-
The following formula may be used to calculate the exact trate USP (containing 2.5% moisture as stated in the Certi-
theoretical weight of an ingredient in a compounded pre- ficate of Analysis) to obtain 200 mEq of lithium (Li+).
paration: [NOTE—One mEq of Li+ is equivalent to 0.00694 g of Li+.]
W= abide, Equation Factor Numerical Value
in which Wis the actual weighed amount; a is the prescribed
or pharmacist-determined weight of the active or functional W weight, in g, of Lithium Citrate
moiety of drug or added substance; b is the chemical formu- USP (tetrahydrate)
la weight of the ingredient, including waters of hydration for a 200 mEq of Li+ or 1.39 g of Li+
hydrous ingredients; d is the fraction of dry weight when the b 282 g/mole
percent by weight of adsorbed moisture content is known d 0.975
from the loss on drying procedure (see Loss on Drying e 3 x 6.94 g/mole or 20.8 g/mole
(731)); and e is the formula weight of the active or func-
tional moiety of a drug or added substance that is provided
w_1.39g(282g/rnole)_
in the formula weight of the weighed ingredient.
0.975 (20.8g/mole) "
Example 4: Accurately weigh an amount of Netilmicin smaller volumes of buffer are used in order to determine the
Sulfate USP, equivalent to 2.5 g of netilmicin. [NOTE— buffer capacity. An approximate formula for calculating the
Using the procedure under Loss on Drying (731), the Netil- buffer capacity is gram equivalents of strong acid or base
micin Sulfate USP that was weighed lost 12% of its weight.] added per liter of buffer solution per unit of pH change,
i.e., (Eq/L)/(pH change) (7).
W weight, in g, of Netilmicin Sulfate EXAMPLE—
USP The addition of 0.01 gram equivalents of sodium hydrox-
a 2.5 g ide to 0.25 liter of a buffer solution produced a pH change of
b 1442 g/mole 0.50. The buffer capacity of the buffer solution is calculated
d 0.88 as follows:
e 951 g/mole
(0.01/0.25)/0.50 = 0.08(Eq/L)/(pH change)
v 2.5f * ( 1 4 4 2 g / m o l e ) „ , , _
DOSAGE CALCULATIONS
0.88 (951 g/mole)
Special Dosage Regimens—Geriatric and pediatric pa-
tients require special consideration when designing dosage
regimens. In geriatric patients, the organs are often not func-
BUFFER SOLUTIONS tioning efficiently as a result of age-related pharmacokinetic
Definition—A buffer solution is an aqueous solution that changes or disease. For these patients, modifications in dos-
resists a change in pH when small quantities of acid or base ing regimens are available in references such as USP Drug
are added, when diluted with the solvent, or when the tem- Information.
perature changes. Most buffer solutions are mixtures of a For pediatric patients, where organs are often not fully de-
weak acid and one of its salts or mixtures of a weak base veloped and functioning, careful consideration must be ap-
and one of its salts. Water and solutions of a neutral salt such plied during dosing. Modifications in dosing regimens for
as sodium chloride have very little ability to resist the pediatric patients are also available in references such as
change of pH and are not capable of effective buffer action. USP Drug Information. General rules for calculating doses
Preparation, Use, and Storage of Buffer Solutions— for infants and children are available in pharmacy calcula-
Buffer solutions for pharmacopeial tests should be prepared tion textbooks (4, 8). These rules are not drug-specific and
using freshly boiled and cooled water (see Standard Buffer should be used only in the absence of more complete infor-
Solutions under Buffer Solutions in Reagents, Indicators, mation.
and Solutions (3). They should be stored in containers such The usual method for calculating a dose for children is to
as Type I glass bottles and used within three months of pre- use the information provided for children for the specific
paration. drug. The dose is frequently expressed as mg of drug per
Buffers used in physiological systems are carefully cho- kg of body weight for a 24-hour period, and is then usually
sen so as not to interfere with the pharmacological activity given in divided portions.
of the medicament or the normal function of the organism The calculation may be made using the following equa-
(3). Commonly used buffers in parenteral products for ex- tion:
ample are acetic, citric, glutamic, and phosphoric acids
(mg of drug per kg of body weight) x kg of body weight =
and their salts (5) and should be freshly prepared.
dose for an individual for a 24-hour period
The Henderson-Hasselbalch equation, noted above, al-
lows the pH of a buffer solution of a weak acid and its salt
to be calculated. Appropriately modified, this equation may A less frequently used method of calculating the dose is
be applied to buffer solutions composed of a weak base and based on the surface area of the individual's body. The dose
its salt. is expressed as amount of drug per body surface area in m2,
Buffer Capacity—The buffer capacity of a solution is as shown in the equation below:
the measurement of the ability of that solution to resist a
change in pH upon addition of small quantities of a strong (amount of drug per m2 of body surface area) x (body
acid or base. An aqueous solution has a buffer capacity of 1 surface area in m2) = dose for an individual for a 24-hour
when 1 liter of the buffer solution requires 1 gram-equiva- period (8).
lent (3) of strong acid or base to change the pH by 1 unit. (3,
6). Therefore, the smaller the pH change upon the addition The body surface area BSA may be determined from no-
of a specified amount of acid or base, the greater the buffer mograms relating height and weight in dosage handbooks.
capacity of the buffer solution. Usually, in analysis, much The BSA for adult and pediatric patients may also be deter-
mined using the following equations (9):
BSA (m2) = square root of {[ Height (in) x Weight (lb)] / weight percent equation above, the calculation is as fol-
3131} lows.
or
Total weight of the solution = 10.00 g + 2.50 g =
2 12.50 g
BSA (m ) = square root of {[ Height (cm) x Weight (kg)]/
3600]}. Weight percent of phenol = (2.50 g x 100%)/12.50 g =
20.0% of phenol
Weight percent of glycerin = (10 g x 100%)/12.50 g
EXAMPLE— = 80.0% of glycerin
Rx for Spironolactone Suspension 25 mg/tsp. Sig: 9 mg 2. A prescription order reads as follows:
BID for an 18 month-old child who weighs 22 lbs.
The USP DI 2001, 21st ed. (10) states that the normal pe- Eucalyptus Oil 3% (v/v) in Mineral Oil
diatric dosing regimen for Spironolactone is 1 to 3 mg per
kg per day. In this case, the weight of the child is 22 lbs, Dispense 30.0 mL
which equals 22 lbs/(2.2 lbs/kg) = 10 kg. Therefore the nor- What quantities should be used for this prescription?
mal dose for this child is 10 to 30 mg per day, and the dose Using the volume percent equation above, the calcula-
ordered is 18 mg per day as a single dose or divided into 2 to tion is as follows.
4 doses. The dose is acceptable based on published dosing Amount of Eucalyptus Oil:
guidelines.
3% = (Volume of oil in mL/30.0 mL) x 100%
PERCENTAGE CONCENTRATIONS
Solving the equation, the volume of oil = 0.90 mL.
Percentage concentrations of solutions are usually ex-
pressed in one of three common forms: Amount of Mineral Oil:
Volume of solute To 0.90 mL Eucalyptus Oil add sufficient Mineral Oil
Volume percent (v/v) = to prepare 30.0 mL.
Volume of solution
Zinc oxide 7.5 g
Calamine 7.5 g
Weight of solute x 100% Starch 15 g
Weight percent (w/w) = White petrolatum 30 g
Weight of solution
Calculate the percentage concentration for each of the
four components. Using the weight percent equation above,
the calculation is as follows.
Weight of solute (in g) Total weight = 7.5 g + 7.5 g + 15 g + 30 g = 60.0 g
Weight in volume percent (w/v) = -xl00% Weight percent of zinc oxide = (7.5 g zinc oxide/60 g
Weight of solution (in mL)
ointment) x 100% = 12.5%
Weight percent of calamine = (7.5 g calamine/60 g oint-
See also Percentage Measurements under Concentrations in
ment) x 100% = 12.5%
the General Notices (3). The above three equations may be
Weight percent of starch = (15 g starch/60 g ointment) x
used to calculate any one of the three values (i.e., weights,
100% = 25%
volumes, or percentages) in a given equation if the other two
values are known. Weight percent of white petrolatum = (30 g White Petro-
Note that weights are always additive, i.e., 50 g plus 25 g latum/60 g ointment) x 100% = 50%
= 75 g. Volumes of two different solvents or volumes of sol- SPECIFIC GRAVITY
vent plus a solid solute are not strictly additive. Thus 50 mL The definition of Specific Gravity is usually based on the
of water + 50 mL of pure alcohol do not produce a volume ratio of weight of a substance in air at 25° to that of the
of 100 mL. Nevertheless, it is assumed that in some pharma- weight of an equal volume of water at the same temperature
ceutical calculations, volumes are additive, as discussed be- (3). The weight of 1 mL of water at 25° is approximately 1
low under Reconstitution of Drugs Using Volumes Other g. The following equation may be used for calculations.
than Those on the Label. Specific Gravity = (Weight of the substance) / (Weight of
an equal volume of water)
EXAMPLES—
1. Calculate the percentage concentrations (w/w) of the EXAMPLES—
constituents of the solution prepared by dissolving 1. A liquid weighs 125 g and has a volume of 110 mL.
2.50 g of phenol in 10.00 g of glycerin. Using the What is the specific gravity?
The weight of an equal volume of water is 110 g. Let (£>,) = 10 g, ( d ) = (1 in 100), and (C2) = (0.001 in
10).
Using the above equation, specific gravity =
125 g/110 g = 1.14 Using the equation for dilution, lOg x (1/100) = (Q2) g
2. Hydrochloric Acid NF is approximately a 37% w/w so- x (0.001/10).
lution of hydrochloric acid (HC1) in water. How many
grams of HC1 are contained in 75.0 mL of HC1 NF? Solving the above equation, (Q2) = 1000 g.
(Specific gravity of Hydrochloric Acid NF is 1.18) Because 10 g of the final mixture contains all of the
drug and some diluent, (1000 g - 10 g) or 990 g of dil-
Calculate the weight of HC1 NF using the above equation. uent is required to prepare the mixture at a concentra-
The weight of an equal volume of water is 75 g. tion of 0.001 g of drug in 10 g of final mixture.
Calculate the percentage strength of a solution obtained
Specific Gravity 1.18 = weight of the HC1 NF g / 75.0 g. by diluting 400 g of a 5.0% solution to 800 g.
Solving the equation, the weight of HC1 NF is 88.5 g
Now calculate the weight of HC1 using the weight percent Let (0,) = 400g, (C.) = 5%, and (Q2) = 800 g.
equation. Using the equation for dilution, 400 g x 5% = 800 g x
37.0 % (w/w) = (weight of solute g / 88.5 g) x 100
Solving the equation, the weight of the HC1 is 32.7 g.
Solving the above equation, (C2) = 2.5%.
DILUTION AND CONCENTRATION
USE OF POTENCY UNITS
A concentrated solution can be diluted. Powders and
other solid mixtures can be triturated or diluted to yield less See Units of Potency in the General Notices (3).
concentrated forms. Because the amount of solute in the di- Because some substances may not be able to be defined
luted solution or mixture is the same as the amount in the by chemical and physical means, it may be necessary to ex-
concentrated solution or mixture, the following relationship press quantities of activity in biological units of potency (5).
applies to dilution problems:
The quantity of Solution 1 (Qx) x concentration of Solu- EXAMPLES—
tion 1 (CO = the quantity of Solution 2 (Q2) x concentration 1. One mg of Pancreatin contains not less than 25 USP
of Solution 2 (C2), or Units of amylase activity, 2.0 USP Units of lipase activ-
ity, and 25 USP Units of protease activity (5). If the pa-
tient takes 0.1 g (100 mg) per day, what is the daily
amylase activity ingested?
Almost any quantity and concentration terms may be 1 mg of Pancreatin corresponds to 25 USP Units of
used. However, the units of the terms must be the same amylase activity.
on both sides of the equation.
100 mg of Pancreatin corresponds to 100 x (25 USP
EXAMPLES— Units of amylase activity) = 2500 Units.
1. Calculate the amount, in g, (Q2), of diluent that must be 2. A dose of penicillin G benzathine for streptococcal in-
added to 60 g of a 10% ointment to make a 5% oint- fection is 1.2 million units intramuscularly. If Bicillin
ment. L-A contains 1180 units per mg, how many milligrams
would be in the dose? (3)
Let (£>,) = 60g, (C,) = 10%, and (C2) = 5%. Using the
above equation, 1180 units of penicillin G benzathine are contained in 1
mg.
60g x 10% = (Q2) x 5%.
1 unit is contained in 1/1180 mg.
1,200,000 units are contained in (1,200,000 x l)/1180
Solving the above equation, the amount of diluent units =1017 mg.
needed, Q2, is 120 g. The initial amount of diluent
added was 60 g, and therefore an additional 60 g of dil- BASE VS. SALT OR ESTER FORMS OF DRUGS
uent must be added to the initial amount to give a total Frequently the base form of a drug is administered in an
of 120 g. altered form such as an ester or salt for stability or other rea-
How much diluent should be added to 10 g of a tritura- sons such as taste or solubility. This altered form of the drug
tion (1 in 100) to make a mixture that contains 1 mg of usually has a different molecular weight (MW), and at times
drug in each 10 g of final mixture? it may be useful to determine the amount of the base form of
the drug in the altered form.
Determine the final concentration by first converting
mg to g. One mg of drug in 10 g of mixture is the same
as 0.001 g in 10 g.
EXAMPLES— 2. What is the volume of dry powder cefonicid, if 2.50 mL

1. Four hundred milligrams of erythromycin ethylsucci- of diluent is added to 1 g of powder to make a solution
nate (molecular weight, 862.1) is administered. Deter- having a concentration of 325 mg per mL?
mine the amount of erythromycin (molecular weight, Volume of solution containing 1 g of the powder =
733.9) in this dose (11).
862.1 g of erythromycin ethylsuccinate corresponds to
733.9 g of erythromycin. 1000 mg 1 mL of solution
1 g of cefonicid x = 3.08mL
1g 325 mg of cefonicid
1 g of erythromycin ethylsuccinate corresponds to
(733.9/862.1) g of erythromycin.
0.400 g of erythromycin ethylsuccinate corresponds to Volume of dry powder cefonicid = 3.08 mL of solution
(733.9/862.1) x 0.400 g or 0.3405 g of erythromycin. - 2.50 mL of dilluent = 0.58 mL
2. The molecular weight of testosterone cypionate is
412.6 and that of testosterone is 288.4. What is the dose ALLIGATION ALTERNATE AND ALGEBRA
of testosterone cypionate that would be equivalent to Alligation—Alligation is a rapid method of determining
60.0 mg of testosterone? (11) the proportions in which substances of different strengths
288.4 g of testosterone corresponds to 412.6 g of testos- are mixed to yield a desired strength or concentration. Once
terone cypionate. (11) the proportion is found, the calculation may be performed to
find the exact amounts of substances required. Set up the
1 g of testosterone corresponds to 412.6 / 288.4 g of problem as follows:
testosterone cypionate. 1. Place the desired percentage or concentration in the
center.
60.0 mg or 0.0600 g of testosterone corresponds to
2. Place the percentage of the substance with the lower
(412.6/288.4) x 0.0600 = 0.0858 g or 85.8 mg of tes-
strength on the lower left-hand side.
tosterone cypionate.
3. Place the percentage of the substance with the higher
RECONSTITUTION OF DRUGS USING VOLUMES OTHER strength on the upper left-hand side.
THAN THOSE ON THE LABEL 4. Subtract the desired percentage from the lower percen-
Occasionally it may be necessary to reconstitute a powder tage, and place the obtained difference on the upper
in order to provide a suitable drug concentration in the final right-hand side.
product. This may be accomplished by estimating the vol- 5. Subtract the higher percentage from the desired percen-
ume of the powder and liquid medium required. tage, and place the obtained difference on the lower
right-hand side.
EXAMPLES— The results obtained will determine how many parts of
1. If the volume of 250 mg of ceftriaxone sodium is 0.1 the two different percentage strengths should be mixed to
mL, how much diluent should be added to 500 mg of produce the desired percentage strength of a drug mixture.
ceftriaxone sodium powder to make a suspension hav-
ing a concentration of 250 mg per mL? EXAMPLES—
1. How much ointment having a 12% drug concentration
Volume of the 250 mg per mL suspension required to and how much ointment having a 16% drug concentra-
contain 500 mg of ceftriaxone sodium powder = tion must be used to make 1 kg of a preparation contain-
ing a 12.5% drug concentration?
_„„ 1 mL _
500 mg x =2mL. (higher) 16% 0.5 parts of 16%
250 mg
12.5%
(desired)
Volume of 500 mg of ceftriaxone sodium = ^ \
|(Iower) 12%| Imparts of 12%
|4.0 parts of 12.5%|
500 mg x ° ' l m L = 0.2mL
250 mg
In a total of 4.0 parts of 12.5% product, 3.5 parts of
12% ointment and 0.5 parts of 16% ointment are
Volume of the diluent required = (2 mL of suspension) needed.
- (0.2 mL of Ceftriaxone Sodium) =1.8 mL.
4 parts correspond to 1 kg or 1000 g
1 part corresponds to 250 g 2. How many mL of 20% dextrose in water and 50% dex-
3.5 parts correspond to 3.5 x 250 g or 875 g
trose in water?
0.5 parts correspond to 0.5 x 250 g or 125 g
Let x be the volume, in mL, of the 20% solution, and let
2. How many mL of 20% dextrose in water and 50% dex-
(750-x) be the volume in mL of the 50% solution. The
equation is as follows:
trose in water?
(20/100)JC + (50/100)(750 - JC) = (35/100)(750)
(higher) 50% 15 parts of 50% Solving the equation, JC equals 375 mL of the 20% solution
35% and (750 - x) equals (750 - 375) or 375 mL of the 50% so-
(desired) lution.
\ MOLAR, MOLAL, AND NORMAL CONCENTRATIONS
|(lower) 20%| 15. parts of 20%
|30 parts of 35%|
See Concentrations in the General Notices (3).
Molarity—The molar concentration, M, of the solution is
the number of moles of the solute contained in one liter of
solution.
In a total of 30 parts of 35% dextrose in water, 15 parts Molality—The molal concentration, m, is the number of
of 50% dextrose in water and 15 parts of 20% dextrose moles of the solute contained in one kilogram of solvent.
in water are required. Normality—The normal concentration, N, of a solution
expresses the number of milliequivalents (mEq) of solute
contained in one mL of solution or the number of equiva-
15 parts correspond to 375 mL. lents (Eq, gram-equivalent weight) of solute contained in
one liter. When using normality, the pharmacist must apply
Thus use 375 mL of the 20% solution and 375 mL of quantitative chemical analysis principles using molecular
the 50% solution to prepare the product. weight (MW). Normality depends on the reaction capacity
Algebra—Instead of using alligation to solve the above of a chemical compound and therefore the reaction capacity
problems, algebra may be used, following the scheme out- must be known. For acids and bases, reaction capacity is the
lined below.
number of accessible protons available from, or the number
of proton binding sites available on, each molecular aggre-
In order to represent the total amount (weights, parts, or gate. For electron transfer reactions, reaction capacity is the
volumes) of the final mixture or solution, 1 or a specified number of electrons gained or lost per molecular aggregate.
amount is used.
Let x be the amount of one portion and [1 (or the specified
EXAMPLES—
amount) - x] be the remaining portion. Set up the equation
1. How much sodium bicarbonate powder is needed to
according to the statement below, and solve.
prepare 50.0 mL of a 0.07 N solution of sodium bicar-
bonate (NaHCO3)? (MW of NaHCO3 is 84.0 g per mol.)
The amount in one part plus the amount in the other part
equals the total amount in the final mixture or solution. In an acid or base reaction, because NaHCO3 may act as
an acid by giving up one proton, or as a base by accept-
EXAMPLES— ing one proton, one Eq of NaHCO3 is contained in each
1. How much ointment having a 12% drug concentration mole of NaHCO3. Thus the equivalent weight of NaH-
and how much ointment having a 16% drug concentra- CO3 is 84 g. [NOTE—The volume, in liters x normality
tion must be used to make 1 kg of a preparation contain- of a solution equals the number of equivalents in the
ing a 12.5% drug concentration? solution.]
Let 1 kg be the total amount of ointment to be prepared, The number of equivalents of NaHCO3 required = (0.07
let x be the quantity, in kg, of the 12% ointment, and let Eq/L)(50.0 mL/1000 mL /L) = 0.0035 equivalents.
(1 — JC) be the quantity, in kg, of the 16% ointment. The
equation is as follows: 1 equivalent weight is 84.0 g.
(12/100) x + (16/100)(l - x) =02.5/100)(l) 0.0035 equivalents equals 84.0 g/Eq x 0.0035 Eq =

0.294 g.
2. A prescription calls for 250 mL of a 0.1 N hydrochloric
Solving the equation, JC equals 0.875 kg of the 12% ointment acid (HC1) solution. How many mL of concentrated hy-
and (1 - JC) equals (1-0.875) or 0.125 kg of the 16% oint- drochloric acid are needed to make this solution?
ment. [NOTE—The specific gravity of concentrated hydro-
chloric acid is 1.18, the molecular weight is 36.46
and the concentration is 37.5% (w/w) (5). Because hy- 2. Calcium (Ca2+) has a gram-atomic weight of 40.08.
drochloric acid functions as an acid and reacts by giv- Calculate its milliequivalent weight (mEq wt).
ing up one proton in a chemical reaction, 1 Eq is
contained in each mole of the compound. Thus the Eq wt = 40.08 g/2 = 20.04 g
equivalent weight is 36.46 g.] mEq wt. = 20.04 g/1000 = 0.02004 g = 20.04 mg
The number of equivalents of HC1 required is 0.250 L NOTE—The equivalent weight of a compound may be
x 0.1 N = 0.025 equivalents. determined by dividing the molecular weight, in g, by
the product of the valence of either relevant ion and the
1 equivalent is 36.46 g.
number of times this ion occurs in one molecule of the
0.025 equivalents correspond to 0.025 Eq x 36.46 g/Eq compound (12).
= 0.9115 g. 3. How many milliequivalents of potassium ion (K+) are
there in a 250-mg Penicillin V Potassium Tablet?
37.5 g of pure HC1 are contained in 100 g of concen- [NOTE—Molecular weight of penicillin V potassium
trated HC1. is 388.48 g per mol; there is one potassium atom in
Thus 1 g of pure HC1 is contained in (100/37.5) g the molecule; and the valence of K+ is 1.]
=2.666 g of concentrated acid, and 0.9115 g is con- Eqwt = 388.48 g/[l (valence) x 1 (number of charges)]
tained in (0.9115 x 2.666) g or 2.43 g of concentrated
= 388.48 g.
acid.
mEq wt = 388.48 g/1000 = 0.38848 g = 388.48 mg.
In order to determine the volume of the supplied acid
required, use the definition for specific gravity as (250 mg per Tablet)/(388.48 mg per mEq) = 0.644 mEq
shown below. of K+ per Tablet.
4. How many equivalents of magnesium ion and sulfate
Specific gravity = (weight of the substance) / (weight of ion are contained in 2 mL of a 50% Magnesium Sulfate
an equal volume of water).
Injection? (Molecular weight of MgSO 4 -7H 2 O is
1.18 = 2.43 g / (weight of an equal volume of water) 246.48 g per mol.)
The weight required is 2.056 g or 2.06 g. Amount of magnesium sulfate in 2 mL of 50% Magne-
sium Sulfate Injection =
MlLLIEQUIVALENTS AND MlLLIMOLES
NOTE—This section addresses milliequivalents (mEq)
and millimoles (mmol) as they apply to electrolytes for do- 50 g of magnesium sulfate _
sage calculations. = 2 mL of Inj ection x
100 mL of Injection
The quantities of electrolytes administered to patients are
usually expressed in terms of mEq. This term must not be
confused with a similar term used in quantitative chemical
analysis as discussed above. Weight units such as mg or g Eq wt of MgS04 • 7H20 = MW (g)/(valence of speci-
are not often used for electrolytes because the electrical fied ion x number of specified ions in one mole of salt)
properties of ions are best expressed as mEq. An equivalent
is the weight of a substance (equivalent weight) that sup-
plies one unit of charge. An equivalent weight is the weight, For the magnesium ion:
in g, of an atom or radical divided by the valence of the atom
or radical. A milliequivalent is one-thousandth of an equiva- The number of equivalents = 246.48/2(valence) x 1
lent (Eq). Because the ionization of phosphate depends on (number of ions in the compound) = 123.24 g/Eq of
several factors, the concentration is usually expressed in magnesium ion.
millimoles, moles, or milliosmoles which are described be- The number of equivalents in 1 g is lg/123.24 g/Eq =
low (3). [NOTE—Equivalent weight (Eq.wt) = wt. of an 0.008114 Eq
atom or radical (ion) in g/valence (or charge) of the atom
or radical. Milliequivalent weight (mEq.wt) = [Eq.wt. (g)]/ The number of mEq may be calculated as follows.
1000. The mEq wt = Eq wt (g)/1000 = (123.24 g/Eq)/1000
= 0.12324 g.
EXAMPLES—
1. Potassium (K+) has a gram-atomic weight of 39.10. The The number of equivalents of magnesium ion in 1 g is
valence of K+ is 1+. Calculate its milliequivalent weight lg/0.12324 g/mEq = 8.114 mEq.
(mEq wt).
Eqwt = 39.10 g/1 = 39.10 g
mEq wt = 39.10 g/1000 = 0.03910 g = 39.10 mg
For the sulfate ion: ISOOSMOTIC SOLUTIONS
The number of equivalents = 246.48/2 (valence) x 1 The following discussion and calculations have therapeu-
(number of ions in the compound) = 123.24 g / Eq of tic implications in preparations of dosage forms intended for
sulfate ion. ophthalmic, subcutaneous, intravenous, intrathecal and neo-
natal use.
The number of equivalents in 1 g is 1 g /123.24 g / Eq = Cells of the body, such as erythrocytes, will neither swell
0.008114 Eq. nor shrink when placed in a solution that is isotonic with the
body fluids. However, the measurement of tonicity, a phy-
The number of mEq may be calculated as follows. siological property, is somewhat difficult. It is found that a
The mEq wt = Eq wt (g)/1000 = (123.24 g/Eq) / 1000 0.9% (w/v) solution of sodium chloride, which has a freez-
= 0.12324 g. ing point of-0.52 °C, is isotonic with body fluids and is said
to be isoosmotic with body fluids. In contrast to isotonicity,
The number of equivalents of sulfate ion in 1 g is 1 g / the freezing point depression is a physical property. Thus
0.12324 g/mEq = 8.114 mEq. many solutions which are isoosmotic with body fluids are
A vial of Sodium Chloride Injection contains 3 mEq of not necessarily isotonic with body fluids, e.g., a solution
sodium chloride per mL. What is the percentage of urea (14). Nevertheless many pharmaceutical products
strength of this solution? (Molecular weight of sodium are prepared using freezing point data or related sodium
chloride is 58.44 g per mol.) chloride data to prepare solutions which are isoosmotic with
1 mEq = 1 Eq/1000 = 58.44 g/1000 = 0.05844 g = the body fluids. A closely related topic is osmolarity (see
58.44 mg. Osmolarity (785) [3]).
Freezing point data or sodium chloride equivalents of
Amount of sodium chloride in 3 mEq per mL = 58.44 Pharmaceuticals and excipients (see Table 1 below) may
mg per mEq x 3 mEq per mL = 175.32 mg per mL. be used to prepare isoosmotic solutions, as shown in the ex-
Weight percent of sodium chloride = amples below.
175.32 mg 17532mg 17.532g Table 1. Sodium Chloride Equivalents (E) and
= 17.5%
lmL 100 mL lOOmL Freezing Point (FP) Depressions for a 1% Solution
of the Drug or Excipent (15,16)
Using mols and mmols— Drug or Excipient FP Depression
A number of countries (4, 13) have adopted the Interna- Atropine sulfate 0.13 0.075
tional System of Units and no longer calculate doses using Sodium chloride 1.00 0.576
mEq as described above, but instead use the terms moles
(mol) and millimoles (mmol). In USP 25-NF 20 (3), the In-
EXAMPLES—
ternational System of Units is used except for the labeling of
electrolytes Determine the amount of sodium chloride required to
prepare 60 mL of an isoosmotic solution of atropine
Definitions—
sulfate 0.5% using the sodium chloride equivalent va-
A mole equals one gram atomic weight or gram molecu-
lues and also the freezing point depression values.
lar weight of a substance.
A millimole equals 1/1000 of a mole (3). Using the sodium chloride equivalent values—
EXAMPLES—
The total amount of substances equivalent to sodium
1. Potassium (K) has a gram-atomic weight of 39.10. Cal- chloride (for a 0.9% solution) = (0.9 g/100 mL) x 60
culate its weight in millimoles (mmol). mL = 0.54 g.
The weight of one mole is 39.10g and the weight in The amount of atropine sulfate required = (0.5 g/100
millimoles is 39.10 g/1000 =0.0391 g or 39.1 mg. mL) x 60 mL = 0.3 g.
2. How many millimoles of PenicillinV are in a tablet that 1 g of atropine sulfate is equivalent to 0.13 g sodium
contains 250 mg of PenicillinV Potassium? (Molecular chloride.
weight of penicillin V potassium is 388.48 g per mol.)
0.3 g atropine sulfate is equivalent to 0.3 x 0.13 g =
The weight of one mole is 388.48 and the weight in 0.039 g of sodium chloride.
millimoles is 388.48/1000 = 0.3848 g or 388.48 mg.
Thus there are 250 mg/388.48 mg/mmol = 0.644 mmol Thus the required amount of sodium chloride is 0.54 -
of PenicillinV ion per tablet. 0.039 = 0.501 g or 0.50 g.
Using freezing point depression values— 18.85 ug are contained in 250 mL x 18.85/50000 =
0.09425 mL D5W, which is administered every minute.
The freezing point depression required is 0.52° C.
In 1 minute, 0.09425 mL are administered.
A 1% solution of atropine sulfate causes a freezing
point depression of 0.075 CC. In 1 hour or 60 minutes, 60 x 0.09425 mL =5.655 or
5.7 mL are administered.
A 0.5% solution of atropine sulfate causes a freezing
point depression of 0.075 °C - 0.5 = 0.0375°C. Calculate the flow rate in drops per minute.
The additional freezing point depression required is 1 mL provides 50 drops per minute.
0.52 °C - 0.0375 °C = 0.482 °C. 0.09425 mL provides 0.09425 x 50 = 4.712 or 4.7
A 1% solution of sodium chloride causes a freezing drops per minute.
point depression of 0.576 °C. TEMPERATURE
A (l%/0.576) solution of sodium chloride causes a The relationship between Celsius degrees (°C) and Fah-
freezing point depression of 1 °C renheit degrees (°F) is expressed by the following equation:
A (l%/0.576) x 0.482 = 0.836% solution of sodium 9(°C) = 5 ( ° F ) - 1 6 0 ,
chloride causes a freezing point depression of 0.482 °C. in which °C and °F are the numbers of Celsius degrees and
Fahrenheit degrees, respectively.
The required amount of sodium chloride is (0.836 g/
100 mL) x 60 mL = 0.502 g or 0.50 g
EXAMPLES—
FLOW RATES IN INTRAVENOUS SETS
1. Convert 77 °F to Celsius degrees.
Some calculations concerning flow rates in intravenous
sets are provided below (7 7). [NOTE—Examples below 9(°C) = 5(°F)-160
are noj to be used for treatment purposes.] °C = [5(°F) - 160]/9 = [(5 x 77) - 160]/9 = 25 °C
2. Convert 30 °C to Fahrenheit degrees.
EXAMPLES—
1. Sodium Heparin 8,000 units in 250 mL of Sodium 9(°C) = 5(°F)-160
Chloride Injection 0.9% solution are to be infused over °F = [9(°C) + 160]/5 = [(9 x 30) + 160]/5 = 86 °F
4 hours. The administration set delivers 20 drops per
mL. The relationship between the Kelvin and the Celsius
scales is expressed by the equation:
What is the flow rate in mL per hour?
K = ° C + 273.1,
In 4 hours, 250 mL are to be delivered. in which K and °C are the numbers of Kelvin degrees and
In 1 hour, 250 mL/4 = 62.5 mL are delivered. Celsius degrees, respectively.
What is the flow rate in drops per minute? APPLICATION OF MEAN KINETIC TEMPERATURE
In 60 minutes, 62.5 mL are delivered. See Stability under Pharmaceutical Dosage Forms
(1151) (3) for the definition of mean kinetic temperature
In 1 minute, 62.5 mL/60 = 1.04 mL are delivered. (MKT). MKT is usually higher than the arithmetic mean
1 mL = 20 drops. temperature and is derived from the Arrhenius equation.
MKT addresses temperature fluctuations during the storage
1.04 mL = 1.04 x 20 drops = 20.8 drops. period of the product. The mean kinetic temperature, TK, is
Thus in 1 minute, 20.8 or 21 drops are administered. calculated by the following equation:
2. A 14.5 kg patient is to receive 50 mg of Sodium Nitro-
prusside in 250 mL of dextrose 5% in water (D5 W) at
the rate of 1.3 ug per kg per minute. The set delivers 50 -AH
drops per mL. R
T = e-AH/RT, +e-AH/RT2
Calculate the flow rate in mL per hour.
The dose for 1 kg is 1.3 ug per minute.
The 14.5 kg patient should receive 14.5 x 1.3 ug =
18.85 ug per minute. in which AH is the heat of activation, which equals 83.144
kJ per mol (unless more accurate information is available
50 mg or 50000 ug of drug are contained in 250 mL of
from experimental studies); R is the universal gas constant,
D5W.
which equals 8.3144 x 10"3 kJ per degree per mol; T{ is the
average temperature, in degrees Kelvin, during the first time

period, e.g., the first week; T2 is the average temperature, in
degrees Kelvin, during the second time period, e.g., second -10,000K
33M5
week; and Tn is the average temperature, in degrees Kelvin 52xe ' \
during the nih time period, e.g., nth week, n being the total
52
number of temperatures recorded. The mean kinetic tem-
perature is calculated from average storage temperatures re-
corded over a one-year period, with a minimum of twelve
equally spaced average storage temperature observations
being recorded (1151) (3). This calculation can be per-
-10,000K
formed manually with a pocket calculator or electronically = 298.1K = 25.0°C
by using computer software. -33.5458
EXAMPLES—
1. The means of the highest and lowest temperatures for
52 weeks are 25 °C each. Calculate the MKT. The calculated MKT is 25.0 °C. Therefore the con-
trolled room temperature requirement is met by this
n = 52 pharmacy.
AH/R= 10,000 K NOTE—If the averages of the highest and lowest
weekly temperatures differed from each other and were
Tu T2, ...., Tn = 25 °C = 273.1 + 25 = 298.1 K in the allowed range of 15 °C to 30 °C (see Controlled
/? = 0.0083144 kjK-'mol-1 Room Temperature under Preservation, Packaging,
Storage, and Labeling in the General Notices) (3), then
A / / = 83.144 kJ per mol each average would be substituted individually into the
equation. The remaining two examples illustrate such
calculations, except that the monthly averages are used.
-AH A pharmacy recorded a yearly MKT on a monthly ba-
R sis, starting in January and ending in December. Each
7' month, the pharmacy recorded the monthly highest
K ~
temperature and the monthly lowest temperature, and
the average of the two was calculated and recorded
for the MKT calculation at the end of the year.
•I0,000K
52
Table 2. Data for Calculation of MKT

Lowest Highest Average Average
Temperature Temperature Temperature Temperature
n Month (in °C) (in °C) (in °C) (inK) AH/RT Q-Afl/RT
1 Jan. 15 27 21 294.1 34.002 1.710 x io- 15

2 Feb. 20 25 22.5 295.6 33.830 2.033 x io- 15
3 Mar. 17 25 21 294.1 34.002 1.710 x io- 15
4 Apr. 20 25 22.5 295.6 33.830 2.033 x io- 15
5 May 22 27 24.5 297.6 33.602 2.551 x io- 15
6 June 15 25 20 293.1 34.118 1.523 x io- 15
7 July 20 26 23 296.1 33.772 2.152 x io- 15
8 Aug. 22 26 24 297.1 33.659 2.411 x io- 15
9 Sept. 23 27 25 298.1 33.546 2.699 x io- 15
10 Oct. 20 28 24 297.1 33.659 2.411 x io- 15
11 Nov. 20 24 22 295.1 33.887 1.919 x io- 15
12 Dec. 22 28 25 298.1 33.546 2.699 x io- 15
From these data the MKT may be estimated or it may n=\2

be calculated. If more than half of the observed tem-
peratures are lower than 25 °C and a mean lower than -AH
23 °C is obtained, the MKT may be estimated without
T = R
performing the actual calculation. 1
K
-AH/RT, . -AH/RT, -AH/RT,,
a. To estimate the MKT, the recorded temperatures

are evaluated and the average is calculated. In this case,
the calculated arithmetic mean is 22.9 °C. Therefore,
the above requirements are met and it can be concluded
that the mean kinetic temperature is lower than 25 °C. -AH
Therefore, the controlled room temperature require- R
ment is met. .1) + j -A///(/b<30U)
b. The second approach is to perform the actual cal- 12

culation.
«=12
-10,000K
-AH 12
T — R
1
K ~
-10,000K
2.9692xl0" 14 +3.7705xl0" 1 \
12
-10,000K
-10,000K
12 3.3463X10"
12
-10,000K -10,000K
,2.585xlO-' /«(2.7886xl0"15)
12
-10,000K
= 298.39K=25.29°C
-33.513
-lO.OOOK
= 296.1 IK = 23.0°C
-33.771 The controlled room temperature requirement is not met
because the calculated MKT exceeds 25 °C. (See Note in
example 2 above.)
The calculated MKT is 23.0 °C, so the controlled room
temperature requirement is met. REFERENCES
NOTE—These data and calculations are used only as an 1. First Supplement to USP 24 and to NF 19; United
example. States Pharmacopeial Convention, Inc.: Rockville,
An article was stored for one year in a pharmacy where MD, 1999; p 2698.
the observed monthly average of the highest and lowest 2. Agenda: Compounding Pharmacy Expert Committee
temperatures was 25 °C (298.1 K), except for one Meeting, Aug., 22, 2001; pp 58-71.
month with an average of 28 °C (301.1 K). Calculate 3. USP25-NF 20, 2002.
the MKT of the pharmacy.
4. Ansel, H.C.; Stoklosa, M.J., 11th ed.; Lippincott, Wil- 11. Martindale, 32nd ed.; Pharmaceutical Press, K.Parfitt
liams and Wilkins: Philadelphia, 2001; pp 23, 63- ed., London, 1999, p204, pl464, pi612 (pancreatin
91,172. dose).
5. DeLuca, P.P.; Boylan, J.C. Pharmaceutical Dosage 12. Tsallas, G. in Total Parenteral Nutrition in the Hospital
Forms: Parenteral Medications, 2nd ed.; K.E.Avis, and at Home, Jeejeebhoy, K.N., ed.; CRC Press: Boca
H.A.Lieberman and L.Lachman, Eds.; Dekker: New Raton, FL, 1983, pp 225-231.
York, 1992; Vol. I,pl94. 13. The SI Manual in Health Care, 2nd ed.; Health and Wel-
6. Niebergall, P.J.; in Remington:The Science and Prac- fare, Metric Commission: Canada, 1982.
tice of Pharmacy, 20th ed.; A.R.Gennaro, ed.; Lippin- 14. Steadman 's Medical Dictionary, 24th ed.; Williams and
cott,Williams and Wilkins: Baltimore, 2000, p 241. Wilkins: Baltimore, 1982, p 732.
7. Martin, A.; Swarbrick J.; Cammarata, A. Physical Phar- 15. Reich, I.; Poon, C.Y.; Sugita, E.T. in Remington: The
macy, 3rd ed.; Lea and Febiger: Philadelphia, 1983, pp Science and Practice of Pharmacy, 20th ed.; Gennaro,
227, 232. A.R. ed.; Lippincott,Williams and Wilkins: Baltimore,
8. Reich, I.; Schnaare, R.L.; Sugita, E.T. in Remington: 2000, pp 256, 260.
The Science and Practice of Pharmacy, 20lh ed.; Gen- 16. Merck Index, 12th ed.; Budavari S., ed; Merck: White-
naro, A.R., ed.; Lippincott,Williams and Wilkins: Bal- house Station, NJ, 1996, p 47-57.
timore, 2000, pp 110-111. 17. Thompson, J.E., A Practical Guide to Contemporary
9. Taketmoto, C.A.; Hodding, J.H.; Kraus, D.M. Pediatric Pharmacy Practice, Williams and Wilkins: Baltimore,
Dosage Handbook, 7th ed.; Lexi-Comp, Hudson: Cle- 1998, pp 32.7, 32.13.
veland, 2000, p 1092.
10. USP DI2001, 21st ed.; pl278.
NOMENCLATURE
This section includes supplements to the latest edition of the USP Dictionary of USAN and International Drug Names that
incorporate new United States Adopted Names (USAN) and revisions to existing Dictionary names. Also listed are Proposed
and Recommended International Nonproprietary Names (INN) when they have been announced by the World Health Orga-
nization.
Possible names suggested for use as USAN and INN are listed for public review and comment along with information on how
nonproprietary names are devised. In addition, readers may find articles relevant to current compendial nomenclature issues
that also occasionally report on related matters pertaining to USAN and INN.
Pharmacopeial Forum
676 NOMENCLATURE Vol. 28(2) [Mar.-Apr. 2002]
USP Dictionary of USAN and International Drug Names

2001 USP DICTIONARY SUPPLEMENT 5
IMPORTANT—Save this Supplement. This and all supplements appearing in PF are needed to keep the 2001 edition of
the USP Dictionary (USPD) up to date. The cumulative contents of the supplements to the current (2001) edition will be
included in the next complete edition of the Dictionary.
New United States Adopted Names (USAN)

The following are newly established United States Adopted Names (USAN). These names will not be listed cumulatively; see preceding
and succeeding numbers of PF for other new USAN to supplement the Dictionary main volume.
Alvameline Maleate [2002] (al va mel' een). C 9 H ]5 N 5 • C4H4O4. Merimepodib [2002] (me ri me' poe dib). C2?H24N4O6. 452.50.
309.40. Pyridine, 3-(2-ethyl-2//-tetrazol-5-yl)-l,2,5,6-tetra- (1) Carbamic acid, [[3-[[[[3-methoxy-4-(5-oxazolyl)phenyl]
hydro-1-methyl-, (2Z)-2-butenedioate (1:1). CAS-219581- amino]carbonyl]amino]phenyl]methyl]-, (35)-; (2) (5)-Tetra-
36-9. A partial M,agonist and M-JMântagonist. (H. Lund- hydro-3-furyl [m-[3-[3-methoxy-4-(5-oxazolyl)phenyl]urei-
beck, A/S; Forest Laboratories) <?Lu 25-109-M do]benzyl]carbamate. CAS-198821-22-6. Inhibition of
inosine monophosphate dehydrogenase (IMPDH), which as
potential antiviral, antiproliferative, antiparasitic, and immu-
Atazanavir Sulfate [2002] (at a za na' veer). C3gH52N6O7 • H2 nosuppressive activity. (Vertex) ^VX-497; VI-21,497
SO,. 801.94. (1) 2,5,6,10,13-Pentaazatetradecanedioic acid,
3-12-bis(l, 1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phe-
nylmethyl)-6-[[-4-(2-pyridinyl)phenyl]methyl]-, dimethyl es- Mitemcinal Fumarate [2002] (mye tern' cin al).
ter, (35,85,95,125)-, sulfate (1:1) (salt); (2) Dimethyl C^H^NO,;, • !/2(C4H4O4). 814.02. (1) Erythromycin, 8,9-di-
(35,85,95,125)-9-benzyl-3,12,di-ter/-butyl-8-hydroxy-4,11 - denyaro-//-demethyl-9-deoxo-6,ll-dideoxy-6,9-epoxy-12-
dioxo-6-(p-2-pyridylbenzyl)-2,5,6,10,13-pentaazatetradeca- O-methyl A^-(l-methylethyl)-ll-oxo-, (2£)-2-butenedioate
nedioate, sulfate (1:1) (salt). CAS-229975-97-7. Treatment of (2:1); (2) 8,9-Didehydro-A^-demethyl-9-deoxo-6,ll-dideoxy-
acute and chronic HIV infection {HIVprotease inhibitor). 6,9-epoxy-iV-isopropyl-12-(l?-methyl-l 1- oxoerythromycin
(Bristol-Myers Squibb) ^BMS-232632-05 fumarate (2:1) (salt). CAS-154802-96-7. Treatment ofgastro-
paresis; gastroesophageal reflux disease (motilin receptor
agonist). (Chugai Pharmaceutical Co., Ltd., Japan) <>GM-
Fadolmidine Hydrochloride [2002] (fa dol' mid ine). 611; 5-1 Ukima 5 Chome; Kita-ku Toyko; 115-8543 Japan
C^H^NÔ • HC1. 250.70. (1) l/7-Inden-5-ol, 2,3-dihydro-3-
(li/-imidazol-4-ylmethyl)-, monohydrochloride; (2) 3-(Imi-
dazol-4-ylmethyl)-5-indanol monohydrochloride. CAS- Onsifocon A [2002] (on si foe' kon). ( C ^ H ^ O ^ /
189353-32-0. Spinal analgesic (p^-adrenoreceptor agonist). ( C l 0 % 0 O 5 S00 u ( C 4 H NC6 O 2 ) v ( C 2;6 H 5 8 O 9 S i , ) w ( C ; 0 H U ^
(Orion Corporation, Finland) <>MPV-2426 O3) (C.H9NO)Z. (1) 2-Propenoic acid, 2-methyl-, polymer
with 1,2-ethanediyl bis(2-methyl-2-propenoate), 1-ethenyl-
2-pyrrolidinone, 2-hydroxyethyl 2-methyl-2-propenoate,
Flindokalner [2002] (flin doe kal' ner). Clf-H,0ClF4NO2. 359.71. [1,1,3,3-tetrakis[(trimethylsilyl)oxy]-l ,3-disiloxanediyl]di-
(1) 2//-Indol-2-one, 3-(5-chloro-2-metnoxyphenyl)-3-fluoro- 3,1-propanediyl bis(2-methyl-2-propenoate), 2,2,2-trifluor-
l,3-dihydro-6-(trifluoromethyl)-, (35)-; (2) (35)-3-(5-Chloro- oethyl 2-methyl-2-propenoate, 3-(trimethoxysilyl)propyl 2-
2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-l,3-dihydro- methyl-2-propenoate and 3-[3,3,3-trimethyl-l,l-bis[(tri-
2//-indol-2-one. CAS-187523-35-9. Neuroprotectant (opener methylsilyl)oxy]disiloxanyl]propyl 2-methyl-2-propenoate;
of large conductance, calcium-activated (maxi-K) K* chan- (2) Trifluoroethyl methacrylate polymer with tris(trimethylsi-
nels. MaxiPost (Bristol-Myers Squibb) <?BMS-204352 loxy)methacryloxypropylsilane 3-trimethoxysilylpropyl
methacrylate methacrylic acid l,3-bis(3-methacryloxypro-
pyl)tetrakis(trimethylsiloxy)disiloxane ethylene glycol di-
Indiplon [2002] (in' di plon). C20H16N4O2S. 376.43. (1) N- m e t h a c r y l a t e 2 - h y d r o x y e t h y l m e t h a c r y l a t e N-
Methyl-JV-[3-[3-(2-thienylcarbonyl)-pyrazolo[ 1,5-a]pyrimi- vinylpyrrolidone. CAS-311330-20-8. Contact lens material
din-7-yl]phenyl]acetamide; (2) iV-Methyl-A43-3-(thiophen- (hydrophobic). (La Jolla) [Note—The water content of the
2-ylcarbonyl)pyrazolo[l,5-a]pyrimidin-7-yl]phenyl]aceta- contact lens material is < 0.2% at ambient temperature
mide; (3) 3-(2-Thienylcarbonyl)-7-(3-iV-methylacetamide)- (23±2°C), and the oxygen permeability is 57 x 70"11
pyrazolo[l,5-a]pyrimidine. CAS-325715-02-4. Sedative/hyp- ( ^ X l O2/ml x mm Hg) at 35°C (Dk value).]
notic (GABA ..agonist). (Neurocrine Biosciences Inc.; Organi-
chem) ^NBI-34060
Sibenadet Hydrochloride [2002] (si ben' a det).
C
Lonafarnib [2002] (loe na far' nib). C^Hj.Br.ClNXL. 638.84. 22 H 28 N 2°5 S 2" HC1> 5 0 L 0 7 - 0 ) 2 (3//)-Benzothiazolone, 4-
(1) 1-Piperidinecarboxamide, 4-[2-[4-t( 112^-3,10-dibromo-8- hydroxy-7-[2-y;2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]
chloro-6,11 -dihydro-5//-benzo[5,6]cyclohepta[l ,2-6]pyridin- aminojethyl]-, monohydrochloride; (2) 4-Hydroxy-7-[2-[2-
ll-yl]-l-piperidinyl]-2-oxoethyl]-; (2) (+)-4-[2-[4-(ll/?)- [3 -phenylethoxy-propane-1 -sulfonyl]-ethylamino]ethyl]-3//-
3,10-Dibromo-8-chloro-6,11 -dihydro-5/7-benzo[5,6]cyclo- benzothiazol-2-one, hydrochloride; (3) 4-Hydroxy-7-[2-[[2-
hepta[ 1,2-fe]pyridin-11 -yl)-piperidin-1 -yl]]-2-oxoethyl]-pi- [[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl]-l,3-
peridine-1-carboxamide. CAS-193275-84-2. benzothiazol-2(3//)-one, hydrochloride. CAS-154189-24-9.
Chemotherapeutic (farnesyl transferase inhibitor). (Scher- Treatment of symptoms of Chronic Obstructive Pulmonary
ing-Plough Research) <>SCH 66336 Disease. Viozan (AstraZeneca) OAR-C68397AA
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] NOMENCLATURE 677
Tebanicline Tosylate [2001] (te ban' i kleen). C 9 H n ClN 2 O- sion HPLC, other methods yield different results). CAS-
C7H19C>3S. 370.85. (1) Pyridine, 5-[(2$)-2-azetidinyl- 225239-31-6. In vivo diagnostic for imaging sites of infection
methoxy]-2-chloro-, mono(4-methylbenzenesulfonate); (2) associated with polymorphonuclear neutrophil (PMN) accu-
5-[[(i?)-2-Azetidnyl]methoxy]-2-chloropyridine mono-/?-to- mulation. LeuTech® (Palatin Technologies, Inc.)
luenesulfonate. CAS-198283-74-8. Analgesic (cholinergic IgM; anti-SSEA-1; Tc 99m anti-SSEA-1; Tc99m RB5 IgM
channel modulator). (Abbott) [Name previously used: Ebani-
cline Tosylate.} Â-166594.47; ABT-594; A-165594 Tenivastatin Calcium [2002] (te ni' va sta tin). C^HygCaOj.,.
911.23 (anhydrous). (1) 1-Naphthaleneheptanoic acid, 8-(2,2-
Technetium Tc 99m Fanolesomab [2002] (fa noe les' oh mab). dimethyl-l-oxobutoxy)-l,2,6,7,8,8a-hexahydro-/3,6-dihy-
(1) Immunoglobulin M, anti-(human CD 15 (antigen)) (mouse d r o x y - 2 , 6 - d i m e t h y l - , calcium salt, (2:1), (pR,6
monoclonal RB5 u-chain), disulfide with mouse monoclonal R,\S,2S,6R,8S,SaR)-; (2) Calcium (3R,5R)-7-
RB5 light chain, pentamer, technetium-99mTc salt; (2) Immuno- [(15,25,6/?,85,8a/?)-8-(2,2-dimethylbutyryloxy)-2,6-di-
globulin M (mouse monoclonal RB5 n-chain anti-human methyl-l,2,6,7,8,8a-hexahydronaphthalen-l-yl]-3,5-dihy-
antigen CD 15), disulfide with mouse monoclonal RB5 light droxyheptanoate (1:2). CAS-151006-18-7 [anhydrous].
chain, pentamer, [99mTc]technetium salt. The molecular weight Antihyperlipidemic (HMG-CoA reductase inhibitor). (Merck)
is approximately 670,000 Daltons (measured by size exclu-
Pharmacopeial Forum
Revisions of United States Adopted Names (USAN)

The following are revisions of existing United States Adopted Names (USAN) and other names.
Carbamazepine
Change the chemical structure to read: Midaxifylline
Change the chemical structure to read:
Ensulizole [1999] (en sul' i zole). USP. C ^ H ^ N - A S . 274.30. (1)

l//-Benzimidazole-5-sulfonic acid-2-phenyl-; (2) 2-Phenyl-
benzimidazole-5-sulfonic acid. CAS-27503-81-7. [Name pre- Midostaurin
viously used: Phenylbenzimidazole Sulfonic Acid.] [Note— Change the chemical structure to read:
The International Cosmetic Ingredient (INCI) name for ensu-
lizole is phenylbenzimidazole sulfonic acid.]
Hydroxypropyl Methylcellulose (previously used name)—See

Hypromellose.
Hypromellose. USP. [Hydroxypropylmethylcellulose is JAN.] (1)

Cellulose, 2-hydroxypropyl methyl ether; (2) Cellulose hy-
droxypropyl methyl ether. CAS-9004-65-3. INN; BAN. Gen-
Teal (Ciba Vision, US Ophthalmics); Goniosol (Ciba Vision,
US Ophthalmics); Isopto Tears (Alcon); Methocel E, F, J, K
(Dow Chemical); Tearisol (Ciba Vision, US Ophthalmics);
Ultra Tears (Alcon); component of Biontears (Alcon); compo-
nent of Estivin II (Alcon); component of Isopto Frin (Alcon);
component of Tears Naturale (Alcon); component of Tears
Naturale II (Alcon); component of Tears Naturale Free (Al-
con) [Name previously used: Hydroxypropyl Methylcellu-
lose.]
USP DI Category: Pharmaceutic aid (suspending agent); phar-
maceutic aid (tablet excipient); pharmaceutic aid (viscosity-in- Motexafin Gadolinium
creasing agent). Change the pronunciation to read:
(moe texs' a fin)
Change to read: Change the name of the manufacturer to read:
(Pharmacyclics, Inc.)
Isoamyl Methoxycinnamate (previously used name)—See Ami-
loxate. Change to read:
Change to read: Octyl Methoxycinnamate (previously used name)—See Octinox-

ate.
Menthyl Anthranilate (previously used name)—See Meradimate.
Change to read:
Change to read:
Octyl Salicylate (previously used name)—See Octisalate.
Methyl Benzylidene Camphor (previously used name)—See Enza-
camene. Olamufloxacine
Midafotel
Pharmacopeial Forum
Change to read: Somatropin

Phenylbenzimidazole Sulfonic Acid (previously used name)—See FPTIPLSRLF DNAMLRAHRL HQLAFDTYQE FEEAYIPKEQ KYSFLQNPQT
Ensulizole. SLCFSESIPT PSNREETQQK SNLELLRISL LLIQSWLEPV QFLRSVFANS
LVYGASDSNV YDLLKDLEEG IQTLMGRLED GSPRTGQIFK QTYSKFDTNS
HNDDALLKNY GLLYCFRKDM DKVETFLRIV QCRSVEGSCGF
Piboserod
Tebipenem
Change the chemical name to read:
[ y y J
[(li?)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-
ene-2-carboxylic acid (2,2-dimethyl-l-oxopropoxy) methyl ester.
Trecetilide
Add the following chemical structure:
Repinotan
Trecetilide Fumarate
Sardomozide
Pharmacopeial Forum
Suggested United States Adopted Names
The United States Adopted Names (USAN) program is Submissions to the USAN Council are expected to con-
the specifically organized effort in the United States directed form to the established Guiding Principles2 and to be rea-
to producing simple and useful nonproprietary names for sonably free from conflict with other names, including
drugs while the drugs are still in the investigational stages. both trademarks and nonproprietary names. An effort is
The American Medical Association (AMA), the American made to discourage the occasional, undesirable practice of
Pharmaceutical Association (APhA), and the United States incorporating in trademarks the syllables used in an estab-
Pharmacopeial Convention (USPC) jointly sponsor the lished nonproprietary name, or syllables recommended for
USAN program with representation from the FDA. USAN. Such trademarks may act as a bar to the subsequent
adoption of appropriate nonproprietary names for closely re-
Each U.S. Adopted Name is chosen with the expectation
lated drugs.
that it will be suitable for prescribing and dispensing pur-
poses and for designation as the title of the monograph, The suggested nonproprietary names for the drugs de-
should the article be recognized in the official United States scribed in the following list are under consideration by the
Pharmacopeia or National Formulary. A measure of the USAN Council. The name(s) being considered for each
prestige and recognition of the value of the USAN program drug substance, and the applicable category, are separated
can be found in the following regulations published by the by double spacing from the name(s) and category for the
Commissioner of Food and Drugs and the Secretary of next listed drug substance. Where two or more names are
Health and Human Services in the Federal Register of Feb- being considered for the same drug substance, the names
ruary 1988. are single-spaced, and the applicable category term is writ-
ten only once to the right of the single-spaced group of
All who are concerned with the prescription,
names.
dispensing, use, sale or manufacture of drugs
may, in the absence of the designation of an of- Any comments or protests should be addressed to Sandra
ficial name by the FDA, rely on the current Van Laan, Technical Associate, USAN Council, American
compendial name or the U.S. Adopted Name Medical Association, 515 North State Street, Chicago, Illi-
(USAN) listed in this volume as being the estab- nois 60610.
lished name in accordance with the Federal Suggested USAN Category
Food, Drug, and Cosmetic Act.
Acamprosate Calcium Treatment of chronic alcohol de-
A formal procedure1 is followed by the USAN Council in pendency
selecting an established name for a drug. The USAN Coun- Aclanermin Treatment of immunodeficien-
cil Secretary is also an ex officio member of the Interna- Aplinermin cies
tional Nonproprietary Names (INN) Committee. USAN Arednermin
Atlanermin
Guiding Principles are concordant with World Health Orga-
nization (WHO) principles, and all USANs for substances Acromeximab Treatment of melanoma
also named by the INN Committee are systematically pro- Ecromeximab
Elimeximab
cessed through the INN Committee. This ensures that, with
very rare exceptions, USANs are identical to INNs and Adafloxacin Antibacterial
available for world-wide use. Bitofloxacin
Desquinoxacin
A suggestion for a USAN originates usually from a firm Garenoxacin
Grenoxacin
or an individual who has developed a substance of potential Panoxacin
therapeutic utility to the point where there is a distinct pos- Quifloxacin
sibility of its being marketed in the United States of Amer- Simfloxacin
ica. Occasionally, the initiative is taken by the USAN Adelizumab Antineoplastic
Council in the form of a request to parties interested in a Amelizumab
substance for which a nonproprietary name appears to be Apolizumab
Atuzumab
lacking. Haltuzumab
1
USP Dictionary of USAN and International Drug Names, Preface. Ibid., Appendix VII.
Pharmacopeia! Forum

Adepovan Antiatherosclerotic Axalizumab Monoclonal antibody
Luvaspion Complezumab
Complizumab
Afolipasim Antiatherogenic Culizumab
Afosilipam Eculizumab
Amodifosnate Ispelizumab
Amifolipam Ospelizumab
Amilipasim Pentazumab
Fosbenamide Volizumab
Fosbepamide Vololizumab
Foslipamide
Ibrilipam Baneliximab Treatment of autoimmune dis-
Ibrolipim Beneliximab eases and prevention of organ
Deneliximab transplant rejection
Algobastoc Antimitotic Teneliximab
/\lgODOalUC
Alnostoculin Batopitant Treats depression, emesis, pain
Balagostoc Cidopitant and asthma; a substance P
Cidanostoc Cilapitant (NKj) receptor antagonist
Cinostoculin Cilopitant
Tidanostoc Zylopitant
Allerbtinib Dihydrochloride Antineoplastic Bencadiol Calcium Atherosclerosis therapy and
Calertinib Dihydrochloride Locadiol Calcium treatment of lipoprotein disor-
Canertinib Dihydrochloride Nebacadiol Calcium ders
Denertinib Dihydrochloride
Panerbtinib Dihydrochloride Biciclounone Treatment of constipation
Panertinib Dihydrochloride Boloprostone
Quaderbtinib Dihydrochloride Lubiprostone
Nobiprostone
Alvimopan Treatment of bowel dysfunction Ubiciclonone
Benzimopan
Benzipramide Bidadenosil Coronary vasodilator
Penimopan Bidenolate
Phenyleridine Bidenosine
Bindenagon
Apaziquone Oncolytic Bindenoson
Epaziquone Binodenise
Indoaziquone Binodisine
Lindaziquone Binosaden
Proaziquone
Cantuzumab Mertansine Treatment of colorectal cancer,
Aplimersen Sodium Antineoplastic Mactuzumab Mertansine pancreatic cancer and other so-
Augmerosen Sodium Taptuzumab Mertansine lid tumor types that express the
Meragirsen Sodium C242 antigen
Meraugsen Sodium
Obclosen Sodium Caremtorib Antitumor agent; cytostatic
Oblicorsen Sodium Carolistat agent (cell cycle inhibitor)
Oblimersen Sodium Casorolimus
Oblocolsen Sodium Emtorolimus
Macitorstat
Aptastatin Treatment of age-related macu- Macrociclistat
Lenapanib lar degeneration disease Mactinistat
Pegaptanib Mactorolimus
Peglenapanib Saticrolimus
Venustatin Sirolimus Bidproate
Asedapine Maleate Antischizophrenic Carfoxiden Antiviral; immunosuppressant
Aseridone Maleate Furimpodib
Cloxepidone Maleate Furinpodimus
Mafinpodimus
Mefuriden
Merimapodib
Merimempodib
Merimepodib
Merimpodib
Pharmacopeial Forum

Carpolizumab Treatment of asthma E2F Decoligo Hexasodium Salt Prevention of graft failure
Etalizumab E2F Oligodecoy Hexasodium
Pascolizumab Salt
Rascolizumab
Deligoparin Sodium Anti-inflammatory
Cefidur Sodium Veterinary antibacterial Doligoparin Sodium
Cefistae Sodium Dolgiparin Sodium
Cefisteve Sodium Oligoparin Sodium
Cefivelin Sodium Roligoparin Sodium
Cefovecin Sodium
Cefovelin Sodium Delnostaurin Hydrochloride Antineoplastic
Ceftopizen Sodium Dionestaurin Hydrochloride
Ceftopozen Sodium Orapistaurin Hydrochloride
Ceftovecin Sodium Pirinostaurin Hydrochloride
Cethromycin Antibacterial Derhepartase Treatment of Hunter Syndrome
Cetiramycin Hepadermsulfatase
Dactromycin Idursulfase
Declomycin Idursulfatase
Rodelcomycin
Vectomycin Doconexent Ethyl Ester Hypolipidemic
Vectromycin Edocatex
Velectomycin Eidocate
Ethyl Doconexentate
Cidtuzumab Treatment of cancers of epithe- Ethyl Icosapentate
Cidtuzumab IL-2 lial origin Icodocotate
Cidtuzumab Interleukin-2 Icodonate
Cidtuzumabkin Icosapent Ethyl Ester
Epcamabkin Idocosanate
Epcamkinab Omega-3-acid Ethyl Esters
Epkinzumab Omega-3 Marine Triglycerides
Pectumuzmab IL-2
Pectuzumab Ebcitabine Antiviral used in treatment of
Pectuzumab Interleukin-2 Elacitabine hepatitis B infections
Pectuzumabkin Epcitabine
Tuctuzumab Tebocitabine
Tuctuzumab IL-2 Tepcitabine
Tuctuzumab Interleukin-2 Torcitabine
Tuctuzumabkin
Efaproxiral Enhacement of radiation ther-
Cinnaptin Hydrochloride Antidepressant apy
Elzasonan Hydrochloride
Inzasonan Hydrochloride Emepitant Antiemetic
Zelanasertan Hydrochloride Lopitant
Zelanosetan Hydrochloride
Zelanquen Hydrochloride Emglumegad Antianxiety; smoking cessation
Zinamoned Hydrochloride Emglumetag
Zinarasertan Hydrochloride Monglumetag
Zinonasetan Hydrochloride Monoglumetagon
Contafocon Hydrophobic contact lens mate- Enceptant Hydrochloride Treatment of hyperparathyroid-
Hycofocon rial Lomimcal Hydrochloride ism
Mocalcept Hydrochloride
Coslizumab Treatment of autoimmune dis- Necalcept Hydrochloride
Imlizumab ease Tecalcept Hydrochloride
Immunelizumab Tecalcet Hydrochloride
Siplizumab
Suplimzumab Ertiprotafib Antidiabetic
Suplizumab Ertiprotifib
Fluphosphokin
Critliximab Monoclonal antibody; treats al- Protyronique
Dalimimab lergic asthma Tyrotransphosin
Denliximab
Mylimimab Esopiclone Treatment of insomnia
Myliximab Eszopiclone
Valimimab Zopiclone
Pharmacopeial Forum

Estarezispin Treatment of sepsis Nemifitide Ditriflutate Antidepressant
Esvarespladib Netamiftide Ditriflutate
Esvarezispin Pemarelix Ditriflutate
Marespladib Penamelatide Ditriflutate
Merespladib Penameltide Ditriflutate
Mevarespladib Pentamide Ditriflutate
Tarespladib
Varespladib Methyl Osehzumab Monoclonal antibody
Relimumab
Fandosentan Potassium Treatment of primary pulmon- Selimumab
Polsentan Potassium ary arterial hypertension and Toralizumab
Vansentan Potassium secondary pulmonary hyperten- Torelizumab
sion Zelimumab
Fintolizumab Immunoregulatory agent to treat Zelizumab
Fontolizumab autoimmune diseases
Gammalizumab Pegfrinercept Anti-inflammatory; Immunomo-
Gandulizumab Pegivonercept dulator
Salcolizumab Pegmapenercept
Zafalizumab Pegrinercept
Pegsunercept
Flumiracoxib Antiarthritic Pegtronercept
Teraldecoxib Sitaxsentan Sodium
Folikadil Treatment of hair loss Perdecylbron Oxygen carrier
Naminidil Perflubrodec
Nekaminidil Perfludec
Furacoxib Analgesic; anti-inflammatory Pravalamer Sodium Antidarrheal
Thiocoxib Provalemer Sodium
Zocoxib Sodium Polystyrene
Trovelamer Sodium
Galiximab Monoclonal antibody
Naliximab Talaporfin Sodium For use in photodynamic ther-
Teliximab apy
Hemoglobin Crosraffimer Blood substitute Tarespladib Treatment of sepsis
Hemoglobin Raflimer Tarezispin
Hemogloraffimer Varespladib
Varezispin
Ifarestat Treatment of diabetic complica-
Indarestat tions Tecadenise Treatment of paroxysmal supra-
Indolerestat Tecadenoson ventricular tachycardia and rate
Indorestat Tecaraden control in atrial fibrillation and
Lidorestat Tecarden atrial flutter
Lindorestat Tecardisine
Tersodisine
Incetrapib Treatment of atherosclerosis Tersoladen
Intorcetrapine Xocadenoson
Liphibinol Xocaraden
Torcetrapib Xocarden
Transceptamine Xocardisine
Transcreptamine
Tilamycin Veterinary antibacterial
Indopagon Fumarate Antischizophrenic Triamycin
Molindore Fumarate Trisamycin
Moloxindore Fumarate Tulamycin
Oxindafren Fumarate Tulanamycin
Padoxinor Fumarate Tulanomycin
Palindore Fumarate Tulathromycin
Paloxindore Fumarate
Ximelagatran Antithrombotic agent
Levocarnitine Propyl Treatment of peripheral arterial
disease Zanaxaban Anticoagulant; antithrombotic
Zoxaxaban
Pharmacopeia! Forum
Suggested International Nonproprietary Names
International Nonproprietary Names (INN) are devised Suggested INN Category

by the World Health Organization (WHO). INNs for sub-
Ampomuctolin Treatment of rheumatoid arthri-
stances originating within the United States are applied for Eftamuctolin tis
through the USAN Council. INN and USAN Guiding Prin- Isbomuctolin
ciples are concordant, which assures that, with very few ex-
Apaziquone Oncolytic
ceptions, INNs and USANs are identical. Epaziquone
Under its charter, the WHO is empowered simply to re- Apixantrone Antineoplastic
commend specific actions or procedures to its Member
States. This limitation is incorporated into the WHO pro- Apolizumab Antineoplastic
gram concerned with the selection of international non- Asedapine Treatment of schizophrenia
proprietary names for pharmaceutical substances, in that Aseridone
the WHO first publishes the selected names as proposals Cloxepidone
("Proposed International Nonproprietary Names"). A peri- Axadol Analgesic
od of four months from the date of publication in WHO Axoladol
Drug Information is allowed for entering comments on, or Triadol
objections to, any proposal on the part of Member States or Bifenazolone Antipsychotic
other interested parties. In general, an objection reflects a Bifeprunox
belief that the proposal concerned is confusingly close to Bifoxadon
(i.e., conflicts with) a name already in use, perhaps in only Bindenoson Coronary vasodilator
a restricted area in which the party has a proprietary interest Binodisine
in the form of trademark rights. In the event that no objec-
Canertinib Antineoplastic
tion is received, the WHO proceeds with listing and publish-
ing the names so devised as recommendations ("Recom- Cantuzumab Mertansine Treatment of colorectal cancer,
mended International Nonproprietary Names"), which pancreatic cancer and other so-
lid tumor types that express the
many Member States then recognize as the sole or preferred C242 antigen
nonproprietary name for use within their respective terri-
tories. Caremtorib Antitumor agent; cytostatic
Casorolimus agent (cell cycle inhibitor)
The names for the drugs that are categorized in the fol- Sirolimus
lowing list are under consideration for the selection of Cefovecin Veterinary antibacterial
new Proposed International Nonproprietary Names. The
name(s) being considered for each drug substance, and the Cethromycin Antibacterial
Cetiramycin
applicable category, are separated by double spacing from
the name(s) and category for the next listed drug substance. Cidanostoc Antimitotic
Where two or more names are being considered for the same Tidanostoc
drug substance, the names are single-spaced, and the applic- Cilapitant Antidepressant
able category term is written only once to the right of the Cilopitant
single-spaced group of names.
Deligoparin Anti-inflammatory
Any comments or protests should be addressed to Sandra Doligoparin
Van Laan, Technical Associate, USAN Council, American Ecromeximab Treatment of melanoma
Medical Association, 515 North State Street, Chicago, Illi-
nois 60610. Eculizumab Monoclonal antibody
Suggested INN Category Elzasonan Antidepressant

Actamibe Sulfate Treatment of atherosclerosis Emglumegad Antianxiety; Smoking cessation
Alvimopan Treatment of bowel dysfunction
Pharmacopeial Forum
Suggested INN Category Suggested INN Category

Enecadin Neuroprotectant
Socaceron Palindore Fumarate Antischizophrenic
Socafluron
Zerafluron Pascolizurnab Treatment of asthma
Rascolizumab
Epicalcitol Antineoplastic
Pegaptanib Treatment of age-related macu-
Ertiprotafib Antidiabetic lar degeneration disease
Ertiprotofib
Pegsunercept Anti-inflammatory; immunomo-
Eszopiclone Treatment of insomnia dulator
Fandosentan Treatment of primary pulmon- Perflubrodec Oxygen carrier
ary arterial hypertension and
secondary pulmonary hyperten- Piperoxadine Cardiovascular therapy
Pyroxadine
Fintohzumab Treatment of autoimmune dis- Plevitrexed Treatment of solid tumors

Fontolizumab eases Vecletrexed
Fortataxel Antineoplastic
Iristotaxel Siplizumab Treatment of autoimmune dis-
Mutataxel eases
Garenoxacin Antibacterial Stebazumab Monoclonal antibody
Hemoglobin Raffimer Blood substitute Stctozumab
Tecadenoson Treatment of paroxysmal supra-
Ibrilipam Antiatherogenic Tecardisine ventricular tachycardia and
Ibrolipim rate control in atrialfibrillation
and atrial flutter
Idursulfase Treatment of Hunter Syndrome
Idursulfatase Tecalcept Treatment of hyperparathyroid-
Tecalcet ism
Lidorestat Treatment of diabetic complica-
Lindolrestat tions Teneliximab Treatment of autoimmune dis-
Lindorestat eases and prevention of organ
transplant rejection
Lubiprostone Treatment of constipation
Tilamycin Antibacterial (veterinary)
Merespladib Treatment of sepsis Tulamycin
Varespladib Tulathromycin
Merimepodib Antiviral; immunosuppresant Topixantrone Antineoplastic
Merimpodib
Toralizumab Monoclonal antibody
Naminidil Treatment of hair loss Torelizumab
Nemifitide Antidepressant Torcetrapib Treatment of atherosclerosis
Nptamiftidf*
Torcitabine Antiviral used in treatment of
Nortopixantrone Antineoplastic hepatitis B infection
Oblimersen Antineoplastic Triplatin Tetranitrate Antineoplastic
INDEX
This is a cumulative directory for the content of all issues of PF beginning with PF 28(1).
Pharmacopeial Forum
688 INDEX Vol. 28(2) [Mar.-Apr. 2002]
[Note—This index covers Vol. 28 No. 1, pp. 1-193, Vol. 28, No. 2 Clorazepate Dipotassium Tablets (USP) 54
pp. 195-691] Clorsulon (USP) 55, 269
Cocaine and Tetracaine Hydrochlorides and Epinephrine
GENERAL NOTICES AND REQUIREMENTS (USP) Topical Solution (USP) 270
"Official" and "Official Articles"—USP 32 Coriander Oil (NF) 629
Preservation, Packaging, Storage, and Labeling— Com Syrup (NF) 403
USP 242 High Fructose Corn Syrup (NF) 408
Corn Syrup Solids (NF) 630
GENERAL NOTICES AND REQUIREMENTS (NF) Cyproheptadine Hydrochloride Oral Solution (USP) 271
"Official" and "Official Articles"—NF 88 Cyproheptadine Hydrochloride Syrup (USP) 272
Dexchlorpheniramine Maleate Oral Solution (USP) 272
MONOGRAPHS Dexchlorpheniramine Maleate Syrup (USP) 273
Acebutolol Hydrochloride Capsules (USP) 33 Dexchlorpheniramine Maleate Tablets (USP) 273
Alendronate Sodium Tablets (USP) 33 Dextrin (NF) 411
Alfentanil Hydrochloride (USP) 244 Dextroamphetamine Sulfate Elixir (USP) 274
Alprostadil (USP) 245 Dextroamphetamine Sulfate Oral Solution (USP) 274
Amantadine Hydrochloride Oral Solution (USP) 250 Dextroamphetamine Sulfate Tablets (USP) 276
Amantadine Hydrochloride Syrup (USP) 251 Dextromethorphan Hydrobromide Oral Solution
Aminocaproic Acid Oral Solution (USP) 251 (USP) 276
Aminocaproic Acid Syrup (USP) 252 Dextromethorphan Hydrobromide Syrup (USP) 277
Ammonio Methacrylate Copolymer Dispersion (NF) 628 Dicyclomine Hydrochloride Oral Solution (USP) 278
Amoxicillin Capsules (USP) 36 Dicyclomine Hydrochloride Syrup (USP) 279
Amoxicillin Tablets (USP) 36 Digoxin Elixir (USP) 279
Amoxicillin and Clavulanate Potassium for Oral Digoxin Injection (USP) 279
Suspension (USP) 36 Digoxin Oral Solution (USP) 279
Amoxicillin and Clavulanate Potassium Tablets Digoxin Tablets (USP) 55, 281
(USP) 37 Dimenhydrinate Oral Solution (USP) 281
Aspartic Acid (USP) 252 Dimenhydrinate Syrup (USP) 282
Atenolol Tablets (USP) 38 Dinoprostone (USP) 56
Barium Sulfate (USP) 38 Diphenhydramine Hydrochloride Elixir (USP) 282
Barium Sulfate Suspension (USP) 38 Diphenhydramine Hydrochloride Oral Solution (USP) 283
Barium Sulfate for Suspension (USP) 39 Divalproex Sodium Delayed-Release Tablets (USP) 284
Benazepril Hydrochloride Tablets (USP) 39 Doxazosin Mesylate (USP) 286
Benzethonium Chloride Concentrate (USP) 41 Doxazosin Mesylate Tablets (USP) 289
Benzylpenicilloyl Polylysine Concentrate (USP) 42 Doxylamine Succinate Oral Solution (USP) 291
Betamethasone Oral Solution (USP) 253 Doxylamine Succinate Syrup (USP) 292
Betamethasone Syrup (USP) 254 Dyphylline Elixir (USP) 292
Bismuth Subsalicylate Magma (USP) 43 Dyphylline Oral Solution (USP) 292
Bismuth Subsalicylate Oral Suspension (USP) 627 Dyphylline and Guaifenesin Elixir (USP) 293
Bismuth Subsalicylate Tablets (NF) 133 Dyphylline and Guaifenesin Oral Solution (USP) 294
Bromodiphenhydramine Hydrochloride Elixir (USP) 254 Enalapril Maleate Tablets (USP) 295
Bromodiphenhydramine Hydrochloride Oral Solution Ephedrine Sulfate Oral Solution (USP) 296
(USP) 255 Ephedrine Sulfate Syrup (USP) 297
Brompheniramine Maleate Elixir (USP) 255 Ergoloid Mesylates Tablets (USP) 59
Brompheniramine Maleate Oral Solution (USP) 256 Erythromycin Ointment (USP) 297
Brompheniramine Maleate and Pseudoephedrine Sulfate Ethylparaben (NF) 574
Oral Solution (USP) 256 Ferrous Gluconate Elixir (USP) 297
Brompheniramine Maleate and Pseudoephedrine Sulfate Ferrous Gluconate Oral Solution (USP) 297
Syrup (USP) 258 Fluoxymesterone (USP) 59
Butabarbital Sodium Elixir (USP) 259 Furosemide Oral Solution (USP) 59
Butabarbital Sodium Oral Solution (USP) 259 Gabapentin Capsules (USP) 298
Butylparaben (NF) 572 Ganciclovir (USP) 301
Calcium Polycarbophil (USP) 260 Garlic Delayed-Release Tablets (NF) 89
Cefazolin Ophthalmic Solution (USP) 261 Glucosamine Hydrochloride (NF) 92
Cefpodoxime Proxetil (USP) 44 Glucosamine Sulfate Potassium Chloride (NF) 94
Cefpodoxime Proxetil for Oral Suspension (USP) 48 Glucosamine Sulfate Sodium Chloride (NF) 95
Cefpodoxime Proxetil Tablets (USP) 49 Glucosamine Tablets (NF) 97
Chaste Tree (NF) 139 Glucosamine and Chondroitin Sulfate Tablets (NF) 98
Powdered Chaste Tree (NF) 142 Glutaral Concentrate (USP) 60
Chloral Hydrate Oral Solution (USP) 261 Glyburide Tablets (USP) 60
Choral Hydrate Syrup (USP) 262 Guaifenesin Oral Solution (USP) ' 302
Chlorothiazide Sodium for Injection (USP) 51 Guaifenesin Syrup (USP) 303
Chlorpheniramine Maleate Oral Solution (USP) 262 Guaifenesin and Codeine Phosphate Oral Solution
Chlorpheniramine Maleate Syrup (USP) 263 (USP) 303
Cholestyramine for Oral Suspension (USP) 51 Guaifenesin and Codeine Phosphate Syrup (USP) 306
Sodium Chromate Cr 51 Injection (USP) 264 Hydralazine Hydrochloride Oral Solution (USP) 306
Ciclopirox Olamine (USP) 265 Hydrochlorothiazide (USP) 60
Cimetidine Tablets (USP) 52 Hydrocodone Bitartrate (USP) 63
Clomipramine Hydrochloride Capsules (USP) 52 Hydrogen Peroxide Concentrate (USP) 65
Clonazepam Tablets (USP) 54 Hydroxyzine Hydrochoride Oral Solution (USP) 307
Clonidine Transdermal System (USP) 265 Hydroxyzine Hydrochoride Syrup (USP) 308
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] INDEX 689
Hydroxyzine Hydrochloride Tablets (USP) 27 Nystatin and Triamcinolone Acetonide Cream (USP) 137
Insulin Human (USP) 65 Nystatin and Triamcinolone Acetonide Ointment
Insulin Lispro (USP) 66 (USP) 138
Insulin Lispro Injection (USP) 69 Compound Orange Spirit (NF) 637
Iohexol (USP) 70 Oxybutynin Chloride Oral Solution (USP) 334
Iohexol Injection (USP) 308 Oxybutynin Chloride Syrup (USP) 336
Ipecac Oral Solution (USP) 308 Oxycodone Hydrochloride (USP) 84
Ipecac Syrup (USP) 310 Oxycodone and Acetaminophen Capsules (USP) 27
Isoniazid Oral Solution (USP) 310 Paclitaxel (USP) 336
Isoniazid Syrup (USP) 311 Paromomycin Oral Solution (USP) 341
Isosorbide Concentrate (USP) 71 Paromomycin Sulfate Syrup (USP) 342
Kava (NF) 100 Pentazocine and Naloxone Hydrochlorides Tablets
Powdered Kava (NF) 104 (USP) 84
Ketoconazole Oral Suspension (USP) 311 Pentobarbital Elixir (USP) 342
Lactulose Concentrate (USP) 71 Pentobarbital Oral Solution (USP) 342
Lemon Tincture (NF) 631 Petrolatum (USP) 570
Letrozole Tablets (USP) 71 White Petrolatum (USP) 570
Lutein (NF) 632 Phenobarbital Elixir (USP) 343
Lutein Preparation (NF) 634 Phenobarbital Oral Solution (USP) 344
Levocarnitine (USP) 71 Polyethylene Glycol (NF) 577
Levothyroxine Sodium Tablets (USP) 312 Potassium Gluconate Elixir (USP) 345
Lincomycin Hydrochloride Soluble Powder (USP) 73 Potassium Gluconate Oral Solution (USP) 345
Lincomycin Hydrochloride Syrup (USP) 313 Praziquantel (USP) 84
Lincomycin Oral Solution (USP) 313 Prazosin Hydrochloride Capsules (USP) 346
Lithium Citrate Syrup (USP) 314 Prednisolone Oral Solution (USP) 346
Lithium Oral Solution (USP) 314 Prednisolone Syrup (USP) 347
Magnesium Aluminometasilicate (NF) 411 Probenecid Tablets (USP) 347
Magnesium Aluminosilicate (NF) 414 Procainamide Hydrochloride Tablets (USP) 347
Mangafodipir Trisodium (USP) 315 Progesterone Vaginal Suppositories (USP) 348
Mannitol Injection (USP) 73 Promethazine Hydrochloride Oral Solution (USP) 348
Mangafodipir Trisodium Injection (USP) 315 Promethazine Hydrochloride Syrup (USP) 349
Mecamylamine Hydrochloride (USP) 321 Propoxyphene Hydrochloride (USP) 350
Mecamylamine Hydrochloride Tablets (USP) 322 Propoxyphene Napsylate (USP) 352
Meperidine Hydrochloride Oral Solution (USP) 323 Propylparaben (USP) 581
Meperidine Hydrochloride Syrup (USP) 323 Pseudoephedrine Hydrochloride Oral Solution (USP) 354
Metaproterenol Sulfate Oral Solution (USP) 324 Pseudoephedrine Hydrochloride Syrup (USP) 355
Metaproterenol Sulfate Syrup (USP) 325 Pseudoephedrine Hydrochloride Tablets (USP) 356
Methadone Hydrochloride Oral Solution (USP) 74 Pseudoephedrine Hydrochloride Extended-Release
Methdilazine Hydrochloride Oral Solution (USP) 325 Tablets (USP) 85
Methdilazine Hydrochloride Syrup (USP) 326 Pyridostigmine Bromide Oral Solution (USP) 356
Methenamine Elixir (USP) 326 Pyridostigmine Bromide Syrup (USP) 357
Methenamine Oral Solution (USP) 327 Ramipril (USP) 357
Methenamine Tablets (USP) 328 Ranitidine Oral Solution (USP) 360
Methylparaben (NF) 575 Reserpine Elixir (USP) 362
Methyltestosterone (USP) 74 Reserpine Oral Solution (USP) 362
Milk Thistle (NF) 414 Rifampin Oral Suspension (USP) 363
Powdered Milk Thistle (NF) 417 Saw Palmetto Extract (NF) 425
Powdered Milk Thistle Extract (NF) 417 Secobarbital Elixir (USP) 364
Milk Thistle Capsules (NF) 420 Secobarbital Oral Solution (USP) 364
Milk Thistle Tablets (NF) 422 Senna Oral Solution (USP) 365
Misoprostol Dispersion (USP) 76 Senna Syrup (USP) 365
Morphine Sulfate (USP) 328 Simethicone (USP) 366
Morphine Sulfate Suppositories (USP) 328 Sodium Hypochlorite Topical Solution (USP) 366
Myristyl Alcohol (NF) 424 Sodium Sulfide Topical Gel (USP) 366
Myrrh (USP) 78 Stanozolol Tablets (USP) 367
Naloxone Hydrochloride (USP) 329 Stearic Acid (NF) 583
Naltrexone Hydrochloride (USP) 329 Streptomycin Injection (USP) 86
Nandrolone Decanoate Injection (USP) 330 Streptomycin for Injection (USP) 86
Nettles (NF) 105 Streptomycin Sulfate (USP) 87
Powdered Nettles Extract (NF) 109 Sucralfate (USP) 367
Powdered Nettles (NF) 108 Sucralfate Tablets (USP) 369
Nifedipine Capsules (USP) 78 Sugar-Free Suspension Structured Vehicle (NF) 428
Norgestimate (USP) 331 Suspension Structured Vehicle (NF) 429
Norgestimate and Ethinyl Estradiol Tablets (USP) 79 Terazosin Hydrochloride (USP) 369
Nystatin (USP) 134 Terpin Hydrate Elixir (USP) 374
Nystatin Cream (USP) 134 Terpin Hydrate Oral Solution (USP) 375
Nystatin Lozenges (USP) 135 Terpin Hydrate and Codeine Elixir (USP) 375
Nystatin Ointment (USP) 135 Terpin Hydrate and Codeine Oral Solution (USP) 376
Nystatin Oral Suspension (USP) 136 Tetracycline Hydrochloride Oral Suspension (USP) 378
Nystatin Tablets (USP) 137 Theophylline Sodium Glycinate Elixir (USP) 378
Nystatin Topical Powder (USP) 136 Theophylline Sodium Glycinate Oral Solution (USP) 378
Pharmacopeial Forum
690 INDEX Vol. 28(2) [Mar.-Apr. 2002]
Thiamine Hydrochloride Elixir (USP) 379 REAGENTS, INDICATORS, AND SOLUTIONS

Thiamine Hydrochloride Injection (USP) 380 Reagent Specifications
Thiamine Hydrochloride Oral Solution (USP) 380 Bacterial Alkaline Protease Preparation (USP) 552
Thiamine Mononitrate Elixir (USP) 381 Bromelain (USP) 552
Thiamine Mononitrate Oral Solution (USP) 381 4-(Butylamino)benzoic Acid (USP) 553
Thyroid Tablets (USP) 88 FD&C Blue No. 1 (USP) 115
Tolu Balsam Syrup (NF) 637 Water, HPLC Grade (USP) 115
Tolu Balsam Tincture (NF) 637
Volumetric Solutions
Torsemide (USP) 382
Triamcinolone Diacetate Oral Solution (USP) 383 Lead Perchlorate, Hundreth Molar (0.01 M) (USP) 553
Triamcinolone Diacetate Syrup (USP) 384 Reagent Footnotes 553
Triazolam (USP) 385
Tricitrates Oral Solution (USP) 385 REFERENCE TABLES
Trifluoperazine Hydrochloride Syrup (USP) 385 Containers Specifications for Capsules and Tablets 115
Trifluoperazine Oral Solution (USP) 385 Description and Relative Solubility 116, 554
Trihexyphenidyl Hydrochloride Elixir (USP) 386
Trihexyphenidyl Hydrochloride Oral Solution (USP) 387 GENERAL SUBJECTS
Trimeprazine Oral Solution (USP) 388 Ambrosio, Thomas: See Medwick, Thomas 656
Trimeprazine Tartrate Syrup (USP) 389 Bailey, Leonard: See Medwick, Thomas 656
Trimethoprirn (USP) 389 Biopharmaceutics
Triprolidine Hydrochloride Oral Solution (USP) 390 Biopharmaceutics Classification System: See Method
Triprolidine Hydrochloride Syrup (USP) 391 Consideration for Caco-2 Permeability Assessment in
Triprolidine Hydrochloride Tablets (USP) 392 the Biopharmaceutics Classification System, Sanna
Triprolidine and Pseudoephedrine Hydrochlorides Oral Tolle-Sander and James E. Polli 164
Solution (USP) 392 FIP Recommendations for Biopharmaceutical
Triprolidine and Pseudoephedrine Hydrochlorides Syrup Characterization of Herbal Medicinal Products by
(USP) 394 Friedrich Lang, Konstantin Keller, Michael Ihrig,
Triprolidine and Pseudoephedrine Hydrochlorides Joy Oudtshoorn-Eckard, Helga Moller, Srini
Tablets (USP) 394 Srinivasan, Yu He-ci 173
Valproic Acid Oral Solution (USP) 395 Canceled Revision Proposals 126, 564
Valproic Acid Syrup (USP) 396 Changes in Reference Standards Prices and Numbers 217
Valsartan (USP) 396 Chromatography
Valsartan Capsules (USP) 399 Chromatographic Reagents Now Available 218
Xanthan Gum Solution (NF) 429 Defining Column Equivalence, by
Preston Poulter 652
GENERAL CHAPTERS Defining Column Equivalence, by Preston Poulter 652
Aerosols, Metered-Dose Inhalers, and Dry Powder First Interim Revision Announcement 25
Inhalers (601) 584 Harmonization
Bacterial Endotoxins Test (85) (USP) 435, 639 Residue on Ignition (281) 129
Biological and Chemical Identification of Articles of He-ci, Yu: See Lang, Friedrich 173
Botanical Origin (563) (USP) 435 Ihrig, Michael: See Lang, Friedrich 173
Botanical Extracts (565) (USP) 451 How To Submit Comments 219
Containers (661) (USP) 453
Containers—Permeation (671) (USP) 456 Interim Revision Announcement
Density of Solids (699) 603 First 25
Disinfectants and Antiseptics (1072) (USP) 143 Second 225
Good Compounding Practices (1075) (USP) 640 International Pharmaceutical Federation: See FIP
Injections (1) (USP) I l l , 460 Recommendations for Biopharmaceutical
Manufacturing Practices for Nutritional Characterization of Herbal Medicinal Products 173
Supplements (2750) (USP) 534 Keller, Konstantin: See Lang, Friedrich 173
Optical Microscopy (776) 607 Kirkpatrick Mary Ann: See Okeke, Claudia C. . 661
Lang, Friedrich, Keller, Konstantin, Ihrig, Michael,
Packaging Practice—Repackaging a Single Solid
Oudtshoorn-Eckard, Joyh, Moller, Helga,
Oral Drug Product into a Unit-Dose Container
(1146) (USP) 467 Srinivasan, Srini, He-ci, Yu: FIP Recommendations
Pharmaceutical Calculations in Prescription for Biopharmaceutical Characterization of Herbal
Medicinal Products 173
Compounding (1160) (USP) 476
Pharmacy Compounding (795) (USP) 458 Medwick, Thomas, Bailey, Leonard, Ambrosio, Thomas,
and Okeke, Claudia C : Polypropylene Containers:
Powder Fineness (811) 611
Powder Flow (1174) 618 Status and Comments Received 656
Reference Standards (11) (USP) I l l , 433 Method Consideration for Caco-2 Permeability
Residue on Ignition (281) (USP) 112, 129 Assessment in the Biopharmaceutics Classification
Shipping and Storage of Labile Preparations System by Sanna Tolle-Sander and
(1186) (USP) $$$ James E. Polli 164
Specific Surface Area (846) 612 Moller, Helga: See Lang, Friedrich 173
Sterile Drug Products for Home Use (1206) (USP) $$$ Nairn, J. Graham: See Okeke, Claudia C 661
Stability Considerations in Dispensing Practice (1191) New Labeling Requirements Proposed for Neuromuscular
Blocking Agents (Paralyzing Agents) 218
(USP) 112
Okeke, Claudia C , Kirkpatrick, Mary Ann F., and Nairn,
Standardized Imprint Codes for Solid Oral Dosage
Forms (1198) (USP) 152 J. Graham: Review of Pharmaceutical Calculations
Validation of Alternative Microbiological Methods in Prescription Compounding (1160) 661
Okeke, Claudia C : See Medwick, Thomas 656
(1223) (USP) 154
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] INDEX 691
Packaging and Storage Update on the Annual Edition of USP-NF 19, 218
Polypropylene Containers: Status and Comments Polli, James E.: See Tolle-Sander, Sanna 164
Received, by Thomas Medwick, Leonard Bailey, Polypropylene Containers: Status and Comments
Thomas Ambrosio, and Claudia C. Okeke 656 Received, by Thomas Medwick, Leonard Bailey,
Pharmaceutical Education Courses 218 Thomas Ambrosio, and Claudia C. Okeke 656
Pharmacy Compounding Poulter, Preston: Defining Column Equivalence 652
Review of Pharmaceutical Calculations in Prescription Previous PF Proposals Still Pending 117, 555
Compounding (1160), by Claudia C. Okeke, Mary Review of Pharmaceutical Calculations in Prescription
Ann F. Kirkpatrick, and J. Graham Nairn 661 Compounding (1160), by Claudia C. Okeke, Mary
Ann F. Kirkpatrick, and J. Graham Nairn 661
Second Interim Revision Announcement 225
Changes in Reference Standard Prices and Numbers . . . . 217
Srinivasan, Srini: See Lang, Friedrich 173
Tolle-Sander, Sanna and Polli, James E.: See Method
How to Submit Comments 20, 219
Consideration for Caco-2 Permeability Assessment in
New Labeling Requirements Proposed for Neuromuscular
Blocking Agents (Paralyzing Agents) 218 the Biopharmaceutics Classification System 164
Pharmaceutical Education Courses 218 Update on the Annual Edition of USP-NF 218
REFERENCE STANDARDS
CATALOG
• Catalog lists NEW Reference Standards
• Quantity discount policy to change
U.S. Pharmacopeia
The Standard of Quality1" • Update to USP 25-NF20 available
Dear USP Reference Standards Customer:
To keep up with your growing need, USP will be providing an increasing number of new Reference
Standards of the highest quality. It's important for you to stay current on the latest standards, so
for your convenient and quick reference, we're adding a section on new Reference Standards to
our catalog. We are committed to keeping all new Reference Standards stocked and ready to ship.
New items at a glance

USP is publishing the new section starting in this issue of the Reference Standards Catalog (see
page 4). In this section, we will list new Reference Standards released by USP over the last year.
The list will be continuously updated on a rolling basis. Newly released Reference Standards will
be added and Reference Standards released more than 12 months prior to the current catalog
period will no longer be included in the list.
Quantity discounts by item

In the January-February 2002 issue of the Reference Standards Catalog, I told you about USP's
plans to implement a new ERP business system and how this would impact you. Based on the
available information, this conversion is expected to take place in early April.
On conversion, the Reference Standards discount policy will automatically change. Quantity
discounts will be applied to the number of units per item, and not to the total number of units
of all items ordered. The discount rates will continue to be 5% for 5 to 24 units and 10% for
25+ units. Please call USP Customer Service at 1-800-227-8772 or 301-881-0666 for updates
on when the conversion is expected to take place.
Consolidate and order now

USP's current quantity discounts, based on your total order, will be available until the beginning
of April. You may want to take advantage of the current system by consolidating your orders.
This is especially recommended if you typically order different types of Reference Standards and
less than 5 to 24 units of each type. Plan ahead, consolidate your future requirements, and send
in a single order right away—you can still get 5 to 10% off the total number of units you order.
Supplement One to USP-NF now available

The new USP 25-NF 20 has been official since January 1, 2002. It's first Supplement is now
available and becomes official on April 1, 2002. The Supplement features 6 new USP monographs
and 21 new NF monographs. Plus, it includes the first-ever pharmacopeial general chapter on Cell
and Gene Therapy Products as well as a chapter on Repackaging a Single Solid Oral Drug Product
into a Unit-Dose Container. Supplement One is included in your USP 25-NF 20 subscription. If you
haven't subscribed yet, do so right away and get the latest information for official compliance.
Feel free to call our Customer Service department at 1-800-227-8772 or 301-881-0666 if you have
any questions about USP Reference Standards or publications.
Sincerely,

Rockville, MD 20852 Alan Nichols
Director, Reference Standards Marketing
301-881-0666
www.usp.org
Official USP Reference Standards Catalog Mar.-Apr. 2002
INTRODUCTION
Catalog on the Internet parentheses following each name (all are in single containers
For the convenience of our online customers, access to this unless otherwise specified).
catalog is available on the Internet at www.usp.org/refstd/. This Column 3 (Current Lot) identifies the current lot designation
online version is updated frequently to include changes in of each official item being distributed as of the date of this list.
official lot status, description, and other pertinent information. Where the Current Lot is blank the item is not in distribution.
Importance of Reference Standards Column 4 (Change Code) lists codes that identify USP
Official USP and NF Reference Standards are made available as Reference Standards that have had a change in lot status,
required for use in assays and tests appearing in USP-NF. They description, or other pertinent information since the printing of
help ensure that quality requirements established by the the January/February 2002, official Catalog. Interpretations of
USP-NF are met, and that the official methods of analysis are these codes are:
performed. They are subject to rigorous testing, evaluation, and
Change Interpretation
quality control, and are approved for use by the USP Reference
Code
Standards Committee.
1 New Standard Available for Distribution
2 New Lot in Distribution
How to Order
3 Change in Package Size or Description
On pages 28-29, you'll find information on how to order by
4 Correction of Typographical Error
phone, mail, internet, or fax, both domestically and
5 New Catalog Number—Use for All Orders
internationally, and other pertinent information. Order forms
6 Previous Lot No Longer Official; Only Current
are located in the back of this catalog. Please note that USP
Lot to be Used
Reference Standards are not returnable for exchange or
7 Valid Use Date of Previous Lot Extended
refund.
8 Change in Catalog Number and Name
Product Listings 9 DISCONTINUED
On pages 6-22, you'll find a full list of USP and NF Reference 10 Special Pricing in Effect
Standards, with information updated as of February 8,2002. 11 Valid Use Date Added For Previous Lot; Next
Additional, authenticated substances, not currently required as Lot in Preparation.
Official USP or NF Reference Standards, are also provided Column 5 (Previous Lot/Valid Use Date) identifies any lot no
under the supervision of the USP Reference Standards longer being distributed, but which is still considered an official
Committee. They fall into three groups: (1) former USP and NF USP Reference Standard through the last day of the indicated
Reference Standards, not required in the current USP or NF, but month and year. (For example, an indicated entry of "F-1
for which sufficient demand remains; (2) FCC Reference (06/00)" means that the previous lot F-l is no longer being
Standards, specified in the current edition of the Food Chemicals distributed, but is considered official through June 30, 2000.) If
Codex; and (3) Authentic Substances (AS), which are highly the word "NONE" appears in this column, it indicates that
purified samples of chemicals, including substances of abuse,
because of a change in monograph requirements, or stability
that are collaboratively tested and made available as a service
limitations, etc., any previous lot is no longer considered official
primarily to analytical, clinical, pharmaceutical, and research
and should not be used.
laboratories.
USP Reference Standards
How to Read Product Listings USP Reference Standards are established and released under the
Column 1 (Catalog Number) designates the catalog number authority of the USPC Board of Trustees upon recommendation
that has been assigned to each Reference Standard and Authentic of the USP Reference Standards Committee, which passes on the
Substance. Please include the catalog number on your orders. selection and suitability of each lot. The critical characteristics of
Column 2 (Description) gives a description of each article as each lot of specimen selected for the standard are usually
designated in the compendium and/or on the label and the Drug determined independently in three or more laboratories. The
Enforcement Administration Control Schedule, if applicable. USP Reference Standards Laboratory (see Preface to USP 25-
The quantity of material provided per container is given in NF 20) and the FDA laboratories participate in testing almost all

Mar.-Apr. 2002 Official USP Reference Standards Catalog
INTRODUCTION
new Standards and replacements for existing Standards. In means. The USP Reference Standards Committee collaborates
addition, laboratories throughout the nation, both academic and closely with the WHO in order to minimize unavoidable
industrial, participate in the testing. differences in the actual units of potency and in some cases to
share in the preparation of a reference standard. Since some USP
Reference Standards are specifically required in many
Reference Standards are standardized in terms of the
Pharmacopeial assays and tests and are provided solely for such
corresponding International Standards, the relevant USP Units
use; suitability for other nonofficial application(s) rests with the
and the International Units of potency are generally identical.
purchaser. Originally introduced for the biological assays of
USP X, reference standards are now required for numerous other Current Lots
procedures as well. This reflects the extensive use of modern It is the responsibility of each analyst to ascertain that his
chromatographic and spectrophotometric methods, which particular supply of USP Reference Standard is current.
require measurements relative to a reference standard to attain
accurate and reproducible results. To ensure ready access to the latest information, the USPC
publishes the Official Catalog of Reference Standards and
USP Reference Standards are substances selected for their high Authentic Substances, and the lot designations, bimonthly in
purity, critical characteristics, and suitability for the intended Pharmacopeial Forum. This system offers more positive control
purpose. Heterogeneous substances, of natural origin, also are and flexibility in responding to revisions in Reference Standard
designated "Reference Standards" where needed. Usually these usage than would expiration dates. The Catalog in the most
are the counterparts of international standards. recent Pharmacopeial Forum identifies items that are official
in the USP Reference Standards collection at the time of
Other Reference Substances publication.
As a service, the USPC tests and distributes additional
authenticated substances not currently required as USP or NF Two columns appear in the Catalog to identify the current
Reference Standards. These also are provided under the official lots. One column identifies the official lot currently
supervision of the USP Reference Standards Committee. These being shipped by USPC. If the field is blank then the current lot
additional substances fall into three groups: is not in distribution. In some cases, the previous lot may still be
considered official. If so, it is identified in the second column.
(1) former USP and NF Reference Standards, not required in the
Ordinarily the previous lot is carried in official status for about
current USP or NF but for which sufficient demand remains;
one year after the current lot has depleted unless, because of a
(2) FCC Reference Standards, specified in the current edition of change in monograph requirements or stability limitation, the
the Food Chemical Codex; previous lot is found to be no longer suitable. Indication is given
(3) Authentic Substances (AS), which are highly purified for the month and year through which previous lots may be used.
samples of chemicals, including substances of abuse, that are
collaboratively tested and made available as a service primarily Proper Use of USP Reference Standards
to analytical, clinical, pharmaceutical, and research laboratories. Unless a USP Reference Standard label states a specific potency
The distribution of controlled substances is subject to the or content, the USP Reference Standard is taken as being
regulations and licensing provisions of the Drug Enforcement 100.0% pure for the USP purposes for which it is provided. The
Administration of the Department of Justice. suitability of a USP Reference Standard for noncompendial
application is left up to the user.
A program to provide international biological standards and
chemical reference substances is maintained by the World To serve its intended purpose, each USP Reference Standard
Health Organization, an agency of the United Nations. The must be properly stored, handled, and used. Generally, USP
WHO program is concerned with reference materials for Reference Standards should be stored in their original stoppered
antibiotics, biologicals, and chemotherapeutic agents. As a rule, containers away from heat and protected from light. Avoid
an International Standard for a material of natural origin is humid storage areas in particular. Where special storage
discontinued once the substance responsible for its characteristic conditions are necessary, directions are given on the label.
activity has been isolated, identified, and prepared in such forms
that it can be completely characterized by chemical and physical

INTRODUCTION
Neither Reference Standards nor Authentic Substances are Instrumental or microanalytical methods are acceptable for this
intended for use as drugs, dietary supplements, or as medical purpose. When using typical amounts, about 50 mg, of the
devices. Reference Standard, titrate with a fourfold dilution of the
Reagent.
Many USP tests and assays are based on comparison of a test
specimen with a USP Reference Standard. In such cases, The USP Reference Standard(s) section of an individual USP or
measurements are made on preparations of both the test NF monograph or general chapter names the USP Reference
specimen and the USP Reference Standard. Where it is directed Standard(s) (11) required for assay and test procedures and refers
that a Standard solution or a Standard preparation be prepared to General Test Chapter (11) USP Reference Standards for
for a quantitative determination by stepwise dilution or additional information and instructions. Instructions for the
otherwise, it is intended that the Reference Standard substance proper use and storage of each required USP Reference Standard
shall be accurately weighed (see General Chapters, Weights and are given in General Chapter (11) of USP 25-NF 20. These
Balances (41) and Volumetric Apparatus (31) in USP 25-NF 20). instructions are to be the same as those appearing on the
Due account should also be taken of the relatively large errors corresponding USP Reference Standard label. Where, in an
associated with weighing small masses (see also Dilution under isolated instance, the specific label instruction differs from the
General Notices). text in the published list, the instruction on the label of the item
from the current lot takes precedence. A situation may be
Assay and test results are determined on the basis of
infrequently encountered where it is necessary, on scientific
comparisons of the specimen under test with a USP Reference
grounds, to effect immediately a change in the instructions.
Standard that has been freed from, or corrected for, volatile
This change can be made easily on the label of the Reference
residues or water content as instructed on the label. Where
Standard, whereas the formal process for revising the
special drying requirements for Reference Standards are found
compendial text requires more time. Thus, it is especially
in specific sections of USP or NF monographs, those supersede
important to refer to the current Supplement to USP-NF for
the usual instructions (see Procedures under Tests and Assays in
official revisions to the following list.
the General Notices). Where a USP Reference Standard is
required to be dried before using, transfer an amount, sufficient USP Reference Standards Specified in USP and NF
after drying, to a clean and dry vessel. Do not use the original
Monographs and General Chapters
container as the drying vessel, and do not dry a specimen
NOTE—Consult the latest Supplement or Interim Revision
repeatedly at temperatures above 25 degrees. Where the
Announcement pertaining to USP and to NF for revisions,
titrimetric determination of water is required at the time a
additions, or deletions. Revisions, additions, and deletions of
Reference Standard is to be used, proceed as directed for
individual USP Reference Standards are listed cumulatively in
Method I under General Chapter, Water Determination (921).
each Supplement to USP-NF under (l 1) USP Reference
Standards.

NEW SECTION
NEW REFERENCE STANDARDS
See what's new in USP Reference Standards. For your convenient and quick
reference, here's a list of Reference Standards released by USP over the past year.
This list is continuously updated with the latest Reference Standards available. And
standards released more than 12 months prior to this catalog period are
dropped from the list.
Cat# Description Lot Price Cat.# Description Lot Price

01305-7 S-Allyl-L-Cysteine (25 mg) F $450 34482-6 lopromide Related F S450
(Limit test) Compound A (50 mg)
04270-3 Arsanilic Acid (25 mg) F $144 (Limit test)
04533-7 Avobenzone (500 mg) F S144 34483-7 lopromide Related F $450
07553-1 Bismuth Citrate (100 mg) F $144 Compound B (50 mg)
(Limit test)
09765-8 Cefixime (500 mg) F $144 34510-4 loversol (200 mg) F S144
13363-8 Chromium Picolinate (100 mg) F $144
34511-5 loversol Related F $450
(For Identification Test Only)
Compound A (50 mg)
15865-0 Cyclosporine Resolution F S381
(Limit test)
Mixture (25 mg) (Replaces
34512-6 loversol Related F $450
Cat. No. 15870-8
Compound B (50 mg)
Cyclosporine U (25 mg)
(Limit test)
18720-7 Dichloralphenazone CIV (200 mg) F0B010 $166
34515-9 loxaglic Acid (100 mg) F $144
20410-2 Dihydroxyacetone (250 mg) F $144
(For Identification Use Only)
22070-0 Dirithromycin (200 mg) F $144 34520-6 loxilan (400 mg) F $144
26282-3 Ethopabate Related F $144
34522-8 loxilan Related F $450
Compound A (25 mg) Compound A (100 mg)
26940-3 Fenbendazole(100mg) (Limit test)
(Limit Test) . F $450 34775-5 Isoamyl Methoxycinnamate F0B017 S144
27040-2 Finasteride (200 mg) F $144 (750 mg/ampule)
28730-3 Gabapentin (250 mg) F $144 35668-7 Lactitol (500 mg) F0B005 $144
28732-5 Gabapentin Related F $450 51084-5 Pergolide Mesylate (200 mg) F $180
Compound A (100 mg)
51086-7 Pergolide Sulfoxide (50 mg) F0B014 $180
(Limit test)
59240-9 Quercetin (500 mg) F0B015 $144
28750-7 Gadodiamide (500 mg) F $144
60460-0 Rimexolone(100 mg) F S144
28751-8 Gadodiamide Related F $450
60982-9 Saquinavir Mesylate (200 mg) F0B008 $144
Compound A (50 mg)
28752-1 Gadodiamide Related F $450 60983-9 Saquinavir Related F0B009 S450
Compound B (50 mg) Compound A (25 mg)
28760-9 Gadopentetate F $144 61195-5 Selenomethionine (100 mg) F0B006 $144
Monomeglumine (500 mg) 61360-0 Sodium Butyrate (25 mg) F $144
28763-1 Gadoteridol (500 mg) F $144 63520-6 Sulfaquinoxaline (200 mg) F0A005 $144
28764-2 Gadoteridol Related F0A002 $450 72400-0 Yohimbine HCI (200 mg) F $144
Compound A (50 mg) (Limit test)
29484-8 L-gamma-Glutamyl-S-allyl-L- F $624
33520-2
cysteine (25 mg)
Hyperoside (50 mg) F $790 H
•1
f£p U.S. PHARMACOPEIA
P£5* • The Standard of QualiffM
34480-4 lopromide (400 mg) F $144
RS009DM
Development Process for USP Reference Standards
New monograph New application for an Inventory depletion

existing reference standard
Bulk material is obtained
Material is tested and characterized through

collaborative testing involving a minimum of
3 labs-industry, FDA, and USP
Data from the collaborative study are reviewed

by USP staff scientists
Compilation of collaborative study is sent to the USP

Reference Standards Committee for evaluation
USP Reference Standards Committee accepts,

recommends further testing, or rejects the material
Once approved, the material is subdivided

and labeled
Material passes through a series of quality control

checks before release into USP inventory for distribution

USP and FCC Reference

Previous
Standards and Authentic Substances Previous
00060-1 AcebutololHCI(125mg) F-1 S144 XREF 3-Amino-4-carboxamid-
00100-3 Acenocoumarol (200 mg) F $144 opyrazole Hemisulfate
00150-2 Acepromazine Maleate F-1 (05/02) $144 (50 mg) (Limit Test)
(250 mg) (Please order Cat. No.
XREF 5-Acetamido-3-amino- 01302-4)
2,4,6-triiodo-benzoic Acid 02250-2 4-Amino-6-chloro-1,3- G-4 $450
(50 mg) (Limit Test) benzenedisulfonamide
(Please order Cat. No. (100 mg) (Limit Test)
18402-7) 02280-8 2-Amino-5-chloroben- I 2 H-2 (01/03) $450
00300-9 Acetaminophen (400 mg) J-1 J (05/02) $114 zophenone (25 mg)
00400-1 Acetanilide Melting Point L $69 (Limit Test)
Standard (500 mg) 02340-3 3-Amino-6-chloro-1 -methyl- I $450
(Approximately 4-phenylcarbostyril (25 mg)
114degree(s)) (Limit Test)
00500-4 Acetazolamide (2 g) J $144 XREF 2-Amino-2'-chloro-5-
00600-7 Acetohexamide (250 mg) H $144 nitrobenzophenone
00650-6 Acetohydroxamic Acid F $144 (25 mg) (Limit Test)
00700-0 Acetophenazine Maleate F-1 $144 14033-8)
(200 mg) XREF 4-Amino-6-chloro-N3-
00800-2 a-d-2-Acetoxy-4-dimethyl- G-3 $450 methyl-m-benzenedi-
amino-1,2-diphenyl-3- sulfonamide (100 mg)
methylbutane (125 mg) (Limit Test) (Please order
(Limit Test) Cat. No. 42401-8)
00850-1 Acetylcholine Chloride G $144 XREF 2-Amino-4-chlorophenol
(200 mg) (50 mg) (Limit Test)
00900-5 Acetylcysteine (200 mg) H $144 (Please order Cat. No.
00990-1 Acetyltributyl Citrate F $144 13052-7, Chlorzoxazone
(500 mg) Related Compound A)
00992-3 Acetyltriethyl Citrate F-1 F (05/02) $144 XREF 3-Amino-4-(2-chloro-
(500 mg) phenyl)-6-nitrocarbostyril
01206-5 Acyclovir (300 mg) I $182 (25 mg) (Limit Test)
01210-1 Adenine (200 mg) G-1 $144 (Please order Cat. No.
01212-3 Adenosine F $144 14032-7)
01214-5 Agigenin (25 mg) F $144 XREF 2-Amino-2',5-dichloroben-
01250-9 L-Alanine (200 mg) F-2 $144 zophenone (25 mg)
01255-3 Albendazole (200 mg) G $144 (Limit Test) (Please order
01260-0 Albuterol (200 mg) I $144 Cat. No. 37033-8)
01263-3 Albuterol Sulfate (200 mg) J $144 02520-5 Aminoglutethimide F $144
01275-7 Alclometasone H $144 (200 mg)
Dipropionate (300 mg) 02530-7 m-Aminoglutethimide G $450
01295-0 Alliin (25 mg) F $1,410 (100 mg) (Limit Test)
01300-2 Allopurinol (250 mg) 1-1 I (07/02) $144 02535-1 Aminohippuric Acid F-1 $144
01302-4 Allopurinol Related G F-3 (05/02) $450 (200 mg)
Compound A (50 mg) 02580-6 2-[3-Amino-5-(n-meth- F $450
(Limit Test) (Formerly Cat. ylacetamido)-2,4,6-
No. 02200-3, 3-Amino-4- triiodobenzamido]-2-deoxy-
carboxamidopyrazole d-glucose (25 mg)
Hemisulfate) (Limit Test)
01305-7 S-Allyl-L-Cysteine (25 mg) F $450 02600-4 m-Aminophenol (300 mg) F $450
(Limit Test) (Limit Test)
01400-5 Alphaprodine HCI Cll F $166 XREF 3-Amino-4-phenoxy-5-
(250 mg) sulfamoylbenzoic Acid
01500-8 Alprazolam CIV (200 mg) H $166 (25 mg) (Limit Test)
01600-0 Alprostadil (25 mg) H $1,410 (Please order Cat. No.
01710-5 Altretamine (500 mg) F $144 07832-5)
01750-2 Dried Aluminum Hydroxide F-1 $144 XREF (-Aminopropiophenone HCI
Gel (200 mg) (50 mg) (Limit Test)
01850-5 Amantadine HCI (200 mg) H $144 (Please order Cat. No.
01920-2 Amcinonide (200 mg) F-1 $144 09680-4)
01950-8 Amikacin (200 mg) I $144 02640-1 Aminosalicylic Acid F-1 $114
01970-1 Amiloride HCI (500 mg) H $144 (125 mg)
01975-6 Aminobenzoate Potassium F-1 $144 02660-5 3-Amino-2,4,6- G $450
(200 mg) triiodobenzoic Acid (50 mg)
01976-7 Aminobenzoate Sodium F $144 (Limit Test)
(200 mg) 02700-7 5-Amino-2,4,6-triiodo-N- F-1 $450
01980-3 Aminobenzoic Acid H $144 methylisophthalamic Acid
(200 mg) (This is the para (50 mg) (Limit Test)
form) 02900-2 Amitriptyline HCI (200 mg) I $144
02000-8 Aminobutanol (500 mg) G-1 $360 02990-9 Ammonio Methacrylate F-1 $144
(Limit Test) Copolymer Type A
02100-0 Aminocaproic Acid F-4 $144 (100 mg)
(200 mg) 02991-0 Ammonio Methacrylate F-1 $144
02170-3 N-(Aminocarbonyl)-N-[([5- F-1 $450 Copolymer Type B
nitro-2-furanyl]-methylene)- (100 mg)
amino]-glycine (25 mg) 03000-1 Amobarbital Cll (200 mg) F-2 $166
(Limit Test) 03100-4 Amodiaquine HCI (500 mg) G-1 $144
03140-1 Amoxapine (200 mg) G F-1 (04/02) $144
03150-3 Amoxicillin (200 mg) I $144



Previous Previous
Cat. Curr Change Lot/Valid Cat. Curr. Change Lot/Valid
03200-7 Amphotericin B (125 mg) J-2 2 J-1 (07/02) $114 04822-2 Baclofen Related H $360
03300-0 Ampicillin (Anhydrous) J-1 6 $144 Compound A (50 mg)
(200 mg) (For Potency (Limit Test) (Formerly Cat.
Determinations) No. 11670-8, 4-(4-
03320-3 Ampicillin Sodium (125 mg) G-1 $114 Chlorophenyl)-2-
(For Identification Use pyrrolidinone)
Only. For Potency Use 04850-6 Beclomethasone K $144
Cat. No. 03300-0) Dipropionate (200 mg)
03340-7 Ampicillin (Trihydrate) G $144 04900-0 Bendroflumethiazide G-1 $144
(200 mg) (For (200 mg)
Identification Use Only. 05000-9 Benoxinate HCI (200 mg) F-2 $114
For Potency Use Cat. No. 05100-1 Benzalkonium Chloride J $144
03300-0) (5 mL of approx. 10%
03400-2 Amprolium (200 mg) F-1 F (04/02) $144 aqueous solution)
03430-8 Amrinone (500 mg) G $144 05400-0 Benzocaine (500 mg) I $144
03432-0 Amrinone Related F $144 05500-2 Benzoic Acid (300 mg) F-5 $144
Compound A (100 mg) 05600-5 Benzonatate (1 g) J0B003 2 H (01/03) $144
03434-1 Amrinone Related F-1 $450 05650-4 1,4-Benzoquinone G 6 $144
Compound B (100 mg) (200 mg) (System
(Limit Test) Suitability Use Only)
03436-3 Amrinone Related F-1 $144 05900-3 Benzphetamine HCI Clll F-1 $166
Compound C (50 mg) (200 mg) (AS)
03600-8 Anileridine HCI Cll F $166 06000-2 Benzthiazide (200 mg) F $144
(250 mg) 06100-5 Benztropine Mesylate H $144
03650-7 3-Anilino-2-(3,4,5- G-1 $450 (200 mg)
trimethoxybenzyl) 06200-8 Benzyl Benzoate (5 g) I $144
acrylonitrile (25 mg) XREF 5-Benzyl-3,6-dioxo-2-
(Limit Test) piperazineacetic Acid
03800-3 Antazoline Phosphate H G-1 (04/02) $144 (250 mg) (Limit Test)
03900-6 Anthralin (200 mg) H $144 04372-8)
04000-5 Antipyrine (200 mg) G 6 $144 06400-3 1 -Benzyl-3-methyl-5- F-1 $450
04070-8 Apigenin-7-glucoside F $450 aminopyrazole HCI (25 mg)
(30 mg) (Limit Test) (Limit Test)
04100-8 Apomorphine HCI (250 mg) G $150 06500-6 Bephenium F $144
04160-9 Apraclonidine HCI G $443 Hydroxynaphthoate
(100 mg) (500 mg)
04200-0 Aprobarbital CHI (200 mg) F-1 $166 06570-9 Betaine Hydrochloride F-1 2 F (11/02) $144
(AS) (200 mg)
04250-0 L-Arginine (200 mg) G-1 $144 06600-9 Betamethasone (200 mg) K $144
04260-1 Arginine HCI (125 mg) F-1 $114 06700-1 Betamethasone Acetate I $144
04270-3 Arsanilic Acid (25 mg) F $144 (500 mg)
04300-3 Ascorbic Acid (1 g) P $144 06730-7 Betamethasone Benzoate F-1 $144
(Vitamin C) (200 mg)
04370-6 Aspartame (200 mg) H $144 06770-4 Betamethasone J $114
04372-8 Aspartame Related H $450 Dipropionate (125 mg)
Compound A (75 mg) 06800-4 Betamethasone Sodium 1-1 $144
(Limit Test) (Formerly Cat. Phosphate (500 mg)
No. 06300-0, 5-Benzyl-3,6- 06900-7 Betamethasone Valerate J $144
dioxo-2-piperazineacetic (200 mg)
Acid) 06990-3 Betaxolol HCI (200 mg) G $144
04400-6 Aspirin (500 mg) H 2 G-1 (11/02) $144 07000-6 Betazole HCI (200 mg) H $144
04430-1 Astemizole (200 mg) F $144 07100-9 Bethanechol Chloride G $144
04440-3 Atenolol (200 mg) H $144 (200 mg)
04500-9 Atropine Sulfate (500 mg) L-2 L-1 (06/02) $144 07130-4 Bile Salts (10 g) (Formerly H-1 $114
04533-7 Avobenzone (500 mg) F $144 Cat. No. 61500-5, Sodium
04550-8 Aurothioglucose (100 mg) G 6 $144 Taurocholate)
04560-0 Azaerythromycin A G 6 $144 07150-8 Biotin (200 mg) H
$144 •
(100 mg) 07200-1 Biperiden (200 mg) F-1 $144 K
04575-6 Azaperone (200 mg) F $144 07300-4 Biperiden HCI (200 mg) F-3 $144 K
04580-3 Azatadine Maleate F-1 $144 XREF 2-(4-Biphenylyl)propionic
(200 mg) Acid (100 mg) (Limit Test) m
04600-1 Azathioprine (200 mg) H $144 (Please order Cat. No. M
04605-6 Azithromycin (100 mg) G $144 28576-0) m
04610-3 Azlocillin Sodium (200 mg) F $144 07400-7 Bisacodyl (125 mg) I $114 m
•=
04614-7 Azoaminoglutethimide F $450 07470-0 2,5-Bis-(D-arabino-1,2,3,4- F $450 K
(100 mg) (Limit Test) tetrahydoxybutyl)pyrazine
04620-5 Aztreonam (200 mg) F-1 $144 (25 mg) (Limit Test)
04630-7 Aztreonam E-isomer F $144 XREF N,N'-Bis-(1,3-dihydroxy-2- •
(50 mg) propyl)-5-amino-2,4,6-
04640-9 Open Ring Aztreonam F $144 triiodoisophthalamide
04730-0
04750-3
(50 mg)
Bacampicillin HCI (200 mg)
Bacitracin (1 g) G
11 F (11/02) $144
$144
(50 mg) (Limit Test)
(Please order Cat. No.
34472-4)
•E
(Susceptibility disk XREF 4,4'-Bis[4-(p-chlorophenyl)- I (07/02)
standard) 4-hydroxypiperidino]-
04800-7 Bacitracin Zinc (200 mg) N0A024 2 M-1 (11/02) $144 butyrophenone (25 mg)
04820-0 Baclofen (500 mg) I $144 (Limit Test) (Please order
Cat. No 30301-3)



Previous
07520-3 Bis (2-ethylhexyl)maleate F-2 S450 08690-2 Calcium Lactobionate F-1 6 $144
(250 mg) (Limit Test) (200 mg)
07550-9 p-Bis (di-n-propyl)carba- F S450 08700-9 Calcium Pantothenate N-1 $144
mylbenzenesulfonamide (200 mg) (Vitamin B5)
(50 mg) (Limit Test) 08720-2 Calcium Saccharate F $144
07553-1 Bismuth Citrate (100 mg) F S144 (200 mg)
07555-3 Bismuth Subsalicylate F $144 08800-1 Candicidin (200 mg) F $144
(100 mg)
07600-2 4,4'-Bis[1,2,3,6-tetrahydro- G $450 08900-4 Cannabidiol Cl (25 mg) F-2 $166
4-(2-oxo-1 -benzimidazol- (AS) (For Qualitiative Use
inyl)-1 -pyridyljbutyro- Only)
phenone (25 mg) 09000-3 Cannabinol Cl (25 mg) F-2 (05/02) $166
(Limit Test) (AS)
07630-8 Bleomycin Sulfate (15 mg) I $284 09100-6 Capreomycin Sulfate G $144
07635-2 Bretylium Tosylate F-1 $144 (200 mg)
(200 mg) 09110-8 Capsaicin(100 mg) G-1 G (03/02) $144
07650-1 Bromocriptine Mesylate I $144 09120-0 Captopril (200 mg) H $144
(150 mg) 09122-1 Captopril Disulfide G $450
07700-5 Bromodiphenhydramine F-1 $144 (100 mg) (Limit Test)
HCI (200 mg) 09200-9 Carbachol (200 mg) G $144
07770-8 8-Bromotheophylline G F (07/02) $144 09300-1 Carbamazepine (100 mg) J $144
(400 mg) 09320-5 Carbarsone (200 mg) F $144
07800-8 Brompheniramine Maleate I0A036 2 I (01/03) $114 09350-0 Carbenicillin Indanyl G $144
(125 mg) Sodium (300 mg)
07830-3 Bumetanide (250 mg) G $144 09400-4 Carbenicillin Monosodium G-2 $144
07832-5 Bumetanide Related F-2 $450 Monohydrate (200 mg)
Compound A (25 mg) 09550-6 Carbidopa (400 mg) I $144
(Limit Test) (Formerly Cat. 09600-0 Carbinoxamine Maleate 11 G-1 (11/02) $144
No. 02610-6, 3-Amino-4- (200 mg)
phenoxy-5- 09640-7 Carboplatin (100 mg) G $147
sulfamoylbenzoic Acid) 09650-9 Carboprost Tromethamine F-1 $450
07833-6 Bumetanide Related F-2 2,3 $450 (25 mg)
Compound B (25 mg) 09660-0 Carisoprodol (1 g) G F-2 (05/02) $144
(Limit Test) (Formerly Cat. 09675-7 Carteolol HCI (200 mg) F-1 $144
No. 46660-8, 3-Nitro-4- 09680-4 Cathinone HCI Cl (50 mg) I $450
phenoxy-5- (Limit Test) (Formerly Cat.
sulfamoylbenzoic Acid) No. 02620-8, (-Aminopro-
07850-7 Bupivacaine HCI (1 g) G-2 2 G-1 (08/02) $144 piophenone HCI)
07870-0 Buprenorphine HCI CV F-1 $166 09690-6 Cefaclor (400 mg) H $144
(50 mg) 09691-7 Cefaclor, Delta-3 Isomer G $144
07871-1 Buprenorphine Related F $144 (30 mg)
Compound A (50 mg) 09710-4 Cefadroxil (125 mg) 1 $114
07880-2 Buspirone HCI (200 mg) G $144 09730-8 Cefamandole Lithium H $144
07900-0 Butabarbital Clll (200 mg) G $166 (200 mg)
08000-0 Butacaine Sulfate (600 mg) F $144 09740-0 Cefamandole Nafate H $144
08100-2 Butalbital Clll (200 mg) G-2 2 G (05/02) $166 (200 mg)
08150-1 Butamben (200 mg) F $144 09750-1 Cefamandole Sodium F $144
08230-0 Butoconazole Nitrate F $144 (250 mg) (For
(200 mg) Identification Use Only)
08250-4 Butorphanol Tartrate CIV J $166 09760-3 Cefazolin (400 mg) K $144
(500 mg) 09765-8 Cefixime (500 mg) F $144
08280-0 Monotertiary-butyl-p- F $144 09777-1 Cefmenoxime HCI F $144
benzoquinone (100 mg) (350 mg)
(FCC) 09778-2 Cefmetazole (200 mg) F-1 F (04/02) $144
08290-1 Butyl 3-(butylamino)-4- F-1 $450 09775-0 Cefonicid Sodium (1 g) G $144
phenoxy-5-sulfamoyl- 09770-5 Cefoperazone Dihydrate H $144
benzoate (25 mg) (200 mg)
(Limit Test) 09780-7 Ceforanide (200 mg) F-1 $144
08300-8 2-tert-Butyl-4-hydroxy- K $144 09790-9 Cefotaxime Sodium I $114
anisole (200 mg) (250 mg)
08310-0 3-tert-Butyl-4- J 6 $144 09797-5 Cefotetan (500 mg) G $144
hydroxyanisole (200 mg) 09800-5 Cefotiam HCI (325 mg) 11 F (01/03) $144
08400-0 Butylparaben (200 mg) H-1 6 $144 09804-9 Cefprozil E-lsomer (50 mg) F-1 $144
08500-3 Caffeine (200 mg) J I (06/02) $144 09805-0 Cefprozil Z-lsomer F $144
08600-6 Caffeine Melting Point I $85 (200 mg)
Standard (1 g) 09810-7 Cefoxitin (500 mg) I $144
(Approximately 09812-9 Ceftazidime, Delta-3- G $144
236 degree(s)) Isomer (25 mg)
08610-8 Calcifediol (75 mg) G $144 09813-0 Ceftazidime Pentahydrate H $144
08635-6 Calcium Ascorbate F-1 $144 (300 mg)
(200 mg) (For 09817-3 Ceftizoxime (200 mg) H $144
Identification Use Only) 09818-4 Ceftriaxone Sodium F $144
XREF Calcium Formyltetra- (350 mg)
hydrofolate (50 mg) (AS) 09819-5 Ceftriaxone Sodium E- H $144
(For Qualitiative Use Only) Isomer (25 mg) (For
(Please Order Cat. No. System Suitability Use
28602-7) Only)
08680-0 Calcium Gluceptate F-1 $144 09820-9 Cefuroxime Sodium H $144
(200 mg) (200 mg)



Previous
09822-0 Cefuroxime Axetil (500 mg) G F-1 (05/02) $144 XREF 2-Chloro-3,5-dimethyI- 6
09823-1 Cefuroxime Axetil Delta-3- G $144 phenol (50 mg)
Isomers (35 mg) (Limit Test) (Please order
09830-0 Cellulose Acetate (125 mg) F-1 $114 Cat. No. 12272-2)
09835-5 Cellulose Acetate F-1 $114 XREF (o-Chlorophenyl)diphenyl-
Phthalate (125 mg) methanol (25 mg)
09870-8 Cephaeline HBr (200 mg) G-1 $450 (Limit Test) (Please order
(Limit Test) Cat. No. 14102-4)
09900-8 Cephalexin (250 mg) I-2 $144 XREF 4-(4-Chlorophenyl)-2-
10200-0 Cephalothin Sodium I $144 pyrrolidinone (75 mg)
(200 mg) (Limit Test) (Please order
10240-8 Cephapirin Benzathine F $144 Cat. No. 04822-2)
(100 mg) 11555-6 beta-Chlorogenin (20 mg) F $144
10250-0 Cephapirin Sodium I (07/02) $144 (For Identification Use
(200 mg) Only)
10280-5 Cephradine (200 mg) J $144 11700-8 Chloroprocaine HCI F-3 $144
10300-3 Cetyl Alcohol (100 mg) I $144 (200 mg)
10400-6 Cetylpyridinium Chloride I $144 11800-0 Chloroquine Phosphate I $144
(500 mg) (500 mg)
10600-1 Chlorambucil (125 mg) G $114 XREF 4-Chloro-5-sulfamoyl-
10700-4 Chloramphenicol (200 mg) N $144 anthranilic Acid (100 mg)
10730-0 Chloramphenicol Palmitate G-1 $144 (Limit Test) (Please order
(200 mg) Cat. No. 28703-0)
10740-1 Chloramphenicol Palmitate F-1 $450 11930-9 4'-Chloro-3'-sulfamoyl-2- F-3 $450
Nonpolymorph A (200 mg) benzophenone Carboxylic
(Limit Test) Acid (100 mg) (Limit Test)
10750-3 Chloramphenicol Palmitate G $450 12100-5 Chlorothiazide (200 mg) G $144
Polymorph A (200 mg) 12200-8 Chlorotrianisene (1 g) F $144
(Limit Test) 12270-0 Chloroxylenol (125 mg) F-1 $114
10900-0 Chlordiazepoxide CIV H-1 $166 12272-2 Chloroxylenol Related F-1 $450
(200 mg) Compound A (50 mg)
11000-9 Chlordiazepoxide HCI CIV G-4 $166 (Limit Test) (Formerly Cat.
(200 mg) No. 11550)
11002-0 Chlordiazepoxide Related G $450 12300-0 Chlorpheniramine Maleate L-1 $114
(Limit Test) (Formerly Cat. 12310-2 Chlorpheniramine Maleate F $144
No. 11500-2, 7-Chloro-1,3- Extended-Release Tablets
dihydro-5-phenyl-2H-1,4- (Drug Release Calibrator,
benzodiazepin-2-one 4- Single-Unit) (60 Tablets)
Oxide) 12400-3 Chlorphenoxamine HCI F-1 $144
XREF p-Chlorobenzhydryl- G-1 (01/02) (200 mg)
piperazine (25 mg) (Please 12500-6 Chlorpromazine HCI J $144
order Cat. No. 33305-8) (200 mg)
11250-3 Chlorobutanol (200 mg) G 6 $144 12600-9 Chlorpropamide (200 mg) H $144
(For Identification Use 12700-1 Chlorprothixene (200 mg) F-1 $144
Only) 12900-7 Chlortetracycline HCI J-1 6 $144
XREF 6-Chloro-4-(o-chloro- (200 mg)
phenyl)-2-quinazoline- 13000-6 Chlorthalidone (125 mg) H-1 $114
carboxaldehyde (25 mg) 13050-5 Chlorzoxazone (500 mg) I $144
(Limit Test) (Please order 13052-7 Chlorzoxazone Related G-1 $450
Cat. No. 37034-9) Compound A (25 mg)
XREF 6-Chloro-4-(o-chloro- (Limit Test) (Formerly Cat.
phenyl)-2-quinazoline- No. 02240-6, 2-Amino-4-
carboxylic Acid (25 mg) chlorophenol)
(Limit Test) (Please order 13100-9 Cholecalciferol L $147
Cat. No. 37035-0) (30 mg/ampul; 5 ampuls)
XREF 6-Chloro-4-(o-chloro- (Vitamin D3)
phenyl)-2-quinazoline 13180-3 Delta 4,6-cholestadienol F $144 •
Methanol (25 mg) (30 mg)
(Limit Test) (Please order 13200-1 Cholesteryl Caprylate F
K
$144 K
Cat. No. 37036-0) (200 mg)
XREF 7-Chloro-1,3-dihydro-5- 13300-4 Cholestyramine Resin I $114 KK
phenyl-2H-1,4-benzo- (500 mg)
diazepin-2-one (50 mg) 13350-3 Cholic Acid (2 g) (AS) 11 F-2 (01/03) $144
H•
(Limit Test) (Please order 13363-8 Chromium Picolinate F 4 $144 K
Cat. No. 46840-0) (100 mg) (For Identification
XREF 7-Chloro-1,3-dihydro-5-
phenyl-2H-1,4-benzo- 13400-7
Test Only)
Chymotrypsin (300 mg) 1 $144
m
m
diazepin-2-one 4-Oxide 13403-0 Ciclopirox Olamine G $114 •
(25 mg) (Limit Test) (125 mg)
(Please order Cat. No. 13405-1 Cilastatin Ammonium Salt F-1 $144 E
11002-0) (100 mg)
XREF 2-Chloro-4-N-furfuryl- 13406-2 Cimetidine (200 mg) I $144 E•
amino-5-sulfamolybenzoic 13407-3 Cimetidine HCI (200 mg) F $144 ™
acid (50 mg) (Limit Test) 13410-9 Cinoxacin (200 mg) F $144
(Please order Cat. No. 13431-3 Ciprofloxacin (125 mg) G-1 $114
28702-0) 13432-4 Ciprofloxacin J0A030 2 I (01/03) $144
Ethylenediamine Analog
(25 mg)


Mar-Apr. 2002 Official USP Reference Standards Catalog

Previous
13433-5 Ciprofloxacin HCI (400 mg) H $144 14900-4 Corticotropin M $114
13435-7 Cisplatin(100mg) H $144 (5.6 Units/vial; 5 vials)
13436-8 Citric Acid (200 mg) F (07/02) S144 15000-3 Cortisone Acetate I $144
13437-9 Clarithromycin (75 mg) F-3 6 $144 (150 mg)
13438-0 Clarithromycin Related G $144 15035-3 Creatinine (100 mg) (For F $144
Compound A (50 mg) Identification Use Only)
13440-4 Clavam-2-carboxylate F $450 15050-2 Cromolyn Sodium J $144
Potassium (1 Pellet) (500 mg)
(Limit Test) 15070-6 Crospovidone (200 mg) G $144
13442-6 Clavulanate Lithium I 2 H (09/02) $144 15100-6 Crotamiton (200 mg) H-1 $144
(200 mg) 15200-9 Cyanocobalamin (1.5 g of N $144
13450-6 Clemastine Fumarate I $144 mixture with mannitol;
(250 mg) 10.7 /yg/mg of mixture)
13500-0 Clidinium Bromide (2 g) G $144 (Vitamin B12)
13502-1 Clindinium Bromide I $450 15250-8 Cyclacillin (200 mg) G $144
Related Compound A 15300-1 Cyclizine (1 g) F $144
(250 mg) (Limit Test) 15400-4 Cyclizine HCI (200 mg) G $144
(Formerly Cat. No. 32720- 15450-3 Cyclobenzaprine HCI F-3 $144
4 3-Hydroxy-1-methyl- (200 mg)
quinuclindinium Bromide) 15455-8 Alpha Cyclodextrin (50 mg) F-1 $144
(250 mg) (Limit Test) 15456-9 Beta Cyclodextrin (250 mg) G 2 F-1 (12/02) $144
13600-2 Clindamycin HCI (200 mg) G-3 $396 15470-7 Cyclomethicone F-2 2 F-1 (06/02) $144
13700-5 Clindamycin Palmitate HCI F-2 $396 4 (200 mg)
(200 mg) 15480-9 Cyclomethicone F-2 $114
13800-8 Clindamycin Phosphate H-2 $198 5 (125 mg)
(125 mg) 15490-0 Cyclomethicone F-1 $144
13820-1 Clioquinol (500 mg) L-1 $144 6 (200 mg)
13840-5 Clobetasol Propionate F-1 6 $144 15600-0 Cyclopentolate HCI H $144
(200 mg) (300 mg)
13842-7 Clobetasol Propionate F-1 2 F (01/03) $144 15700-2 Cyclophosphamide J $114
Related Compound A (500 mg)
(50 mg) 15750-1 2-Cyclopropylmethyl- F $450
13850-7 Clocortolone Pivalate G $144 amino-5- chlorobenzo-
(200 mg) phenone (50 mg)
13890-4 Clofazimine (200 mg) F $144 (Limit Test)
13900-0 Clofibrate (1 g) I $144 15800-5 Cycloserine (200 mg) G $144
14000-0 Clomiphene Citrate H $144 15850-4 Cyclosporine (50 mg) H-1 2 H (11/02) $443
(500 mg) 15865-0 Cyclosporine Resolution F $381
14010-1 Clomiphene Related F $144 Mixture (25 mg) (Replaces
Compound A (100 mg) Cat. No. 15870-8
14030-5 Clonazepam CIV (200 mg) G $166 Cyclosporine U (25 mg))
14032-7 Clonazepam Related G-1 $450 XREF Cyclosporine U (25 mg)
Compound A (25 mg) (Please order Cat. No.
(Limit Test) (Formerly Cat. 15865-0)
No. 02460-0, 3-Amino-4- 15900-8 Cyclothiazide (200 mg) F-1 $144
(2-chlorophenyl)-6- 16100-0 Cyproheptadine HCI 11 F-4 (11/02) $144
nitrocarbostyril) (500 mg)
14033-8 Clonazepam Related H $450 16150-9 L-Cysteine HCI (200 mg) H $144
Compound B (25 mg) 16200-2 Cytarabine (250 mg) G-2 $144
(Limit Test) (Formerly Cat. 16230-8 Dacarbazine (125 mg) H $114
No. 02380-0,2-Amino-2'- 16232-0 Dacarbazine Related G $450
chloro-5-nitrobenzo- Compound A (50 mg)
phenone) (Limit Test)
14040-7 Clonidine HCI (200 mg) G $144 16233-0 Dacarbazine Related F-1 6 $450
14050-9 Clorazepate Dipotassium F-1 $166 Compound B (100 mg)
CIV (125 mg) (Limit Test)
14070-2 Clorsulon (200 mg) F $144 16240-0 Dactinomycin (50 mg) I $395
14100-2 Clotrimazole (200 mg) J $114 16250-1 Danazol (200 mg) H $144
14102-4 Clotrimazole Related I 6 $450 16400-8 Dapsone (125 mg) G-3 $114
Compound A (25 mg) 16470-0 Daunorubicin HCI (100 mg) K $443
(Limit Test) (Formerly Cat. 16500-0 Decamethonium Bromide F $144
No. 11650-4) (250 mg)
14190-9 Cloxacillin Benzathine F-1 F (03/02) $144 16600-3 Deferoxamine Mesylate I $144
(200 mg) (For (500 mg)
Identification Use Only) 16630-9 Dehydroacetic Acid F $144
14200-5 Cloxacillin Sodium K $144 (200 mg)
(200 mg) 16640-0 Dehydrocarteolol HCI F $450
14300-8 Cocaine HCI Cll (250 mg) H-2 $166 (100 mg) (Limit Test)
14380-2 Codeine N-Oxide Cl 11 F-1 (11/02) $166 16650-2 Dehydrocholic Acid F $144
(50 mg) (200 mg)
14400-0 Codeine Phosphate Cll I $166 16900-1 Demecarium Bromide F $144
(100 mg) (250 mg)
14500-3 Codeine Sulfate Cll H-2 6 $166 17000-0 Demeclocycline HCI H $144
(250 mg) (200 mg)
14600-6 Colchicine (300 mg) J I (05/02) $144 17100-3 Denatonium Benzoate 11 H (09/02) $144
14650-5 Colestipol HCI (200 mg) F-1 $144 (200 mg)
14700-9 Colistimethate Sodium H $144 17170-6 Desacetyl Diltiazem HCI I $450
14800-1 Colistin Sulfate (200 mg) G-1 $144 17200-6 Desipramine HCI (125 mg) H-1 $114
10



Previous
17300-9 Deslanoside(100mg) H-1 $144 20300-8 Dihydrostreptomycin J $144
17350-8 Desoximetasone (200 mg) G $144 Sulfate (200 mg)
17400-1 Desoxycorticosterone I $144 20400-0 Dihydrotachysterol I $144
Acetate (200 mg) (30 mg/ampul; 4 ampuls)
17500-4 Desoxycorticosterone G $114 20410-2 Dihydroxyacetone F $144
Pivalate(125mg) (250 mg)
17600-7 Dexamethasone (125 mg) J $114 20500-3 Diltiazem HCI (200 mg) I $144
17650-6 Dexamethasone Acetate G $144 20600-6 Dimenhydrinate (100 mg) I $144
(200 mg) 20800-1 Dimethisoquin HCI (2 g) G $144
17700-0 Dexamethasone J $144 XREF a-d-4-Dimethylamino-1,2- G-4 (04/02)
Phosphate (200 mg) diphenyl-3-methyl-2-
17800-2 Dexbrompheniramine I $144 butanol HCI (125 mg)
Maleate (200 mg) (Limit Test) (Please Order
17900-5 Dexchlorpheniramine G1A025 2 G (12/02) $144 Cat. No. 57520)
Maleate (500 mg) 21010-5 N-(3-Dimethylamino- F $144
17950-4 Dexpanthenol (500 mg) I 6 $148 propyl)-2-aza-8,8-diethyl-8-
18000-4 Dextroamphetamine G $174 germaspiro [4:5]decane-
Sulfate Cll (500 mg) 1,3-dione
18050-3 Dextromethorphan (2 g) H $450 21100-6 Dimethyl Sulfoxide (3 g) F-3 F-2 (05/02) $144
18100-7 Dextromethorphan HBr I $144 21300-1 Dinoprost Tromethamine F $1,410
(500 mg) (50 mg)
18130-2 Dextrose (1 g) J-1 2 J (11/02) $114 21400-4 Dioxybenzone (150 mg) F $144
18150-6 Diacetylated Mono- G $144 21600-0 Diphemanil Methylsulfate H $144
glycerides (200 mg) (500 mg)
18200-0 Diacetylfluorescein H 6 $144 21790-9 Diphenhydramine Citrate G $114
(200 mg) (125 mg)
18300-2 Diacetylmorphine HCI J $166 21800-5 Diphenhydramine HCI I $144
(Heroin HCI) Cl (25 mg) (200 mg)
(AS) 21900-8 Diphenoxylate HCI Cll I H (03/02) $166
18400-5 Diatrizoic Acid (100 mg) G $144 (200 mg)
18402-7 Diatrizoic Acid Related I $450 22030-2 Dipivefrin HCI (200 mg) I $144
Compound A (50 mg) 22050-6 Dipyridamole (200 mg) H $144
(Limit Test) (Formerly Cat. 22070-0 Dirithromycin (200 mg) F $144
No. 00200-6,5-Acetamido- 22100-0 Disodium Guanylate F-1 $144
3-amino-2,4,6-triiodo- (300 mg) (FCC)
benzoic Acid) 22200-2 Disodium Inosinate F $144
18500-8 Diazepam CIV (100 mg) I 6 $166 (500 mg) (FCC)
18502-0 Diazepam Related I 2 H-1 (11/02) $450 22250-1 Disopyramide Phosphate H-1 H (03/02) $144
(Limit Test) (Formerly Cat. 22300-5 2,4-Disulfamyl-5-trifluoro- G $450
No. 42420-0,2-Methyl- methylaniline (125 mg)
amino-5-chlorobenzo- (Limit Test)
phenone) 22400-8 Disulfiram (200 mg) F-3 F-2 (07/02) $144
18600-0 Diazoxide (200 mg) G $144 22450-7 Dobutamine HCI (600 mg) H-1 $144
18700-3 Dibucaine HCI (200 mg) I 2 H-2 (01/03) $144 22470-0 Docusate Calcium 11 G-1 (07/02) $144
18720-7 Dichloralphenazone CIV F0B010 1 $166 (500 mg)
(200 mg) 22480-2 Docusate Sodium (500 mg) J 1-1 (05/02) $144
18800-6 Dichlorphenamide G-1 $144 22490-4 Docusate Potassium F-1 $144
(200 mg) (100 mg)
18880-0 Diclofenac Sodium G-1 $144 22520-4 Dopamine HCI (200 mg) G F-5 (05/02) $144
(200 mg) 22500-0 Doxapram HCI (200 mg) F-3 $144
18881-1 Diclofenac Related G (05/02) $453 22550-0 Doxepin HCI (500 mg) I $144
Compound A (100 mg) 22570-3 Doxorubicin HCI (50 mg) K 2 J (06/02) $443
(Limit Test) 22600-3 Doxycycline Hyclate I $144
18900-9 Dicloxacillin Sodium H $144 (200 mg)
(500 mg) 22700-6 Doxylamine Succinate H $144
19000-8 Dicumarol (200 mg) G $144 (300 mg)
19100-0 Dicyclomine HCI (125 mg) H $114 22900-1 Droperidol (250 mg) H-1 $144 B
19200-3 Dienestrol (125 mg) I $114 23000-0 Dyclonine HCI (200 mg) G $144 K
19300-6 Diethylcarbamazine Citrate G-1 $144 23100-3 Dydrogesterone (200 mg) H $144 K
(200 mg) 23150-2 Dyphylline (200 mg) G-2 2 G-1 (11/02) $144 K
19350-5 Diethyl Phthalate (200 mg) G $144 23180-8 Econazole Nitrate (200 mg) G $144 K
19400-9 Diethylpropiort HCI CIV H $166 23200-6 Edetate Calcium Disodium G-3 $144 m.
(200 mg) (200 mg)
19500-1 Diethylstilbestrol (200 mg) K-4 $144 23300-9 Edetate Disodium (200 mg) H G-2 (04/02) $144 m
•=
19700-7 Diethyltoluamide (3 g) H $114 23350-8 Edetic Acid (200 mg) F-1 $144 K
19730-2 Diflorasone Diacetate G $144 23400-1 Edrophonium Chloride H $144 •=
(200 mg) (200 mg)
19750-6 Diflunisal (200 mg) G $144 23500-4 Emetine HCI (300 mg) G $144 mK
19800-0 Digitalis (3 g) F $144 23527-4 Enalaprilat (300 mg) I $114 K
19900-2 Digitoxin (200 mg) M $144 23530-0 Enalapril Maleate (200 mg) J $144 •=
20000-0
20060-0
20080-4
Digoxin (250 mg)
Dihydrocapsaicin (50 mg)
Dihydrocodeine Bitartrate
N-1
F-1
H
$144
$144
$166
23550-3
23580-9
Endotoxin (10,000 USP
Endotoxin Units)
Enflurane (1 mL)
G-1
G-1
$144
$144
•
B=
Cll (200 mg) 23600-7 Ephedrine Sulfate 11 H-1 (11/02) $144

20100-2 17a-Dihydroequilin H $144 (200 mg)
(50 mg) 23650-6 4-Epianhydrotetracycline 1-1 $450
20200-5 Dihydroergotamine I $144 HCI (50 mg) (Limit Test)
Mesylate (250 mg)
11


Previous
Cat Curr Change Lot/Valid Cat Curr. Change Lot/Valid
23680-1 Epilactose (200 mg) G $450 26850-2 Etidronate Disodium F-2 $144
(Limit Test) (200 mg)
23700-0 Epinephrine Bitartrate O $144 26860-4 Etidronic Acid G $144
(200 mg) Monohydrate (1 g)
23750-9 Epitetracycline HCI F S450 26870-6 Etodolac (400 mg) G 6 $144
(200 mg) (Limit Test) 26872-8 Etodolac Related F-1 F (05/02) $144
23800-2 Equilin (25 mg) I $144 Compound A (25 mg)
23900-5 Ergocalciferol (150 mg; O $156 26880-8 Etoposide (300 mg) G $114
30 mg/ampul; 5 ampuls) 26882-0 Etoposide Related F-1 $144
(Vitamin D2) Compound A (25 mg)
23950-4 Ergoloid Mesylates 1 $144 26900-6 Evans Blue (200 mg) G $144
(300 mg) 26920-0 Famotidine(125 mg) H-1 2 H (11/02) $114
24000-4 Ergonovine Maleate N M-1 (07/02) $144 26938-9 Felodipine (200 mg) F $144
(100 mg) 26940-3 Fenbendazole (100 mg) F 1 $450
24100-7 Ergosterol (50 mg) (For H $144 (Limit Test)
Identification Use Only) 26950-5 Fenoprofen Calcium G-1 $144
24150-6 Ergotamine Tartrate H $144 (500 mg)
(150 mg) 26955-0 Fenoprofen Sodium G F-1 (05/02) $144
24155-0 Ergotaminine (100 mg) F-1 $144 (500 mg)
24200-0 Erythromycin (250 mg) M $144 27000-5 Fentanyl Citrate CM J (05/02) $166
24201-0 Erythromycin B (150 mg) G $144 (100 mg)
24202-1 Erythromycin C (50 mg) F-3 2 F-2 (01/03) $144 27040-2 Finasteride (200 mg) F $144
24203-2 Erythromycin Related F-1 $144 27080-0 Flecainide Acetate F $144
Compound N (50 mg) (200 mg)
(Resolution Solution Use 27082-1 Flecainide Related F $450
Only) Compound A (75 mg)
24300-2 Erythromycin Estolate H 2 G (01/03) $144 (Limit Test)
(200 mg) (For Identification 27100-8 Floxuridine (250 mg) F-2 $144
Use Only. For Potency Use 27200-0 Flucytosine (200 mg) F $144
Cat. No. 24200-0) 27300-3 Fludrocortisone Acetate H $144
24500-8 Erythromycin H $144 (250 mg)
Ethyls uccinate (200 mg) 27400-6 Flumethasone Pivalale I 6 $144
(For Identification Use (200 mg)
Only. For Potency Use 27450-5 Flunisolide (200 mg) I $144
Cat. No. 24200-0) 27460-7 Flunixin Meglumine F-1 $144
24600-0 Erythromycin Gluceptate G $144 (300 mg)
(200 mg) (For Identification 27500-9 Fluocinolone Acetonide J $144
Use Only. For Potency Use (100 mg)
Cat. No. 24200-0) 27600-1 Fluocinonide (100 mg) I $144
24700-3 Erythromycin Lactobionate H-1 6 $144 27700-4 Fluorescein (200 mg) F-1 $144
(200 mg) (For Identification 27720-8 Fluoride Dentifrice: Sodium F $450
Use Only. For Potency Use Fluoride-Calcium
Cat. No. 24200-0) Pyrophosphate (high beta-
24800-6 Erythromycin Stearate G-1 $144 phase) (180 g)
(200 mg) (For Identification 27725-2 Fluoride Dentifrice: Sodium I $423
Use Only. For Potency Use Fluoride/Silica (4.5 oz)
Cat. No. 24200-0) 27727-4 Fluoride Dentifrice; Sodium F $450
24900-9 Erythrosine Sodium F $144 Fluoride/Sodium Bicarb-
(100 mg) onate Powder (4 oz.)
25000-8 Estradiol (500 mg) K $144 27730-0 Fluoride Dentifrice: Sodium G $450
25100-0 Estradiol Benzoate G-1 $144 Monofluorophosphate-
(250 mg) (AS) Calcium Carbonate
25200-3 Estradiol Cypionate G-1 $144 (4.6 oz.)
(200 mg) 27735-4 Fluoride Dentifrice: Sodium G $450
25400-9 Estradiol Valerate (100 mg) K (05/02) $144 Monofluorophosphate/Di-
25450-8 Estriol (100 mg) J $144 calcium Phosphate
25500-1 Estrone (200 mg) K $144 (4.6 oz.)
25550-0 Estropipate (350 mg) I 6 $144 27740-1 Fluoride Dentifrice: Sodium G-1 $450
25600-4 Ethacrynic Acid (200 mg) F $144 Monofluorophosphate
25700-7 Ethambutol HCI (200 mg) H 2 G (08/02) $144 (1000ppm)/Silica
26000-1 Ethinyl Estradiol (150 mg) P $144 (5.25 oz.)
26100-4 Ethionamide (200 mg) G $144 27742-3 Fluoride Dentifrice: Sodium F-1 $450
26280-1 Ethopabate (125 mg) F $144 Monofluorophosphate
26282-3 Ethopabate Related F $144 (1500ppm)/Silica
Compound A (25 mg) (5.25 oz.)
26300-0 Ethopropazine HCI G $144 27745-6 Fluoride Dentifrice: 11 G (11/02) $450
(300 mg) Stannous Fluoride-Silica
26400-2 Ethosuximide (125 mg) H 6 $114 (4 oz.)
26450-1 Ethotoin (200 mg) F $144 27800-7 Fluorometholone (200 mg) 11 H-1 (11/02) $144
26500-5 Ethoxzolamide (200 mg) F $144 27810-9 Fluorometholone Acetate F $144
26550-4 Ethylcellulose (1 g) H-1 $144 (200 mg)
26600-8 Ethyl Maltol (1 g) (FCC) H $144 27830-2 Fluoroquinolonic Acid G $450
26650-7 Ethylnorepinephrine HCI F $144 (50 mg) (Limit Test)
(200 mg) 27900-0 Fluorouracil (250 mg) H-1 6 $144
26700-0 Ethylparaben (200 mg) H $144 27980-4 Fluoxetine HCI (200 mg) F-1 $144
26750-0 Ethyl Vanillin (200 mg) F-1 $144 27981-5 Fluoxetine Related G 4 $450
26800-3 Ethynodiol Diacetate I0A033 2 H-1 (01/03) $144 Compound A (15 mg) (For
(200 mg) System Suitability Use
Only)
12


Previous Previous
27982-6 Fluoxetine Related F-2 2 F-1 (09/02) $144 28800-0 Gallamine Triethiodide F $144
Compound B (5 mL of a (200 mg)
0.01 NHCI solution, 28850-0 Gemfibrozil (200 mg) H $144
approx. 2 mg/mL) (For 28900-3 Gentamicin Sulfate K $144
System Suitability Use (200 mg)
Only) 29000-2 Gentian Violet (650 mg) F $144
28000-9 Fluoxymesterone CHI G-2 $166 29100-5 Gibberellic Acid (200 mg) G $144
(200 mg) (FCC)
28080-3 Fluphenazine Decanoate G 6 $147 29150-4 Powdered Ginger (500 mg) F $144
Dihydrochloride (500 mg) 29200-8 Gitoxin (50 mg) G $450
28100-1 Fluphenazine Enanthate H $114 (Limit Test)
Dihydrochloride (125 mg) 29250-7 Glipizide (125 mg) G $114
28200-4 Fluphenazine HCI H $114 29260-9 Glipizide Related G-1 $450
28400-0 Flurandrenolide (100 mg) H $144 (Limit Test)
28500-2 Flurazepam HCI CIV I $166 29400-3 Glucagon (25 mg, H $144
(200 mg) 0.95 U/mg)
28530-8 Flurazepam Related H-1 $450 29484-8 L-gamma-Glutamyl-S-allyl- F $624
Compound C (50 mg) L-cysteine (25 mg)
(Limit Test) 29500-6 Glutethimide Cll (500 mg) F $166
28560-3 Flurazepam Related H $450 29550-5 Glyburide (200 mg) G 2 F-2 (11/02) $144
Compound F (50 mg) 29560-7 Glycerin (2 mL) G1A001 2 G (12/02) $144
(Limit Test) 29570-9 Glyceryl Behenate F-2 $144
28575-0 Flurbiprofen (200 mg) G $144 (200 mg)
28576-0 Flurbiprofen Related H $450 29580-0 Glycine (200 mg) F-3 $144
Compound A (100 mg) 29600-9 Glycopyrrolate (200 mg) G $144
(Limit Test) (Formerly Cat. 29700-1 Human Chorionic H $144
No. 07350-3, 2-(4- Gonadotropin (1 vial,
Biphenylyl)propionic Acid) 5,760 USP Units per
28580-7 Flurbiprofen Sodium F $144 package)
(200 mg) (For 29800-4 Gramicidin (200 mg) H-1 (07/02) $144
Identification Use Only) 29900-7 Griseofulvin (200 mg) I 2 H-1 (09/02) $144
28585-1 Flutamide (200 mg) G $144 29920-0 Griseofulvin Permeability H $144
28586-2 o-Flutamide (50 mg) F-1 $144 Diameter (2 g)
(System Suitability Use) 30000-4 Guaiacol (1 g) K $144
28600-5 Folic Acid (500 mg) P $144 30100-7 Guaifenesin (200 mg) 11 H (09/02) $144
(Vitamin M or Vitamin Be) 30140-4 Guanabenz Acetate G $144
28602-7 Folic Acid Related H-1 $144 (200 mg)
Compound A (50 mg) 30160-8 Guanadrel Sulfate F-1 $144
(Fomerly Cat. No. 08650-5, (200 mg)
Calcium Formyltetra- 30180-1 Guanethidine Monosulfate F $144
hydrofolate) (200 mg)
28620-9 4-Formylbenzenesulfon- F $450 30200-0 Guanethidine Sulfate G-1 $144
amide (50 mg) (Limit Test) (500 mg)
28630-0 10-Formylfolic Acid F-1 $144 30210-1 Guanfacine HCI (125 mg) 11 F-1 (02/03) $114
(25 mg) 30230-5 Halazepam CIV (200 mg) F $166
28650-4 Fructose (125 mg) I-2 2 1-1 (11/02) $114 30250-9 Halcinonide (300 mg) F $144
28670-8 Fumaric Acid (200 mg) G (04/02) $144 30300-2 Haloperidol (200 mg) I H-1 (05/02) $144
28680-0 Furazolidone (200 mg) G-2 6 $144 30301-3 Haloperidol Related J 2 $450
28700-8 Furosemide (125 mg) J $114 Compound A (25 mg)
28702-0 Furosemide Related J 2 I (08/02) $450 (Limit Test) (Formerly Cat.
Compound A (50 mg) No. 07500 4,4-Bis[4-p-
(Limit Test) (Formerly Cat. chlorophenyl)-4-hydroxy-
No. 11510-4, 2-Chloro-4-N- piperidino]-butyrophenone
furfurylamino-5-sulfa- 30330-8 Haloprogin (200 mg) F $144
molybenzoic Acid) 30350-1 Halothane (1 mL) F-1 $144
28703-0 Furosemide Related
Compound B (100 mg)
(Limit Test) (Formerly Cat.
H $450 30400-5
30500-8
Heparin Sodium
(10x1 mL)
Hexachlorophene (500 mg)
K-4
I
$144
$144
•_
K
No. 11900-3, 4-Chloro-5- 30700-3 Hexobarbital Clll (500 mg) F $166 K
sulfamoylanthranilic Acid) 30800-6 Hexylcaine HCI (1 g) F-1 $144 K
28730-3 Gabapentin (250 mg) F $144 30820-0 Hexylene Glycol (125 mg) G F-2 (04/02) $144 •=
28732-5 Gabapentin Related F $450 30830-7 Hexylresorcinol (200 mg) F $144 Kj
Compound A (100 mg) 30850-5 L-Histidine (200 mg) 11 F-2 (01/03) $144 K
(Limit Test) 30900-9 Histamine Dihydrochloride L $144 K
28750-7 Gadodiamide (500 mg) F $144 (250 mg)
28751-8 Gadodiamide Related F $450 31000-8 Homatropine HBr (200 mg) 11 H (08/02) $144 mK
Compound A (50 mg) 31100-0 Homatropine 6 $144 K
28752-1 Gadodiamide Related F $450 Methylbromide (250 mg)
Compound B (50 mg) 31200-3 Hyaluronidase (500 mg) H $144 m
W
28760-9 Gadopentetate F 1 $144 31300-6 Hydralazine HCI (200 mg) 11 J-1 (09/02) $144 K
Monomeglumine (500 mg) 31400-9 Hydrochlorothiazide I H (05/02) $144 RE
28763-1 Gadoteridol (500 mg) F 1 $144 (200 mg)
28764-2 Gadoteridol Related F0A002 1 $450 31500-1 Hydrocodone Bitartrate Cll J0A026 2 I (07/02) $166
Compound A (50 mg) (250 mg) 1-1 (12/02)
(Limit Test) 31600-4 Hydrocortisone (200 mg) M $144
28770-0 Galactose (200 mg) F-4 $450 31700-7 Hydrocortisone Acetate K $144
13


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31730-2 Hydrocortisone Butyrate H $144 34450-9 lodoquinol (100 mg) G (07/02) $144
(200 mg) 34460-0 lohexol (100 mg) F-1 $114
31800-0 Hydrocortisone Cypionate F $144 34462-2 lohexol Related Compound F-1 6 $450
(200 mg) A (100 mg) (Limit Test)
31900-2 Hydrocortisone H G-3 (03/02) $144 34464-4 lohexol Related Compound F $450
Hemisuccinate (200 mg) B (50 mg) (Limit Test)
32000-1 Hydrocortisone Phosphate F-1 $144 34466-6 lohexol Related Compound F $144
Triethylamine (200 mg) C(100mg)
32100-4 Hydrocortisone Valerate F-1 F (07/02) $144 34470-2 lopamidol (200 mg) G $144
(200 mg) 34472-4 lopamidol Related G $450
32200-7 Hydroflumethiazide F-2 $144 Compound A (50 mg)
(200 mg) (Limit Test) (Formerly Cat.
32300-0 Hydromorphone HCI CII I $166 No. 07480-1, N,N'-Bis-(1,3-
(50 mg) dihydroxy-2-propyl)-5-
32400-2 Hydroquinone (500 mg) G-1 6 $144 amino-2,4,6-triiodoiso-
32500-5 Hydroxyamphetamine HBr G $144 phthalamide)
(200 mg) 34473-5 lopamidol Related F $450
32700-0 Hydroxychloroquine I $144 Compound B (100 mg)
Sulfate (200 mg) (Limit Test)
32720-4 3-Hydroxy-1 -methylqui- H (04/02) $450 34480-4 lopromide (400 mg) F $144
nuclidinium Bromide 34482-6 lopromide Related F $450
(250 mg) (Limit Test) Compound A (50 mg)
[Name Change Cat. No. (Limit Test)
13502-1] 34483-7 lopromide Related F $450
32900-6 Hydroxyprogesterone H $144 Compound B (50 mg)
Caproate (200 mg) (Limit Test)
32950-5 9-Hydroxypropantheline F-1 $450 34500-2 lothalamic Acid (200 mg) G $144
Bromide (50 mg) 34510-4 loversol (200 mg) F $144
(Limit Test) 34511-5 loversol Related F $450
32980-0 Hydroxypropyl Cellulose F-1 $144 Compound A (50 mg)
33000-5 Hydroxypropyl G-1 6 $144 34512-6 loversol Related F $450
Methylcellulose (250 mg) Compound B (50 mg)
XREF Hydroxypropyl (Limit Test)
Methylcellulose Phthalate 34515-9 loxaglic Acid (100 mg) (For F $144
(100 mg) (Please order Indentification Use Only)
Cat. No. 33530-4, 34520-6 loxilan (400 mg) F 1 $144
Hypromellose Phthalate) 34522-8 loxilan Related Compound F $450
33200-0 Hydroxyurea (200 mg) H $144 A (100 mg) (Limit Test)
33300-3 Hydroxyzine HCI (500 mg) H $144 34600-5 Ipodate Calcium (200 mg) F $144
33305-8 Hydroxyzine Related H 4 $144 34700-8 Ipodate Sodium (200 mg) F-1 $144
Compound A (25 mg) 34775-5 Isoamyl Methoxycinnamate F0B017 1 $144
(Formerly Cat. No. 11230; (750 mg/ampule)
p-Chlorobenzhydryl- 34800-0 Isocarboxazid (200 mg) F-1 $144
piperazine) 34850-0 Isoetharine HCI (250 mg) F-2 $144
33400-6 Hydroxyzine Pamoate 11 G-1 (01/03) $144 34900-3 Isoflurane (1 mL) H $144
(500 mg) 34950-2 L-lsoleucine (200 mg) 11 F-1 (09/02) $144
33500-9 Hyoscyamine Sulfate G2A007 2 G-1 (08/02) $114 34960-4 Isomalathion (50 mg) 11 F (01/03) $450
33520-2 Hyperoside (50 mg) F 1 $790 34965-9 Isometheptene Mucate F $144
33530-4 Hypromellose Phthalate F-1 $144 (200 mg)
(100 mg) (Formerly Cat. 34970-6 Isoniazid (200 mg) H $144
No. 33010-7) 35000-2 Isopropamide Iodide F-2 $144
33550-8 Ibuprofen (750 mg) J I (06/02) $144 (200 mg)
33570-1 Idarubicin HCI (50 mg) G $443 35040-0 Isopropyl Myristate I $144
33600-1 Idoxuridine (250 mg) H $144 (500 mg)
33620-5 Ifosfamide (500 mg) G $144 35060-3 Isopropyl Palmitate I $144
33650-0 Imidazole (200 mg) G $450 (500 mg)
(Limit Test) 35100-5 Isoproterenol HCI (125 mg) K $114
33680-6 Imidurea (200 mg) H $144 35200-8 Isosorbide (75% solution, I $144
33700-4 Iminodibenzyl (25 mg) H $450 10)
(Limit Test) 35300-0 Diluted Isosorbide Dinitrate 1-1 $144
33780-9 Imipenem Monohydrate G $144 (500 mg of 25% mixture
(100 mg) with mannitol)
33800-7 Imipramine HCI (200 mg) I 6 $144 35350-0 Isotretinoin (200 mg) I $144
33880-1 Indapamide (250 mg) H 2 G (07/02) $144 35400-3 Isoxsuprine HCI (200 mg) F-3 $144
33900-0 Indigotindisulfonate H $144 35420-7 Isradipine (200 mg) F $144
Sodium (200 mg) 35421-8 Isradipine Related F $144
34000-9 Indocyanine Green 6 $144 Compound A (25 mg)
(200 mg) 35500-6 Kanamycin Sulfate J $144
34100-1 Indomethacin (200 mg) I $144 (200 mg)
34200-4 Insulin (100 mg) H $144 35600-9 Ketamine HCI Clll G-2 $166
34210-6 Insulin Human (100 mg) H1A031 2 H (11/02) $144 (250 mg)
34220-8 Insulin (Beef) (100 mg) F $144 35650-8 Ketoconazole (200 mg) G-3 $144
34230-0 Insulin (Pork) (100 mg) F $144 35663-2 Ketoprofen (200 mg) G $144
34250-3 locetamic Acid (200 mg) F $144 35664-3 Ketoprofen Related G $450
34300-7 lodipamide (200 mg) G $144 Compound A (25 mg)
34430-5 o-lodohippuric Acid F $144 (Limit Test)
(100 mg)
14



Previous Previous
Cat Curr Change Lot/Valid Cat. Curr. Change Lot/Valid
35666-5 Ketorolac Tromethamine G $144 37060-0 Lovastatin (125 mg) H $114
(200 mg) 37070-2 Loxapine Succinate F-2 $114
35665-4 Labetalol HCI (200 mg) G 6 $144 (125 mg)
35667-6 Anhydrous Lactose G $144 37100-2 Lysergic Acid Diethylamide i $166
(100mg) Tartrate (LSD) Cl (10 mg)
35668-7 Lactitol (500 mg) F0B005 1 $144 (AS) (For Qualitiative Use
35670-1 Lactose Mo no hydrate G-1 2 G (08/02) $144 Only)
(500 mg) 37150-1 L-Lysine Acetate (200 mg) F $144
35680-3 Lactulose (1 g) H $144 37200-5 L-Lysine HCI (200 mg) H $144
35688-0 Lanolin (20 g) F $144 37300-8 Mafenide Acetate (200 mg) F $144
35690-5 Lanolin Alcohols (5 g) F $144 37400-0 Magaldrate (200 mg) F-1 $144
35700-1 L-Leucine (200 mg) G-1 $144 37430-6 Magnesium Salicylate F-1 $144
35800-4 Leucovorin Calcium J-1 4 J (05/02) $148 (200 mg)
(500 mg) 37440-8 Malathion (500 mg) 6 $144
35900-7 Levallorphan Tartrate G $144 37450-0 Maleic Acid (300 mg) G $450
35930-2 Levamisole HCI (125 mg) F-1 $114 37460-1 Malic Acid (Racemic) F-1 $144
35950-6 Levmetamfetamine CM F $166 (200 mg) (For
(75 mg) Identification Use Only)
35980-1 Levobunolol HCI (200 mg) G $144 37490-7 Maltitol (200 mg) G $144
35990-3 Levocarnitine (400 mg) F-2 $144 37500-3 Maltol (4 g) (FCC) G $144
35992-5 Levocarnitine Related F-1 $144 37505-8 Mandelic Acid (500 mg) F $144
Compound A (100 mg) 37510-5 Mannitol (200 mg) H $144
36100-9 Levodopa (200 mg) I $144 37520-7 Maprotiline HCI (200 mg) H 2 G (07/02) $144
36101-0 Levodopa Related K 2,3 J(01/03) $450 37530-9 Mazindol CIV (350 mg) G $166
Compound A (50 mg) 37550-2 Mebendazole (200 mg) G $144
(Limit Test) (Formerly Cat. 37570-6 Mebrofenin (100 mg) (For F $144
No. 68800-9, 3-(3,4,6- Identification Use Only)
Trihydroxyphenyl)-alanine) 37600-6 Mecamylamine HCI F-2 $144
36200-1 Levo-(-acetylmethadol HCI F-1 $166 (200 mg)
Cll (25 mg) (AS) 37650-5 Mechlorethamine HCI F-1 $144
36250-0 Levonordefrin (200 mg) F-1 $144 (100 mg)
36300-4 Levopropoxyphene G $144 37700-9 Meclizine HCI (500 mg) 1-1 $144
Napsylate (200 mg) 37750-8 Meclocycline G $144
36400-7 Levorphanol Tartrate Cll H $166 Sulfosalicylate (300 mg)
(500 mg) 37780-3 Meclofenamate Sodium H $144
36500-0 Levothyroxine (500 mg) K $144 (500 mg)
36600-2 Lidocaine (250 mg) L $144 37800-1 Medroxyprogesterone H-1 $144
36700-5 Lincomycin HCI (200 mg) H-1 $144 Acetate (200 mg)
36750-4 Lindane (200 mg) F-2 $144 37900-4 Medrysone (500 mg) F $144
36800-8 Liothyronine (250 mg) L $144 37960-5 Mefenamic Acid (200 mg) F3A032 2 F-2 (01/03) $144
36860-9 Lisinopril (300 mg) I 6 $144 37910-6 Megestrol Acetate I $144
36900-0 Lithium Carbonate F-2 $144 (500 mg)
(300 mg) 37930-0 Melphalan HCI (200 mg) G $144
37000-0 Loperamide HCI (200 mg) G-1 $144 XREF Melting Point Standard -
37020-3 Loracarbef (200 mg) F $144 Acetanilide (500 mg;
37022-5 Loracarbef L-lsomer F $144 approximately
(25 mg) 114 degree(s)) (Please
37030-5 Lorazepam CIV (200 mg) G-2 $166 order Cat. No. 00400-1)
37032-7 Lorazepam Related G $450 XREF Melting Point Standard -
Compound A (25 mg) Caffeine (1 g;
(Limit Test) (Formerly Cat. approximately
No. 11300-7, 7-Chloro-5- 236 degree(s)) (Please
(o-chlorophenyl)-i ,3- order Cat. No. 08600-6)
dihydro-3-acetoxy-2H-1,4- XREF Melting Point Standard -
benzodiazepin-2-one) Phenacetin (500 mg;
37033-8 Lorazepam Related
Compound B (25 mg)
F-2 $450 approximately
135 degree(s)) (Please
order Cat. No. 51400-8)
•
No. 02490-5, 2-Amino-2',5- XREF Melting Point Standard -
dichlorobenzophenone) Sulfanilamide (1 g; m
37034-9 Lorazepam Related H 2 G (01/03) $450 approximately m
Compound C (25 mg) 165 degree(s)) (Please
(Limit Test) (Formerly Cat. order Cat. No. 63300-7) K
No. 11310-9, 6-ChIoro-4- XREF Melting Point Standard - m
(o-chlorophenyl)-2-quinaz- Sulfapyridine (2 g;
olinecarboxaldehyde) approximately
37035-0 Lorazepam Related
Compound D (25 mg)
F-2 $450 191 degree(s)) (Please
•=
No. 11320-0, 6-Chloro-4-
XREF Melting Point Standard -
Vanillin (1 g; approximately
m
37036-0
(o-chlorophenyl)-2-
quinazolinecarboxylic Acid)
Lorazepam Related G F-3 (07/02) $450 38100-6
82 degree(s)) (Please
Menadione (200 mg) H-3 $144
•
Compound E (25 mg) (Vitamin K3)
(Limit Test) (Formerly Cat. 38170-9 Menthol (250 mg) H $144
No. 11330-2, 6-Chloro-4- 38200-9 Mepenzolate Bromide F $144
(o-chlorophenyl)-2- (200 mg)
quinazoline Methanol)
15


Previous
38300-1 Meperidine HCI Cll I S166 42423-3 Methyl Caprate (300 mg) F $144
(200 mg) 42424-4 Methyl Caproate (300 mg) F $144
38400-4 Mephentermine Sulfate F-1 $144 42425-5 Methyl Caprylate (300 mg) F $144
(250 mg) 42430-2 3-O-Methylcarbidopa G $450
38500-7 Mephenytoin (250 mg) G S144 (50 mg) (Limit Test)
38600-0 Mephobarbital CIV G $166 42450-6 Methylcellulose (1 g) (AS) F-2 $144
(250 mg) 42500-0 4-Methyl-2,5-dimethoxy- F $166
38700-2 Mepivacaine HCI (200 mg) H $144 amphetamine HCI (STP) Cl
38800-5 Meprednisone (200 mg) G $144 (25 mg) (AS)
38900-8 Meprobamate CIV G-1 G (03/02) $166 42600-2 Methyldopa (500 mg) I $144
(200 mg) 42700-5 Methyldopate HCI G-2 $144
39000-7 Meprylcaine HCI (200 mg) F $144 (200 mg)
39100-0 3-Mercapto-2-methyl- G $450 42800-8 Methylene Blue (250 mg) G $144
propanoic Acid 1,2- 42900-0 Methylenedioxy-3,4- F-1 $166
Diphenylethylamine Salt amphetamine HCI (MDA)
(75 mg) (Limit Test) Cl (25 mg) (AS)
39200-2 Mercaptopurine (500 mg) 1(07/02) $144 43000-0 Methylergonovine Maleate J I (05/02) $144
39270-5 Mesalamine (200 mg) G1B001 2 G (01/03) $144 (50 mg)
39300-5 Mesoridazine Besylate 1-1 $144 43030-5 Methyl Laurate (500 mg) F $144
(250 mg) 43032-7 Methyl Linoleate (5 x F $144
39400-8 Mestranol (200 mg) J $144 50 mg)
39550-0 Metaproterenol Sulfate F-3 $144 43034-9 Methyl Linolenate (5 x F $144
(200 mg) 50 mg)
39600-3 Metaraminol Bitartrate F-3 $144 43050-9 3-O-Methylmethyldopa G-1 $450
39640-0 Methacrylic Acid F-2 $144 43100-2 Methyl 5-methyl-3-isox- F-1 $450
Copolymer A (200 mg) azolecarboxylate (25 mg)
39650-2 Methacrylic Acid F-2 $144 (Limit Test)
Copolymer B (200 mg) 43150-1 Methyl Myristate (300 mg) F $144
39660-4 Methacrylic Acid G $114 43155-6 Methyl Oleate (500 mg) F $144
Copolymer C (100 mg) 43160-3 Methyl Palmitate (300 mg) F $144
39700-6 Methacycline HCI (200 mg) H $144 43162-5 Methyl Palmitoleate F $144
39800-9 Methadone HCI Cll H-1 $166 (300 mg)
(200 mg) 43200-5 Methylparaben (125 mg) J $114
39900-1 Methamphetamine HCI Cll I $166 43300-8 Methylphenidate HCI Cll I $133
(125 mg) (125 mg)
40100-1 Methantheline Bromide F-1 $144 43400-0 Methylphenidate HCI I0A006 2 H-1 (01/03) $450
(200 mg) Erythro Isomer (Cll)
40200-4 Methapyrilene Fumarate F-1 $144 (50 mg) (Limit Test)
(200 mg) 43402-2 Methylphenidate Related G $450
40400-0 Methaqualone Cl (500 mg) F-1 $166 Compound A (50 mg)
40500-2 Metharbital CHI (200 mg) F-2 $166 (Limit Test) (Formerly Cat.
40600-5 Methazolamide (500 mg) G-1 $144 No. 53350-1, a-Phenyl-2-
40700-8 Methdilazine (200 mg) F-1 $144 piperidineacetic Acid HCI)
40800-0 Methdilazine HCI (200 mg) G $144 43500-3 Methylprednisolone H $144
40900-3 Methenamine (500 mg) G $144 (200 mg)
40950-2 Methenamine Hippurate F $144 43600-6 Methylprednisolone G-2 $144
(200 mg) Acetate (200 mg)
40960-4 Methenamine Mandelate F-2 $144 43700-9 Methylprednisolone H $144
(200 mg) Hemisuccinate (200 mg)
41000-2 Methicillin Sodium I $144 43750-8 Methyl Stearate (300 mg) F $144
(500 mg) 43800-1 Methyltestosterone CHI J 6 $166
41100-5 Methimazole (200 mg) G $144 (200 mg)
41150-4 L-Methionine (200 mg) G $144 44000-3 Methysergide Maleate H $144
41200-8 Methocarbamol (200 mg) H-1 $144 (200 mg)
41300-0 Methohexital CIV (500 mg) F-2 $166 44080-8 Metoclopramide G $144
41400-3 Methotrexate (500 mg) I $144 Hydrochloride (500 mg)
41500-6 Methotrimeprazine F-2 $114 44100-6 Metocurine Iodide G $144
(125 mg) (300 mg)
41600-9 Methoxamine HCI F $144 44120-0 Metolazone (200 mg) F-1 $144
(200 mg) 44128-7 Metoprolol Fumarate F $144
41700-1 Methoxsalen (500 mg) H $144 (200 mg)
41800-4 Methoxyflurane (1 mL) G $144 44130-1 Metoprolol Tartrate H $144
41900-7 Methoxyphenamine HCI F $144 (200 mg)
(250 mg) 44150-5 Metrizamide (500 mg) F $144
42000-6 3-Methoxytyrosine (50 mg) H $450 44200-9 Metronidazole (100 mg) I $144
(Limit Test) 44300-1 Metyrapone (200 mg) H $144
42100-9 Methscopolamine Bromide G $144 44320-5 Metyrosine (200 mg) F $144
(200 mg) 44325-0 Mexiletine HCI (200 mg) F-1 $144
42200-1 Methsuximide (500 mg) F-2 $144 44330-7 Mezlocillin Sodium G $144
42400-7 Methyclothiazide (200 mg) G $144 (350 mg)
42401-8 Methyclothiazide Related G $450 44340-9 Miconazole (200 mg) G-1 G (07/02) $144
Compound A (100 mg) 44350-0 Miconazole Nitrate I $144
(Limit Test) (Formerly Cat. (200 mg)
No. 02420-2) 44400-4 Minocycline HCI (200 mg) H-2 (07/02) $144
XREF 2-Methylamino-5-chloro- 44420-8 Minoxidil (125 mg) H $114
benzophenone (25 mg) 44470-7 Mitomycin (50 mg) K $443
(Limit Test) (Please order 44500-7 Mitotane (500 mg) F $144
Cat. No. 18502-0) 44520-0 Mitoxantrone HCI (400 mg) H $461
16

Official USP Reference Standards Catalog Mar-Apr. 2002

Previous
44522-2 Mitoxantrone Related F-1 $144 XREF 3-Nitro-4-phenoxy-5- 2,3 F-1 (01/03)
Compound A HCI (30 mg) sulfamoylbenzoic Acid
44545-9 Molindone HCI (500 mg) F $144 (25 mg) (Limit Test)
44547-0 Mometasone Furoate F-1 $144 (Please order Cat. No.
(200 mg) 07833-6)
44550-6 Monobenzone (200 mg) F $144 46780-4 Nizatidine (200 mg) G $144
44580-1 Mono- and Di-acetylated F $144 46795-0 Nonoxynol 9 (0.5 mL) H-1 H (03/02) $144
Monoglycerides (200 mg) 46800-2 Nonoxynol 10 (200 mg) F $144
44600-0 Monoglycerides (125 mg) H $114 46840-0 Nordazepam CIV (50 mg) H $450
44680-4 Monostearyl Maleate G $450 (Limit Test) (Formerly Cat.
(100 mg) (Limit Test) No. 11400-0,7-Chloro-1,3-
44695-0 Moricizine HCI (100 mg) F $144 dihydro-5-phenyl-2H-1,4-
44700-2 Morphine Monohydrate Cll G $166 benzodiazepin-2-one)
(50 mg) (AS) 46850-1 Norepinephrine Bitartrate H $114
44800-5 Morphine Sulfate K $266 (125 mg)07.00)
(Pentahydrate) Cll 46900-5 Norethindrone (200 mg) J-1 2 J (07/02) $144
(500 mg) 47000-4 Norethindrone Acetate I $144
44850-4 Moxalactam Disodium F-1 $144 (100 mg)
(500 mg) 47100-7 Norethynodrel (200 mg) G $144
44890-1 Mupirocin (50 mg) (For F-1 F (03/02) $144 47150-6 Norfloxacin (200 mg) H $144
Identification Use Only- For 47200-0 Norgestrel (125 mg) I $114
Assay Use Cat. 47300-2 Noroxymorphone HCI Cll H $450
No. 44892-3) (50 mg) (Limit Test)
44892-3 Mupirocin Lithium (100 mg) G $144 47400-5 Nortriptyline HCI (200 mg) I $144
44900-8 Myristyl Alcohol (1 g) G 6 $144 47450-4 Noscapine (500 mg) G $144
44970-0 Nadolol (200 mg) F-3 F-2 (04/02) $144 47500-8 Novobiocin (200 mg) G-2 $144
45000-7 Nafcillin Sodium (200 mg) H $144 47600-0 Nylidrin HCI (200 mg) F-2 $144
45040-4 Naftifine HCI (200 mg) F $144 47700-3 Nystatin (200 mg) N1B004 2 N (01/03) $144
45100-0 Nalidixic Acid (200 mg) G $144 47750-2 Octoxynol 9 (200 mg) G $144
45200-2 Nalorphine HCI Clll $166 47780-8 Octyldodecanol (200 mg) G $144
(250 mg) 47810-8 Ofloxacin (200 mg) F-2 2 F-1 (08/02) $144
45300-5 Naloxone (125 mg) 11 K-1 (12/02) $114 47850-5 Omeprazole (200 mg) H 4 G-1 (04/02) $144
45350-4 Naltrexone (200 mg) 11 G (02/03) $144 47900-9 Orphenadrine Citrate G 2 F-4 (05/02) $144
45352-6 Naltrexone Related F $166 (200 mg)
Compound A Cll (30 mg) 48100-0 Oxacillin Sodium (200 mg) J I (03/02) $144
(System Suitability Use 48150-0 Oxamniquine (200 mg) F $144
Only) 48170-3 Oxamniquine Related F $450
45400-8 Nandrolone Clll (50 mg) F-3 $450 Compound A (25 mg)
(Limit Test) (Limit Test)
45500-0 Nandrolone Decanoate Clll I $166 48180-5 Oxamniquine Related F $450
(250 mg) Compound B (25 mg)
45600-3 Nandrolone Phenprop- H $166 (Limit Test)
ionate Clll (250 mg) 48200-3 Oxandrolone Clll (50 mg) F-4 $166
45700-6 Naphazoline HCI (200 mg) K $144 48300-6 Oxazepam CIV (200 mg) G-1 $166
45730-1 Naproxen (200 mg) I $144 48350-5 Oxprenolol HCI (200 mg) H $144
45740-3 Naproxen Sodium I $144 48400-9 Oxtriphylline (500 mg) G $144
(200 mg) 48500-1 Oxybenzone (150 mg) G $144
45750-5 Natamycin (200 mg) I $144 48510-3 Oxybutynin Chloride 11 G (11/02) $144
45800-9 Neomycin Sulfate (125 mg) L-2 6 $114 (200 mg)
45900-1 Neostigmine Bromide G $144 48511-4 Oxybutynin Related G $450
46000-0 Neostigmine Methylsulfate I $144 (Limit Test) (Formerly Cat.
(200 mg) No. 53180-1)
46050-0 Netilmicin Sulfate (500 mg) H G (05/02) $144 48519-1 Oxycodone Cll (200 mg) 11 H (01/03) $166
46100-3 Niacin (200 mg) H-1 $144 48600-4 Oxymetazoline HCI I $144
46200-6 Niacinamide (500 mg) M-1 $144 (200 mg)
(Vitamin B3) 48700-7 Oxymetholone Clll G $166 M
46330-4 Nicotine Bitartrate G $144 (200 mg)
Dihydrate (500 mg) 48800-0 Oxymorphone Cll (500 mg) G $166 K
46350-8 Nifedipine (125 mg) 1-1 $114 48900-2 Oxyphenbutazone (1 g) H $144 K
46360-0 Nifedipine Nitrophenyl- K $450 49010-3 Oxyquinoline Sulfate F-1 F (07/02) $144 K
pyridine Analog (25 mg) (200 mg)
46370-1
(Limit Test)
Nifedipine Nitrosophenyl- K J (07/02) $450
49100-4
49130-0
Oxytetracycline (200 mg)
Oxytocin (5 vials, 46 USP
1-1
F
$144
$144
P
Bp
• :
pyridine Analog (25 mg) units per vial)
(Limit Test) 49150-3 Padimate O (300 mg) G $144 l |
46400-1 Nitrofurantoin (500 mg) 11 1-1(11/02) $144 49200-7 Palmitic Acid (500 mg) I $144 •=
46500-4 Nitrofurazone (200 mg) H-1 6 $144 49300-0 Pamoic Acid (250 mg) G-4 2 G-3 (01/03) $144 K
46550-3 Nitrofurfural Diacetate F-1 $450 XREF Pancreatin (2 g) (Please
(100 mg) (Limit Test) order Cat. No. 49405- m
46600-7 5-Nitro-2-furfuraldazine G $450 7 and/or Cat. No. 49407-9)
W
46650-6
Diluted Nitroglycerin
(5 amps, each has approx.
G $144
49405-7
49407-9
Pancreatin Amylase and
Protease (2 g)
Pancreatin Lipase (2 g)
I
I
$144
$144
•
K=
200 mg of a 0.948% 49450-1 Racemic Panthenol G $144

solution in propylene (200 mg)
glycol) 49480-7 Pantolactone (500 mg) F $450
(Limit Test)
49500-5 Papain (1 g) H 6 $144
17


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49600-8 Papaverine HCI (200 mg) H $144 52600-7 Phenoxybenzamine HCI G $144
49700-0 Paramethadione (500 mg) G S144 (250 mg)
49800-3 Paramethasone Acetate G $144 52700-0 Phenprocoumon (200 mg) F-1 $144
(200 mg) 52800-2 Phensuximide (500 mg) G $144
49870-6 Parbendazole (200 mg) F $144 52850-1 Phentermine HCI CIV G $166
49900-6 Pargyline HCI (200 mg) F-1 $144 (200 mg)
50000-3 Paromomycin Sulfate G $144 52900-5 Phentolamine HCI F $144
(125 mg) (300 mg) (To be
50040-0 Parthenolide (25 mg) F $144 discontinued on depletion
50050-2 Particle Count Set I 4 H (09/02) $450 of this lot)
(2 blanks and 53000-4 Phentolamine Mesylate I $144
2 suspensions) (200 mg)
50080-8 Penbutolol Sulfate F $144 53050-3 L-Phenylalanine (200 mg) H 6 $144
(200 mg) 53080-9 Phenylbenzimidazole F $144
50100-6 Penicillamine (200 mg) H $144 Sulfonic Acid (200 mg)
50110-8 Penicillamine bisulfide H $450 53100-7 Phenylbutazone (250 mg) 1-1 $144
(100 mg) (Limit Test) XREF Phenylcyclohexylglycolic
50200-9 Penicillin G Benzathine J $144 Acid (100 mg) (Limit Test)
(200 mg) (For Identification (Please order Cat. No.
Use Only-For Potency Use 48511-4, Oxybutynin
Cat. No. 50250-8) Related Compound A)
50250-8 Penicillin G Potassium 1 $144 53300-2 Phenylephrine HCI K $114
(200 mg) (125 mg)
50255-2 Penicillin G Procaine F-1 $144 53330-8 5-Phenylhydantoin F $450
(200 mg) (For Identification (100 mg) (Limit Test)
Use Only-For Potency Use XREF a-Phenyl-2-piperidineacetic
Cat. No. 50250-8) Acid HCI (50 mg)
50270-1 Penicillin G Sodium L-3 6 $144 (Limit Test) (Please order
(200 mg) (For Identification Cat. No. 43402-2)
Use Only-For Potency Use 53385-1 Phenylpropanediol F $450
Cat. No. 50250-8) (100 mg) (Limit Test)
50448-9 Penicillin V (200 mg) (For F $144 53390-9 Phenylpropanolamine F $144
Identification Use Only-For Bitartrate(IOOmg)
Potency Use Cat. No. 53400-5 Phenylpropanolamine HCI J 6 $144
50450-3) (250 mg)
50450-3 Penicillin V Potassium G-1 $144 53500-8 Phenytoin (200 mg) 1-1 $144
(200 mg) 53550-7 Phenytoin Sodium H $144
50500-7 Pentazocine CIV (500 mg) H $166 (200 mg)
50550-6 Pentetic Acid (100 mg) F-1 6 $144 53570-0 Phosphated Riboflavin G $114
50700-2 Pentobarbital Cll (200 mg) 11 H-1 (08/02) $166 (50 mg)
51000-7 Pepsin (5 g) F-2 $144 53700-3 Physostigmine Salicylate H-1 $144
51080-1 Perflubron (0.5 mL) F $144 (200 mg)
51084-5 Pergolide Mesylate F 1 $180 53800-6 Phytonadione (500 mg) M-1 6 $144
(200 mg) (Vitamin K1)
51086-7 Pergolide Sulfoxide F0B014 1 $180 53850-5 Pilocarpine (300 mg) F $144
(50 mg) 53890-2 Pilocarpine HCI (200 mg) H $144
51100-0 Perphenazine (200 mg) I $144 53900-9 Pilocarpine Nitrate I $144
51120-3 Perphenazine Sulfoxide G-1 2 G (07/02) $450 (200 mg)
(100 mg) (Limit Test) 53950-8 Pimozide (200 mg) G $144
51200-2 Phenacemide (250 mg) F $144 53970-1 Pindolol (200 mg) H-1 $144
51300-5 Phenacetin (500 mg) H-1 $144 54100-0 Piperacetazine (250 mg) F $144
51400-8 Phenacetin Melting Point H-2 $85 54150-0 Piperacillin (500 mg) H $144
Standard (500 mg) 54170-3 Piperazine Adipate F $144
(Approximately (200 mg)
135 degree(s)) 54180-5 Piperazine Citrate F $144
51500-0 Phenazopyridine HCI G-4 $144 (200 mg)
(200 mg) 54190-7 Piperazine Dihydrochloride F $144
51600-3 Phencyclidine HCI Cll 11 G (12/02) $166 (200 mg)
(25 mg) (AS) 54200-3 Piperazine Phosphate F $144
51650-2 Phendimetrazine Tartrate G $166 (200 mg)
CHI (350 mg) 54300-6 Piperidolate HCI (200 mg) F $144
51700-6 Phenelzine Sulfate G 2 F-1 (04/02) $144 54450-8 Piroxicam (200 mg) H $144
(200 mg) XREF Plastic, Negative Control
51730-1 D-Phenethicillin Potassium F $450 (Please order Cat. No.
(200 mg) (Limit Test) 54670-7)
51760-7 L-Phenethicillin Potassium F $144 54520-5 Plicamycin (50 mg) H 2 $443
(200 mg) 54540-9 Polacrilex Resin (100 mg) F $144
52000-0 Phenformin HCI (200 mg) G $144 54550-0 Polacrilin Potassium F-2 $144
52200-6 Phenindione (250 mg) F $144 (200 mg)
52230-1 Pheniramine Maleate F $144 54630-0 Polydimethylsiloxane G-5 $144
(100 mg) (500 mg)
52300-9 Phenmetrazine HCI Cll F-2 $166 54670-7 Polyethylene, High Density G $144
(200 mg) (3 strips) (Formerly Cat.
52400-1 Phenobarbital CIV J $166 No. 54500-1, Plastic,
(200 mg) Negative Control)
52490-8 Phenolphthalein (250 mg) F-3 $144 54680-9 Polyethylene, Low Density G $144
52500-4 Phenolsulfonphthalein F-2 $144 (3 strips)
(100 mg)
18



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54685-3 Polyethylene Oxide F-1 $144 57050-8 Propantheline Bromide 11 H (11/02) $144
(100 mg) (For (200 mg)
Identification Use Only) 57100-1 Proparacaine HCI (200 mg) G $144
54690-0 Polyethylene Tereph- F $144 57300-7 Propoxycaine HCI F $144
thalate (PET) (3 Strips) (200 mg)
54692-2 Polyethylene Tereph- F $144 57400-0 Propoxyphene HCI Cll K $166
thalate G (PETG) (3 Strips) 0g)
54700-7 Polymyxin B Sulfate K $144 57500-2 Propoxyphene Napsylate H $166
(200 mg) Cll (1 g)
54740-4 Polyoxyl 50 Stearate F $144 57520-6 Propoxyphene Related G-5 $450
54790-3 Polyoxyl 40 Stearate F-2 $144 (Limit Test) (Formerly Cat.
(200 mg) No. 21000)
54800-0 Polythiazide (200 mg) F-1 $144 57600-5 Propranolol HCI (200 mg) H-1 6 $144
55000-1 Potassium Gluconate G $144 57650-4 Propylene Carbonate F $144
(200 mg) (200 mg)
55100-4 Potassium Guaiacol- 1-1 $144 57670-8 Propylene Glycol (1 mL) H $144
sulfonate (500 mg) (For Identification Use
55115-0 Potassium Sucrose G-1 $144 Only)
Octasulfate (300 mg) 57672-0 Propylene Glycol Diacetate F $144
55130-0 Potassium Trichloro- 11 G-1 (01/03) $450 (250 mg)
ammineplatinate (20 mg) 57680-0 Propyl Gallate (200 mg) G-1 2 G (01/03) $144
(Limit Test) 57700-8 Propylparaben (200 mg) I $144
55150-3 Povidone (100 mg) F-1 6 $144 57800-0 Propylthiouracil (200 mg) G $144
55300-0 Pralidoxime Chloride G-2 $144 57850-0 Prostaglandin A1 (25 mg) G $489
55400-2 Pramoxine HCI (500 mg) 11 H (11/02) $144 58000-2 Protriptyline HCI (200 mg) F-1 $144
55450-1 Prazepam CIV (500 mg) 11 F-1 (11/02) $166 58100-5 Pseudoephedrine HCI J 2 1 (05/02) $114
55460-3 Praziquantel (200 mg) G 2 F-3 (07/02) $144 (125 mg)
55465-8 Praziquantel Related F-1 $450 58150-4 Pseudoephedrine Sulfate G F-2 (05/02) $144
(Limit Test) 58400-3 Pyrahtel Pamoate (1 g) I $144
55466-9 Praziquantel Related F-2 $450 58500-6 Pyrazinamide (200 mg) G $144
Compound B (50 mg) 58600-9 Pyridostigmine Bromide H $144
55467-0 Praziquantel Related F-2 $450 58700-1 Pyridoxine HCI (200 mg) P $144
Compound C (50 mg) (Vitamin B6)
(Limit Test) 58800-4 Pyrilamine Maleate H $144
55470-5 Prazosin HCI (500 mg) G-1 $144 (200 mg)
55500-5 Prednisolone (200 mg) M L-1 (04/02) $144 58900-7 Pyrimethamine (200 mg) G (07/02) $144
55600-8 Prednisolone Acetate J 6 $144 59200-1 Pyrvinium Pamoate G $144
(200 mg) (500 mg)
55650-7 Prednisolone H-1 $114 59220-5 Quazepam CIV (200 mg) F $166
Hemisuccinate (125 mg) 59222-7 Quazepam Related F $450
55800-3 Prednisolone Tebutate F $144 Compound A (30 mg)
55900-6 Prednisone (250 mg) L 6 $144 59240-9 Quercetin (500 mg) F0B015 1 $144
55950-5 Prednisone Tablets N 2 M (09/02) $166 59300-4 Quinacrine HCI (200 mg) F-1 $144
(Dissolution Calibrator, 59400-7 Quinethazone (1.5 g) G $144
Disintegrating) (30 tablets) 59450-6 Quinic Acid (200 mg) F $144
56100-8 Prilocaine HCI (200 mg) F-2 $144 59500-0 Quinidine Gluconate H $144
56150-7 Primaquine Phosphate F-1 $144 (200 mg)
(200 mg) 59550-9 Quinidine Sulfate (500 mg) H-1 $144
56200-0 Primidone (200 mg) G $144 59700-5 Quinine Sulfate (200 mg) H $144
56300-3 Probenecid (200 mg) H-1 $144 59750-4 Quininone (50 mg) G-1 $450
56330-9 Probucol (200 mg) G 6 $144 (Limit Test)
56332-0 Probucol Related
Compound A (25 mg)
(Limit Test)
F-1 $450 59800-8
59840-5
3-Quinuclidinyl Benzilate
Ranitidine HCI (200 mg)
H
G
6 $476
$144
• K
^
56333-1 Probucol Related F-1 $450 59850-7 Ranitidine Related H $144 K

Compound B (25 mg) Compound A (50 mg)
(Limit Test) 59860-9 Ranitidine Related G F-4 (04/02) $450
K• =
56334-2 Probucol Related F-2 $450 Compound B (50 mg)
Compound C (25 mg) (Limit Test) K
56350-2
(Limit Test)
Procainamide HCI H $144
59870-0 Ranitidine Related
Compound C (50 mg)
I $144 mK
(200 mg) 59900-0 Rauwolfia Serpentina G $144 m
m=
56400-6 Procaine HCI (200 mg) H $144 (15 g)
56500-9 Procarbazine HCI (200 mg) F $144 60100-0 Reserpine (200 mg) N $144 m
m.
56600-1 Prochlorperazine Maleate H-1 $144 60200-3 Resorcinol (200 mg) H-1 $144 m.
(200 mg) 60270-6 Ribavirin (200 mg) H $267 K
56700-4
56800-7
56850-6
Procyclidine HCI (200 mg)
Progesterone (200 mg)
L-Proline (200 mg)
G
H-5
F-2
2
6
H-4 (07/02)
$144
$114
$144
60300-6
60380-0
Riboflavin (500 mg)
(Vitamin B2)
Rifabutin (50 mg)
M-1
11 F (11/02)
$144
$144
•
•£
56900-0 Promazine HCI (200 mg) G $144 60400-9 Rifampin (300 mg) J $144
57000-9 Promethazine HCI K $144 60420-2 Rifampin Quinone (50 mg) H 6 $144
(500 mg) 60460-0 Rimexolone (100 mg) F $144
57030-4 Propafenone HCI (200 mg) G $144 60470-1 Ritodrine HCI (200 mg) G-1 $144
60620-8 Roxarsone (200 mg) F $144
19



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60650-3 Rutin (100 mg) F $144 63150-0 Sulfamethoxazole N4- H 6 $450
60700-7 Saccharin (200 mg) G-3 6 $144 glucoside (25 mg)
60800-0 Salicylamide (200 mg) F-3 $144 (Limit Test)
60900-2 Salicylic Acid (125 mg) J-1 2 J (10/02) $114 63200-4 Sulfanilamide (5 g) N $144
60950-1 Salicylic Acid Tablets O 6 $144 63300-7 Sulfanilarnide Melting Point J-1 $69
(Dissolution Calibrator, Standard (500 mg)
Non-disintegrating) (Approximately
(33 tablets) 165 degree(s))
60980-7 Salsalate (125 mg) G $114 63350-6 Sulfanilic Acid (200 mg) G $450
60982-9 Saquinavir Mesylate F0B008 1 $144 (Limit Test)
(200 mg) 63400-0 Sulfapyridine (200 mg) H $144
60983-9 Saquinavir Related F0B009 1 $450 63500-2 Sulfapyridine Melting Point J $85
Compound A (25 mg) Standard (1 g)
61000-1 Scopolamine HBr (250 mg) 11 1-1 (01/03) $144 (Approximately
61100-4 Secobarbital CII (200 mg) H $166 191 degree(s))
61190-0 Selegiline HCI (200 mg) G $144 63520-6 Sulfaquinoxaline (200 mg) F0A005 1 $144
61195-5 Selenomethionine F0B006 1 $144 63600-5 Sulfasalazine (125 mg) G-2 $114
(100 mg) 63650-4 Sulfathiazole (350 mg) H $144
61200-7 Sennosides (250 mg) H $144 63700-8 Sulfinpyrazone (200 mg) G $144
61250-6 L-Serine (200 mg) G $144 63800-0 Sulfisoxazole (200 mg) J $144
61260-8 Silver Sulfadiazine I $144 63900-3 Sulfisoxazole Acetyl H-1 $144
(200 mg) (200 mg)
61263-0 Silybin (50 mg) F $144 64000-2 Sulfisoxazole Diolamine F $144
61264-1 Silydianin (20 mg) F $144 (500 mg)
61265-2 Simethicone (50 g) G $144 64200-8 Sulindac (200 mg) H 6 $144
61270-0 Simvastatin (200 mg) H 6 $144 64250-7 Suprofen (200 mg) F $144
61280-1 Sisomicin Sulfate (500 mg) H $144 64300-0 Talbutal Clll (250 mg) F $166
61350-9 Sodium Ascorbate G-1 $144 64330-6 Tamoxifen Citrate (200 mg) H 6 $144
(200 mg) 64340-8 Temazepam CIV (200 mg) G $166
61360-0 Sodium Butyrate (25 mg) F $144 64350-0 Terbutaline Sulfate H $114
61400-2 Sodium Fluoride (1 g) H-1 $144 (125 mg)
61430-8 Sodium Lactate (200 mg) H $144 64370-3 Terconazole (200 mg) G-2 $144
61450-1 Sodium Nitroprusside H $144 64380-5 Terfenadine (200 mg) H $144
(500 mg) 64390-7 Terfenadine Related G $144
61460-3 Sodium Propionate F-1 F (03/02) $144 Compound A (100 mg)
(200 mg) (For 64392-9 Terfenadine Related F $450
Identification Use Only) Compound B (50 mg)
61470-5 Sodium Stearyl Fumarate G $144 (Limit Test)
(200 mg) 64400-3 Terpin Hydrate (750 mg) G $144
XREF Sodium Taurocholate 64500-6 Testolactone Clll (125 mg) F-1 $133
(20 g) (Please order Cat. 64600-9 Testosterone Clll (125 mg) I $133
No. 07130-4) 64700-1 Testosterone Cypionate G-1 $166
61600-8 1,4-Sorbitan (200 mg) H $144 Clll (200 mg)
61700-0 Sorbitol(125mg) H $114 64800-4 Testosterone Enanthate J $166
61800-3 Spectinomycin HCI F-2 $144 Clll (200 mg)
(200 mg) 64900-7 Testosterone Propionate L 6 $166
61900-6 Spironolactone (125 mg) J-1 $114 Clll (200 mg)
61950-5 Squalane (500 mg) G-1 $144 65000-6 Tetracaine HCI (200 mg) J $144
62000-5 Stanozolol Clll (200 mg) F-3 $166 65100-9 Tetracycline HCI (200 mg) K $144
62100-8 Stearic Acid (500 mg) J 6 $144 65200-1 Tetrahydrozoline HCI G $144
62200-0 Stearyl Alcohol (125 mg) H-1 $114 (200 mg)
62300-3 Streptomycin Sulfate I $144 65300-4 Theophylline (200 mg) I $144
(200 mg) 65310-6 Theophylline Extended- F-1 $144
62350-2 Succinylcholine Chloride H $144 Release Beads (Drug
(500 mg) Release Calibrator,
62360-4 Succinylmonocholine G $450 Multiple-Unit) (20 g)
Chloride (150 mg) 65500-0 Thiabendazole (100 mg) F-1 $144
(Limit Test) 65600-2 Thiamine HCI (500 mg) N $144
62362-6 Sucralose (400 mg) F $144 (Vitamin B1 Hydrochloride)
62363-7 Sucrose (100 mg) G-1 $144 65630-8 Thiamylal Clll (200 mg) F $166
62364-8 Sufentanil Citrate CII G F-1 (04/02) $166 65700-5 Thiethylperazine Malate G $144
(25 mg) (200 mg)
62367-0 Sulbactam (250 mg) G $144 65800-8 Thiethylperazine Maleate F-1 $144
62368-1 Sulconazole Nitrate F-1 F (05/02)) $144 (200 mg)
(200 mg) 65900-0 Thimerosal (500 mg) H $144
62370-6 Sulfabenzamide (200 mg) G $144 66000-0 Thioguanine (200 mg) F-1 $144
62380-8 Sulfacetamide (300 mg) G-1 $144 66100-2 Thiopental Clll (250 mg) I $166
62400-6 Sulfacetamide Sodium I $144 66250-4 Thioridazine (200 mg) H $144
(500 mg) 66300-8 Thioridazine HCI (200 mg) H $144
62450-5 Sulfachlorpyridazine F $144 66370-0 Thiostrepton (200 mg) 11 F (11/02) $144
(200 mg) 66400-0 Thiotepa (500 mg) I $144
62500-9 Sulfadiazine (200 mg) 1 $144 66500-3 Thiothixene (250 mg) G $144
62600-1 Sulfadimethoxine (200 mg) F-3 $144 66600-6 (E)-Thiothixene (100 mg) H $450
62650-0 Sulfadoxine (200 mg) F-1 (07/02) $144 (Limit Test)
62800-7 Sulfamerazine (1 g) H $144 66710-0 Thonzonium Bromide F $144
62900-0 Sulfamethazine (1 g) G-3 $144 (200 mg)
63000-9 Sulfamethizole (200 mg) F-2 $144 66720-2 L-Threonine (200 mg) G $144
63100-1 Sulfamethoxazole 1-1 I (04/02) $144
(200 mg)
20



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66727-9 Thromboplastin, Human F $144 68900-1 Trimeprazine Tartrate F-3 $144
Recombinant (set) (1 vial (200 mg)
Thromboplastin and 1 vial 69000-0 Trimethadione (200 mg) G $144
Diluent) 69200-6 Trimethobenzamide HCI H-2 H-1 (06/02) $144
66730-4 Ticarcillin Monosodium H $144 (500 mg)
Monohydrate (200 mg) 69250-5 Trimethoprim (300 mg) I $144
66740-6 Timolol Maleate (200 mg) G-1 $144 69300-9 Trioxsalen (200 mg) G $144
66743-9 Tioconazole (200 mg) H G (04/02) $144 69400-1 Tripelennamine Citrate F $144
66745-0 Tioconazole Related G $450 (200 mg)
Compound A (25 mg) 69500-4 Tripelennamine HCI J $144
66746-1 Tioconazole Related G $450 69600-7 Triprolidine HCI (500 mg) I 6 $144
Compound B (25 mg) 69610-9 Triprolidine HCI Z Isomer G 6 $450
(Limit Test) (100 mg) (Limit Test)
66747-2 Tioconazole Related G $450 69620-0 Trisalicylic Acid (100 mg) G $450
Compound C (25 mg) (Limit Test)
(Limit Test) 69700-0 Troleandomycin (250 mg) F-1 $144
66750-8 Tobramycin (200 mg) J $144 69800-2 Tromethamine (125 mg) G $114
66755-2 TocainideHCI (125 mg) F-1 $114 69900-5 Tropicamide (125 mg) G-1 $114
66760-0 Alpha Tocopherol (250 mg) M $144 70000-2 Trypsin Crystallized H $144
(Vitamin E Alcohol) (300 mg)
66770-1 Alpha Tocopheryl Acetate K $144 70050-1 L-Tryptophan (200 mg) G-1 $144
(250 mg) (Vitamin E 70200-8 Tubocurarine Chloride K-1 $144
Acetate) (250 mg)
66780-3 Alpha Tocopheryl Acid F-5 6 $144 70400-3 Tyloxapol (600 mg) H $144
Succinate (250 mg) 70450-2 Tyropanoate Sodium F $144
(Vitamin E Succinate) (500 mg)
66800-1 Tolazamide (200 mg) G-2 $144 70500-6 L-Tyrosine (500 mg) J $144
66900-4 Tolazoline HCI (300 mg) F $144 70550-5 Undecylenic Acid (200 mg) G-1 6 $144
67000-3 Tolbutamide (200 mg) I $144 70580-0 Uracil Arabinoside (50 mg) G $144
67050-2 Tolmetin Sodium (1 g) H $144 (For Non-Quantitative Use
67100-6 Tolnaftate (200 mg) I $144 Only)
67200-9 Toluenesulfonamides, F-4 $450 70600-9 Uracil Mustard (500 mg) F $144
ortho and para (200 mg of 70780-6 Ursodiol (125 mg) G 6 $144
each supplied in a set) 70790-8 Valerenic Acid (25 mg) F $643
(Limit Test) 70850-3 L-Valine (200 mg) F-2 F-1 (05/02) $144
67280-3 Transplatin (25 mg) G $450 70870-7 Valproic Acid (500 mg) J $144
(Limit Test) 70872-9 Valproic Acid Related 11 F (01/03) $144
67350-0 Trazodone HCI (200 mg) F-2 $144 Compound A (0.25 mL)
67400-4 Tretinoin (30 mg/amp; 1-1 6 $144 70900-7 Vancomycin HCI (4 vials, L 2 $144
5 amps) each vial contains
67500-7 Triacetin (1 g) G-1 $144 101,400 /;g of vancomycin
67600-0 Triamcinolone (250 mg) H-1 $144 activity)
67700-2 Triamcinolone Acetonide K $144 71000-6 Vanillin (200 mg) I $144
(500 mg) 71100-9 Vanillin Melting Point 1-1 $85
67800-5 Triamcinolone Diacetate G $144 Standard (1 g)
(200 mg) (Approximately
67900-8 Triamcinolone G $114 82 degree(s))
Hexacetonide (125 mg) 71120-2 Verapamil HCI (200 mg) G $144
68000-7 Triamterene (200 mg) I $144 71130-4 Verapamil Related H $450
68050-6 Triazolam CIV (200 mg) G-1 $166 Compound A (50 mg)
68060-8 Tributyl Citrate (500 mg) F $144 (Limit Test)
68080-1 Trichlorfon (200 mg) F $144 71140-6 Verapamil Related G $144
68100-0 Trichlormethiazide H $144 Compound B (50 mg)
(200 mg) 71150-8 Vidarabine (200 mg) G-1 $144
68300-5 Tridihexethyl Chloride F-1 $144 71300-4 Vinblastine Sulfate L $327
(200 mg) (50 mg/ampul)
68350-4 Trientine HCI (125 mg) F-1 (03/02) $114 71400-7 Vincristine Sulfate 11 N (01/03) $443 •
68360-6 Triethyl Citrate (500 mg) F-1 F (03/02) $144 (50 mg/ampul)
68500-0 Trifluoperazine HCI G $144 71500-0 Viomycin Sulfate (200 mg) F $144 m
K
(200 mg) 71600-2 Vitamin A (24 capsules U $144 B
68550-0 2-[IM-(2,2,2-Trifluoro- F $450 each containing vitamin A
ethyl)amino-5]- acetate in cottonseed oil) m
chlorobenzophenone XREF Vitamin B1 Hydrochloride m
(25 mg) (Limit Test) (Please order Cat. No. m
68600-3 Triflupromazine HCI F-1 $144 65600-2)
(200 mg) XREF Vitamin B2 (Please order
68630-9 Trifluridine (200 mg) F $144 Cat. No. 60300-6) m
68631-0 Trifluridine Related F $450 XREF Vitamin B3 (Please order m
m
Compound A (20 mg) Cat. No. 46200-6)
(Limit and System XREF Vitamin B5 (Please order m
68700-6
Suitability Test)
Trihexyphenidyl HCI
(200 mg)
J $144 XREF
Cat. No. 08700-9)
Vitamin B6 (Please order
Cat. No. 58700-1)
•E
XREF 3-(3,4,6-Trihydroxyphenyl)- 2,3 J (01/03) XREF Vitamin B12 (Please order
alanine (50 mg) Cat. No. 15200-9)
(Limit Test) (Please order XREF Vitamim Be (Please order
Cat No. 36101-0) Cat. No. 28600-5)
21


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XREF Vitamin C (Please order 72020-3 Xanthone (100 mg) F-1 $450
Cat. No. 04300-3) (Limit Test)
71750-4 Vitamin D Assay System F S144 72040-7 Xylazine (200 mg) F $144
Suitability (1.5 g) 72042-9 Xylazine HCI F $144
XREF Vitamin D2 (Please order 72060-0 Xylitol (1 g) 11 F-3 (11/02) $144
Cat. No. 23900-5) 72100-2 Xylometazoline HCI H-1 $114
XREF Vitamin D3 (Please order (125 mg)
Cat. No. 13100-9) 72200-5 Xylose (1 g) F $144
XREF Vitamin E Alcohol (Please 72400-0 Yohimbine HCI (200 mg) F $144
order Cat. No. 66760-0) 72430-6 Zalcitabine (200 mg) F $144
XREF Vitamin E Acetate (Please 72450-0 Zidovudine (400 mg) G 6 $144
order Cat. No. 66770-1) 72452-1 Zidovudine Related F-1 $144
XREF Vitamin E Acid Succinate Compound B (25 mg)
(Please order Cat. No. 72453-2 Zidovudine Related F-1 6 $450
66780-3) Compound C (100 mg)
XREF Vitamin K1 (Please order (Limit Test)
Cat. No. 53800-6) 72480-5 Zolazepam HCI (500 mg) F-1 2 F (05/02) $144
XREF Vitamin K3 (Please order
Cat. No. 38100-6)
XREF Vitamin M (Please order
Cat. No. 28600-5)
71900-0 Warfarin (200 mg) H-2 6 $144
71910-2 Warfarin Related G $144
Compound A (50 mg)
72000-0 Xanthanoic Acid (100 mg) G-1 $450
(Limit Test)
22



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FEVERFEW
AMINO ACIDS 50040-0 Parthenolide (25 mg) F $144
GARLIC FLUIDEXTRACT
01250-9 L-Alanine (200 mg) F-2 $144 01305-7 S-Allyk-Cysteine (25 mg) F $450
02100-0 Aminocaproic Acid F-4 $144 (Limit test)
(200 mg) GINGER
04250-0 L-Arginine (200 mg) G-1 $144 09110-8 Capsaicin (100 mg) G-1 G (03/02) $144
04260-1 Arginine HCI (125 mg) F-1 $114 29150-4 Powdered Ginger (500 mg) F $144
16150-9 L-Cysteine HCI (200 mg) H $144
29580-0 Glycine (200 mg) F-3 $144 GINKGO
30850-5 L-Histidine (200 mg) F-2 $144 59240-9 Quercetin (500 mg) F0B015 1 $144
34950-2 L-lsoleucine (200 mg) 11 F-1 (09/02) $144 60650-3 Rutin(100mg) F $144
35700-1 L-Leucine (200 mg) G-1 $144 MILK THISTLE
35990-3 Levocarnitine (400 mg) F-2 $144 61263-0 Silybin (50 mg) F $144
35992-5 Levocarnitine Related F-1 $144 61264-1 Silydianin (20 mg) F $144
Compound A (100 mg)
SAW PALMETTO
37150-1 L-Lysine Acetate (200 mg) F $144
37200-5 L-Lysine HCI (200 mg) H $144 42423-3 Methyl Caprate (300 mg) F $144
41150-4 L-Methionine (200 mg) G $144 42424-4 Methyl Caproate (300 mg) F $144
53050-3 L-Phenylalanine (200 mg) H $144 42425-5 Methyl Caprylate (300 mg) F $144
56850-6 L-Proline (200 mg) F-2 $144 43030-5 Methyl Laurate (500 mg) F $144
61250-6 L-Serine (200 mg) G $144 43032-7 Methyl Linoleate F $144
66720-2 L-Threonine (200 mg) G $144 (5 x 50 mg)
70050-1 L-Tryptophan (200 mg) G-1 $144 43034-9 Methyl Linolenate F $144
70500-6 L-Tyrosine (500 mg) J $144 (5 x 50 mg)
70850-3 L-Valine (200 mg) F-2 F-1 (05/02) $144 43150-1 Methyl Myristate (300 mg) F $144
43155-6 Methyl Oleate (500 mg) F $144
43160-3 Methyl Palmitate (300 mg) F $144
BOTANICALS 43162-5 Methyl Palmitoleate F $144
(300 mg)
43750-8 Methyl Stearate (300 mg) F $144
CHAMOMILE
04070-8 Apigenin-7-Glucoside F $450 ST. JOHN'S WORT
(30 mg) (Limit test) 33520-2 Hyperoside (50 mg) F $790
CAPSA1CIN/CAPS1CUM VALERIAN
09110-8 Capsaicin (100 mg) G-1 G (03/02) $144 70790-8 Valerenic Acid (25 mg) F $643
20060-0 Dihydrocapsaicin (50 mg) F-1 $144
CRANBERRY LIQUID VITAMINS-MINERALS
13436-8 Citric Acid (200 mg) F (07/02) $144
18130-2 Dextrose (1 g) J-1 2 J (11/02) $114 04300-3 Ascorbic Acid (1 g) P $144
28650-4 Fructose (125 mg) I-2 2 1-1(11/02) $114 (Vitamin C)
37460-1 Malic Acid (Racemic) F-1 $144 07150-8 Biotin (200 mg) H $144
(200 mg) (For ORRIS R Calcium Ascorbate F-1 $144
Identification Use Only) uOvJOJ U
(200 mg) (For 1
59450-6 Quinic Acid (200 mg) F $144 Identification Use Only)
61700-0 Sorbitol(125mg) H $114 08700-9 Calcium Pantothenate N-1 $144
62363-7 Sucrose (100 mg) G-1 $144 (200 mg) (Vitamin B5)
GARLIC 13100-9 Cholecalciferol L $147 |
01214-5 Agigenin (25 mg) F $144 (30 mg/ampul; 5 ampuls)
01295-0 Ailiin (25 mg) F $1410 (Vitamin D3)
11555-6 beta-Chlorogenin (20 mg) F $144 13180-3 Delta 4,6-cholestadienol F $144
(For Identification Use (30 mg)
Only) 15200-9 Cyanocobalamin (1.5 g of N $144
29484-8 L-gamma-Glutamyl-S-allyl- F $624 mixture with mannitol; 10.7
ng/mg of mixture) (Vitamin
L-cysteine (25 mg) I
41150-4 L-Methionine (200 mg) G $144 Bis)
17950-4 Dexpanthenol (500 mg) I 6 $148
23



Previous Previous
61350-9 Sodium Ascorbate G-1 $144
(200 mg)
VITAMINS-MINERALS Cont. 61400-2 Sodium Fluoride (1 g) H-1 $144
65600-2 Thiamine HCI (500 mg) N $144
23900-5 Ergocalciferol (150 mg; 0 $156 (Vitamin B1 Hydrochloride)
30 mg/ampul; 5 ampuls) 66760-0 Alpha Tocopherol (250 M $144
(Vitamin D2) mg) (Vitamin E Alcohol)
24100-7 Ergosterol (50 mg) (For H $144 66770-1 Alpha Tocopheryl Acetate K $144
Identification Use Only) (250 mg) (Vitamin E
28600-5 Foiic Acid (500 mg) P $144 Acetate)
(Vitamin M or Vitamin Be) 66780-3 Alpha Tocopheryl Acid F-5 F-4 (01/02) $144
28602-7 Folic Acid Related H-1 $144 Succinate (250 mg)
Compound A (50 mg) (Vitamin E Succinate)
(Fomerly Cat. No. 08650-5, 71600-2 Vitamin A (24 capsules U $144
Calcium Formyltetra- each containing vitamin A
hydrofolate) acetate in cottonseed oil)
38100-6 Menadione (200 mg) H-3 $144 71750-4 Vitamin D Assay System F $144
(Vitamin K3) Suitability (1.5 g)
46100-3 Niacin (200 mg) H-1 $144
ARO(Y\ R M 1 <t1AA
4otUU-D Niacinamide (500 mg) IVM >p 144
(Vitamin B3)
OTHER DIETARY SUPPLEMENTS
49450-1 Racemic Panthenol G $144
(200 mg) 13363-8 Chromium Picolinate F 4 $144
49480-7 Pantolactone (500 mg) F $450 (100 g) (For Identification
(Limit test) Test Only)
53800-6 Phytonadione (500 mg) M-1 6 $144 15035-3 Creatinine (100 mg) (For F $144
(Vitamin K1) Identification Test Only)
55000-1 Potassium Gluconate G $144 61195-5 Selenomethionine F0B006 1 $144
(200 mg) (100 mg)
58700-1 Pyridoxine HCI (200 mg) P $144
(Vitamin Be)
60300-6 Riboflavin (500 mg) M-1 $144
(Vitamin B2)
24


CONTROLLED SUBSTANCES REFERENCE STANDARDS AVAILABLE FROM USP

Previous Previous
01400-5 Alphaprodine HCI Cll (250 mg) F $166 41300-0 MethohexitalCIV(500mg) F-2 $166
01500-8 Alprazolam CIV (200 mg) H $166 42500-0 4-Methyl-2,5-dimethoxy- F $166
03000-1 Amobarbital Cll (200 mg) F-2 $166 amphetamine HCI (STP) Cl
03600-8 Anileridine HCI Cll (250 mg) F $166 (25mg)(AS)
04200-0 Aprobarbital Clll (200 mg) F-1 $166 42900-0 Methylenedioxy-3,4- F-1 $166
(AS) amphetamine HCI (MDA) Cl
05900-3 Benzphetamine HCI Clll F-1 $166 (25mg)(AS)
(200mg)(AS) 43300-8 Methylphenidate HCI Cll I $133
07900-0 Butabarbital Clll (200 mg) G $166 (125 mg)
08100-2 Butalbital Clll (200 mg) G-2 2 G (05/02) $166 43400-0 Methylphenidate HCI Erythro I0A00 2 H-1 (01/03) $450
08250-4 Butorphanol Tartrate CIV J $166 Isomer (Cll) (50 mg) 6
08900-4 Cannabidiol Cl (25 mg) (AS) F-2 $166 43800-1 Methyltestosterone Clll J 6 $166
(For Qualitative Use Only) (200 mg)
09000-3 Cannabinol Cl (25 mg) (AS) F-2 (05/02) $166 44700-2 Morphine Monohydrate Cll G $166
09680-4 Cathinone HCI Cl (50 mg) I $450 (50mg)(AS)
(Limit Test) (Formerly Cat. 44800-5 Morphine Sulfate K $266
No. 02620-8, (-Aminopro- (Pentahydrate) Cll (500 mg)
piophenone HCI) 45200-2 Nalorphine HCI Clll (250 mg) $166
10900-0 Chlordiazepoxide CIV H-1 $166 45352-6 Naltrexone Related Compound F $166
(200 mg) A Cll (30 mg) (System
11000-9 Chlordiazepoxide HCI CIV G-4 $166 Suitability Use Only)
(200 mg) 45400-8 Nandrolone Clll (50 mg) F-3 $450
14030-5 Clonazepam CIV (200 mg) G $166 (Limit Test)
14050-9 Clorazepate Dipotassium CIV F-1 $166 45500-0 Nandrolone Decanoate Clll I $166
(125 mg) (250 mg)
14300-8 Cocaine HCI Cll (250 mg) H-2 $166 45600-3 Nandrolone Phenprop-ionate H $166
14380-2 Codeine N-Oxide Cl (50 mg) 11 F-1 (11/02) $166 Clll (250 mg)
14400-0 Codeine Phosphate Cll I $166 46840-0 Nordazepam CIV (50 mg) H $450
(100 mg) (Limit Test) (Formerly Cat.
14500-3 Codeine Sulfate Cll (250 mg) H-2 6 $166 No. 11400-0,7-Chloro-1,3-
18000-4 Dextroamphetamine Sulfate G $174 dihydro-5-phenyl-2H-1,4-
Cll (500 mg) benzodiazepin-2-one)
18300-2 Diacetylmorphine HCI (Heroin J $166 47300-2 Noroxymorphone HCI Cll H $450
HCI)CI(25mg)(AS) (50 mg) (Limit Test)
18500-8 DiazepamCIV(IOOmg) I 6 $166 48200-3 Oxandrolone Clll (50 mg) F-4 $166
18720-7 Dichloralphenazone CIV FOBO 1 $144 48300-6 Oxazepam CIV (200 mg) G-1 $166
(200 mg) 10 48519-1 Oxycodone Cll (200 mg) 11 H (01/03) $166
19400-9 Diethylpropion HCI CIV H $166 48700-7 Oxymetholone Clll (200 mg) G $166
(200 mg) 48800-0 Oxymorphone Cll (500 mg) G $166
20080-4 Dihydrocodeine Bitartrate Cll H $166 50500-7 Pentazocine CIV (500 mg) H $166
(200 mg) 50700-2 Pentobarbital Cll (200 mg) 11 H-1 (08/02) $166
21900-8 Diphenoxylate HCI Cll 1 H (03/02) $166 51600-3 Phencyclidine HCI Cll (25 mg) 11 G (12/02) $166
(200 mg) (AS)
27000-5 Fentanyl Citrate Cll (100 mg) J (05/02) $166 51650-2 Phendimetrazine Tartrate Clll G $166
28000-9 Fluoxymesterone Clll (200 mg) G-2 $166 (350 mg)
28500-2 Flurazepam HCI CIV (200 mg) 1 $166 52300-9 Phenmetrazine HCI Cll F-2 $166
29500-6 Glutethimide Cll (500 mg) F $166 (200 mg)
30230-5 HalazepamCIV(200mg) F $166 52400-1 Phenobarbital CIV (200 mg) J $166
30700-3 Hexobarbital Clll (500 mg) F $166 52850-1 Phentermine HCI CIV G $166
31500-1 Hydrocodone Bitartrate Cll J0A02 2 1 (07/02) $166 (200 mg)
(250 mg) 6 1-1 (12/02) 55450-1 Prazepam CIV (500 mg) 11 F-1 (11/02) $166
32300-0 Hydromorphone HCI Cll 1 $166 57400-0 Propoxyphene HCI Cll (1 g) K $166
(50 mg) 57500-2 Propoxyphene Napsylate Cll H $166
35600-9 Ketamine HCI Clll (250 mg) G-2 $166 dg)
35950-6 Levmetamfetamine Cll (75 mg) F $166 59220-5 Quazepam CIV (200 mg) F $166
36200-1 Levo-(-acetylmethadol HCI Cll F-1 $166 61100-4 Secobarbital Cll (200 mg) H $166
(25mg)(AS) 62000-5 Stanozolol Clll (200 mg) F-3 $166
36400-7 Levorphanol Tartrate Cll H $166 62364-8 Sufentanil Citrate Cll (25 mg) G F-1 (04/02) $166
(500 mg) 64300-0 Talbutal Clll (250 mg) F $166
37030-5 Lorazepam CIV (200 mg) G-2 $166 64340-8 Temazepam CIV (200 mg) G $166
37100-2 Lysergic Acid Diethylamide I $166 64500-6 Testolactone Clll (125 mg) F-1 $133
Tartrate (LSD) Cl (10 mg) (AS) 64600-9 Testosterone Clll (125 mg) 1 $133
(For Qualitative Use Only) 64700-1 Testosterone Cypionate Clll G-1 $166
37530-9 MazindolCIV(350mg) G $166 (200 mg)
38300-1 MeperidineHCICII(200mg) I $166 64800-4 Testosterone Enanthate Clll J $166
38600-0 MephobarbitalCIV(25Omg) G $166 (200 mg)
38900-8 Meprobamate CIV (200 mg) G-1 G (03/02) $166 64900-7 Testosterone Propionate Clll L 6 $166
39800-9 MethadoneHCICII(200mg) H-1 $166 (200 mg)
39900-1 Methamphetamine HCI Cll I $166 65630-8 Thiamylal Clll (200 mg) F $166
(125 mg) 66100-2 Thiopental Clll (250 mg) I $166
40400-0 Methaqualone Cl (500 mg) F-1 $166 68050-6 Triazolam CIV (200 mg) G-1 $166
40500-2 Metharbital Clll (200 mg) F-2 $166
25
For the convenience of our customers outside the United States, USP has authorized distribution by the organizations or companies
listed below. Customers who order through these distributors should obtain information on ordering, pricing, and shipping directly
from the distributors. USP products distributed are listed in italics below each listing.
KOREA Royal Pharmaceutical LGC Promochem GmbH

ASIA Samchum Chemical Co. Ltd.
Society of Great Britain
Medicines Testing Laboratory
Mercatorstr. 51
46485 Wesel
INDIA 236-3, Nonhun-Dong, 36 York Place GERMANY
Kangnam-Ku Edinburgh EH1 3HU Tel: (49) 0-281-9887270
LGC Promochem India Private Seoul, KOREA UNITED KINGDOM Fax: (49) 0-281-9887199
Ltd. Tel: (82) 2-515-3081/5 Tel: (44) 131-557-1284 E-mail: de@promochem.com
No. 142,3rd Floor, 5th Cross Fax: (82) 2-547-5258 Fax: (44) 131-556-0723 Reference Standards
9th Main RMV Ext. Reference Standards Reference Standards
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Bangalore 560 080 EXPORTER TO KOREA The Stationery Office (TSO)
INDIA Licosa S.P.A.
C&S Specialties, Inc. 51 Nine Elms Lane Ufficio di Milano
Tel: 91)80-336-4774 121 PiermontRoad London SW8 5DR
Fax: (9f) 80-334-3859 Via Bartolin, 29
Norwood, NJ 07648 UNITED KINGDOM 20155 Milano
E-mail: in@promochem.com USA Tel: (44) 171-873-8236
USP-NF Asian Edition (Print}; Tel: (02) 3926-5083
Tel: 201-750-7740 Fax: (44) 171-873-8203 Fax: (02) 3921-7304
Reference Standards Fax:201-750-7742 USP-NF (Electronic) E-mail: licosami@licosa.com
LGC Promochem India Private Reference Standards FRANCE USP-NF (Print or Electronic);
Ltd. PF and USP Dictionary
Flat 1204-B, 12th Floor BEDI - Bureau d'etudes Et
Jalvay Vilar Sector 1 AUSTRALIA de documentation Nova Chimica
Adi Snankaracharya Marg. Selby Biolab industrielle Via Galileo Galilei, 47
Powai, Mumbai 400 076 8, place de la Republique 20092 Cinisello Balsamo (Ml)
2 Clayton Road ITALY
INDIA Clayton, VIC 3168 75011 Paris
Tel: (91) 22-570-0244 FRANCE Tel: (39) 02-66045392
AUSTRALIA Fax: (39) 02-66045394
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E-mail: in@promochem.com Fax: (33) 1-47-00-04-69 E-mail: info@novachjmica.com
Fax: (61) 3-9562-9840 http://www.novachimica.com
USP-NF Asian Edition {Print}; E-mail: USP-NF (Print or Electronic);
Reference Standards PF and USP Dictionary Reference Standards
info @ selbybiolab.com.au
http://www.selbybiolab.com.au Librairie Lavoisier OEMF, S.P.A.
JAPAN Via Palizzi, 88
Reference Standards 14, rue de Provigny
Maruzen International Co. F-94236 Cachan Cedex 20157 Milano
3-10Nihombashi FRANCE ITALY
2-Chome EUROPE Tel: (33) 1-47-40-6700 Tel: (39) 2-33-2101
Chuo-ku.Tokyo I03 Fax: (33) 1-47-40-6702 Fax: (39) 2-33-210-200
JAPAN ENGLAND USP-NF (Print or Electronic);
USP-NF on CD; USP-NF
Tel: (81) 3-3275-8591 Info Technology Supply, Ltd. Pharmacopeial Forum
Fax: (81) 3-3278-1937 Talbot House LGC Promochem S.A.R.L.
USP-NF (Print or Electronic); 204-226 Imperial Drive 6 rue Alfred Kastler - BP 76 NETHERLANDS/BELGIUM
Pharmacopeial Forum; USP Middlesex HA2 7HH 67123 Molsheim cedex
France C.N. Schmidt B.V., Amsterdam
Dictionary UNITED KINGDOM Tel: (33) (0)-3-88-04-82-82 Postbus 9696
Nankodo Company Ltd. Tel: (44) 181-429-3970 Fax:(33)(0)-3-88-04-82-90 1006 GD Amsterdam
42-6, Hongo 3 Chome Fax: (44) 181-429-3642 E-mail: fr@promochem.com NETHERLANDS
Bunkyo-ku, Tokyo 113 USP-NF (Electronic) Reference Standards Tel: (31 0-20-410-6868
JAPAN Pharmaceutical Press Fax: (31) 0-20-410-6878
GERMANY E-mail: cns@cnschmidt.nl
Tel: (81) 3-3811-9950 I Lambeth High Street
Fax: (81)3-3811-5031 London SE1 7JN Deutscher Apothekar Reference Standards
USP-NF (Print or Electronic) UNITED KINGDOM Verlag Kooyker Ginsberg
Tel: (44) 0-20-7735-9141 Postfach1010 61 Booksellers
Society of JapaDanese D-70 009 Stuttgart
Pharmacopeia Fax: (44) 0-20-7735-5085 Postbus 24,2300 AA
USP-NF (Print or Electronic); GERMANY Leiden
USP Ref Stds Order Department Tel: (49 711-2582-341
2-12-15 Shibuya PF and USP Dictionary NETHERLANDS
Fax: (49) 711-2582-390 Tel: (31 71-516-0531
Shibuya-ku LGC Promochem Ltd. USP-NF (Print or Electronic);
Tokyo 150-0002 St. David's House Fax: (31)71-519-1499
Pharmacopeial Forum USP-NF (Print or Electronic)
JAPAN I1 Blenheim Court, Brownfields
Tel: (81) 33-400-5634 Welwyn Garden City Laboratory Quality POLAND
Fax: (81) 33-400-3158 Hertfordshire AL7 IAD Services (LQS) Labor-und-
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Fax: (44) 0-1707-39-1335 03-236 Warsaw
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Reference Standards Tel: (48) 228-11-23-99
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E-mail: info@lqs-gmbh.de Reference Standards
http://www.lqs-gmbh.de
Reference Standards
26

SPAIN/PORTUGAL BRAZIL EXPORTER TO LATIN Login Brothers Canada

324 Saulteaux Crescent
LGC Promochem S.L. Ayalla Marketing e AMERICA Winnipeg, Manitoba R3J 3T2
Peru, 104-Nave 3 Representa$6es Ltda. Farma International CANADA
08018 Barcelona (Ricera American Corp. - Filial 9501 Old South Dixie Hwy. Tel: 800-665-1148
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Reference Standards; BRAZIL USP-NF (Print or Electronic);
USP-NF (Print or Electronic); Tel: 0115561-7486 Nucro Technics
Pharmacopeial Forum; 2000 Ellesmere Road, Unit 16
Pharmacopeial Forum; USP Fax: 011-5041-8434/5535-9606 Reference Standards
Dictionary E-mail: ayalla@ayalla.com.br Scarborough, Ontario Ml H 2W4
Reference Standards; CANADA
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LGC Promochem AB Pharmacopeial Forum; and Fax:416-438-3463
P.O. Box 1737 USP Dictionary ISRAEL Reference Standards
SE-501 17 Boras )phir Analytic
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Fax: (46) 0 33 165310 Asociacion Farmaceutica ISRAEL CANADA
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27

HOW TO ORDER
DIRECT FROM USP Quantity Discounts

5% discount will be given on any assortment of 5 to 24
Telephone Orders standards per order, and 10% will be given on any assortment
of 25 or more. These discounts are subject to change without
U.S. and Canada: (800) 227-8772 notice.
International: (301) 881-0666
Please note: The quantity discount policy will soon change
Orders by telephone are accepted (except for DEA controlled to a line item discount. For example: a 5% discount will be
substances), but customers are reminded that errors may be given on 5-24 units of any one type of Reference Standard in
more frequent with verbal communications and that an order, and a 10% discount will be given on 25 or more
standards are not returnable for exchange or refund. units of any one type of Reference Standard in an order. This
new discount policy will go into effect automatically when
FAX Orders our new ERP business system is turned on in early 2002.
Fax: (301) 816-8148 Please contact Customer Service for the latest information.
FAX orders are accepted for customers (except for DEA Important Order / Policy Information
controlled substances). Customers are responsible for any A Reference Standard unit may include several individual
errors in transmission or for order duplication. containers; in such an instance, do not order in terms of the
total number of containers. Where an order contains an item
Online Orders that is not currently available, a backorder record will be
made by USP. A notice of availability will be provided to the
www.usp.org customer if the item becomes available within 6 months of
the original order (see backorder policy below). No items
Reference Standards may be ordered online (except for DEA will be shipped without prior written authorization by
controlled substances). Go to www.usp.org. Click on the customer.
"Products" and select "Reference Standards". Orders may be
charged to your USP account or by credit card via our secure
Confirmation orders may be sent and must be clearly
server. Errors in ordering are the responsibility of the
designated as such. The USP does not assume responsibility
customer.
for duplication of orders not clearly marked as confirmation.
Mail Orders
See International section for special requirements
Please send all mail orders to: pertaining to orders outside the U.S. and Canada.
U.S. Pharmacopeial Convention, Inc.
Customer Service Department DEA Requirements
12601 Twinbrook Parkway For all domestic purchases of items regulated by the Drug
Rockville, Maryland 20852 Enforcement Administration (DEA), a copy of the customer's
USA current DEA Registration Certificate must be on file with
Order forms are located in the back of this catalog. USP. In addition, customers ordering DEA Schedules III and
IV, must provide on purchase orders their DEA registration
Pricing number for the appropriate schedule. To order Schedule I and
Prices noted in individual product descriptions are effective II standards, the customer must submit with their hard copy
January 1, 2002. Please note that prices and package sizes are purchase orders a DEA Form 222-C, properly completed.
subject to change without notice. Also note that catalog items
are not returnable for exchange or refund.
Controlled substances (CI, CII, CHI, CIV, CV) shipped to
foreign address, including Canada and Puerto Rico, add
$25.00 per unit.
For additional shipping charges, see order form.
28

HOW TO ORDER
The following Reference Standards are "List Chemicals" and Canadian orders from Ontario for non-controlled substances
require certain documentation in order to be purchased: are shipped prepaid via air courier of USP's choice at a
charge of $9 (U.S. dollars) to a STREET ADDRESS ONLY
Dihydroergotamine Mesylate (no P.O. Boxes). Shipments via air courier of the Customer's
Ephedrine Sulfate choice will be at a charge of $25. Orders from all other
Ergonovine Maleate Canadian Provinces are shipped by air courier at a charge of
Ergotamine Tartrate US$60. Canadian orders for controlled substances will be
Methylergonovine Maleate shipped by air courier with an additional charge of
Phenylpropanolamine Bitatrate US$195.00 per order. Appropriate import documents are
Phenylpropanolamine HC1 required for USP to ship controlled substances to Canada.
Pseudoephedrine HC1 Any fees relating to customs duties, tariffs, and other taxes
Pseudoephedrine Sulfate are the responsibility of the customer.
Rush shipments, add $25.00 per order.
An organization in the United States seeking to purchase a
List Chemical Reference Standard for resale to another International Orders
customer must have a DEA registration (either a controlled Foreign orders (orders to be shipped outside the U.S. or
substance or List Chemical registration). If an organization in Canada) for catalog items, except items regulated or
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29
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CHROMATOGRAPHIC REAGENTS
USED IN USP-NF AND
PHARMACOPEIAL FORUM
This is an update based on the proposals published in this issue of PF.
Pharmacopeial Forum
Vol. 28(2) [Mar.-Apr. 2002] CHROMATOGRAPHIC REAGENTS
Chromatographic Reagents Used in USP-NFand

Pharmacopeial Forum
March-April 2002 PF
CARBIDOPA DSD Mgh #12810

08(6) L1 MicroBondapak C18 Limit of. Limit of methyldopa and 3-O-methylcarbidopa.
CEFAZOLIN DSD Mgh #13970

09(6) L1 MicroBondapak C18 Identity
CEFTAZIDIME DSD Mgh #14120

16(1) L1 Spherisorb ODS Assay
CHLOROTHIAZIDE DSD Mgh #16210

13(3) L1 Zorbax ODS Limit of. Limit of 4-amino-6-chloro-1,3-
benzenedisulfonamide.
CHLORPHENIRAMINE MALEATE EXTENDED-RELEASE CAPSULES DSD Mgh #16460

14(4) L1 MicroBondapak C18 Uniformity of dosage units
DEXTROMETHORPHAN HYDROBROMIDE DSD Mgh #24120

10(4) L1 AlltechC18 5-u.m.
DIGOXIN DSD Mgh #26000

08(2) L1 None Cited Assay
DIHYDROERGOTAMINE MESYLATE DSD Mgh #26080

24(1) L1 Zorbax SB-C18 Chromatographic purity
DIMENHYDRINATE TABLETS DSD Mgh #26420

18(6) L7 Zorbax RX-C8 Assay
DOCUSATE SODIUM CAPSULES DSD Mgh #27930

17(5) L1 Ultracarb ODS (30) 15-cm; 5-um
Pharmacopeia! Forum
DOCUSATE SODIUM SOLUTION DSD Mgh #27940

17(5) L1 Ultracarb ODS (30) See Capsules
DOXAZOSIN MESYLATE DSD Mgh #28090

28(2) L1 LunaCi8 Assay 4.6 mm x 25 cm, manuf. Phenomenex.
28(2) L7 Zorbax SB C8 Chromatographic purity 4.0 mm x 8 cm, manuf. Agilent.
DOXAZOSIN MESYLATE TABLETS DSD Mgh #28095

28(2) L1 LunaC18 Identity 4.6-mm x 25-cm, manuf. Phenomenex.
DOXYCYCLINE HYCLATE DSD Mgh #28340

21(4) L21 PRP-1 Manuf. Hamilton
ETHOTOIN DSD Mgh #31720

mmmmm
14(4) L1 MicroBondapakC18 Limit of. Limit of 5-phenylhydantion and related compounds.

Manuf. Waters.
INSULIN DSD Mgh #40520

16(1) L20 Zorbax GF250 Chromatographic purity Test B: High molecular weight proteins;
silica gel pre-column;
9.4-mm. This column is not available anymore,
possible alternatives: Waters Insulin HMWP, 7.8
mm x 30 cm (WAT201549), YMC-Pack Diol 120, 8
mm x 30 cm (DL12S05-3008WT).
LACTULOSE CONCENTRATE DSD Mgh #44210

15(2) L8 Hypersil APS-2 Assay and Limit of Assay and Limit of related substances; 15-cm, 3-
um. Manuf. Thermo Hypersil-Keystone.
15(2) L8 Hypersil APS-2 Identity Manuf. Thermo Hypersil-Keystone.
LACTULOSE SOLUTION DSD Mgh #44240

15(2) L8 Hypersil APS-2 Assay and Limit of Assay and limit of related substances; 15-cm, 3-
urn. Manuf. Thermo Hypersil-Keystone.
15(2) L8 Manuf. Thermo Hypersil-Keystone.
Hypersil APS-2 Identity
Pharmacopeia! Forum
METHOCARBAMOL DSD Mgh #51200

09(2) L1 ODS Ultrapak Related impurities
METOPROLOL TARTRATE TABLETS DSD Mgh #53550

17(3) L1 None Cited Identity
17(3) L1 None Cited Uniformity of dosage units
MILK THISTLE DSD Mgh #54061

28(2) L1 YMC-Pack ODS-A Content of Content of silymarin. 4.6 mm x 15 cm, manuf. YMC
Inc.
POWDERED MILK THISTLE DSD Mgh #54062

••••••Mi
28(2) L1 YMC-Pack ODS-A Content of. content of silymarin. 4.6 mm x 15 cm, manuf. YMC
Inc.
MILK THISTLE CAPSULES DSD Mgh #54067

28(2) L1 YMC-Pack ODS-A Content of. Content of silymarin. 4.6 mm x 15 cm, manuf.
YMC, Inc.
MILK THISTLE TABLETS DSD Mgh #54068

•••••••••••
28(2) L1 YMC-Pack ODS-A Content of. Content of silymarin. 4.6 mm x 15 cm, manuf. YMC
Inc.
NANDROLONE DECANOATE INJECTION DSD Mgh #55580
28(2) L1 EconosphereC18 Assay 4.6 mm x 15 cm, 5 urn, manuf. Alltech.
PADIMATE O LOTION DSD Mgh #60225

14(4) L1 SupelcosilLC-18-DB
PENICILLAMINE DSD Mgh #61380

16(2) L1 MicroBondapak C18 Manuf. Waters.
ASPARTAME DSD Mgh #6195

09(6) S1A None Cited Limit of. Limit of 5-benzyl-3,6-dioxo-2-piperazineacetic acid.
Pharmacopeia! Forum
PROPOXYPHENE HYDROCHLORIDE DSD Mgh #70590

28(2) L1 MicroBondapak C18 Assay and Related 3.9 mm x 30 cm, manuf. Waters.
Compounds
RAMIPRIL DSD Mgh #73030

26(2) L1 NucIeosilC18 Related compounds 4.0-mm x 25-cm, 3 urn, manufacturer Macherey-
Nagel.
RANITlDINE ORAL SOLUTION DSD Mgh #73046

28(2) L9 PartisiMOSCX Assay & Chrom. purity 4.6-mm x 25-cm, manuf. Whatman.
SULFAMETHOXAZOLE AND TRIMETHOPRIM ORAL SUSPENSION DSD Mgh #79290

11(6) L1 ASIC18 Alternative reagent
11(6) L1 MicroBondapak C18 Assay
TOLMETIN SODIUM CAPSULES DSD Mgh #84150

10(3) L7 Zorbax C8 15-cm, 5-um.
TRIMETHOPRIM DSD Mgh #85940

28(2) L1 HypersilBDSC-18 Chromatographic purity 4.6 mm x 25 cm, 5 um, manuf. Thermo Hypersil
Keystone.
VINCRISTINE SULFATE DSD Mgh #88250

08(2) L7 Zorbax C8 Related substances 5-jim.
PHARMA M
U.S. PHARMACOPEIA
The United States Pharmacopeia

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jfff The Journal of Standards Development and Official Compendia Revision
• • • • • • • • • • • • • • • i i • • mlim m m m m i ••••••••••••i
• ••••
a •••*•••
a •••,.••
PHARMACOPEIAL
FORUM
NUMBER 3
BIMONTHLY: May-June 2002
HIGHLIGHTS
• Third Interim Revision Announcement

Pertaining to USP25-NF20
• Changes in Reference Standards

Prices and Numbers
U.S. PHARMACOPEIA
Table of Contents*
PHARMACOPEIAL FORUM VOL. 28 No. 3 MAY-JUNE 2002

HOW TO USE PF 703
Section Descriptions 705
Staff Directory 708
Changes in Reference Standards Prices and Numbers 713
Pharmaceutical Education Courses 714
How to Comment 715
Schedules 716
Errata List for USP 25-NF 20 717
THIRD INTERIM REVISION ANNOUNCEMENT 725
Furosemide Oral Solution 727
Glycerin 727
Levothyroxine Sodium Tablets 727
Ingredients and Processes—USP 733
Alendronate Sodium [new] (1st Supp) 737
Alendronate Sodium Tablets [new] (1st Supp) 740
Amphetamine Sulfate (1 st Supp) 744
Astemizole Tablets (1st Supp) 745
Bacitracin (1st Supp) 745
Benzethonium Chloride Concentrate [new] (1st Supp) 745
Benzylpenicilloyl Polylysine Concentrate (1 st Supp) 746
Carbamazepine Extended-Release Tablets (1st Supp) 746
Carbidopa and Levodopa Tablets (1st Supp) 747
Cefpiramide (1st Supp) 747
Cyanocobalamin Co 58 Capsules (1st Supp) 748
Cycloserine Capsules (1 st Supp) 750
Dextroamphetamine Sulfate (1st Supp) 751
Dimenhydrinate Injection (1st Supp) 752
Dimenhydrinate Oral Solution [new] (1st Supp) 753
Dimenhydrinate Syrup (1 st Supp) 755
Dimenhydrinate Tablets (1st Supp) 756
Ferumoxides Injection [new] (1st Supp) 758
Fluorodopa F 18 Injection (1st Supp) 762
Flurbiprofen Sodium [erratum] (USP 26) 762
Ganciclovir [new] (1 st Supp) 762
Glutaral Concentrate (1 st Supp) 764
Glycerin (USP 26) 764
Hydrocortisone (1st Supp) 764
Hydrogen Peroxide Concentrate (1 st Supp) 765
Pharmacopeial Forum
694 Contents* Vol. 28(3) [May-June 2002]
Indocyanine Green (Proposal for 4th IRA) 765

Isosorbide Concentrate (1st Supp) 766
Lactulose Concentrate [erratum] (1st Supp) 766
Lansoprazole Delayed-Release Capsules [new] (1 st Supp) 766
Mafenide Acetate (1 st Supp) 769
Methyldopa (1st Supp) 769
Methyldopa Tablets (1 st Supp) 770
Minocycline Hydrochloride (1 st Supp) 770
Misoprostol Dispersion [new] (1st Supp) 772
Moricizine Hydrochloride [errata] (USP 26) 774
Neomycin and Polymyxin B Sulfates and Pramoxine Hydrochloride Cream (1st Supp) 774
Nifedipine Extended-Release Tablets (Proposal for 5th IRA) 775
Paroxetine Tablets [new] (USP 26) 777
Extended Phenytoin Sodium Capsules (Proposal for 5th IRA) 780
Potassium Chloride Extended-Release Tablets (Proposal for 4th IRA) (1 st Supp) 783
Propofol [new] (1 st Supp) 784
Sorbitol Solution (1 st Supp) 787
Sulfasalazine Delayed-Release Tablets (1st Supp) 788
Thyroid (1 st Supp) 789
Tobramycin Inhalation Solution [new] (1st Supp) 789
Triamterene Capsules (1 st Supp) 792
Triamterene and Hydrochlorothiazide Tablets [errata] (1st Supp) 794
Crystallized Trypsin for Inhalation Solution (Proposal for 5th IRA) 794
Xylometazoline Hydrochloride Nasal Solution (1 st Supp) 795
EXCIPIENTS 796
Tapioca Starch (1 st Supp) 796
MONOGRAPHS (NF) 797
Horse Chestnut [new\{Y{ Supp) 797
Powdered Horse Chestnut [new] (1 st Supp) 799
Powdered Horse Chestnut Extract [new] (1st Supp) 800
Chondroitin Sulfate Sodium [new] (1 st Supp) 801
Chondroitin Sulfate Tablets [new] (1st Supp) 804
Red Clover [new] (1 st Supp) 807
Powdered Red Clover [new] (1 st Supp) 810
Powdered Red Clover Extract [new] (1 st Supp) 811
Red Clover Tablets [new] (1st Supp) 812
Dimethicone (1 st Supp) 813
Ginger Capsules [new] (1st Supp) 814
Powdered Kava Extract [new] (1 st Supp) 815
Semisolid Kava Extract [new] (1 st Supp) 817
Kava Capsules [new] (NF 21) 818
Kava Tablets [new] (NF 21) 820
a-Lipoic Acid Capsules [new] (1st Supp) 822
a-Lipoic Acid Tablets [new] (1st Supp) 824
Maltitol Solution (1 st Supp) 824
Monoethanolamine [erratum] (NF 21) 826
Monosodium Glutamate (1st Supp) 826
Poloxamer [erratum] (NF 21) 827
Polyethylene Glycol [erratum] (NF 21) 827
Saw Palmetto Extract [new] (1 st Supp) 827
Sesame Oil (1st Supp) 832
Sorbitol (1 st Supp) 833
Noncrystallizing Sorbitol Solution (1 st Supp) 835
Starch (1 st Supp) 837
Tapioca Starch [new] (1st Supp) 838
Stearic Acid (1 st Supp) 839
Purified Stearic Acid (1 st Supp) 839

Pharmacopeial Forum
Vol. 28(3) [May-June 2002] Contents* 695

(11) USP Reference Standards (1st Supp) 839
(621) Chromatography (1 st Supp) 843
(776) Optical Microscopy (1st Supp) 847
dl-10-Camphorsulfonic Acid [erratum] (USP 26) 848
Cesium Chloride [new] (1st Supp) 849
Cyclohexylmethanol [new] (1 st Supp) 849
Dicyclohexyl [new] (1 st Supp) 849
l,2-Dilinoleoyl-3-oleoyl-rac-glycerol [new] (1st Supp) 849
l,2-Dilinoleoyl-3-palmitoyl-rac-glycerol [new] (1st Supp) 849
l,2-Dioleoyl-3-linoleoyl-rac-glycerol (deleted) 849
Ethylbenzene [new] (1st Supp) 850
Glucose [new] (1st Supp) 850
Hexamethylenetetramine [new] (1 st Supp) 850
Hydroxy Naphthol Blue [new] (1 st Supp) 850
Lanthanum Oxide [new] (1st Supp) 851
Monoethanolamine [erratum] (USP 26) 851
Ninhydrin (1st Supp) 851
Nitric Acid, Lead-Free [new] (1 st Supp) 851
l-Palmitoyl-2-oleoyl-3-linoleoyl-rac-glycerol (1st Supp) 851
Triketohydrindene Hydrate (1st Supp) 852
Test Solutions 852
Ninhydrin TS (l sl Supp) 852
Triketohydrindene Hydrate TS (1 st Supp) 852
Cyanocobalamin Co 58 Capsules (1 st Supp) 853
a-Lipoic Acid Capsules (1st Supp) 853
a-Lipoic Acid Tablets (1 st Supp) 853
Red Clover Tablets (1 st Supp) 853
Description and Relative Solubility of USP and NFArticles 853
Metoprolol Succinate (1 st Supp) 853
Tapioca Starch (1st Supp) 853
HARMONIZATION 865
IN-PROCESS 867
Carboxymethylcellulose Sodium 867
Citric Acid 872
Citric Acid, Anhydrous 872
Citric Acid, Monohydrate 876
MONOGRAPHS (NF) 879
Benzyl Alcohol 879
Corn Starch 882
Potato Starch 885
Wheat Starch 888
GENERAL INFORMATION CHAPTERS 891
(1216) Tablet Friability 891
Pharmacopeia! Forum
696 Contents* Vol. 28(3) [May-June 2002]

Description and Relative Solubility of Harmonization Articles 892
Corn Starch 892
Potato Starch 892
Wheat Starch 893
PREVIEWS 893
GENERAL TEST CHAPTERS 893
(267) Porosimetry by Mercury Intrusion 893
(429) Light Diffraction Measure of Particle Size 895
(616) Bulk Density and Tapped Density 901
(943) X-Ray Diffraction Solids 905
(1111) Microbial Contamination Limits for Non-sterile Products 916
Amiodarone Hydrochloride [new] 923
Amiodarone Hydrochloride Tablets [new] 925
Gadoversetamide [new] 926
Gadoversetamide Injection [new] 931
Diluted Isosorbide Mononitrate [new] 933
Isosorbide Mononitrate Tablets [new] 936
Isosorbide Mononitrate Extended-Release Tablets [new] 939
Oxaprozin [new] 942
Oxaprozin Tablets [new] 944
Pentazocine Hydrochloride and Acetaminophen Tablets 945
NF MONOGRAPHS 948
Copovidone [new] 948
Maltose [new] 951
Anhydrized Liquid Sorbitol [new] 953
Talc [new] 955
(621) Chromatography 959
Comparison of Microbiological Testing Practices in the Clinical, Food, Water, and Pharmaceutical Microbiology
in Relation to the Microbiological Attributes of Nutritional and Dietary Supplements, Anthony M. Cundell . . . 964
A New Assay System for Accuracy Validation of Serum-antibody Titration Methods: Mechanistic and Operational
Considerations, Gideon Halperin and Hadar Marcus 986
NOMENCLATURE 993
INDEX 1011
ORDER FORM
Pharmacopeial Forum
Vol. 28(3) [May-June 2002] Contents* 697
John W. Gasper, J.D. http://www.usp.org
Jerry T. Wadsworth
Meredith Hassall; Reuben Meisel; Anthony Owens Sciences.
Editorial Coordinator
Susan Maida The United States Pharmacopeial Convention comprises represen-
Production Editor tatives from colleges and national and state organizations of med-
Evelyn Bryant icine and pharmacy. It publishes the U.S. Pharmacopeia and
Senior Editorial Assistant National Formulary, the legally recognized compendia of stan-
M. T. Samahon dards for drugs and products of other health care technologies.
Editorial Assistants The USP and NF include assays and tests for the determination
Micheline Tranquille; Milagro Welter of strength, quality, and purity and requirements for packaging
Director, Product Development and labeling.
Linda M. Guard
Debbie Miller Moving?
Production Coordinators Our subscribers' records and publication labels are computer-gen-
Erika L. Barrowclough; Celia Hamilton erated. Please send your new address, and your latest label, or an
Electronic and Desktop Publishing exact copy of it, to: USPC, PF Customer Service Dept., 12601
Debbie James; Donna A. Singh Twinbrook Parkway, Rockville, MD 20852.
Fax (301) 816-8148.
This section presents an overview of the public review and comment process, conducted through Pharmacopeial Forum
Pharmacopeia! Forum
Vol. 28(3) [May-June 2002] STANDARDS DEVELOPMENT 701
peial Previews)
3. Adopted revisions—new or revised standards that become official and binding before the publication of the next USP-
USP welcomes comments and data on potential, proposed, or official standards. Comments, along with USP's responses,
will be published either in PF Briefings, the Commentary section of PF, the Commentary section of Supplements to USP-NF,
or the Commentary section of USP-NF.


for publication in


and responds to the
USP Scientific Stafif Liaison compiles and

/ Revision proposal becomes official; \

/ revision published in Interim \
/ Revision Announcement or \
\ Supplement to USP-NF; comments /
\ and responses published under /
\ Commentary in Supplement/ I
\ PF/USP-NF /
Questions on the process should be addressed to John W. Gasper, M.A., J.D., Director, Office of the Executive Secretariat,
U.S. Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852 (e-mail: jg@usp.org).
* If you are not immediately able to submit comments but you intend to do
HOW TO USE PF
This section provides descriptions of the various parts of PF. It also includes Committee Designations and the StaffDirectory.
Pharmacopeial Forum
Vol. 28(3) [May-June 2002] HOW TO USE PF 705

sues such as
study
velopment). New or revised text is marked with symbols (" B or
* # or A . ) to specify the tentative earliest date on which the revision
would be officially adopted.
Items the Pharmacopeial change or for the proposed change. The designated stage of harmo- ments to the appropriate staff liaison ci-
•For In-Process Revision, new or revised text is marked with sym-
bols ("B) to specify the tentative, earliest date on which the revi-
item. New or revised text is set off by the symbols come official and ensure compliance.
••
Pharmacopeial Forum
706 HOW TO USE PF Vol. 28(3) [May-June 2002]
Other Sections
dards.
Staff Directory


Nomenclature
Revisions to existing names as a supplement to the USP Dictionary of USAN and International Drug Names
Suggested, proposed, and recommended USAN and INN
Information on how nonproprietary drug names are devised
Articles relevant to compenaial nomenclature issues
Index
Cumulative directory for the content of all issues of PF beginning with PF 28(1).

Chromatographic Reagents Used in USP—NF and Pharmacopeial Forum

Pharmacopeial Forum
EXPERT COMMITTEE DESIGNATIONS

AER Aerosols
BST Biostatistics
EMC Excipient Monograph Content1"
ESC Excipients—Substances and Characterization*
HDQ Indicates USP Headquarters items.

The Expert Committee has been renamed. The old name, Excipients—Substances and Characterization (ESC) has been changed to Excipient Monograph Content (EMC).
Pharmacopeial Forum
708 HOW TO USE PF Vol. 28(3) [May-June 2002]
STAFF DIRECTORY
This is an updated directory that reflects assignment changes based on the reorganization of USP. The general USP tele-
phone number, (301) 881 -0666, may still be used for general inquiries or when a particular Committee is not identified. The FAX
number is (301) 816-8373.

Clydewyn M. Anthony, cma@usp.org (301) 816-8139 Pharmaceutical Analysis (PA1)
Frank P. Barletta, Scientist fpb@usp.org (301) 816-8328 Pharmaceutical Waters (PW)
Industrial(PPI);
Charles H. Barnstein, Consultant chbarnstein@ (301) 774-9457 Nomenclature and Labeling (NL)
email.msn.com
John R. Bergeron, Director jxb@usp.org (301) 816-8289 USP Reference Standards
Reference Standards
Production
Lokesh Bhattacharyya, Senior lb@usp.org (301) 816-8201 Blood and Blood Products (BBP);
Scientist Vaccines, Virology, and
Immunology (VVI)
Barbara A. Bowman, bab@usp.org (301) 816-8278 USP Correspondence
Manager,
Administrative Services
William E. Brown, Scientist web@usp.org (301) 816-8380 Biopharmaceutics (BPC);
Biostatics (BST)
Todd L. Cecil, Director, tlc@usp.org (301) 816-8234 New monograph development
Non-Complex Actives
Elizabeth Cowley, epc@usp.org (301) 816-8217 Safe Medication Use (SMU)
Communications Coordinator,
Experience
Roger Dabbah, Director, Complex rd@usp.org (301) 816-8336 Blood and Blood Products (BBP)
Actives
Ian F. DeVeau, Scientist ifd@usp.org (301) 816-8178 Cell Therapy, Gene
Therapy and Tissue
Engineering (CGT);
Veterinary Products
and Natural Products
Monographs
Shawn F. Dressman, Scientist sfd@usp.org (301) 816-8261 Pharmaceutical Analysis
6—Actives (PA6)
John L. Esker, Scientist je@usp.org
(301) 816-8193 Pharmaceutical Analysis 5 (PA5)
L. Valentin Feyns, Director, lvf@usp.org
Reference Standards Evaluation (301) 816-8121 USP Reference Standards

Gabriel I. Giancaspro, Scientist gig@usp.org (301) 816-8343 Dietary Supplements—Botanicals
Supplements—
Non-Botanicals(DSN);
Bioavailability and
Elena Gonikberg, Scientist eg@usp.org (301) 816-8251 Excipient Monograph Content
(EMC)
Pharmacopeial Forum
STAFF DIRECTORY (continued)

Sue C. Harris, Director, Excipients sch@usp.org (301)816-8275 Excipient Monograph Content
Methods (ETM)
Gloria Huang, Senior Scientific ggh@usp.org (301)816-8183 Pharmaceutical Dosage Forms
Associate (PDF)
Associate (PA2)
Justin J. Lane, Senior Scientific jl@usp.org (301)816-8323 Excipients—Test Methods
Associate (ETM)
Anju K. Malhotra, Manager, akm@usp.org (301)816-8346 USP Conferences and
Conferences and Meetings Meetings
President, Standards Operations
Azra M. Medjedovic, Scientific am@usp.org (301)816-8179
Associate Pharmaceutical Analysis 4 (PA4)
C. David Nash, Director, dn@usp.org (301)816-8298
Veterinary Medicine Veterinary Issues
Claudia C. Okeke, Scientist cco@usp.org (301)816-8243 Compounding Pharmacy (CRX);

Distribution (PSD)
David A. Porter, Scientist dap@usp.org (301)816-8225 Analytical Microbiology (AMB);
Salvador Salado, Scientist and ss@usp.org (301)816-8165 Pharmaceutical Analysis (PA1),
Stefan P. Schuber, Director, sps@usp.org (301)816-8551
Information and
Administration
Methods (ETM)
Development
V. Srini Srinivasan, Vice vs@usp.org (301)816-8334
President, Dietary
Supplements
Verification Program
(DSVP)
Jerry T. Wadsworth, Manager, jtw@usp.org (301)816-8353 Standards Publications
William W. Wright, Scientific www@usp.org (301)816-8335 Pharmaceutical Analysis 7—
Kahkashan Zaidi, kxz@usp.org (301)816-8269 Aerosols (AER)
POLICIES AND
ANNOUNCEMENTS
Pharmacopeial Forum
Vol. 28(3) [May-June 2002] POLICIES AND ANNOUNCEMENTS 713
CHANGES IN REFERENCE STANDARDS PRICES New Reference Standards vials already are carrying the new
AND NUMBERS. lot numbers. You will see the expanded numbers in the cat-
alog starting with the March/April 2002 issue.
Below is an overview of four key changes taking place re-
garding USP Reference Standards. Please note that these Further changes, as listed below, will take effect as USP estab-
changes take effect on different dates. lishes its comprehensive new ERP business system designed to en-
hance customer service. We expect to convert to this system in early
2002. Please call USP Customer Service at 1-800-227-8772 or
301-881-0666 for updates on when the conversion is expected to
Annual price increase take place.
Effective January 1, 2002, prices of USP Reference Stan-
dards increased by 4%. This price increase rate is tied to Quantity discounts by item
the Consumer Price Index (CPI) for medical commod-
ities—prescription and OTC drugs and medical supplies. Historically, USP offered discounts on the purchase of Ref-
For the one-year period ending September 2001, the average erence Standards based on the total number of all items or-
CPI for medical commodities was 4.3%. dered. In early 2002 this policy will change such that a
quantity discount will be applied based on the number of
The current prices are reflected in the Reference Standards units of all items ordered, as was previously done. This pol-
catalog. Please note that a few Reference Standards may be icy change is set to coincide with the implementation of
subject to different pricing adjustments (and not a 4% in- USP's new ERP business system mentioned above.
crease) based on market value, cost of materials, and/or ex-
traordinary expenses. Catalog numbers expanded by one digit
New system of lot numbers A leading digit " 1" will be added to all existing catalog
numbers of Reference Standards. For example, the catalog
New Reference Standards lots are identified by unique ex- number 03150-3 will become 103150-3. The old catalog
panded lot numbers that provide important information. number will be maintained as the root.
These numbers allow each Reference Standard to be easily
traced to specific lots. Until current Reference Standards lots are depleted, vials
will continue to show the old catalog number. The new cat-
The new lot numbers will have three parts as this example alog numbers will appear on all catalogs, invoices, and ship-
indicates: ping documents. As such, it is recommended that you start
G1A001 preparing to incorporate the new catalog numbers in your
I I ' 1 Reference Standards ordering documents.
Current lot Calendar year Sequential
configuration (A=2001,B=2O02,etC.) number
Please call USP Customer Service at 1-800-227-8772 or
301-881-0666 if you have any questions about the changes
and their impact.
Pharmacopeial Forum
714 POLICIES AND ANNOUNCEMENTS Vol. 28(3) [May-June 2002]
UPDATE ON THE ANNUAL EDITION OF USP-NF. CHROMATOGRAPHIC REAGENTS NOW AVAILABLE.

Starting in 2002, USP-NF will be published annually. Chromatographic Reagents lists the brand names of the
Traditionally, USP-NF has been published every five column reagents cited in every proposal for new or
years with two Supplements a year. Now, one main revised gas- or liquid-chromatographic test methods that
edition and two Supplements will be published every year, have been published in Pharmacopeial Forum (PF) since
bringing users more frequent updates—at shorter intervals- 1980. Chromatographic Reagents also helps to track
on the latest official standards and test methods. The first which column reagents were used to validate methods that
annual edition was shipped in November 2001 and have become official and are included in USP-NF. The
became official on January 1, 2002. The annual edition branded column reagents list is updated bimonthly
will be available in hardcover and electronic formats for through Pharmacopeial Forum. Chromatographic
user convenience. First Supplement becomes official on Reagents can be ordered by calling USP's Customer
April 1, 2002, and Second Supplement becomes official Service Department at 1-800-227-8772 or 301-881-0666.
on August 1, 2002 (deadline to submit comments is
February 15, 2002). Comments on previously published PHARMACOPEIAL EDUCATION COURSES. USP's
Pharmacopeial Forum proposals that are received too late Pharmacopeial Education series has been developed to
to permit adequate review and evaluation will be enhance the knowledge, skills, and expertise of
considered as suggestions for future revisions. pharmaceutical industry personnel. Three interactive
courses are currently being offered:
VISIT THE USP WEB SITE AT (http://www.usp.org). • "Fundamentals of Dissolution" helps participants be-
Various resources related to Pharmacopeial standards are come proficient in USP-NF-based dissolution equip-
presented, including highlights from PF. ment, calibration, tests, methods development, and
validation.
USP-NF AVAILABLE IN THREE ELECTRONIC
F O R M A T S . The t r u s t e d reference for official • "Standards 100: USP-NF Overview, Applications, and
pharmaceutical standards is available in three convenient Development Process" provides an overview of USP-
electronic formats—CD, intranet, and online. The CD is NF sections and applications, use of USP Reference
ideal for single users who prefer to have USP-NF on their Standards, and participation in the official standards de-
hard drives. The intranet format allows Web browser-based velopment process.
access to multiple users within a company, through their • "Standards 101: USP-NF Monograph Development,
own intranet server. The online format can be accessed by General Notices & Chapters" builds on Standards
individual registered users through the World Wide Web. 100, with an in-depth review of USP-NF monographs,
All three electronic formats provide fast and easy access General Notices, and General Chapters, and focuses on
to official USP-NF content. More information can be the technical aspects of the monograph development
obtained by visiting www.usp.org/products or by calling process.
USP's Customer Service Department at 1-800-227-8772
or 301-881-0666. The following list indicates tentatively scheduled course
dates.

June 17 and 18 Titration (tentative) USP Headquarters, Rockville, MD
Pharmacopeial Forum
Vol. 28(3) [May-June 2002] POLICIES AND ANNOUNCEMENTS 715
For further information, contact Barbara B. Hubert, Direc- HOW TO SUBMIT COMMENTS. The USP welcomes
tor, P h a r m a c o p e i a l E d u c a t i o n , B B H @ u s p . o r g , and encourages interested parties to submit comments and
301-816-8333, or Diana Lenahan, Program Associate, data regarding potential, proposed, or adopted (official)
DPL@usp.org, 301-816-8530. standards. Submissions concerning a particular item that
has appeared in a PF should be submitted to the
INTERNATIONAL CORRESPONDENCE. Individuals appropriate USP scientific staff liaison identified at the
who wish to correspond with the European and Japanese end of the Briefing accompanying each item. To submit
Pharmacopoeias concerning monographs in the Official comments and data to a liaison, use the e-mail address
Inquiry and Consensus stages of international and telephone numbers listed in the Staff Directory
harmonization should address their comments to the included in every PF.
coordinating pharmacopeia for a given article. The
Please note that starting in 2002, USP-NF is being pub-
addresses for the European and Japanese Pharmacopoeias
lished in an annual edition with one main book and two Sup-
are as follows:
plements a year. In addition, the following schedule will
Technical Secretariat of the repeat every year so that users will know what to expect
European Pharmacopoeia Commission and become familiar with the deadlines.
B.P. 907
F 67029 Strasbourg Cedex 1 The publication and comment schedule for USP 25-NF 20
France is as follows:
NAKASHIMA Nobumasa
Evaluation and Licencing Division
Pharmaceutical and Medical Safety Bureau
Ministry of Health, Labour and Welfare, Japan
Tel. +81-3-3595-2431, Fax. +81-3-3597-9535
E-mail nakashima-nobumasa@mhlw.go.jp

Main Book May 15,2001 November 2001 January 2002
Supplement One October 15,2001 February 2002 April 2002
The publication and comment schedule for USP 26-NF 21

is as follows:
Supplement One October 15,2002 February 2003 April 2003
In the future, USP anticipates including the comment sub- For general inquiries or in cases where a particular liaison is
mission deadline in each briefing of every revision proposal not identified, use the general USP telephone number (301)
when it is published for public review and comment. 881-0666 or FAX number (301) 816-8373.
Pharmacopeial Forum
716 POLICIES AND ANNOUNCEMENTS Vol. 28(3) [May-June 2002]
All official revisions are published in Supplements to USP-NF (twice yearly). Between Supplements, official revisions are
published in PF in the Interim Revision Announcement; these revisions are also incorporated in the upcoming Supplement.
st
7 Supplement Feb. 2002 Apr. 1,2002
PF 28(2) [Mar.-Apr. 2002] Mar. 2002 Not Applicable
2nd IRA [published in PF 28(2)] Mar. 2002 Apr. 1,2002
PF 28(3) [May-June 2002*] May 2002* Not Applicable
rd
3 IRA [published in PF 28(3)] May 2002* June 1, 2002*
nd
2 Supplement June 2002* Aug. 1,2002*
PF 28(4) [July-Aug. 2002] July 2002* Not Applicable
th
4 IRA [published in PF 28(4)] July 2002* Aug. 1, 2002*
PF 28(5) [Sept.-Oct. 2002] Sept. 2002* Not Applicable
5th IRA [published in PF 28(5)] Sept. 2002* Oct. 1,2002*
PF 28(6) [Nov.-Dec. 2002] Nov. 2002* Not Applicable
th
6 IRA [published in PF 28(6)] Nov. 2002* Dec. 2, 2002*
Tentative
Pharmacopeia! Forum
Vol. 28(3) [May-June 2002] Errata 717
ADDENDA-ERRATA
Following is a list of additional errata and corrections to USP 25-NF20. The page number indicates where the item is found in USP 25-
NF 20. If necessary, this list will be updated with every issue of PF. This information will also be cumulative in the next available annual
edition or Supplement. USP staff are available to respond to questions regarding the accuracy of a particular requirement by calling 1-800-
822-USPC.
Page Title Section Description
11 USP General No- Weights and Measures Line 21: Delete "psi = pounds per'
tices and Require-
ments
264 Butabarbital Sodium Chemical name Line 2: Change "2,4,6(l//,3 H,5pH)
-Pyrimidinetrione, 5-ethyl-5-( 1 -methylpropyl)-,
monosodium salt." to: 2,4,6(l//,3 H,5H)
-Pyrimidinetrione, 5-ethyl-5-
(1-methylpropyl)-, monosodium salt.
487 Cupric Sulfate Assay Line 1: Change "Place about 650 mg of Cupric Sul-
fate in an accurately N " to: Place about 650 mg of
Cupric Sulfate in an accurately weighed container
fitted with a ground-glass stopper, dry, allow to cool
in a desiccator, and weigh again to obtain the weight
of the specimen. Dissolve in 50 mL of water, add 4
mLof6N
535 Dextran 70 Molecular weight distribution Line 5 under Procedure: Change "Chromatography
and weight and number average (621)." to: Chromatographic system.
molecular weights
585 Dimenhydrinate In- Definition Chemical formula reprinted for clarity:
jection C17H?1NOC7H7C1N4O,
587 Dimenhydrinate Assay Line 8 under Procedure: Change: "Wfiy/Ry),"
Tablets to: W{RVIRS),
1230 Nitrofurantoin Chemical structure Replace chemical structure with the following gra-
phic:
1415 Potassium Nitrate CAS number Line 3: Change "[7757-P7-7]." to:

[7757-79-1].
1502 Quinidine Gluco- Drug release Line 3 under Acceptance Table 1: Change "between
nate Extended-Re- 45% and 60%" to: between 45% and 65%
lease
Tablets
1595 Sorbitol Solution Reducing sugars Line 2: Change "test for Reducing sugars under."
to: test for Reducing sugars under Sorbitol
1750 Triamterene and Hy- Identification Line 5 under B: Change "{Standard solution 1) and
drochlorothiazide containing 1 mg of USP Hydrochlorothiazide RS
Tablets per mL of methoxyethanol {Standard solution / ) . "
to: {Standard solution 1) and containing 1 mg of
USP Hydrochlorothiazide RS per mL of methox-
yethanol {Standard solution 2).
Pharmacopeial Forum
718 Errata Vol. 28(3) [May-June 2002]
2010 (701) Disintegration Apparatus Line 10 under Basket-rack Assembly: Change ".063
+ .003 mm." to: 0.63 4- 0.03 mm
2340 Standard Buffer So- Composition of Standard Buffer Table is reprinted in its entirety on the following
lutions Solutions page for clarity:
Pharmacopeial Forum
Composition of Standard Buffer Solutions

Hydrochloric Acid Buffer
Place 50 mL of the potassium chloride solution in a 200-mL volumetric flask, add the specified volume of the hydrochloric acid solution,
then add water to volume.
pH 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2
HC1, mL 85.0 67.2 53.2 41.4 32.4 26.0 20.4 16.2 13.0 10.2 7.8
Acid Phthalate Buffer

Place 50 mL of the potassium biphthalate solution in a 200-mL volumetric flask, add the specified volume of the hydrochloric acid
solution, then add water to volume.
pH 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0
HC1, mL 49.5 42.2 35.4 28.9 22.3 15.7 10.4 6.3 2.9 0.1
Neutralized Phthalate Buffer

Place 50 mL of the potassium biphthalate solution in a 200-mL volumetric flask, add the specified volume of the sodium hydroxide
solution, then add water to volume.
pH 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8
NaOH, mL 3.0 6.6 11.1 16.5 22.6 28.8 34.1 38.8 42.3
Phosphate Buffer
Place 50 mL of the monobasic potassium phosphate solution in a 200-mL volumetric flask, add the specified volume of the sodium
hydroxide solution, then add water to volume.
pH 5.8 6.0 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6 7.8 8.0
NaOH,mL 3.6 5.6 8.1 11.6 16.4 22.4 29.1 34.7 39.1 42.2 44.5 46.1
Alkaline Borate Buffer

Place 50 mL of the boric acid and potassium chloride solution in a 200-mL volumetric flask, add the specified volume of the sodium
hydroxide solution, then add water to volume.
pH 8.0 8.2 8.4 8.6 8.8 9.0 9.2 9.4 9.6 9.8 10.0
NaOH, mL 3.9 6.0 8.6 11.8 15.8 20.8 26.4 32.1 36.9 40.6 43.7
Acetate Buffer
Place the specified amount of sodium acetate NaC2H3O2 • 3H2O in a 1000-mL volumetric flask, add the specified volume of the ace
acid solution, then add water to volume, and mix.
pH 4.1 4.3 4.5 4.7 4.9 5.1 5.2 5.3 5.4 5.5
pH (measured) 4.10 4.29 4.51 4.70 4.90 5.11 5.18 5.30 5.40 5.48
NaC2H3O2- 3H2O 1.5 1.99 2.99 3.59 4.34 5.08 5.23 5.61 5.76 5.98
CHXOOH, mL 19.5 17.7 14.0 11.8 9.1 6.3 5.8 4.4 3.8 3.0
Pharmacopeial Forum
720 Errata Vol. 28(3) [May-June 2002]

2350 Iodine, Tenth-Normal {0.1 N) Line 5: Change "add 1 mL or 1 N hydro-
chloric acid," to: add 1 mL of 1 N hydro-
chloric acid,
2526 Microcrystalline Cellulose Microbial limits Line 5: Change "for absence of Escherichia
and Salmonella species." to: for absence of
Escherichia coli and Salmonella species.
2543 Dimethicone Assay Line 10: Change "at 1259 cm-1" to:
at about 1259 cm"1
2547 Ferric Oxide Identification Line 3: Change "test for Ferric Salts under
Iron." to: test for Ferric Salts under Iron
(191).
2602 Polyoxyl 40 Stearate Identification Change "Infrared Absorption (197K)," to:
Infrared Absorption (197M),
1866 (16) Automated Methods of Analysis Content Uniformity of Under Procedure, replace "Diagram of Dis-
Nitroglycerin Tablets solution Test Method for Erythromycin
Ethylsuccinate Tablets Labeled as Chew-
able" with the following graphic:
Pharmacopeial Forum
Return to Pump
Diagram of Dissolution Test Method for Erythromycin Ethylsuccinate Tablets Labeled as Chewable
INTERIM REVISION
ANNOUNCEMENT
Symbols—Interim revisions are shown with new text (if any) enclosed in circles, *new text.. Text enclosed in squares, "new
textB, has already been adopted in a Supplement. Where the symbols appear together with no enclosed text, such as * m or • a
it means that text has been deleted and no new text was proposed to replace it. In all revisions, the closing symbol is accom-
panied by a number that indicates the IRA or Supplement in which the revision first appeared. For example, #2 indicates that
the revision was officially adopted in the Second Interim Revision Announcement, and 1 2 indicates that the revision was
officially adopted in the Second Supplement.
Pharmacopeial Forum
724 THIRD INTERIM REVISION ANNOUNCEMENT Vol. 28(3) [May-June 2002]
INTERIM REVISION ANNOUNCEMENT 725

Furosemide Oral Solution 727
Glycerin 727
Levothyroxine Sodium Tablets 727
Pharmacopeial Forum
Vol. 28(3) [May-June 2002] THIRD INTERIM REVISION ANNOUNCEMENT 725
THIRD INTERIM REVISION

ANNOUNCEMENT
to USP 25 and to NF 20


Official June 3, 2002. Released May 1, 2002.
All inquiries and comments regarding USP 25 text and NF 20 text should be addressed to the Executive Secretariat, USP-
NF, 12601 Twinbrook Parkway, Rockville, MD 20852.
Pharmacopeia! Forum
New USP Reference Standards USP Ginseng Extract RS

USP Gonadorelin Hydrochloride RS
The following USP Reference Standards, which were in- USP Homosalate RS
USP Hypericin RS
dicated in past Supplements to USP-NF as being not yet USP Hyperoside RS
available, have since become available. Thus, the official USP Ioversol RS
date of each USP 25 or NF 20 standard, test, or assay requir- USP Ioxaglic Acid RS
USP Ioxilan RS
ing the use of the following Reference Standards is indi- USP Isometheptene Mucate RS
cated individually in this list. USP Lactase RS
USP Lactitol RS
USP 5-Allyl-L-Cysteine RS (June 1, 2002) USP Menotropins RS
USP Chromium Picolinate RS (June 1, 2002) USP Meradimate RS
USP Iopromide RS (June 1, 2002) USP Ondansetron Hydrochloride RS
USP Iopromide Related Compound B RS (June 1, 2002) USP Ondansetron Related Compound A RS
USP Ioxilan Related Compound A RS (June 1, 2002) USP Ondansetron Related Compound B RS
USP Ondansetron Related Compound C RS
The official dates of any USP 25 or NF 20 standards, tests, USP Ondansetron Related Compound D RS
or assays requiring the use of the following new USP Ref- USP Oxfendazole RS
USP Poloxalene RS
erence Standards are postponed until further notice pending USP Potassium Perchlorate RS
availability of the respective Reference Standards. USP Pyrethrum Extract RS
USP Quercetin RS
USP Alfentanil Hydrochloride RS USP Rimexolone RS
USP Alteplase RS USP Sargramostim RS
USP Amiloxate RS USP Selenomethionine RS
USP Amitraz RS USP Sulfaquinoxaline RS
USP Positive Bioreaction RS USP Sulfaquinoxaline Related Compound A RS
USP Cefpiramide RS USP Sulisobenzone RS
USP Cinoxate RS USP A8-tetrahydrocannabinol RS
USP Decoquinate RS USP A9-tetrahydrocannabinol RS
USP Desflurane RS USP Thiacetarsamide RS
USP Desflurane Related Compound A RS USP Tiletamine Hydrochloride RS
USP Dextran 40 RS USP Tilmicosin RS
USP Dextran 40 System Suitability RS USP Tinidazole RS
USP Dextran 70 RS USP Tinidazole Related Compound A RS
USP Dextran 70 System Suitability RS USP Tinidazole Related Compound B RS
USP Dextran Calibration RS USP Trenbolone RS
USP Dextran V Marker RS USP Trenbolone Acetate RS
USP Dichloralpnenazone RS USP Triclosan RS
USP Diethylene Glycol Monoethyl Ether RS USP Triclosan Related Compound A RS
USP Diethylstilbestrol Diphosphate RS USP Triclosan Related Compound B RS
USP Dirithromycin RS USP Tylosin RS
USP Enalapril Related Compound B RS USP Valerenic Acid RS
USP Enzacamene RS USP Powdered Valerian RS
USP Ethchlorvynol RS USP Vasopressin RS
USP Fenbendazole RS USP Zalcitabine Related Compound A RS
USP Fludeoxyglucose RS
USP Gadopentetate Monomeglumine RS
Pharmacopeial Forum
Vol. 28(3) [May-June 2002] THIRD INTERIM REVISION ANNOUNCEMENT 727
about 2 mL per minute. Chromatograph the Standard solution, and

USP 25 MONOGRAPHS record the peak responses as directed for Procedure: the tailing fac-
tor is not more than 1.5; and the relative standard deviation is not
more than 4.0%.
the Standard solution and the Test solution into the chromatograph,
record the chromatograms, and measure the responses for the ma-
jor peaks. Calculate the amount of CjjHjQLiNNaCh dissolved.
Tolerances—Not less than 70% (Q) or the laoeled amount
Furosemide Oral Solution of C, 5 H, 0 LNNaO 4 is dissolved in 45 minutes.
*Test 2: if the product complies with this test, the labeling indi-
Change to read: cates that it meets USP Dissolution Test 2.
Medium, Apparatus, Mobile phase, Standard solution, Test
pH (791): between 7.0 and # 10.0. #3 solution, Chromatographic system, and Procedure—Proceed as
directed for Test 1.
Time: 15 minutes.
C15H10I4NNaO4 is dissolved in 15 minutes.#3
Glycerin
Change to read:
Identification— GENERAL CHAPTERS
B: "Prepare the Test solution and the Resolution solution as
directed in the test for Limit ofdiethylene glycol and related com-
pounds. Dilute a portion of each solution, stepwise if necessary,
with water to obtain the Diluted test solution and the Diluted reso-
lution solution having concentrations of about 0.1 mg per mL. Pro- General Tests and Assays
ceed as directed for Procedure in the test for Limit of diethylene
glycol and related compounds: the retention time of the glycerin
peak in the chromatogram of the Diluted test solution corresponds
to that obtained in the chromatogram of the Diluted resolution so-
lution.^ General Requirements for
Tests and Assays
Levothyroxine Sodium Tablets

(11) USP REFERENCE
STANDARDS
Add the following:
"Labeling—When more than one Dissolution test is given, the la-
beling states the Dissolution test used only if Test 1 is not used. -3 Change to read:
USP Arginine Hydrochloride RS—Dry portion at 105° for 2
Change to read: hours before using. Keep container tightly closed. "Starting with
Dissolution (711)—[NOTE—All containers that are in contact with Lot G label as: Do not dry. Keep container tightly closed.#3
solutions containing levothyroxine sodium are to be made of
glass.] Add the following:
-
Test 7:. 3 USP Carbidopa Related Compound A RS—See USP 3-O-
Medium: 0.01 N hydrochloric acid containing 0.2% sodium do- Methylcarbidopa RS. (CyH^NjC^ <> 240.26)—Do not dry. Keep
decyl sulfate; 500 mL. container tightly closed. Protect from light.#3
Time: 45 minutes. Change to read:
Determine the amount of C15H10I4NNaO4 dissolved by employ- USP Chlorpheniramine Maleate RS—Dry portion at 105° for 3
ing the following method. hours before using. Keep container tightly closed. Protect from
Mobile phase—Prepare a filtered and degassed mixture of light. 'Starting with Lot M label as: Do not dry. Keep container
methanol and 0.1% phosphoric acid (60:40). tightly closed. Protect from light. -3
Standard solution—Prepare a stock solution of USP Levothyr-
oxine RS in methanol having a known concentration of about 0.1 Change to read:
mg per mL. Dilute this stock solution with Dissolution Medium to USP L-Histidine RS—Dry portion at 105° for 3 hours before
obtain a solution having a concentration similar to that expected in using. Keep container tightly closed. "Starting with Lot G label
the Test solution. as: Do not dry before using. Keep container tightly closed.-3
Test solution—[NOTE—Prior to use, check the filters for absorp-
tive loss of drug.] Use a filtered portion of the solution under test.
Chromatographic system (see Chromatography (621))—The li-
quid chromatograph is equipped with a 225-nm detector and a 4.6-
mm x 25-cm column that contains packing LI. The flow rate is
Pharmacopeial Forum

USP 3-0-Methylcarbidopa RS (C, 1 H 16 N 2 O 4 <0> 240.26)—Do USP Rifabutin RS—Do not dry before using. Keep container
not dry. Keep container tightly closed. Protect from light. "(NAME tightly closed. "Starting with Lot G label as: Do not dry before
CHANGE) Starting with Lot H, the name is changed to USP Carbi- using. Keep container tightly closed. Store in a freezer.#3
dopa Related Compound A RS. (See USP Carbidopa Related Com-
pound A RS).92 Change to read:
USP Rimexolone RS—Dry portion in vacuum at 105° for 3 hours
Change to read: before using. "Protect from light. Keep container tightly closed.#3
USP Metoprolol Tartrate RS—Dry portion in vacuum at 60° for
4 hours before using. Keep container tightly closed. Protect from Change to read:
light. "Starting with Lot H-l label as: Keep container tightly USP Sucralose RS—Do not dry. For quantitative applications, de-
closed. Protect from light.-3 termine the water content titrimetrically at the time of use. Keep
container tightly closed. "Starting with Lot G label as: Do not
Change to read: dry. Keep container tightly closed.-3
USP 5-Nitro-2-furfuraldazine RS ("C 10 H.N 4 O 6 . 3 <> 278.18)—
Dry portion at 105° for 1 hour before using. Keep container tightly Change to read:
closed and protected from light. USP Torsemide * #3 RS—Do not dry before using. Keep container
tightly closed. "Protect from light..3
IN-PROCESS REVISION
to official status.
BRIEFING
*new text.
A
new textAUSP26
"new textB
if slated for a Supplement to USP-NF. The same symbols not set off by an extra paragraph break and enclosing text with no
increase in type size indicate recent revisions that are already official. Where the symbols appear together with no enclosed
text, such as * , or • m or AA, it means that text has been deleted and no new text was proposed to replace it. In all revisions, the
closing symbol is accompanied by an identifier that indicates the particular IRA or Supplement or indicates the USP or NF, as
the publication where the revision will appear if approved. For example, #2 indicates that the revision is proposed for the
Second Interim Revision Announcement, and B2 indicates that the proposed revision is slated for the Second Supplement, and
an
AUSP26 d ANF2I indicate that the revisions are proposed for USP 26 and NF 21, respectively.
Experts. Changes based on these Errata will appear in the next published Supplement and become official with that Supple-
ment.
Pharmacopeial Forum
730 IN-PROCESS REVISION Vol. 28(3) [May-June 2002]

Ingredients and Processes—USP 733
Alendronate Sodium [new] (1st Supp) 737
Alendronate Sodium Tablets [new] (1st Supp) 740
Amphetamine Sulfate (1st Supp) 744
Astemizole Tablets (1st Supp) 745
Bacitracin (1st Supp) 745
Benzethonium Chloride Concentrate [new] (1st Supp) 745
Benzylpenicilloyl Polylysine Concentrate (1st Supp) 746
Carbamazepine Extended-Release Tablets (1st Supp) 746
Carbidopa and Levodopa Tablets (1st Supp) 747
Cefpiramide (Is1 Supp) 747
Cyanocobalamin Co 58 Capsules (1st Supp) 748
Cycloserine Capsules (1st Supp) 750
Dextroamphetamine Sulfate (1st Supp) 751
Dimenhydrinate Injection (1st Supp) 752
Dimenhydrinate Oral Solution [new] (1st Supp) 753
Dimenhydrinate Syrup (1st Supp) 755
Dimenhydrinate Tablets (1st Supp) 756
Ferumoxides Injection [new] (1st Supp) 758
Fluorodopa F 18 Injection (1st Supp) 762
Flurbiprofen Sodium [erratum] (USP 26) 762
Ganciclovir [new] (1st Supp) 762
Glutaral Concentrate (1st Supp) 764
Glycerin (USP 26) 764
Hydrocortisone (1st Supp) 764
Hydrogen Peroxide Concentrate (1st Supp) 765
Indocyanine Green (Proposal for 4th IRA) 765
Isosorbide Concentrate (1st Supp) 766
Lactulose Concentrate [erratum] (1st Supp) 766
Lansoprazole Delayed-Release Capsules [new] (1st Supp) 766
Mafenide Acetate (1st Supp) 769
Methyldopa (1st Supp) 769
Methyldopa Tablets (1st Supp) 770
Minocycline Hydrochloride (1st Supp) 770
Misoprostol Dispersion [new] (1st Supp) 772
Moricizine Hydrochloride [errata] (USP 26) 774
Neomycin and Polymyxin B Sulfates and Pramoxine Hydrochloride Cream (l sl Supp) 774
Nifedipine Extended-Release Tablets (Proposal for 5th IRA) 775
Paroxetine Tablets [new] (USP 26) 777
Extended Phenytoin Sodium Capsules (Proposal for 5th IRA) 780
Potassium Chloride Extended-Release Tablets (Proposal for 4th IRA) (1st Supp) 783
Propofol [new] (1st Supp) 784
Sorbitol Solution (1st Supp) 787
Sulfasalazine Delayed-Release Tablets (1st Supp) 788
Thyroid (1st Supp) 789
Tobramycin Inhalation Solution [new] (1st Supp) 789
Triamterene Capsules (1st Supp) 792
Triamterene and Hydrochlorothiazide Tablets [errata] (1st Supp) 794
Crystallized Trypsin for Inhalation Solution (Proposal for 5th IRA) 794
Xylometazoline Hydrochloride Nasal Solution (1st Supp) 795
EXCIPIENTS 796
Tapioca Starch (1st Supp) 796
MONOGRAPHS (NF) 797
Horse Chestnut [new] (1st Supp) 797
Powdered Horse Chestnut [new] (1st Supp) 799
Pharmacopeial Forum
Vol. 28(3) [May-June 2002] IN-PROCESS REVISION 731
Powdered Horse Chestnut Extract [new] (1st Supp) 800

Chondroitin Sulfate Sodium [new] (1st Supp) 801
Chondroitin Sulfate Tablets [new] (1st Supp) 804
Red Clover [new] (1st Supp) 807
Powdered Red Clover [new] (1st Supp) 810
Powdered Red Clover Extract [new] (1st Supp) 811
Red Clover Tablets [new] (1st Supp) 812
Dimethicone (1 st Supp) 813
Ginger Capsules [new] (1 st Supp) 814
Powdered Kava Extract [new] (1st Supp) 815
Semisolid Kava Extract [new] (1st Supp) 817
Kava Capsules [new] (NF 21) 818
Kava Tablets [new] (NF 21) 820
a-Lipoic Acid Capsules [new] (1st Supp) 822
a-Lipoic Acid Tablets [new] (1st Supp) 824
Maltitol Solution (1 st Supp) 824
Monoethanolamine [erratum] (NF 21) 826
Monosodium Glutamate (1 st Supp) 826
Poloxamer [erratum] (NF 21) 827
Polyethylene Glycol [erratum] (NF 21) 827
Saw Palmetto Extract [new] (1st Supp) 827
Sesame Oil (1 st Supp) 832
Sorbitol (1 st Supp) 833
Noncrystallizing Sorbitol Solution (1 st Supp) 835
Starch (1 st Supp) 837
Tapioca Starch [new] (Is1 Supp) 838
Stearic Acid (1 st Supp) 839
Purified Stearic Acid (1 st Supp) 839
(11) USP Reference Standards (1 st Supp) 839
(621) Chromatography (1 st Supp) 843
(776) Optical Microscopy (1 st Supp) 847
dl-10-Camphorsulfonic Acid [erratum] (USP 26) 848
Cesium Chloride [new] (1st Supp) 849
Cyclohexylmethanol [new] (1st Supp) 849
Dicyclohexyl [new] (1st Supp) 849
l,2-Dilinoleoyl-3-oleoyl-rac-glycerol [new] (1st Supp) 849
l,2-Dilinoleoyl-3-palmitoyl-rac-glycerol [new] (1st Supp) 849
l,2-Dioleoyl-3-linoleoyl-rac-glycerol (deleted) 849
Ethylbenzene [new] (1st Supp) 850
Glucose [new] (1st Supp) 850
Hexamethylenetetramine [new] (1st Supp) 850
Hydroxy Naphthol Blue [new] (1st Supp) 850
Lanthanum Oxide [new] (1st Supp) 851
Monoethanolamine [erratum] (USP 26) 851
Ninhydrin (1 st Supp) 851
Nitric Acid, Lead-Free [new] (1st Supp) 851
l-Palmitoyl-2-oleoyl-3-linoleoyl-rac-glycerol (1 st Supp) 851
Triketohydrindene Hydrate (1 st Supp) 852
Test Solutions 852
Ninhydrin TS (1 st Supp) 852
Triketohydrindene Hydrate TS (1 st Supp) 852
Pharmacopeial Forum

Cyanocobalamin Co 58 Capsules (1 st Supp) 853
a-Lipoic Acid Capsules (1 st Supp) 853
oc-Lipoic Acid Tablets (1 st Supp) 853
Red Clover Tablets (1 st Supp) 853
Description and Relative Solubility ofUSP and NFArticles 853
Metoprolol Succinate (1 st Supp) 853
Tapioca Starch (1 st Supp) 853
Pharmacopeia! Forum
Where an article differs from the standards of strength, quality,

and purity, as determined by the application of the assays and tests
set forth for it in the Pharmacopeia, its difference shall be plainly
BRIEFING stated on its label. Where an article fails to comply in identity with
the identity prescribed in the USP, or contains an added substance
that interferes with the prescribed assays and tests, such article
General Notices and Requirements, USP 25 page 1, page shall be designated by a name that is clearly distinguishing and dif-
2711 of the First Supplement, and page 240 of PF 28(2) [Mar- ferentiating from any name recognized in the Pharmacopeia.
Apr. 2002]. To avoid confusion in determining the intent of assay Articles listed herein are official and the standards set forth in the
methods for compounded preparations, it is proposed to remove monographs apply to them only when the articles are intended or
references to the heading "Compliance assay" under Ingredients labeled for use as drugs, as nutritional or dietary supplements, or as
and Processes. medical devices and when bought, sold, or dispensed for these pur-
(CRX: C. Okeke) RTS—36443-1 An article is deemed to be recognized in this Pharmacopeia
when a monograph for the article is published in it, including its
supplements, addenda, or other interim revisions, and an official
Change to read: The following terminology is used for distinguishing the articles
for which monographs are provided: an official substance is an ac-
dient, or a pharmaceutic ingredient (see also NF 20) or a
"OFFICIAL" AND "OFFICIAL ARTICLES" component of a finished device for which the monograph title in-
cludes no indication of the nature of the finished form; an official
The word "official", as used in this Pharmacopeia or with ref- preparation is a drug product, a nutritional supplement, a dietary
erence hereto, is synonymous with "Pharmacopeial", with supplement or a finished device. It is the finished or partially fin-
"USP", and with "compendial". ished (e.g., as in the case of a sterile solid to be constituted into a
The designation "USP" in conjunction with the official title or solution for administration) preparation or product of one or more
elsewhere on the label of an article moana that tho artiolo official substances formulated for use on or for the patient or con-
sumer; an article is an item for which a monograph is provided,
indicates that a monograph is included in the USP and that whether an official substance or an official preparation.
'Products Not Marketed in the United States—Interest in the
the articleAUsW(s USP outside the United States has always existed. From time to
purports to comply with time, monographs may be adopted for articles not legally marketed
A
n11 in the United States as a service to authorities in other countries
dll
lUSP26 where USP standards are recognized and applied. Appearance of
USP standards. any such monograph does not grant any marketing rights whatso-
A ever, and the status of the article in the United States must be
Any language modifying or limiting this representation checked with the U.S. Food and Drug Administration in the event
shall be accompanied by a statement that the article is of any question. B ,
Nutritional and Other Dietary Supplements—The designation
"notUSP".AKSPAj of an official preparation containing one or more recognized nutri-
ouoh apooifio ents as "USP" or the use of the designation "USP" in conjunction
with the title of such nutritional or dietary supplement preparation
AVSP26 may be made only if the preparation meets
designation A
n11
dll
AUSP26
u o r
A.USP26 the applicable requirements contained in the individual monograph
on the label and general chapters. Any additional ingredient in such article that
A is not recognized in the Pharmacopeia and for which nutritional
m a y not andAUSP26
value is claimed shall not be represented nor imply that such ingre-
does not constitute a representation, endorsement, or incorporation dient is of USP quality or recognized by USP. If a preparation does
by the manufacturer's labeling of the informational material con- not comply with
tained in the USP monograph, nor does it constitute assurance by
USP that the article is known to comply with USP standards. An ±USP26
article may only purport to comply with a USP standard applicable requirements but contains nutrients or dietary supple-
A
or other requirements Aas . W(5 ment ingredients that are recognized in the USP, the article may
when the article is recognized in the USP. The standards apply not designate the individual nutrients or ingredients as complying
equally to articles bearing the official titles or names derived by with USP standards or being of USP quality without designating
transposition of the definitive words of official titles or transposi- on the label that the article itself does not comply with USP stan-
tion in the order of the names of two or more active ingredients in dards.
Names considered to be synonyms of the official titles may not be Change to read:
they remain separate compendia. The designation USP-NF or sim- INGREDIENTS AND PROCESSES
ilar combination may be used on the label of an article, provided
the label also bears a statement such as "Meets NF standards as Official drug products and finished devices are prepared from
published by the USP," indicating the particular compendium to ingredients that meet the requirements of the compendial mono-
which the article purports to apply. graphs for those individual ingredients for which monographs
are provided (see also NF 20). Generally, nutritional and dietary
supplements are prepared from ingredients that meet requirements
Pharmacopeial Forum
of the compendial monographs for those ingredients for which ture of Pharmacopeial preparations intended for internal or topical
monographs are provided, except that substances of acceptable use, provided that the denaturant is volatile and does not remain in
food grade quality may be utilized in the event of a difference. the finished product. A finished product that is intended for topical
Official substances are prepared according to recognized princi- application to the skin may contain specially denatured alcohol,
ples of good manufacturing practice and from ingredients comply- provided that the denaturant is either a normal ingredient or a per-
ing with specifications designed to assure that the resultant missible added substance; in either case the denaturant must be
substances meet the requirements of the compendial monographs identified on the label of the topical preparation. Where a process
(see also Foreign Substances and Impurities under Tests and As- is given in the individual monograph, the preparation so made must
says). be identical with that prepared by the given process.
Preparations for which a complete composition is given in this Added Substances—An official substance, as distinguished
Pharmacopeia, unless specifically exempted herein or in the indi- from an official preparation, contains no added substances except
vidual monograph, are to contain only the ingredients named in the where specifically permitted in the individual monograph. Where
formulas. However, there may be deviation from the specified pro- such addition is permitted, the label indicates the name(s) and
cesses or methods of compounding, though not from the ingredi- amount(s) of any added substance(s).
ents or proportions thereof, provided the finished preparation Unless otherwise specified in the individual monograph, or else-
conforms to the relevant standards laid down herein and to prepara- where in the General Notices, suitable substances such as antimi-
tions produced by following the specified process. crobial agents, bases, carriers, coatings, colors, flavors,
The tolerances specified in individual monographs and in the preservatives, stabilizers, and vehicles may be added to an official
general chapters for compounded preparations are based on those preparation to enhance its stability, usefulness, or elegance or to
attributes of quality as might be expected to characterize an article facilitate its preparation. Such substances are regarded as unsuita-
compounded from suitable bulk drug substances and ingredients in ble and are prohibited unless (a) they are harmless in the amounts
accordance with the procedures provided or under recognized prin- used, (b) they do not exceed the minimum quantity required to pro-
ciples of good pharmaceutical practice as described in this Pharma- vide their intended effect, (c) their presence does not impair the
copeia (see Pharmacy Compounding Practices (1161) bioavailability or the therapeutic efficacy or safety of the official
A
preparation, and (d) they do not interfere with the assays and tests
Pharmaceutical Compounding—Nonsterile Preparations prescribed for determining compliance with the Pharmacopeial
standards.
\795))AUSP26 Nutritional and Dietary Supplements—Unless otherwise speci-
and elsewhere. fied in the individual monograph, or elsewhere in the General No-
Monographs for preparations intended to be compounded pur- tices, consistent with applicable regulatory requirements, suitable
suant to prescription may contain assay methods, undor tho hoad added substances such as bases, carriers, coatings, colors, flavors,
ing Compliance assay Assay methods undor thio heading preservatives, and stabilizers may be added to a nutritional supple-
"Assay methods B1 ment preparation to enhance its stability, usefulness, or elegance, or
are not intended for evaluating a compounded preparation prior to to facilitate its preparation. Such added substances shall be re-
dispensing. Compliance assay garded as suitable and shall be permitted unless they interfere with
the assays and tests prescribed for determining compliance with
• Assay B1 Pharmacopeial standards.
methods are intended to serve as the official test methods in the Additional Ingredients—Additional ingredients, including exci-
event of a question or dispute as to whether or not the compounded pients, may be added to nutritional supplement preparations con-
preparation complies with official standards. taining recognized nutrients, consistent with applicable regulatory
Where a monograph on a preparation calls for an ingredient in requirements, provided that they do not interfere with the assays
an amount expressed on the dried basis, the ingredient need not be and tests prescribed for determining compliance with Pharmaco-
dried prior to use if due allowance is made for the water or other peial standards.
volatile substances present in the quantity taken. Inert Headspace Gases—The air in a container of an article for
Unless specifically exempted elsewhere in this Pharmacopeia, parenteral use may be evacuated or be replaced by carbon dioxide,
the identity, strength, quality, and purity of an official article are helium, or nitrogen, or by a mixture of these gases, which fact need
determined by the definition, physical properties, tests, assays, not be declared in the labeling.
and other specifications relating to the article, whether incorporated Colors—Added substances employed solely to impart color may
in the monograph itself, in the General Notices, or in the section be incorporated into official preparations, except those intended for
General Chapters. parenteral or ophthalmic use, in accordance with the regulations
Water—Water used as an ingredient of official preparations pertaining to the use of colors issued by the FDA provided such
meets the requirements for Purified Water, for Water for Injection, added substances are otherwise appropriate in all respects. (See
or for one of the sterile forms of water covered by a monograph in also Added Substances under Injections (1).)
this Pharmacopeia. Ointments and Suppositories—In the preparation of ointments
Potable water meeting the requirements for drinking water as set and suppositories, the proportions of the substances constituting
forth in the regulations of the U.S. Environmental Protection the base may be varied to maintain a suitable consistency under
Agency may be used in the preparation of official substances. different climatic conditions, provided the concentrations of active
Alcohol—All statements of percentages of alcohol, such as un- ingredients are not varied and the bioavailability, therapeutic effi-
der the heading Alcohol content refer to percentage, by volume, of cacy or safety of the preparation is not impaired.
C2H5OH at 15.56°. Where reference is made to "C 2 H 5 OH," the
chemical entity possessing absolute (100 percent) strength is in- Change to read:
tended.
Alcohol—Where "alcohol" is called for in formulas, tests, and
assays, the monograph article Alcohol is to be used.
Dehydrated Alcohol—Where "dehydrated alcohol" (absolute PRESERVATION, PACKAGING, STORAGE, AND LABELING
alcohol) is called for in tests and assays, the monograph article De-
hydrated Alcohol is to be used. Containers—The container is that which holds the article and is
Denatured Alcohol—Specially denatured alcohol formulas are or may be in direct contact with the article. The immediate contain-
available for use in accordance with federal statutes and regulations er is that which is in direct contact with the article at all times. The
of the Internal Revenue Service. A suitable formula of specially closure is a part of the container.
denatured alcohol may be substituted for Alcohol in the manufac-
Pharmacopeial Forum
Prior to its being filled, the container should be clean. Special Single-Dose Container (see also Containers for Injections under
precautions and cleaning procedures may be necessary to ensure Injections (1))—A single-dose container is a single-unit container
that each container is clean and that extraneous matter is not intro- for articles intended for parenteral administration only. A single-
duced into or onto the article. dose container is labeled as such. Examples of single-dose contain-
The container does not interact physically or chemically with the ers include pre-filled syringes, cartridges, fusion-sealed containers,
article placed in it so as to alter the strength, quality, or purity of the and closure-sealed containers when so labeled.
article beyond the official requirements. Unit-Dose Container—A unit-dose container is a single-unit
The Pharmacopeial requirements for the use of specified con- container for articles intended for administration by other than
tainers apply also to articles as packaged by the pharmacist or other the parenteral route as a single dose, direct from the container.
dispenser, unless otherwise indicated in the individual monograph. Unit-of-Use Container—A unit-of-use container is one that con-
Tamper-Resistant Packaging—The container or individual car- tains a specific quantity of a drug product and that is intended to be
ton of a sterile article intended for ophthalmic or otic use, except dispensed as such without further modification except for the addi-
where extemporaneously compounded for immediate dispensing tion of appropriate labeling. A unit-of-use container is labeled as
on prescription, shall be so sealed that the contents cannot be used such.
without obvious destruction of the seal. Multiple-Unit Container—A multiple-unit container is a con-
Articles intended for sale without prescription are also required tainer that permits withdrawal of successive portions of the con-
to comply with the tamper-resistant packaging and labeling re- tents without changing the strength, quality, or purity of the
quirements of the FDA where applicable. remaining portion.
Preferably, the immediate container and/or the outer container or Multiple-Dose Container (see also Containers for Injections un-
protective packaging utilized by a manufacturer or distributor for der Injections (1))—A multiple-dose container is a multiple-unit
all dosage forms that are not specifically exempt is designed so as container for articles intended for parenteral administration only.
to show evidence of any tampering with the contents. Storage Temperature and Humidity—Specific directions are
Light-Resistant Container (see Light Transmission under Con- stated in some monographs with respect to the temperatures and
tainers (661))—A light-resistant container protects the contents humidity at which Pharmacopeial articles shall be stored and dis-
from the effects of light by virtue of the specific properties of the tributed (including the shipment of articles to the consumer) when
material of which it is composed, including any coating applied to stability data indicate that storage and distribution at a lower or a
it. Alternatively, a clear and colorless or a translucent container higher temperature and a higher humidity produce undesirable re-
may be made light-resistant by means of an opaque covering, in sults. Such directions apply except where the label on an article
which case the label of the container bears a statement that the opa- states a different storage temperature on the basis of stability stu-
que covering is needed until the contents are to be used or admi- dies of that particular formulation. Where no specific storage direc-
nistered. Where it is directed to "protect from light" in an tions or limitations are provided in the individual monograph, but
individual monograph, preservation in a light-resistant container the label of an article states a storage temperature that is based on
is intended. stability studies of that particular formulation, such labeled storage
Where an article is required to be packaged in a light-resistant directions apply (see also Stability under Pharmaceutical Dosage
container, and if the container is made light-resistant by means of Forms (1151).) The conditions are defined by the following terms.
an opaque covering, a single-use, unit-dose container or mnemonic Freezer—A place in which the temperature is maintained ther-
pack for dispensing may not be removed from the outer opaque mostatically between -25° and -10° (-13° and 14 °F).
covering prior to dispensing. Cold—Any temperature not exceeding 8° (46 °F). A refrigerator
Well-Closed Container—A well-closed container protects the is a cold place in which the temperature is maintained thermosta-
contents from extraneous solids and from loss of the article under tically between 2° and 8° (36° and 46 °F).
the ordinary or customary conditions of handling, shipment, sto- Cool—Any temperature between 8° and 15° (46° and 59 °F). An
rage, and distribution. article for which storage in a cool place is directed may, alterna-
Tight Container—A tight container protects the contents from tively, be stored and distributed in a refrigerator, unless otherwise
contamination by extraneous liquids, solids, or vapors, from loss specified by the individual monograph.
of the article, and from efflorescence, deliquescence, or evapo- Room Temperature—The temperature prevailing in a working
ration under the ordinary or customary conditions of handling, area.
shipment, storage, and distribution, and is capable of tight reclo- Controlled Room Temperature—A temperature maintained ther-
sure. Where a tight container is specified, it may be replaced by mostatically that encompasses the usual and customary working
a hermetic container for a single dose of an article. environment of 20° to 25° (68° to 77 °F); that results in a mean
A gas cylinder is a metallic container designed to hold a gas un- kinetic temperature calculated to be not more than 25°; and that
der pressure. As a safety measure, for carbon dioxide, cyclopro- allows for excursions between 15° and 30° (59° and 86 °F) that
pane, helium, nitrous oxide, and oxygen, the Pin-index Safety are experienced in pharmacies, hospitals, and warehouses. Pro-
System of matched fittings is recommended for cylinders of Size vided the mean kinetic temperature remains in the allowed range,
E or smaller. transient spikes up to 40° are permitted as long as they do not ex-
NOTE—Where packaging and storage in a tight container or a ceed 24 hours. Spikes above 40° may be permitted if the manufac-
well-closed container is specified in the individual monograph, turer so instructs. Articles may be labeled for storage at "controlled
the container utilized for an article when dispensed on prescription room temperature" or at "up to 25°", or other wording based on
meets the requirements under Containers—Permeation (671). the same mean kinetic temperature. The mean kinetic temperature
Hermetic Container—A hermetic container is impervious to air is a calculated value that may be used as an isothermal storage tem-
or any other gas under the ordinary or customary conditions of perature that simulates the nonisothermal effects of storage tem-
handling, shipment, storage, and distribution. perature variations. (See also Stability under Pharmaceutical
Single-Unit Container—A single-unit container is one that is de- Dosage Forms (1151).)
signed to hold a quantity of drug product intended for administra- An article for which storage at Controlled room temperature is
tion as a single dose or a single finished device intended for use directed may, alternatively, be stored and distributed in a cool
promptly after the container is opened. Preferably, the immediate place, unless otherwise specified in the individual monograph or
container and/or the outer container or protective packaging shall on the label.
be so designed as to show evidence of any tampering with the con-
tents. Each single-unit container shall be labeled to indicate the
identity, quantity and/or strength, name of the manufacturer, lot
number, and expiration date of the article.
Pharmacopeial Forum
Warm—Any temperature between 30° and 40° (86° and 104 °F). Labeling of Salts of Drugs—It is an established principle that
Excessive Heat—Any temperature above 40° (104 °F). Pharmacopeial articles shall have only one official name. For pur-
Protection from Freezing—Where, in addition to the risk of poses of saving space on labels, and because chemical symbols for
breakage of the container, freezing subjects an article to loss of the most common inorganic salts of drugs are well known to prac-
strength or potency, or to destructive alteration of its characteris- titioners as synonymous with the written forms, the following al-
tics, the container label bears an appropriate instruction to protect ternatives are permitted in labeling official articles that are salts:
the article from freezing. HC1 for hydrochloride; HBr for hydrobromide; Na for sodium;
'Dry Place—The term "dry place" denotes a place that does not and K for potassium. The symbols Na and K are intended for
exceed 40% average relative humidity at Controlled Room Tem- use in abbreviating names of the salts of organic acids; but these
perature or the equivalent water vapor pressure at other tempera- symbols are not used where the word Sodium or Potassium appears
tures. The determination may be made by direct measurement at at the beginning of an official title (e.g., Phenobarbital Na is accep-
the place or may be based on reported climatic conditions. Deter- table, but Na Salicylate is not to be written).
mination is based on not less than 12 equally spaced measurements Labeling Vitamin-Containing Products—The vitamin content of
that encompass either a season, a year, or, where recorded data dean official drug product shall be stated on the label in metric units
monstrate, the storage period of the article. There may be values of per dosage unit. The amounts of vitamins A, D, and E may be sta-
up to 45% relative humidity provided that the average value is 40% ted also in USP Units. Quantities of vitamin A declared in metric
relative humidity. units refer to the equivalent amounts of retinol (vitamin A alcohol).
Storage in a container validated to protect the article from moist- The label of a nutritional supplement shall bear an identifying lot
ure vapor, including storage in bulk, is considered a dry place. B , number, control number, or batch number.
Storage under Nonspecific Conditions—For articles, regard- Labeling Parenteral and Topical Preparations—The label of a
less of quantity, where no specific storage directions or limitations preparation intended for parenteral or topical use states the names
are provided in the individual monograph, it is to be understood of all added substances (see Added Substances in these General
that conditions of storage and distribution include protection from Notices, and see Labeling under Injections (1)), and, in the case
moisture, freezing, and excessive heat. of parenteral preparations, also their amounts or proportions, ex-
Labeling—The term "labeling" designates all labels and other cept that for substances added for adjustment of pH or to achieve
written, printed, or graphic matter upon an immediate container of isotonicity, the label may indicate only their presence and the rea-
an article or upon, or in, any package or wrapper in which it is en- son for their addition.
closed, except any outer shipping container. The term "label" des- Labeling Electrolytes—The concentration and dosage of electro-
ignates that part of the labeling upon the immediate container. lytes for replacement therapy (e.g., sodium chloride or potassium
A shipping container containing a single article, unless such chloride) shall be stated on the label in milliequivalents (mEq). The
container is also essentially the immediate container or the outside label of the product shall indicate also the quantity of ingredient(s)
of the consumer package, is labeled with a minimum of product in terms of weight or percentage concentration.
identification (except for controlled articles), lot number, expira- Labeling Alcohol—The content of alcohol in a liquid preparation
tion date, and conditions for storage and distribution. shall be stated on the label as a percentage (v/v) of C2HÔH.
Articles in this Pharmacopeia are subject to compliance with Special Capsules and Tablets—The label of any form of Capsule
such labeling requirements as may be promulgated by governmen- or Tablet intended for administration other than by swallowing in-
tal bodies in addition to the Pharmacopeial requirements set forth tact bears a prominent indication of the manner in which it is to be
for the articles. used.
Amount of Ingredient per Dosage Unit—The strength of a drug Expiration Date and Beyond-Use Date—The label of an official
product is expressed on the container label in terms of micrograms drug product, nutritional or dietary supplement product shall bear
or milligrams or grams or percentage of the therapeutically active an expiration date. All articles shall display the expiration date so
moiety or drug substance, whichever form is used in the title, un- that it can be read by an ordinary individual under customary con-
less otherwise indicated in an individual monograph. Both the ac- ditions of purchase and use. The expiration date shall be promi-
tive moiety and drug substance names and their equivalent nently displayed in high contrast to the background or sharply
amounts are then provided in the labeling. embossed, and easily understood (e.g., "EXP 6/89," "Exp. June
Pharmacopeial articles in capsule, tablet, or other unit dosage 89," "Expires 6/89"). [NOTE—For additional information and gui-
form shall be labeled to express the quantity of each active ingre- dance, refer to the Nonprescription Drug Manufacturers Associa-
dient or recognized nutrient contained in each such unit; except tion's Voluntary Codes and Guidelines of the OTC Medicines
that, in the case of unit-dose oral solutions or suspensions, whether Industry.]
supplied as liquid preparations or as liquid preparations that are The monographs for some preparations state how the expiration
constituted from solids upon addition of a designated volume of date that shall appear on the label is to be determined. In the ab-
a specific diluent, the label shall express the quantity of each active sence of a specific requirement in the individual monograph for a
ingredient or recognized nutrient delivered under the conditions drug product or nutritional supplement, the label shall bear an ex-
prescribed in Deliverable Volume (698). Pharmacopeial drug piration date assigned for the particular formulation and package of
products not in unit dosage form shall be labeled to express the the article, with the following exception: the label need not show
quantity of each active ingredient in each milliliter or in each gram, an expiration date in the case of a drug product or nutritional sup-
or to express the percentage of each such ingredient (see Percen- plement packaged in a container that is intended for sale without
tage Measurements), except that oral liquids or solids intended to prescription and the labeling of which states no dosage limitations,
be constituted to yield oral liquids may, alternatively, be labeled in and which is stable for not less than 3 years when stored under the
terms of each 5-milliliter portion of the liquid or resulting liquid. prescribed conditions.
Unless otherwise indicated in a monograph or chapter, such de- Where an official article is required to bear an expiration date,
clarations of strength or quantity shall be stated only in metric units such article shall be dispensed solely in, or from, a container la-
(see also Units of Potency in these General Notices). beled with an expiration date, and the date on which the article
Use of Leading and Terminal Zeros—In order to help minimize is dispensed shall be within the labeled expiry period. The expira-
the possibility of errors in the dispensing and administration of tion date identifies the time during which the article may be ex-
drugs, the quantity of active ingredient when expressed in whole pected to meet the requirements of the Pharmacopeial
numbers shall be shown without a decimal point that is followed by monograph provided it is kept under the prescribed storage condi-
a terminal zero (e.g., express as 4 mg [not 4.0 mg]). The quantity of tions. The expiration date limits the time during which the article
active ingredient when expressed as a decimal number smaller than may be dispensed or used. Where an expiration date is stated only
one shall be shown with a zero preceding the decimal point (e.g., in terms of the month and the year, it is a representation that the
express as 0.2 mg [not .2 mg]). intended expiration date is the last day of the stated month. The
Pharmacopeial Forum
beyond-use date is the date after which an article must not be used. *Pharmaceutical Compounding—Nonsterile Preparations
The dispenser shall place on the label of the prescription container
a suitable beyond-use date to limit the patient's use of the article
based on any information supplied by the manufacturer and the
General Notices and Requirements of this pharmacopeia. The be-
yond-use date placed on the label shall not be later than the expira-
tion date on the manufacturer's container.
For articles requiring constitution prior to use, a suitable be-
yond-use date for the constituted product shall be identified in
the labeling. MONOGRAPHS (USP)
For all other dosage forms, in determining an appropriate period
of time during which a prescription drug may be retained by a pa-
tient after its dispensing, the dispenser shall take into account, in
addition to any other relevant factors, the nature of the drug; the
container in which it was packaged by the manufacturer and the
expiration date thereon; the characteristics of the patient's contain-
er, if the article is repackaged for dispensing; the expected storage BRIEFING
conditions to which the article may be exposed; any unusual sto-
rage conditions to which the article may be exposed; and the ex-
pected length of time of the course of therapy. The dispenser shall, Alendronate Sodium, page 2688 of PF 27(4) [July-Aug.
on taking into account the foregoing, place on the label of a multi- 2001]. The previously proposed derivatization procedure in the test
ple-unit container a suitable beyond-use date to limit the patient's for Chromatographic purity is being revised to reflect the appro-
use of the article. Unless otherwise specified in the individual priate order in which the reagents are being added. More precise
monograph, or in the absence of stability data to the contrary, such figures for flow rates are being proposed in the test for Chromato-
beyond-use date shall be not later than (a) the expiration date on the graphic purity and in the Assay, Other changes are editorial.
manufacturer's container, or (b) one year from the date the drug is
dispensed, whichever is earlier. For nonsterile solid and liquid do- (PA4: A. Medjedovic) RTS—35821-1
sage forms that are packaged in single-unit and unit-dose contain-
ers, the beyond-use date shall be one year or loss,
A
from the date the drug is packaged into the single-unit or Add the following:
unit-dose container or the expiration date on the manufac-
turer's container, whichever is earlier, j>USp26 •Alendronate Sodium
unless stability data or the manufacturer's labeling indicates other-
wise. For all other typoo of nonatorilo dosage- forma, the beyond (Chemical structure to come)
uao dato ia ono year or tho time remaining of tho oxpiration dato,
whichever ia loss: C4H12NNa07P2 • 3H2O 325.13 325.12
•
A.USP26
Phosphonic acid, (4-amino-l-hydroxybutylidene)bis-,
The dispenser must maintain the facility where the dosage forms
are packaged and stored, at a temperature such that the mean ki- monosodium salt, trihydrate.
netic temperature is not greater than 25°. The plastic material used
in packaging the dosage forms must afford better protection than Sodium trihydrogen (4-amino-l-hydroxybutylidene)dipho-
polyvinyl chloride, which does not provide adequate protection
against moisture permeation. Records must be kept of the tempera- sphonate, trihydrate [121268-17-5].
ture of the facility where the dosage forms are stored, and of the
plastic materials used in packaging.
Pharmacy
^PharmaceuticalAUSP26
Compounding—The label on the container or package of an offi-
cial compounded preparation shall bear a beyond-use date. The be- » Alendronate Sodium contains not less than
yond-use date is the date after which a compounded preparation is
not to be used. Because compounded preparations are intended for 98.0 percent and not more than 101.0 102.0 per-
administration immediately or following short-term storage, their
beyond-use dates may be assigned based on criteria different from cent of C4Hi2NNa07P2 • 3H2O.
those applied to assigning expiration dates to manufactured drug
products.
The monograph for an official compounded preparation typi- Packaging and storage—Preserve in well-closed contain-
cally includes a beyond-use requirement that states the time period
following the date of compounding during which the preparation, ers.
properly stored, is to be used. In the absence of stability informa-
tion that is applicable to a specific drug and preparation, recom- USP Reference standards (11)—USP Alendronate Sodium
mendations for maximum beyond-use dates have been devised
for nonsterile compounded drug preparations that are packaged RS.
in tight, light-resistant containers and stored at controlled room
temperature unless otherwise indicated (see Stability Criteria and
Beyond-Use Dating under Stability of Compounded Preparations
in the general tests chapter Pharmacy Compounding ( )
Pharmacopeial Forum
Identification— Mobile phase—Use variable mixtures of Solution A and

A: Infrared Absorption (197M). Solution B as directed for Chromatographic system. Make
B: It meets the requirements of the flame test for So- adjustments if necessary (see System Suitability under
dium (191). Chromatography (621)).
Loss on drying (731)—Dry it at a pressure not exceeding 5 Standard stock solution—Transfer about 30 mg of USP
mm of mercury at 140° to constant weight: it loses not less Alcndronatc Sodium RS, accurately weighed, to a 50 mL
than 16.1% and not more than 17.1% of its weight. volumetric flaok, dissolve in and dilute with Diluent to vol
umo, and mix. Prepare a solution of USP Alendronate So-
Heavy metals, Method III (231): 0.001%.
dium RS in Diluent having a known concentration of
about 0.6 mg per mL.
Buffer solution—Transfer 5.88 g of sodium citrate dihy-
Standard solution—Transfer 5.0 mL of the Standard stock
drate and 2.84 g of anhydrous dibasic sodium phosphate
solution to a 50-mL polypropylene screw-cap centrifuge
to a 2-liter volumetric flask, dilute with water to volume,
tube containing 5 mL of Borate solution. a»4 Add 5 mL
and mix. Adjust with phosphoric acid to a pH of 8.0, and
of acetonitrile . Add and 5 mL of 9-Fluorenylmethyl chlor-
pass the solution through a filter having a 0.5-um or finer
oformate solution, and shake for 45 seconds. Allow to stand
porosity.
at room temperature for 30 minutes. Add 20 mL of methyl-
9-Fluorenylmethyl chloroformate solution—Transfer 200
ene chloride, and shake for 1 minute. Centrifuge for 5 to 10
mg of 9-fluorenylmethyl chloroformate to a 50-mL volu-
minutes, and use a portion of the clear upper aqueous layer.
metric flask, dilute with acetonitrile to volume, and mix.
Diluted standard solution—Dilute a portion of Standard
Prepare fresh just prior to use. [NOTE—This solution con-
stock solution with Diluent to obtain a solution having a
tains about 4 mg of 9-fluorenylmethyl chloroformate per
known concentration of about 0.6 ug per mL. Using 5 mL
mL.]
of this solution, proceed as directed for Standard solution,
Borate solution—Dissolve 19.1 g of sodium borate in
beginning with "to a 50-mL polypropylene screw-cap cen-
water in a 1-liter volumetric flask, dilute with water to vol-
trifuge tube."
ume, and mix.
Reagent blank—Using a 5.0-mL portion of Diluent, pro-
Diluent—Dissolve 29.4 g of sodium citrate dihydrate in
ceed as directed for Standard solution, beginning with "to a
50-mL polypropylene screw-cap centrifuge tube."
ume, and mix.
Test solution—Transfer about 30 mg of Alendronate So-
Solution A—Prepare a filtered and degassed mixture con-
dium, accurately weighed, to a 50-mL volumetric flask, dis-
taining 1700 mL of Buffer solution and 300 mL of acetoni-
solve in and dilute with Diluent to volume, and mix. Using a
trile.
5.0-mL volume of this solution, proceed as directed for
Solution B—Prepare a filtered and degassed mixture con-
Standard solution, beginning with "to a 50-mL polypropy-
taining 300 mL of Buffer solution and 700 mL of acetoni-
lene screw-cap centrifuge tube."
trile.
tor and a 4.1-mm x 25-cm column that contains 10-um
Pharmacopeial Forum
packing L21. The flow rate is about 2 1.8 mL per minute. Assay—
The column temperature is maintained at about 45°. The Buffer solution—Transfer 14.7 g of sodium citrate dihy-
chromatograph is programmed as follows. drate and 7.05 g of anhydrous dibasic sodium phosphate
to a 1-liter volumetric flask, dilute with water to volume,
mix, and adjust with phosphoric acid to a pH of 8.0.
Diluent—Dissolve 29.4 g of sodium citrate dihydrate in
ume, and mix.
Borate solution—Dissolve 19.1 g of sodium borate in
15-25 50-+0 50-»100 linear gradient
ume, and mix.
9-Fluorenylmethyl chloroformate solution—Transfer 25
mg of 9-fluorenylmethyl chloroformate to a 50-mL volu-
Chromatograph the Standard solution and the Diluted metric flask, dilute with acetonitrile to volume, and mix.
standard solution, and record the peak responses as directed Prepare fresh just prior to use. [NOTE—This solution con-
for Procedure: the tailing factor for the principal peak in the tains about 0.5 mg of 9-fluorenylmethyl chloroformate per
chromatogram of the Standard solution is not more than 2.0; mL.]
and the peak at that locus in the chromatogram of the Di- Mobile phase—Prepare a filtered and degassed mixture of
luted standard solution is detectable with a signal-to-noise Buffer solution, acetonitrile, and methanol (70:25:5). Make
ratio of not less than 3. adjustments if necessary (see System Suitability under
Procedure—Separately inject equal volumes (about 20 Chromatography (621)).
uL) of the Test solution and the Reagent blank into the chro- Standard preparation—Transfer about 25 mg of USP
matograph, record the chromatograms, and measure the re- Alondronato Sodium RS, aoeuratoly weighed, to a 250 mL
sponses for all the peaks. Calculate the percentage of each volumetric? flask, dissolve? in-and dilute with Diluent to vol
impurity in the portion of Alendronate Sodium taken by the umo, and mix. Prepare a solution of USP Alendronate So-
formula: dium RS in Diluent having a known concentration of

about 0.1 mg per mL. Transfer 5.0 mL of this solution to
a 50-mL polypropylene screw-cap centrifuge tube contain-
in which r, is the response of each peak, other than the prin- ing 5.0 mL of Borate solution. Add 5.0 mL of 9-Fluorenyl-
cipal peak and peaks corresponding in retention time to any methyl chloroformate solution, and shake for 30 seconds.
observed in the chromatogram obtained from the Reagent Allow to stand at room temperature for 25 minutes. Add
blank; and rs is the sum of all impurity peaks and the prin- 25 mL of methylene chloride, and shake for 1 minute. Cen-
cipal peak: not more than 0.1% of any individual impurity is trifuge for 5 to 10 minutes. Use a portion of the clear upper
found; and not more than 0.5% total impurities is found. aqueous layer.
Pharmacopeial Forum
Reagent blank—Using 5 mL of Diluent, proceed as direc-

BRIEFING
ted for Standard preparation, beginning with "to a 50-mL
Alendronate Sodium Tablets, page 33 of PF 28(1) [Jan.-Feb.
polypropylene screw-cap centrifuge tube." 2002]. It is proposed to change the title of this proposed new mono-
graph to Alendronic Acid Tablets. This monograph title is pro-
Assay preparation—Using about 25 mg of Alendronate posed by the Expert Committee on Nomenclature and Labeling
to be in conformance with USP policy. A previous USP Nomen-
Sodium, accurately weighed, proceed as directed for Stan- clature Committee adopted a policy to name the active moiety in
the title if the strength is expressed in terms of the active moiety,
dard preparation. and name the derivative in the title if the strength is expressed in
terms of the derivative. The nomenclature thus proposed for this
Chromatographic system (see Chromatography (621))— proposed monograph is changed from naming the drug ingredient
as the salt to naming the active moiety to be consistent with policy.
The liquid chromatograph is equipped with a 266-nm detec- The Expert Committee on Pharmaceutical Analysis 4 is propos-
ing a new liquid chromatographic method in the tests for Dissolu-
tor and a 4.1-mm x 25-cm column that contains 10-um tion and Uniformity of dosage units and in the Assay. This method
is simpler than the currently proposed precolumn derivatization
packing L21. The flow rate is about 4-1.2 mL per minute. method, and it does not require use of organic solvents in the Mo-
bile phase. A test for Limit of phosphate is being proposed, and it
The column temperature is maintained at about 35°. Chro- employs the same new liquid chromatographic method. The new
liquid chromatographic method is based on analyses performed
matograph the Standard preparation, and record the peak with the 10-um Hamilton PRP-X100 brand of L53 column. The
typical retention times for alendronate and phosphate are about
responses as directed for Procedure: the column efficiency 3.1 minutes and 4.1 minutes, respectively.
is not less than 1500 theoretical plates; the tailing factor is
(NL:C. Barnstein; PA4: A. Medjedovic) RTS—34280-1;
not more than 1.5; and the relative standard deviation for 36758-1
replicate injections is not more than 1.0% 2.0%.

Procedure—Separately inject equal volumes (about 10 Add the following:
uL) of the Standard preparation, Assay preparation, and "Alendronate Sodium Tablets
Reagent blank into the chromatograph, record the chroma- Alendronic Acid Tablets
tograms, and measure the responses for the major peaks.
Calculate the quantity, in mg, of C4Hi2NNa07P2 • 3H2O in
the portion of Alendronate Sodium taken by the formula:
» Alondronato Sodium Tablets contain Alendronic
Acid Tablets contain an amount of Alendronate
Sodium, equivalent to not less than 90.0 percent
in which W is the weight, in mg, of USP Alendronate So-
and not more than 110.0 percent of the labeled
dium RS taken to prepare the Standard preparation; and
amount of alondronato—sodium
rv and rs are the peak responses for alendronic acid obtained
alendronic acid
respectively. B1
(C 4 H 13 NO 7 P 2 ).

USP Reference standards (11)—USP Alendronate Sodium
RS.
Pharmacopeial Forum
Identification—The retention time of the major peak in the lutionbuffer, and mix for about 3 minutes. Add 3.0 mL of
chromatogram of the Assay preparation corresponds to that 0.05% 9 Fluorcnylmcthyl chloroformatc solution, and agi
in the chromatogram of the Standard preparation, as ob- tato for about 30 sooonds. Allow tho solution to stand at
tained in the Assay. room temperature for 25 minutes. Add 25 mL of mothylono
Dissolution (711)— chloride; and agitato for about 40 sooonds. Centrifuge tho
Medium: water; 900 mL. mixture for10 minutos. Uso a portion of tho oloar upper
Apparatus 2: 50 rpm. aqueous layor.
Time: 50 15 minutes. Reagent blank Using 5 mL of watery proceed as direoted
Determine tho amount of C^^NNaeXjV-l&laO dissolved for Standard solution^ beginning with "to a 50 mL polypro
by employing the following method; pylono sorow oap centrifuge tube."
Buffer solution and Mobile phase—Prepare as dirootod in Test solution—After 30 minutos, withdraw a portion of
tho Assay. the solution undor tost, and filter immodiatoly. Using 5.0
0.05% 9Fluorcnylmcthyl chloroformatc solution— mL of tho filtrate, proceed as dirootod for Standard solution,
Transfer 100 mg of 9 fluoronylmothyl ohloroformato to a beginning with "to a 50 mL polypropylene sorow cap cen-
200 mL volumetric flask, dilute with aootonitrilo to volume, trifuge tube."
and mix. This solution must bo freshly prepared. Chwmatographic system (sec Chromatography (634-))—-
Boratc solution—Transfer 38.1 g of sodium borato to a 1 Prepare as dirootod in tho Assay. Chromatograph the Stan-
liter volumetric flask, dissolve in and dilute with water to dard solution, and rooord tho peak responses a3 dircotod
volume, and mix. for Pmccdurc: the capacity factor, U, is not less than 2.0;
Borate buffer—Dissolve 6.2 g of borio aoid in approx tho column offioionoy is not loss than 1500 theoretical
imatoly 950 mL of water, adjust with 1 N sodium hydroxide plates; the tailing factor is not more than 1.5; and tho relative
to a pH of 9.0, and dilute with water to 1 liter. standard deviation for roplioatc injootionsis not more than
n no/
Diluent—Transfer 176.4 g of sodium oitrato dihydrato to a
1000 mL volumetric flask, dissolve in and dilute with Dis- Procedure—Separately injoot equal volumes (about 50
solution Medium to volume, and mix. uL) of tho Standard solution, tho Test solution, and tho Re
Standai«d stock solution—Dissolve an accurately weighed agent blank into tho ohromatograph, rooord tho ohromato-
quantity of US? Alondronato Sodium RS in Dissolution grams, and measure tho responses for tho major peaks.
Medium, and dilute quantitatively and stopwiso with tho Calculate tho quantity, in mg, of alondronato sodium
same solvent to obtain a solution having a known oonoon V"3ttsO) dissolved by the formula:
tration corresponding to tho oonoontration that would be ob

tainod by dissolving one Tablet in 900 mL of the same
in whioh C is tho oonoontration, in ug por mL, of USP Alon •
dronate Sodium RS in the Standard stock solution; and. ru
Standard solution—Transfer 5.0 mL of tho Standai*d stock
and rg are tho peak responses obtained from tho Test solution
solution to a 50 mL polypropylene sorow oap centrifuge
and tho Standard solution, rospootivoly.
tube containing 1.0 mL of Diluent and 5.0 mL of Boratc so-
Pharmacopeial Forum
Procedure—Determine the amount of C4H13NO7P2 dis- Buffer solution—Transfer 14.7 g of aodium oitrato dihy
solved, by employing the procedure set forth in the Assay, drato and 7.05 g of anhydroua dibasio sodium phosphate
except to make any necessary volumetric adjustment and to to a1000 mL volume-trio flask, dissolve in about 900 mL
use 200-uL injection volumes. of water, adjust with phosphoric acid to a pH of 8.0, dilute
Tolerances—-Not less than 80% (Q) of the labeled amount with water to volume, and mix.
of G 4 H w >Wa0^ y -3« a O-alendronic acid (C4H13NO7P2) is 0.1% 9 Fluownylmcthyl chloroformatc solution Trano
dissolved in 30 minutes 15 minutes. for 250 mg of 9 fluoronylmothyl ohloroformate to a 250
Uniformity of dosage units (905): meet the requirements. mL volume-trio flask, dilute with aootonitrilo to volume,
and mix. Prepare this solution fresh just prior to use.
Limit of phosphate—
Mobile phase, System suitability solution, and Boratc solution—Transfer 38.1 g of sodium borato to a
Chromatographic system—Proceed as directed inthe Assay.100 mL volumetric flask, dissolve in and dilute with water
Test solution—Weigh and finely powder not fewer than 20 to volume, and mix. Prepare a 0.1 M sodium borato solution.
Tablets. Transfer an accurately weighed portion of the pow- Mobile phase—Prepare a filtered and dogassod mixture of
der, equivalent to about 100 mg of alendronic acid, to a 50- Buffer solution, aootonitrilo, and mothanol (75:20:5). Mako
mL volumetric flask, dissolve in HPLC grade water, soni- adjustments if necessary (soo System Suitability under
cate for 30 minutes, and shake for 10 minutes. Dilute with Chromatography (€5A-)}r
HPLC grade water to volume, and mix. Pass a portion of Standard stock preparation—Transfer about 25 mg of
this solution through a filter having a 0.45-um or finer po- USP Alondronato Sodium RS, accurately weighed, to a
rosity, and use the filtrate. 1000 mL volumetric flask, dissolve in and dilute with Dil
Procedure—Inject a volume (about 100 uL) of the Test ucnt to volume; and mix:
solution into the chromatograph, record the chromatogram, Standard preparation—Transfer 5.0 mL of tho Standard
and measure all of the peak responses. Calculate the percen- stockpwparation to a 50 mL polypropylene scrow oap oon
tage of phosphate in the portion of Tablets taken by the for- trifugo tubo containing 5 mL of Boratc solution, and mix for
mula: about 3 minutos. Add 1 mL of 0.1% 9 Fluorcnylmcthyl

chlowformatc solution, and agitato for about 30 seconds.
lOOfo/r,),
Allow tho solution to stand at room tomporaturo for 25 min
in which r, is the phosphate peak response, and rs is the sum utos: Add 25 mL of mothylono chlorido, and agitato for
of the responses of all the peaks: not more than 0.1% is about 40 30oonds. Centrifuge tho mixture for 10 minutos.
found. Uso tho oloar upper aquoous layer.
Assay— Assay preparation—Woigh and finely powdor not fowor
Diluent—Transfer 29.4 g of sodium oitrato dihydrato to a than 20 Tablets: Transfer an accurately weighed portion of
1000 mL volumctrioflaolc,disgolvo in and dilute with water tho powdor, equivalent to about 25 mg of alondronato so
to volume, and mix. dium, to a 1000 mL volumctrio flask, dilute with Diluent
to volumo, and mix. Stir with tho aid of a magnetic stirrcr
for 30 minutos. Contrifugo a portion of this solution for
about 20 minutos .Using 5.0 mL of tho solution so obtained,
Pharmacopeial Forum
proceed as dirootod for Standard preparation, beginning Standard preparation—Prepare a solution of USP Alen-
with "to a 50 mL polypropylene sorow oap oontrifugo dronate Sodium RS in HPLC grade water having a known
concentration of about 0.52 mg of alendronate sodium trihy-
Reagent blank—Uoing 5 mL of Diluent,prooood ao diroo drate per mL.
ted for Standard preparation, beginning with "to a 50 mL Assay preparation—Weigh and finely powder not fewer
polypropylene aorow oap oontrifugo tube." than 20 Tablets. Transfer an accurately weighed portion of
Chwmatographic system (ace Chromatography(6£4-))— the powder, equivalent to about 100 mg of alendronic acid,
The liquid ohromatograph is equipped with a 266 nm detoo to a 250-mL volumetric flask, dissolve in HPLC grade
tor and a <1.1 mm x 25 om oolumn that oontaino 10 urn water, sonicate for 30 minutes, and shake for 10 minutes.
packing L21. The column is maintained at a oonotant torn Dilute with HPLC grade water to volume, and mix. Pass a
porature-of about 35°. The flow rate io about 1 mL per min portion of this solution through a filter having a 0.45-mm or
uto. Chromatograph the Standard preparation, and record finer porosity, and use the filtrate.
the peak responses as directed for Procedure: the capacity Chromatographic system (see Chromatography (621))—
factor, K, io not leas than 2.0; the column efficiency io not The liquid chromatograph is equipped with a 240-nm detec-
loos than 1500 thoorotioal plates; the tailing faotor io not tor and a 4.1-mm x 25-cm column that contains packing
more than 1.5; and the relative standard deviation for ropli L53. The flow rate is about 1.6 mL per minute. Chromato-
cato injections io not more than 2.0%. graph the System suitability solution, and record the peak
Procedure—Separately injoot equal volumes (about 50 responses as directed for Procedure: the resolution, R, be-
uL) ofthe Standard preparation, Assay preparation, and tween alendronate and phosphate is not less than 2.0; the
the Reagent blank into the ohromatograph, record the ohro tailing factor is not more than 1.5; and the relative standard
matograms, and moaouro the responses for the major poaka. deviation for replicate injections is not more than 2.0%.
Caloulato the quantity, in mg, of alondronato oodium Procedure—Separately inject equal volumes (about 100
(G4ftttNNaOâ—SHaO), in the portion of Tablcto taken by uL) of the Standard preparation and the Assay preparation
the formula: into the chromatograph, record the chromatograms, and
measure the responses for the major peaks. Calculate the
quantity, in mg, of alendronic acid (C4H13NO7P2) in the por-
in which W io the weight, in mg, of USP Alondronato So
tion of Tablets taken by the formula:
dium RS taken to prepare the Standard stock preparation;
250(249.10/325.12)C(r{/ lrs),
and ru and rg are the peak rosponaoo obtained from the Assay
preparation and the Standard preparation, respectively: in which 249.10 and 325.12 are the molecular weights of
Mobile phase—Prepare a 7.2 mM solution of nitric acid in alendronic acid and alendronate sodium trihydrate, respec-
HPLC grade water. tively; C is the concentration, in mg per mL, of alendronate
System suitability solution—Prepare a solution of USP sodium trihydrate in the Standard preparation; and rv and rs
Alendronate Sodium RS and sodium biphosphate in HPLC are the peak responses obtained from the Assay preparation
grade water containing 0.2 mg per mL and 0.1 mg per mL, and the Standard preparation, respectively.B1
respectively.
Pharmacopeial Forum

BRIEFING
Amphetamine Sulfate, USP 25 page 137 and page 2518 of PF
27(3) [May-June 2001]; Dextroamphetamine Sulfate, USP 25 packing LI. The flow rate is about 1 mL per minute. Chro-
page 536 and page 2533 PF 27(3) [May-June 2001]. In the test
for Chromatographic purity, it is proposed to (1) modify the sys- matograph the Standard stock solution, and record the peak
tem suitability parameters to better reflect the actual values ob-
tained in the validation of the method and (2) revise the responses as directed for Procedure: the tailing factor is not
concentration of the Standard solution and the formula used for
the calculation in the Procedure. more than 3^ 2.0; and the relative standard deviation for re-
(PA3: S. Salado) RTS—36060-1 plicate injections is not more than 2.0%. Chromatograph the
Test Solution, as directed for Procedure: the resolution, R,
between the amphetamine peak and any adjacent peak, if
Add the following:
any, is not less than 1.5.
•Chromatographic purity—
Diluent—Dilute 3.12 mL of phosphoric acid with water to
1000 mL.
Buffer solution—Dissolve 2.16 g of sodium 1-octanesul-
peak responses. Calculate the percentage of each impurity in
fonate in 1000 mL of water, and add 1.0 mL of 0.1 % triethy-
the portion of Amphetamine Sulfate taken by the formula:
lamine solution (v/v). Mix, and adjust with phosphoric acid
to apH of 2.5.
Buffer solution, acetonitrile, and methanol (144:37:19). /rs),
Make adjustments if necessary (see System Suitability under in which C is the concentration, in mg per mL, of USP Dex-
Chromatography (621)). troamphetamine Sulfate RS in the Standard solution; W is
Standard stock solution—Dissolve an accurately weighed the weight, in mg, of Amphetamine Sulfate taken to prepare
quantity of USP Dextroamphetamine Sulfate RS in Diluent the Test solution; r, is the peak response for each impurity
to obtain a solution having a known concentration of about obtained from the Test solution; and rs is the peak response
0.3 mg per mL. for amphetamine obtained from the Standard solution: not
Standard solution—Dilute an accurately measured vol- more than 0.1% of any individual impurity is found; and not
ume of Standard stock solution in Diluent to obtain a solu- more than 0.5% of total impurities is found.B1
tion having a known concentration of about ©:03- 0.003 mg Delete the following:
per mL. 'Ordinary impurities (464)—
Test solution: mothanol.
Test solution—Transfer about 30 mg of Amphetamine Standard solution: mothanol.
Eluant: a mixture of mothanol and ammonium hydroxide (50:1).
Sulfate, accurately weighed, to a 100-mL volumetric flask. Visualisation: 1.,,
Dissolve in 50 mL of Diluent, sonicate for 5 minutes, dilute

with Diluent to volume, and mix.
Pharmacopeial Forum
oping chamber, mark the solvent front, and allow the solvent to
BRIEFING evaporate. Locate the spots by spraying the plate lightly with a 1
in 100 solution of trikotohydrindono hydrate
Astemizole Tablets, USP 25 page 177. On the basis of com- •ninhydrinB1
ments received, it is proposed to revise the limit of any individual in a mixture of butyl alcohol and pyridine (99:1). Heat the plate at
impurity found in the test for Chromatographic purity to agree about 110° for about 5 minutes: the RF value of the principal spot
with the limits proposed in the test for Chromatographic purity un- obtained from the solution under test corresponds to that obtained
der Astemizole. from the Standard solution.
(AER: K. Zaidi) RTS—34376-1
Change to read:
Mobile phase, Standard preparation, and Chromatographic sys-
tem—Proceed as directed in the Assay under Astemizole.
Test solution—Use the Assay preparation. BRIEFING
Procedure—Inject a volume (about 10 uL) of the Test solution
into the chromatograph, record the chromatogram, and measure the
peak responses. Calculate the percentage of each impurity in the Benzethonium Chloride Concentrate, page 41 of PF 28(1)
portion of Tablets taken by the formula: [Jan.-Feb. 2002]; Benzylpenicilloyl Polylysine Concentrate,
USP 25 page 218 and page 42 of P F 28(1) [Jan.-Feb. 2002]; Glu-
taral Concentrate, USP 25 page 806 and page 60 of P F 28(1)
[Jan.-Feb. 2002]; Hydrogen Peroxide Concentrate, USP 25 page
in which r, is the peak response for each impurity, and rs is the sum 865 and page 65 of P F 28 (1) [Jan.-Feb. 2002]; Isosorbide Con-
of the responses of all of the peaks: not more than 0.1% centrate, USP 25 page 965 and page 71 of PF 28(1) [Jan.-Feb.
•0.25%_, 2002]; Lactulose Concentrate, USP 25 page 983 and page 71
of any individual impurity is found, and the sum of all impurities is of P F 28(1) [Jan.-Feb. 2002]; Misoprostol Dispersion, page 76
not more than 1.0%. of P F 28(1) [Jan.-Feb. 2002]. The changed language proposed
here for the Labeling statement in this proposed monograph is that
which was specifically adopted by the Expert Committee on No-
menclature and Labeling. The purpose of this particular wording is
to explicitly require that the container label is to bear the statement
that the article is not intended for direct administration to humans
or animals (see the briefing under Benzethonium Chloride Concen-
trate, page 41 of PF 28(1) [Jan.-Feb. 2002].
It is also proposed to specify this same Labeling statement for
monographs on five official articles and one proposed monograph
on an article, all six of which are concentrated preparations that
must be subjected to further processing to prepare formulations
BRIEFING that are suitable for administration to humans or animals. The pro-
posed revisions are indicated elsewhere in this number of PF for
Bacitracin, USP 25 page 193; Carbidopa and Levodopa Tab- Benzylpenicilloyl Polylysine Concentrate, Isosorbide Concentrate,
lets, USP 25 page 307; Mafenide Acetate, USP 25 page 1028; Glutaral Concentrate, Hydrogen Peroxide Concentrate, Lactulose
Methyldopa, USP 25 page 1120; Methyldopa Tablets, USP 25 Concentrate, and Misoprostol Dispersion.
page 1122; Neomycin and Polymyxin B Sulfates and Pramoxine
Hydrochloride Cream, USP 25 page 1214. It is proposed to re- (NL: C. Bamstein) RTS—36763-1
place the reagent triketohydrindene hydrate with its synonym nin-
hydrin. The use of ninhydrin will be standardized throughout all of
USP-NF.
Add the following:
(BPC: M. Marques) RTS—36575
•Benzethonium Chloride Concentrate
Change to read:
Identification—Apply 1 uL each of a solution of Bacitracin con-
taining 6.0 mg per mL in edetate disodium solution (1 in 100) and a » Benzethonium Chloride Concentrate contains
similar solution of USP Bacitracin Zinc RS to a suitable thin-layer
chromatographic plate (see Chromatography (621)) coated with a not less than 94.0 percent and not more than
0.25-mm layer of chromatographic silica gel mixture. Allow the
spots to dry, and develop the chromatogram in a solvent system 106.0 percent of the labeled amount of benzetho-
consisting of a mixture of butyl alcohol, glacial acetic acid, water,
pyridine, and alcohol (60:15:10:6:5), equilibrated in the chamber nium chloride (C27H42CINO2).
for 30 minutes, until the solvent front has moved about three-
fourths of the length of the plate. Remove the plate from the devel-
Pharmacopeial Forum

BRIEFING
containers.
Benzylpenicilloyl Polylysine Concentrate, USP 25 page 218
Labeling—Label it to otato that it is for manufacturing pur and page 42 of PF 28(1) [Jan.-Feb. 2002]—See briefing under
Benzethonium Chloride Concentrate.
poooo only. Label it to atato The label states that this article is
not intended for direct administration to humans or animals.
Identification—Evaporate a volume of Concentrate,
equivalent to about 200 mg of benzethonium chloride, on Add the following:
a steam bath: the residue so obtained meets the requirements •Labeling—Label it to state The label states that this article
of the tests for Identification under Benzethonium Chloride. is not intended for direct administration to humans or ani-
Oxidizing substances—To 5 mL of Concentrate add 0.5 mals. B1
mL of potassium iodide TS and a few drops of 3 N hydro-
chloric acid: the solution does not acquire a yellow color.
Limit of nitrites—To 1 drop of Concentrate on a spot plate
add 1 drop each of glacial acetic acid, sulfanilic acid in ace-
tic acid solution (1 in 100), and 1-naphthylamine—acetic
BRIEFING
acid solution (prepared by boiling 30 mg of 1-naphthyl-
amine in 70 mL of water, decanting the colorless solution Carbamazepine Extended-Release Tablets, USP 25 page 303
and page 3261 of P F 27(6) [Nov.-Dec. 2001]. Based on comments
from the blue-violet residue, and mixing with 30 mL of gla- received, it is proposed to change the method used in the test for
Water. Data indicate that more precise results are obtained when
cial acetic acid): no red color develops in the resulting solu- Method la is used when compared with results obtained using
Method Ic.
tion within 10 minutes.
Assay—Transfer a volume of Concentrate, equivalent to
about 200 mg of benzethonium chloride, to a glass-stop-
pered flask, and proceed as directed in the Assay under Ben- Change to read:
Packaging and storage—Preserve in tight containers; proforably
zethonium Chloride, beginning with "Add 0.4 mL of © T frrftSTTT
bromophenol blue solution (1 in 2000)." m "at controlled room temperature.a2
Change to read:
Drug release (724)—
Medium: water; 900 mL
', 1800 mL for 400-mg Tablets. •2
Pharmacopeial Forum

Times: 3, 6, 12, and 24 hours.
Procedure—Determine the amount of CjrH^NjO dissolved by
employing UV absorption at the wavelength or maximum absor- BRIEFING
bance at about 284 nm on filtered portions of the solution under
test, suitably diluted with Dissolution Medium, if necessary, in Cefpiramide, USP 25 page 350. Based on data received, revi-
comparison with a Standard solution having a known concentra- sions of the liquid chromatographic tests for Related compounds
tion of USP Carbamazepine RS in the same Medium. and Assay are proposed. Even though several different 15-cm LI
Tolerances—The percentages (Q) of the labeled amount of columns were used (YMC-Pack Pro C18, Supelco Sil C18, and
CJJHJJNOO dissolved at the times specified conform to Accep- LiChrosorb C18), the system suitability requirements specified in
tance Table I. the monograph were not met, specifically that the resolution be-
tween cefpiramide and cefpiramide lactone is not less than 6.0,
Time (hours) Amount dissolved and that the capacity factor is between 2 and 3. A LiChrosorb
3 between 10% and 35% C18 column was tried and the system suitability requirements were
6 between 35% and 65% not met. Improved resolution was obtained for both the test for Re-
12 between 65% and 90% lated compounds and the Assay by using a 5-^m 4.6-mm x 25-cm
24 not less than 75% Phenomenex Luna Cl 8 brand of LI column. In the Assay, a differ-
ent Mobile phase composition of (900:20:60:20) (pH 6.8 buffer:
acetonitrile:tetrahydrofuran:rnethanol) was used. This yielded a re-
Change to read: solution factor of 5.4 and a capacity factor of 4. The typical reten-
tion times were about 7 minutes for cefpiramide and 10 minutes for
Water, Method ie- cefpiramide lactone. It is therefore proposed to specify the 4.6-mm
x 25-cm LI column and the revised Mobile phase composition for
(92 F): not more than 5.0%. the Assay. It is also proposed that the resolution should be not less
than 5 and the capacity factor should be between 2 and 5. Based on
data and suggestions received, it is proposed to provide improve-
ments in the method for the determination of the Water content of
the sodium 5-mercapto-l-methyltetrazole used as reference in the
test for Related compounds. It was found that without the sug-
gested revisions the end-point of the Karl Fischer titration was
not very sharp and the precision was poor. It is proposed to react
the sodium 5-mercapto-l-methyltetrazole with 7V-ethylmaleimide
as recommended in the Reidel-deHaen Hydranal Manual, 1992
ed., page 97, prior to the titration with Karl Fischer Reagent. Using
this procedure, the endpoint was sharp and precision was good.
BRIEFING

Carbidopa and Levodopa Tablets, USP 25 page 307—See
briefing under Bacitracin.

Change to read:
pH 7.5 buffer—Dissolve 4.08 g of monobasic potassium phos-
phate in 800 mL of water, adjust with 1 N sodium hydroxide to a
Change to read: pH of 7.5 ± 0 . 1 , dilute with water to 1000 mL, and mix.
Identification—Transfer a portion of powdered Tablets, equiva- Mobile phase—Prepare a suitable filtered and degassed mixture
lent to about 10 mg of carbidopa, to a 100-mL volumetric flask oipH 7.5 buffer and methanol (750:250). Make adjustments if nec-
containing about 50 mL of 0.05 N hydrochloric acid. Agitate for essary (see System Suitability under Chromatography (621)).
20 minutes, add methanol to volume, mix, and filter or centrifuge. Resolution solution and Chromatographic system—Proceed as
Separately prepare 2 Standard solutions containing 0.1 mg per mL directed in the Assay.
of USP Carbidopa RS and USP Levodopa RS, respectively, in a Standard solution—Transfer about 15 mg of sodium 5-mercap-
solvent prepared by mixing equal volumes of 0.05 N hydrochloric to-l-methyltetrazole and 25 mg of USP Cefpiramide RS, both ac-
acid and methanol. Apply 20 uL of the test solution and 20 uL of curately weighed, to a 100-mL volumetric flask, dissolve in and
each Standard solution at separate points to a thin-layer chromato- dilute with/?// 7.5 buffer to volume, and mix. Transfer 2.0 mL
graphic plate (see Chromatography (621)) coated with a 0.25-mm of this solution to a second 100-mL volumetric flask, dilute with
layer of chromatographic silica gel. Develop the chromatogram Mobile phase to volume, and mix. This solution contains about 3
using a solvent system consisting of a mixture of acetone, chloro- ug of sodium 5-mercapto-l-methyltetrazole and about 5 (j.g of USP
form, M-butanol, glacial acetic acid, and water (60:40:40:40:35) un- Cefpiramide RS per mL.
til the solvent front has moved about 15 cm. Air-dry, spray Test solution—Transfer about 25 mg of Cefpiramide, accurately
uniformly with about 0.5 mL of trikotohydrindono weighed, to a 50-mL volumetric flask, dissolve in and dilute with
•ninhydrin^j Procedure—[NOTE—Use peak areas where peak responses are
reagent (prepared by dissolving 0.3 g of trikctohydrindono indicated.] Separately inject equal volumes (about 20 uL) of the
•ninhy drill-, Standard solution and the Test solution into the chromatograph, re-
in 100 mL of n-butanol acidified with 3 mL of glacial acetic acid), cord the chromatograms, and measure the responses for all of the
and heat at 105° for about 10 minutes: the solution under test ex- peaks. Calculate the percentage of 5-mercapto-l-methyltetrazole in
hibits two spots (reddish brown for levodopa and yellow-orange the portion of Cefpiramide taken by the formula:
for carbidopa) having RF values that correspond to those exhibited
by the Standard solutions. (115.14/138.13)[5C,(100-wyiOO»]('-i//rs)»
Pharmacopeial Forum
in which 115.14 and 138.13 are the molecular weights of 5-mer- Chromatographic system (see Chromatography (621))—The li-
capto-1-methyltetrazole and anhydrous sodium 5-mercapto-l - quid chromatograph is equipped with a 254-nm detector and a 4-
methyltetrazole, respectively; C, is the concentration, in u,g per mm x 15 om
mL, of sodium 5-mercapto-l -methyltetrazole in the Standard solu- •4.6-mm x 25-cm B1
tion; w is the percentage of water, determined by the titrimetric
method (aoo Water Determination (924)) column that contains packing LI. The flow rate is about 2 mL
•1.5 mL B 1
"(See Water Determination (921), but prepare the Test per minute. Chromatograph the Resolution solution, and record the
peak responses as directed for Procedure: the relative retention
Preparation as follows. Transfer about 100 mg of sodium times are about OS
5-mercapto-l-methyltetrazole, accurately weighed, to a "0.7
for cefpiramide and 1.0 for cefpiramide lactone, and the resolution
stoppered centrifuge tube. Add 10.0 mL of a solution of between the cefpiramide lactone peak and the cefpiramide peak is
not less than €S
iV-ethylmaleimide in methanol (4 in 100), and sonicate for
•5-.1
15 minutes. Titrate 5.0 mL of this Test Preparation.)B1 Chromatograph the Standard preparation, and record the peak re-
in the sodium sponses as directed for Procedure: the capacity factor, k', is be-
tween 2 and 3?
•5-.,
mercapto-1-methyltetrazole taken to prepare the Standard solu- %i
tion; W is the weight, in mg, of Cefpiramide taken to prepare the ana the column efficiency is not less than 1700 theoretical plates
Test solution; and rv and rs are the 5-mercapto-l-methyltetrazole when calculated by the formula:
peak responses obtained from the Test solution and the Standard 5.545(tr/Wh/2f,
solution, respectively: not more than 0.7% of 5-mercapto-l -
methyltetrazole is found. Calculate the percentage of each other the tailing factor for the cefpiramide peak is not less than 0.95 and
impurity in the portion of Cefpiramide taken by the formula: not more than 1.4, and the relative standard deviation for replicate
5(CEn000W)(ry/rs), Procedure—[NOTE—Use peak areas where peak responses are
in which C is the concentration, in |ig per mL, of USP Cefpiramide indicated.] Separately inject equal volumes (about 20 uL) of the
RS in the Standard solution; E is the designated cefpiramide con- Standard preparation and the Assay preparation into the chro-
tent, in ug per mg, of USP Cefpiramide RS; Wis the weight, in mg, matograph, record the chromatograms, and measure the responses
of Cefpiramide taken to prepare the Test solution; rv is the response for the major peaks. Calculate the quantity, in u.g, of
of each other impurity obtained from the Test solution; and rs is the C25H24NgO7S2 in each mg of the Cefpiramide taken by the formu-
cefpiramide peak response obtained from the Standard solution: la:
not more than 0.7% of any other individual impurity is found.
The total of the percentages of 5-mercapto-l-methyltetrazole and
all other impurities is not more than 2.0%. in which C is the concentration, in mg per mL, of USP Cefpiramide
RS in the Standard preparation; E is the designated cefpiramide
Change to read: (C25H24N8O7S2) content, in ug per mg, of USP Cefpiramide RS;
Assay— W is the weight, in mg, of the Cefpiramide taken to prepare the
pH 6.8 buffer—Dissolve 1.36 g of monobasic potassium phos- Assay preparation; and rv and rs are the cefpiramide peak re-
phate in 900 mL of water, adjust with 1 N sodium hydroxide to a sponses obtained from the Assay preparation and the Standard
pH of 6.8 ± 0 . 1 , dilute with water to 1000 mL, and mix. preparation, respectively.
Mobile phase—Prepare a suitable filtered and degassed mixture
of pH 6.8 buffer, acetonitrile, tetrahydrofuran, and methanol
(880:10:40:10)
•(900:20:60:20). Bl
Make adjustments if necessary (see System Suitability under
Resolution solution—Prepare a solution of USP Cefpiramide RS
in 0.01 N sodium hydroxide containing about 1 mg per mL. Heat
this solution at 95° for 10 minutes. Mix 1 mL of this solution with
19 mL of Mobile phase. This solution contains a mixture of cefpir-
amide and cefpiramide lactone. BRIEFING
of USP Cefpiramide RS in Mobile phase to obtain a solution hav- Cyanocobalamin Co 58 Capsules, page 3395 of PF 27(6)
ing a known concentration of about 0.25 mg per mL. [Nov.-Dec. 2001]. This new monograph, which previously ap-
Assay preparation—Transfer about 50 mg of Cefpiramide, accu- peared in Pharmacopeial Previews, is now forwarded to In-Pro-
rately weighed, to a 200-mL volumetric flask, dissolve in and di- cess Revision.
lute with Mobile phase to volume, and mix.
Pharmacopeial Forum
Add the following:

A: Its gamma-ray spectrum is identical to that of a spe-
•Cyanocobalamin Co 58 Capsules cimen of 58Co that exhibits major photopeaks at 0.511 MeV
(anniliation radiation) and 0.811 MeV.
58
Vitamin B12- Co B: The retention time of the major peak in the radio-
» Cyanocobalamin Co 58 Capsules contain Cy- chromatogram of the Test solution corresponds to that in
anocobalamin in which a portion of the molecules
the test for Radiochemical purity.
contain radioactive cobalt (58Co) in the molecular
structure. Each Capsule contains not less than
Procedure for content uniformity—Determine the instru-
ment response of each of 10 Capsules by measurement in a
the labeled amount of 58Co as cyanocobalamin ex- suitable counting assembly and under identical geometric
pressed in megabecquerels (or microcuries) at the conditions. Calculate the average radioactivity per Capsule.
time indicated in the labeling. The cyanocobala- The radioactivities of none of the Capsules differ by more
min content is not less than 90.0 percent and not than 10% from the average. The relative standard deviation
more than 110.0 percent of the labeled amount. is less than 3.5%
Radiochemical purity—
Specific activity: not less than 0.02 MBq (or 0.5 uCi) per ug
Mobile phase—Prepare a solution of 10.0 g of dibasic so-
of cyanocobalamin.
dium phosphate in 1000 mL of water, and adjust with phos-
Packaging and storage—Preserve in well-closed, light-re-
phoric acid to a pH of 3.5 . Prepare a mixture of the solution
sistant containers, and store in a cold place.
so obtained and methanol (73.5:26.5), mix, and degas. Use
Labeling—Label it to include the following: the date of ca-
within 2 days. Make adjustments if necessary (see System
libration; the amount of cyanocobalamin expressed in ug
Suitability under Chromatography(62l)).
per Capsule; the amount of 58Co as cyanocobalamin ex-
Standard solution—Transfer about 10 mg of USP Cyano-
pressed in MBq (or ju.Ci) per Capsule at the time of calibra-
cobalamin RS, accurately weighed, to a 100-mL volumetric
tion; the expiration date; and the statement "Caution—
flask, dilute with Mobile phase to volume, and mix. Transfer
Radioactive Material." The labeling indicates that in mak-
2.0 mL of the solution so obtained to a 100-mL volumetric
ing dosage calculations, correction is to be made for radio-
flask, dilute with Mobile phase to volume, and mix.
active decay, and also indicates that the radioactive half-life
Test solution—Dissolve the contents of one Capsule in 1
58
of Co is 70.9 days.
mL of water, allow to stand for about 10 minutes, and cen-
USP Reference standards (11)—USP Cyanocobalamin trifuge. Use the supernatant.
RS.
Disintegration (701): 30 minutes, testing one Capsule in 1 The liquid chromatograph is equipped with a 361-nm detec-
N hydrochloric acid maintained at 37 + 2° as the immer- tor, a gamma detector adjusted for 58Co, and a 4.6-mm x
sion fluid. 25-cm stainless steel column that contains 5-um packing
Radionuclide identification (821)—
Pharmacopeial Forum
L7. The flow rate is about 1 mL per minute. Chromatograph Assay for radioactivity (821)—Using a suitable counting
the Standard solution, and record the peak responses as di- assembly (see Selection of a Counting Assembly) and cali-
rected for Procedure. brated system, determine the radioactivity, in MBq (or uCi)
Procedure—Inject about 100 uL of the Standard solution per Capsule, of Cyanocobalamine Co 58 Capsules.B1
into the chromatograph, record the chromatogram for 30
minutes, and note the retention time of the cyano-
cobalamin peak. Inject 100 uL of the Test solution into the-
chromatograph, record the chromatogram for three times the
retention time of cyanocobalamin, and measure the peak
areas using the gamma detector. Calculate the percentage BRIEFING
58
of cyanocobalamin present as cyanocobalamin Co in the Cycloserine Capsules, USP 25 page 493 and page 2998 of PF
27(5) [Sept.-Oct. 2001]. A correction is made in the Test solution
portion of Capsules taken by the formula: specified in the proposed determinative step of the proposed revi-
sion of the Dissolution test.

58
in which rv is the peak area for cyanocobalamin Co ob-
tained from the Test solution; and rs is the sum of all the Change to read:
peak areas in the radiochromatogram obtained from the Test
» Cycloserine Capsules contain not less than 90.0 per-
solution: not less than 90% of the total radioactivity is found cent and not more than 120.0 percent of the labeled
amount of
as cyanocobalamin 58Co.
•cycloserine B2
Radionuclidic purity—Using a suitable, calibrated instru- (C3H6N2O2).
ment (see Radioactivity (821)) and standardized solutions
Change to read:
58
of Co, 57Co, and ^Co, record the gamma spectrum. The Dissolution (711)—
Medium: wator;-
spectrum does not differ significantly from that of the stan- m
pH 6.8 Phosphate buffer (see Buffer Solutions under Solu-
58
dardized Co solution. Determine the relative amounts of tions in the section Reagents, Indicators, and Solutions);ml
58 900 mL.
Co, 57Co, and 60Co present. Cobalt 57 has a half-life of
270.9 days, and its presence is shown by 0.122 MeV gamma Time: 15 minutoa.
photons. Cobalt 60 has a half-life of 5.27 years and its pre- "30 minutes.
sence is shown by 1.173 MeV and 1.333 MeV gamma Determine the amount of C3H6N2O2 dissolved by employing
photons. Not more than 1% of the total radioactivity is the following method.
due to 60Co, and not more than 2% of the total radioactivity pH 6.8 Phosphate buffer, Mobile phase, and
is due to "Co, 60Co, and other radionuclidic impurities. Chromatographic system—Proceed as directed in the Assay.
Content of cyanocobalamin—Determine the content, in Standard solution—Quantitatively dissolve an accurately

weighed quantity of USP Cycloserine RS in pH 6.8 Phos-
ug per Capsule, of cyanocobalamin as directed under Vita-
phate buffer to obtain a solution having a known concentra-
min Bl2 Activity Assay (171).
tion of about 0.25 mg per mL.
Pharmacopeial Forum
Test solution—Use tho Assay preparation- a filtered por- 250C(/v/r 5 ),

tion of the solution under test.Bl
in which the terms are as defined therein.,
Procedure—Dotormino tho amount of Catf^4aOa dissolved from
ultraviolet aboorbanoog at tho wavolongth of maximum aboorbanoo
at about 210 nm of filtered portions of tho solution undor toat, aui
tably dilutod with Dissolution Medium, if noooosary, in comparison
with a Standard solution having a known oonoontration of USP Cy
olosorino RS in tho same modium.
•Separately inject equal volumes (about 10 uL) of the Stan-
dard solution and the Test solution into the chromatograph,
record the chromatograms, and measure the peak responses
BRIEFING
for cycloserine. Calculate the quantity, in mg, of cycloserine
Dextroamphetamine Sulfate, USP 25 page 536 and PF 27(3)
(C3H6N2O2) dissolved by the formula: page 2533 [May-June 2001]—See briefing under Amphetamine
Sulfate.

in which C is the concentration, in mg per mL, of USP Cy-
closerine RS in the Standard solution; and rv and rs are the

Add the following:
peak responses for cycloserine obtained from the Test solu-
"Chromatographic purity—
tion and the Standard solution, respectively. B1
Diluent—Dilute 3.12 mL of phosphoric acid with water to
Tolerances—Not less than 75%
1000 mL.
•80%-.
( 0 ofthe labeled amount of C3H6N2O2 is dissolved in <15 minutos. Buffer solution—Dissolve 2.16 g of sodium 1-octanesul-
"30 minutes.-.
fonate in 1000 mL of water, and add 1.0 mL of 0.1 % triethy-
Change to read: lamine solution (v/v). Mix, and adjust with phosphoric acid
Assay—Place not loss than 5 Capsules in a high speed glass blon
dor jar containing an aoouratoly measured volume of water to ob to a pH of 2.5.
tain a suitable stock tost solution, and blond for <\ + 1 minutos.
Prooood as dirootod undor Antibiotioa—Miorobial Assays (&4-)? Mobile phase—Prepare a filtered and degassed mixture of
using an aoouratoly measured volume of thi3 stock t03t solution di-
luted quantitatively with wator to obtain a Teat Dilution having a Buffer solution, acetonitrile, and methanol (144:37:19).
oonoontration assumed to bo equal to tho modian doso lovol of tho
Make adjustments if necessary (see System Suitability under
u
pH 6.8 Phosphate buffer, Mobile phase, Standard Chromatography (621)).
preparation, and Chromatographic system—Proceed as di- Standard stock solution—Dissolve an accurately weighed
rected in the Assay under Cycloserine. quantity of USP Dextroamphetamine Sulfate RS in Diluent
Assay preparation—Remove, as completely as possible, to obtain a solution having a known concentration of about
the contents of not fewer than 20 Capsules. Transfer an ac- 0.3 mg per mL.
curately weighed portion ofthe powder, equivalent to about Standard solution—Dilute an accurately measured vol-
100 mg of cycloserine, to a 250-mL volumetric flask, dilute ume of Standard stock solution in Diluent to obtain a solu-
with pH 6.8 Phosphate buffer to volume, mix, and filter. tion having a known concentration of about QTQ£ 0.003 mg
Procedure—Proceed as directed in the Assay under Cy- per mL.
closerine. Calculate the quantity, in mg, of cycloserine

(C3H6N2O2) in the portion of Capsules taken by the formula:
Pharmacopeial Forum
Test solution—Transfer about 30 mg of Dextroampheta- Delete the following:

"Ordinary impurities (466)—
mine Sulfate, accurately weighed, to a 100-mL volumetric Tost solution: mothanol.
Standard solution: mothanol.
flask. Dissolve in 50 mL of Diluent, sonicate for 5 minutes, Eluant: a mixture of mothanol and ammonium hydroxide (50:1).
Visualisation: I.,,
dilute with Diluent to volume, and mix.
tor and a 4.6-mm x 15-cm column that contains 5-jim
packing LI. The flow rate is about 1 mL per minute. Chro-
matograph the Standard stock solution, and record the peak
BRIEFING
responses as directed for Procedure: the tailing factor is not
Dimenhydrinate Injection, USP 25 page585; Dimenhydri-
more than 3f 2.0; and the relative standard deviation for re- nate Oral Solution, page 281 of PF 28(2) [Mar-Apr. 2002]; Di-
menhydrinate Syrup, USP 25 page 586 and page 282 of PF 28(2)
plicate injections is not more than 2.0%. Chromatograph [Mar-Apr. 2002]; Dimenhydrinate Tablets, USP 25 page 586.
The proposed revisions in these monographs are intended to update
the Test solution, and record the peak responses as directed the cross-references and the editorial style.
for Procedure: the resolution, R, between the dextroamphe-
tamine peak and any adjacent peak is not less than 1.5.
Change to read:
» Dimenhydrinate Injection is a solution of Dimenhy-
drinate in a mixture of Propylene Glycol and water. It
peak responses. Calculate the percentage of each impurity in contains not less than 95.0 percent and not more than
105.0 percent of the labeled amount of
the portion of Dextroamphetamine Sulfate taken by the for-
•dimenhydrinate B j
mula: (C17H21NO • C7H7C1N4O2).
Change to read:
Content of 8-chlorotheophylline—
Mobile phase—Dissolve 0.81 g of <i/-10-camphorsulfonic acid
and 0.70 g of sodium acetate in 700 mL of water. Add 300 mL
of methanol, mix, and pass through a membrane filter having a
0.5-u.m or finer porosity.
Standard solution—Dissolve an accurately weighed quantity of
in which C is the concentration, in mg per mL, of USP Dex- USP Dimenhydrinate RS in methanol to obtain a Standard stock
solution having a known concentration of about 0.5 mg per mL.
troamphetamine Sulfate RS in the Standard solution; W is Retain a portion of this Standard stock solution for use in the Assay.
Pipet 5 mL into a 50-mL volumetric flask, dilute with methanol to
the weight, in mg, of Dextroamphetamine Sulfate taken to volume, mix, and pass through a membrane filter having a 0.5-um
or finer porosity.
prepare the Test solution; r, is the peak response for each Test solution—Transfer an accurately measured volume of Injec-
tion, equivalent to about 50 mg of dimenhydrinate, to a 100-mL
impurity obtained from the Test solution; and rs is the peak volumetric flask, dilute with methanol to volume, and mix to obtain
a stock solution. Retain a portion of this stock solution for use in
response for amphetamine obtained from the Standard solu- the Assay. Pipet 5 mL of this stock solution into a 50-mL volu-
metric flask, dilute with methanol to volume, mix, and pass
tion: not more than 0.1% of any individual impurity is through a membrane filter having a 0.5-|am or finer porosity.
found; and not more than 0.5% of total impurities is quid chromatograph is equipped with a 280-nm detector, a 2-mm
x 12.5-cm guard column that contains packing L2, and a 4.6-mm
found. _, x 25-cm analytical column that contains packing LI. The flow
rate is about 2 mL per minute. Chromatograph three replicate in-
Pharmacopeial Forum
jections of the Standard solution, and record the peak responses as

directed for Procedure: the relative standard deviation is not more BRIEFING
than 1.0%.
Procedure—Separately inject equal volumes (about 10 uL) of Dimenhydrinate Oral Solution, page 281 of PF 28(2) [Mar-
the Standard solution and the Test solution into the chromatograph, Apr. 2002]—See briefing under Dimenhydrinate Injection.
record the chromatograms, and measure the responses for the ma-
jor peaks. Calculate the quantity, in mg, of
•8-chlorotheophylline B ,
(C7H7C1N4O2) in each m l of the Injection taken by the formula:
Add the following:
A
Dimenhydrinate Oral Solution
l
(214.61/469.96)(1000C/F)(r(;/r5),1 (Monograph under this new title—to become official
June 1, 2005)
(Current monograph title is Dimenhydrinate Syrup)
in which 214.61 and 469.97
•469.96.1
are the molecular weights of 8-chlorotheophylline and dimenhydri-
nate, respectively; C is the concentration, in mg per mL, of USP » Dimenhydrinate Oral Solution contains not less
Dimenhydrinate RS in the Standard solution; V is the volume, in
mL, of Injection taken; and rv and rs are the peak responses ob- than 90.0 percent and not more than 110.0 percent
tained from the Test solution and the Standard solution, respec-
tively. An amount of 8-chlorotheophylline that is between 43.4% of the labeled amount of dimenhydrinate
and 47.9% of the amount of dimenhydrinate obtained in the Assay
is found.
(C17H21NO • C7H7C1N4O2)-
Change to read:
Assay— Packaging and storage—Preserve in tight containers.
Mobile phase A, Mobile phase B;
'Solution A, Solution B, Mobile phase,,, USP Reference standards (11)—USP Dimenhydrinate RS.
Internal standard solution, and Chromatographic system—Prepare
as directed in the Assay under Dimenhydrinate Tablets. USP Diphenhydraminc Hydmchloridc RS.
Standard preparation—Use a portion of the Standard stock so- m
lution that was prepared for the Standard solution in the test for •1
Content of 8-chlorotheophylline. Mix 5.0 mL of this Standard
stock solution and 5.0 mL of Internal standard solution, and pass Identification—The relative retention times of the 8-chlor-
through a membrane filter having a 0.5-um or finer porosity.
Assay preparation—Use a portion of the stock solution that was otheophylline and diphenhydramine peaks in the chromato-
prepared for the Test solution in the test for Content of 8-chlor-
otheophylline. Mix 5.0 mL of this stock solution and 5.0 mL of gram of the Assay preparation correspond to those in the
Internal standard solution, and pass through a membrane filter
having a 0.5-um or finer porosity. chromatogram of the Standard preparation, as obtained in
Procedure—Proceed as directed for Procedure in the Assay un-
der Dimenhydrinate Tablets. Calculate the quantity, in mg, of the Assay.
•dimenhydrinate., Content of 8-chlorotheophylline—

(C17H2jNO • C7H7C1N4O2) in each mL of the Injection taken by
the formula: Ammonium bicarbonate solution, Diluent solution,
Mobile phase A, Mobile phase B, Internal standard
in which C is the concentration of USP Dimenhydrinate RS in the
Standard preparation; Fis the volume, in mL, of Injection taken; solution^ Standard preparation,As say preparation,
and the other terms are as defined therein.
Chromatographic system, and Proccdwv—Proceed as di •
rootod under the Assay.
'Ammonium bicarbonate solution, Diluent, Solution A,

Solution B, Mobile phase, Internal standard solution, and
Chromatographic system—Proceed as directed in the Assay
under Dimenhydrinate Tablets.
Pharmacopeial Forum
Standard solution—Prepare as directed for Standard Assay preparation—Pipet 5.0 mL of Oral Solution into a
preparation in the Assay under Dimenhydrinate Tablets. suitable container, add 5.0 mL of Internal standard solution,
Test solution—Prepare as directed for Assay preparation and mix. Transfer about 1 mL of this solution to a suitable
in the Assay. container, add about 5 mL of Diluent solution
•
Procedure—Separately inject equal volumes (about 10 •l
uL) of the Standard solution and the Test solution into the , and mix.
chromatograph, record the chromatograms, and measure the Procedure—Proceed as directed for Procedure in the As-
areas for the major peaks. Calculate the quantity, in mg per say under Dimenhydrinate Tablets. Calculate the quantity,
mL, of 8-chlorotheophylline (C7H7C1N4O2) in the portion of in mg per mL, of dimenhydrinate (C 1 7 H 2 1 NO-C 7 H 7
Oral Solution taken by the formula: C1N4O2) in the portion of the Oral Solution taken by the for-
mula:
0.05 WiRy/Rs),
in which 214.61 and 469.96 are the molecular wieghts of 8-
chlorotheophylline and dimenhydrinate, respectively; W is in which Wis the weight, in mg, of USP Dimenhydrinate RS
the weight, in mg, of USP Dimenhydrinate RS in the Stan- in the Standard preparation; and Rv and Rs are the peak area
dard solution; and Rv and Rs are peak area ratios of 8-chlor- ratios of diphenhydrinate to the internal standard obtained
otheophylline to the internal standard obtained from the Test from the Assay preparation and the Standard preparation,
solution and the Standard solution, respectively. B1 respectively. Caloulato tho quantity, in mg per mL, of
a taken by tho formula:
An amount of 8-chlorotheophylline that is between 43.4%
and 47.9% of the amount of dimenhydrinate is found.
in which Wis tho weight, in mg, of USP Dimcnhydrinato RS
C2H5OH.
mtho-Standaj«dp}«cpai«ation; and R& and Rg aro tho 8 ohlor-
Assay—
othoophyllino peak area ratios obtained from tho Assay
Ammonium bicarbonate solution, Diluent solution,
preparation and tho Standard preparation, roopootivoly.
Mobile phase A, Mobile phase B,—Internal standard •
•l
preparation;
'Solution A, Solution B, Mobile phase, Internal standard (Official June 1, 2005)AayP25
solution,ml
Standard preparation, and Chromatographic system—Pro-
ceed as directed in the Assay under Dimenhydrinate Tablets.
Pharmacopeial Forum
Standard solution—Prepare as directed for Standard

BRIEFING
preparation in the Assay under Dimenhydrinate Tablets.
Dimenhydrinate Syrup, USP 25 page 586 and page 282 of PF
28(2) [Mar.-Apr. 2002]—See briefing under Dimenhydrinate In- Test solution—Prepare as directed for Assay preparation
jection.
in the Assay.
(PA4: A. Medjedovic) RTS—36702-2 Procedure—Separately inject equal volumes (about 10
Dimenhydrinate Syrup chromatograph, record the chromatograms, and measure the

(Current title--not to change until June 1, 2005) areas for the major peaks. Calculate the quantity, in mg per
2005 mL, of 8-chlorotheophylline (C7H7C1N4O2) in the portion of
cess Revision): Syrup taken by the formula:
See Dimenhydrinate Oral Solution
Change to read: (2U.6\/469.96)(0.05W)(Ru/Rs),
» Dimenhydrinate Syrup contains not less than 90.0 in which 214.61 and 469.96 are the molecular weights of 8-
percent and not more than 110.0 percent of the labeled
amount of chlorotheophylline and dimenhydrinate, respectively; W is
•dimenhydrinate., the weight, in mg, of USP Dimenhydrinate RS in the Stan-

(C17H21NO-C7H7C1N4O2). dard solution; and Rv and Rs are peak area ratios of 8-chlor-
Change to read: otheophylline to the internal standard obtained from the Test
USP Reference standards (11)—USP Dimenhydrinate RS.
solution and the Standard solution, respectively.m.
Diphcnhydraminc Hydrochloridc RS.
An amount of 8-chlorotheophylline that is between 43.4% and
•l
47.9% of the amount of dimenhydrinate is found.

Assay—
Identification—Tho ohromatogram of tho Assay preparation ob-
tained as dirootod in tho Assay exhibits major poako for 8 ohlor Ammonium bicarbonate solution, Diluent, solution, Mobile
othoophyllino and diphonhydramino, tho retention times of phase A, Mobile phase B, Internal standard preparation,-
whioh, relative to tho intomal otandard, correspond to that oxhib 'Solution A, Solution B, Mobile phase, Internal standard
itod in tho ohromatogram of tho Standa>"d preparation obtained as
dirootod in tho Assay. solution, ml
Standard preparation, and Chromatographic system—Proceed as
"The relative retention times of the 8-chlorotheophylline directed in the Assay under Dimenhydrinate Tablets.
Assay preparation—Pipet 5.0 mL of Syrup into a suitable con-
and diphenhydramine peaks in the chromatogram of the As- tainer, add 5.0 mL of Internal standard solution, and mix. Transfer
about 1 mL of this solution to a suitable container, add about 5 mL
say preparation correspond to those in the chromatogram of of Diluent solution
the Standard preparation, as obtained in the Assay. m m
, and mix.
Procedure—Proceed as directed for Procedure in the Assay un-
Change to read: der Dimenhydrinate Tablets. Calculate the quantity, in mg per mL,
of
Ammonium bicarbonate solution, Diluent solution; Mobile •dimenhydrinate^
phase A,Mobilc phase B, Internal standard solution, Standard (C17H21NO • C7H7C1N4O2) in the portion of the Syrup taken by
preparation, Assay preparation, Chromatographic system, and the formula:
Procedure—Proceed as directed under tho Assay.
0.05 WiRy/Rs),
'Ammonium bicarbonate solution, Diluent, Solution A, in which Wis the weight, in mg, of USP Dimenhydrinate RS in the
Standard preparation; and Rv and Rs are the peak area ratios of
Solution B, Mobile phase, Internal standard solution, and diphenhydrinate to the internal standard obtained from the Assay
preparation and the Standard preparation, respectively. Calculate
Chromatographic system—Proceed as directed in the Assay tho quantity, in mg per mL, of C^,tf?€B44Oa talcon by tho formula:
under Dimenhydrinate Tablets.
Pharmacopeial Forum
in whioh Win tho weight; in ing, of USP Dimenhydrinato RS in tho Change to read:
Standard preparation, and Ry and Rg aro tho 8 ohlorothoophyllino Uniformity of dosage units (905): meet the requirements, the fol-
poak aroa ratios obtained from tho Assay preparation and tho Stan • lowing procedure being used where the test for Content Uniformity
dard preparation, respectively. is required. Transfer 1 Tablet to a 50-mL volumetric flask, add
about 5 mL of Ammonium bicarbonate solution obtained from
the Assay, and shake gently to disperse, sonicating, if necessary.
Add 20.0 mL of Internal standard solution obtained from the As-
say, shake by mechanical means for 30 minutes, and centrifuge. To
1 mL of the clear supernatant add about 9 mL of Diluent solution
obtained from the Assay, and mix. Continue as directed for Proce-
dure in the Assay.
Change to read:
Ammonium bicarbonate solution, Diluent solution, Mobile
BRIEFING phase A, Mobile phase B, Internal standard solution, Standard
preparation, Assay preparation, Chromatographic system, and
Procedure—Proceed as directed under tho Assay.
Dimenhydrinate Tablets, USP 25 page 586—See briefing un-
der Dimenhydrinate Injection. 'Ammonium bicarbonate solution, Diluent, Solution A,
(PA4: A. Medjedovic) RTS—36702-3 Solution B, Mobile phase, Internal standard solution, and
Chromatographic system—Prepare as directed in the Assay.
Change to read: Standard solution—Prepare as directed for Standard
preparation in the Assay.
» Dimenhydrinate Tablets contain not less than 90.0
percent and not more than 110.0 percent of the labeled Test solution—Prepare as directed for Assay preparation
amount of
in the Assay.
•dimenhydrinate,,,
(C17H21NO • C7H7C1N4O2). Procedure—Separately inject equal volumes (about 10
Change to read:
Identification—The chromatogram of tho Assay preparation ob chromatograph, record the chromatograms, and measure the
tainod as directed in the Assay exhibits major peaks for 8 ohlor
othoophyllino and diphenhydramino, tho rotontion times of areas for the major peaks. Calculate the quantity, in mg, of
which, relative to tho internal standard, correspond to that oxhib
itod in tho ohromatogram of the- Standard preparation obtained as 8-chlorotheophylline (C7H7C1N4O2) per Tablet taken by the
directed in tho Assay.
formula:
•The relative retention times of the 8-chlorotheophylline
and diphenhydramine peaks in the chromatogram of the As- (214.61/469.96)W(RU/RS),
say preparation correspond to those in the chromatogram of

in which 214.61 and 469.96 are the molecular weights of 8-
the Standard preparation, as obtained in the Assay. ml
chlorotheophylline and dimenhydrinate, respectively; W is
Change to read: the weight, in mg, of USP Dimenhydrinate RS in the Stan-

Dissolution (711)— dard solution; and Rv and Rs are peak area ratios of 8-chlor-
Apparatus 2: 50 rpm. otheophylline to the internal standard obtained from the Test
Time: 45 minutes.
Procedure—Determine the amount of C17H21NO • C7H7C1N4O2 solution and the Standard solution, respectively.,.
dissolved from ultraviolet absorbanoos
An amount of 8-chlorotheophylline that is between 43.4% and
"by employing UV absorption, { 47.9% of the amount of dimenhydrinate is found.
at the wavelength of maximum absorbance at about 276 nm on fil-
tered portions of the solution under test, suitably diluted with Dis- Change to read:
solution Medium, if necessary, in comparison with a Standard Assay—
solution having a known concentration of USP Dimenhydrinate Ammonium bicarbonate solution—Dissolve 4 g of ammonium
RS in the same Medium. bicarbonate in 250 mL of water.
Tolerances—Not less than 75% ( 0 of the labeled amount of Diluent solution
Ci7H21NO • C7H7C1N4O2 is dissolved in 45 minutes.
Pharmacopeial Forum
—Dissolve 4 g of ammonium bicarbonate in 200 mL of water. Add 'The chromatograph is programmed as follows.
50 mL of methanol, and mix.
Mobile phase
u
Solution mx
A—Dissolve 0.8 g of ammonium bicarbonate in 800 mL of water. Time Solution A Solution B Elution
Add 200 mL of methanol, filter, and degas. Mako adjuatmonto if
nooo33ary (300 System Suitability under Chromatography ( ) } (minutes) (%) (%)
Mobile phase 0-7.0 100 0 isocratic
"'Solution B1
B—Dissolve 0.8 g of ammonium bicarbonate in 150 mL of water. 7.0-7.1 100->0 0->100 linear gradi-
Add 850 mL of methanol, filter, and degas. Make adjustmonto if
neooooary (900'System Suitability undor Chromatography (634-))? ent
7.1-15 0 100 isocratic
'Mobile phase—Use variable mixtures of Solution A and 15-15.1 0->100 100-»0 linear gradi-
Solution B as directed for Chromatographic system. Make ent
adjustments if necessary (see System Suitability under 15.1-22.0 100 0 isocratic
Chromatography {621)).B1
Internal standard solution—Prepare a solution in methanol con-

taining 2.0 mg of 2-hydroxybenzyl alcohol per mL. Chromatograph the Standard preparation, and record the peak
Standard preparation—Accurately weigh about 50 mg of USP areas as directed for Procedure: the relative retention times are
Dimenhydrinate RS, add about 5 mL of Ammonium bicarbonate about 0.3 for 8-chlorotheophylline, 0.5 for the internal standard,
solution and 20.0 mL of Internal standard solution, and mix. To and 1.0 for diphenhydramine; the resolution, R, between 8-chlor-
1 mL of this solution add about 9 mL of Diluent solution otheophylline and the internal standard is not less than 4.5; and the
m relative standard deviation for replicate injections is not more than
, and mix. 2.0%.
Assay preparation—Transfer 5 Tablets into a 250-mL volu- Procedure—Separately inject equal volumes (about 10 uL) of
metric flask, add 25 mL of Ammonium bicarbonate solution, and the Standard preparation and the Assay preparation into the chro-
shake gently to disperse, sonicating if necessary. Add 100.0 mL of matograph, record the chromatograms, and measure the areas for
Internal standard solution, shake vigorously for 30 minutes, and the major peaks. Calculate the quantity, in mg, of
centrifuge. To 1 mL of the clear supernatant add about 9 mL of •dimenhydrinateB,
Diluent solution (C17H21NO • C7H7C1N4O2) per Tablet taken by the formula:
m
, and mix.
Chromatographic system (see Chromatography (621))— The
liquid chromatograph is equipped with a 229-nm detector and a in which Wis the weight, in mg, of USP Dimenhydrinate RS in the
4.6-mm x 25-cm column that contains packing L7. The flow rate Standard preparation; and Rv and Rs are the peak area ratios of
is about 1.5 mL per minute. Tho atop gradient is as follows: diphenhydramine to the internal standard obtained from the Assay
preparation and the Standard preparation, respectively. Gftletriate
tho quantity, in mg, of C^H^QN^Qg per Tablot takon by the formu
Time (min.) % Mobilo phaao A % Mobilo phase B 4
i no 0
1UU
i r\o 1 QQ inwhich Wia tho weight, in mg; of USP Dimonhydrinato RS in tho

1UU
0 | QQ Standard preparation, and Ry and R^ aro tho 8 ohlorothoophyllino
0 0 peak area ratios obtained from tho Assay preparation and tho Stan
1 QQ dardpreparation, roapootivoly.
1 QQ
Pharmacopeial Forum
Identification—Transfer about 1 mL of the Injection to a

BRIEFING test tube, and add 2 drops of ammonium hydroxide: no pre-
Ferumoxides Injection, page 2543 of PF 27(3) [May-June cipitate is formed. Add 2 mL of hydrochloric acid, mix, and
2001]. This monograph is presented again to make an editorial cor-
rection in the test for Specific gravity by revising the upper limit in add 2 mL of ammonium hydroxide: a brown precipitate is
the range of specific gravity values.
formed.
Specific gravity (841): between 1.031 and 11.(Ml 1.041.
Bacterial endotoxins (85)—It contains not more than 12.5
Add the following:
USP Endotoxin Units per mL.
A
Ferumoxides Injection pH (791): between 5.0 and 9.0.
Colloidal particle size—
Apparatus—Use a submicron laser light-scattering instru-
» Ferumoxides Injection is a sterile colloidal sus-
ment.
pension of superparamagnetic iron oxide asso-
Standards—Use 90- and 270-nm NIST-traceable poly-
ciated with dextran in Water for Injection. It
styrene monospheres.
contains not less than 95 percent and not more Standard dilutions—Transfer 3 mL of 0.2-um filtered
than 105 percent of the labeled amount of iron. water to each of two clear acrylic cuvettes. Add a sufficient
It contains in each mL not less than 5.6 mg and amount of the 90-nm monospheres to one of the cuvettes
not more than 9.1 mg of dextran. It contains in and a sufficient amount of the 270-nm monospheres to the
other cuvette t0 m a k e the
each mL not less than 0.25 mg and not more than dilutions slightly turbid, place in
the A
0.53 mg of citrate. It also contains mannitol. It PP<™«", *nd then measure the particle sizes: the par-
tide size in the Standards is within 10% of the certified dia-
contains no antimicrobial agents. Ferumoxides is
meter.
a nonstoichiometric forrous iron oxide magnetite
Procedure—Transfer about 40 uL of the Injection to a
of average formula FeOi.44, with particles having
clear acrylic cuvette, and add 3 mL of 0.2-um filtered water.
a diameter between 100 and 250 nm. Cover, invert to mix (without shaking), place in the Appa-
Packaging and storage—Preserve in single-dose contain- ratus, and measure the intensity-weighted effective dia-
ers of Type I glass, at controlled room temperature. Avoid meter. [NOTE—Several minutes are necessary for the
freezing. sample to reach equilibrium.] The intensity-weighted effec-

tive diameter is between 100 and 250 nm.
Labeling—Label it to indicate that it is to be administered
Magnetic susceptibility—
through a 5-um filter and that it is not to be used if there are
indications that the package has been exposed to freezing Apparatus: a calibrated magnetic susceptibility balance.
temperatures. Standard solutions—Transfer 118.85 g of nickel chloride

hexahydrate, accurately weighed, to a 500-mL volumetric
USP Reference standards (11)—USP Dextran T-10 RS.
flask, dilute with water to volume, and mix to obtain 1 M
USP Dextrose RS. USP Endotoxin RS.
1
Brookhaven Instruments 90Plus or equivalent.
Pharmacopeial Forum
nickel chloride. Transfer 356.55 g of nickel chloride hexa- in which AT is the Balance constant as obtained above; and L
hydrate, accurately weighed, to a separate 500-mL volu- and Ware as defined above.
metric flask, dilute with water to volume, and mix to Diluted sample—Transfer about 0.2 g of the Injection, ac-
obtain 3 M nickel chloride. curately weighed, to a 10-mL volumetric container, dilute
Balance constant—[NOTE—Each magnetic susceptibility with water to volume, mix, and accurately weigh the con-
balance has a Balance constant, K, that is determined each tents.
time the balance is moved to a new location. The Balance Procedure—[NOTE—Use the same susceptibility tube
constant is referenced to the known magnetic susceptibility throughout the procedure.] Fill the susceptibility tube with
of nickel chloride hexahydrate.] Measure the length, L, in water to the black band. Insert the tube into the susceptibil-
cm, of the large-bore susceptibility tube, from the bottom ity balance, and adjust to zero. Remove the tube from the
of the inside of the tube to the bottom of the black band. Tare balance, pour the water from the tube, rinse the tube with
the susceptibility tube on a balance, fill it with water to the 1 M nickel chloride, and then fill the tube with fresh 1 M
bottom of the black band, and weigh again. Record the nickel chloride. Insert the tube into the balance, and record
weight, W, in g, of the water in the tube, zero the suscept- the magnetic susceptibility in cgs units. Similarly, measure
ibility balance, and then place the tube containing water in the magnetic susceptibility of 3 M nickel chloride. The bal-
the susceptibility balance. Zero the balance again. Rinse the ance readings are within 5% of the expected values, which
tube with 1 M nickel chloride, and then fill the tube with are (4.24 x lO^yCyfor 1 M nickel chloride and (12.72 x
fresh 1 M nickel chloride. Insert the tube into the suscept- 10^)/Cr for 3 M nickel chloride. Rinse the tube with well-
ibility balance, and record the magnetic susceptibility, R, in mixed Injection, then fill the tube with the Injection to the
cgs units, of 1 M nickel chloride. Calculate the Balance con- black band, and weigh. Insert the tube into the susceptibility
stant, K, by the formula: balance, and proceed as directed for the Standard solutions.
Calculate the magnetic susceptibility, in cgs units, per g of
(4.24 x \^){W x \09)/RL,
iron in the Injection by the formula:
in which 4.24 x 10~^ is the magnetic susceptibility, in cgs
\000CTRT/WI,
units, of nickel chloride hexahydrate; and the other terms are
as defined above. in which C r is the Tube constant as obtained above; R is the
Tube constant—[NOTE—For each susceptibility tube, a balance reading, in cgs units; T is the weight, in g, of the
tube constant, CT, is determined.] Measure the length of Diluted sample; W is the weight, in g, of the ferumoxides
the tube, L, in cm, from the bottom of the inside of the tube in the Diluted sample; and / is the concentration of iron,
to the bottom of the black band. Tare the tube on a balance, in mg per g, in the Injection, obtained by using specific
fill it with water to the bottom of the black band, and weigh gravity to convert the concentration of iron, in mg per
again. Record the weight, W, in g, of the water in the tube. mL, as determined in the Assay for iron, to mg per g. The
Calculate the tube constant, CT, by the formula: magnetic susceptibility is not less than 17,100 x 10"6 in cgs
KLIiW x 109), units per g of iron.

Osmolality (28#): between 325 and 365 mOsmol per kg.
Pharmacopeial Forum
Other requirements—It meets the requirements for Injec- in which Av is the absorbance of the Assay preparation; A20
tions (1) with the exception of Foreign Matter and Particu- is the absorbance of the Standard preparation containing 20
late Matter. ug per mL; S is the specific gravity of the Injection; and Wis
Assay for iron— the weight, in g, of the volume of Injection taken to prepare
Iron standard solution—Use a NIST-traceable iron stan- the Assay preparation.
dard containing 1000 ug per mL (1000 ppm). Assay for dextran—
Standard preparations—-Pipet 5.0, 10.0, 15.0, and 20.0 Control preparation—Transfer about 50 mg of USP Dex-
mL of the Iron standard solution into separate 1000-mL vol- trose RS, accurately weighed, to a 1000-mL volumetric
umetric flasks, dilute each with water to volume, and mix to flask, dilute with water to volume, mix, and filter.
obtain solutions having known concentrations of 5 ug per Standard preparation—Transfer about 50 mg of USP
mL, 10 jig per mL, 15 ug per mL, and 20 ug per mL, respec- Dextran T-10 RS, accurately weighed, to a 1000-mL volu-
tively. metric flask, dilute with water to volume, mix, and filter.
Assay preparation—Accurately weigh 100 uL of the In- Assay preparation—Transfer 0.25 g of the Injection, ac-
jection, and transfer to a test tube. Add 2 mL of hydrochloric curately weighed, to a test tube, add about 0.25 mL of hy-
acid, and mix.[NOTE—The Injection dissolves to yield a drochloric acid, then add about 9 mL of water, and mix.
medium yellow solution.] Add 2 mL of water, and then Remove the free iron from this solution by passing it
transfer the contents of the tube to a 100-mL volumetric through a cation-exchange column into a 25-mL volumetric
flask, dilute with water to volume, and mix. flask. Rinse the column with about 9 mL of water, collecting
Procedure—Using an atomic absorption spec- the washings in the 25-mL volumetric flask, dilute with
trophotometer (see Spectrophotometry and Light-Scattering water to volume, and mix.
(851)) equipped with an iron hollow-cathode lamp and an Procedure—To each of four test tubes, separately add 0.2
air-acetylene flame, set the instrument to zero with water, mL of the Assay preparation, the Standard preparation, the
and measure the absorbance, A2o, of the Standard prepara- Control preparation, and water (to be used as the blank).
tion containing 20 ug per mL at the iron emission line of Add 0.2 mL of a 5% phenol solution to each test tube.
296.7 nm. Concomitantly determine the absorbances of Mix each tube briefly on a vortex mixer, rapidly add 1.0
the Standard preparations. Calculate the iron concentration, mL of sulfuric acid to each test tube, and again mix briefly
in ug per mL, of each Standard preparation by the formula: on a vortex mixer. [Caution—Reaction is exothermic] Cov-
er the test tubes, and let stand at room temperature for at
20(As/A20),
least 15 minutes. [NOTE—The resultant solution is or-
in which As is the absorbance of the relevant Standard prep- ange-yellow in color and free of any solid material.] Mix
aration. The reading for each Standard preparation is with-
each tube on a vortex mixer. Using a suitable spec-
in 0.3ug per mL of its nominal concentration. Measure the
trophotometer, determine the absorbances of the solutions
absorbance of the Assay preparation, and calculate the con-
from the Standard preparation, the Control preparation,
tent of iron, in mg per mL, in the Injection by the formula:
and the Assay preparation against the blank at the wave-
Pharmacopeial Forum
length of maximum absorbance at about 490 nm. Calculate to volume, and mix to obtain solutions having known con-
the percent recovery of dextran in the Control preparation centrations of 5 ug per mL, 10 ug per mL, and 20 ug per
by the formula: mL.
System suitability solution—Use the filtered Standard
100(1. U)(C/CD)(AC/AS),
preparation containing 5 ug per mL.
in which 1.11 is a correction factor (to account for dextrose
Assay preparation—Transfer about 0.5 mL of the Injec-
being a monomer of dextran); C is the concentration, in mg
tion, accurately weighed, to a test tube, add 0.2 mL of hy-
per mL, of the USP Dextran T-10 RS in the Standard prep-
drochloric acid and about 9 mL of water, and mix. Remove
aration; CD is the concentration, in mg per mL, of USP Dex-
the free iron from this solution by passing the solution
trose RS in the Control preparation; and Ac and As are the
through a cation-exchange column2 into a 25-mL volu-
absorbances of the solutions from the Control preparation
metric flask. Rinse the column with about 9 mL of water,
and the Standard preparation, respectively: not less than
collecting the washings in the flask, dilute with water to vol-
90% to 110% is found. Calculate the quantity, in mg per
ume, and mix.
mL, of dextran in the volume of Injection taken by the for-
mula:
The liquid chromatograph is equipped with an ion detector
with suppressed conductivity at 30 uS, a 4-mm x 25-cm
separator column4 that contains 15-um packing L48, a 4-
in which S is the specific gravity of the Injection; C is the
mm x 50-mm guard column,5 and integrators. The flow
concentration, in mg per mL, of USP Dextran T-10 RS in the
rate is about 1 mL per minute. Chromatograph the System
Standard preparation; Wis the weight, in g, of the portion
suitability solution, and record the peak responses as direc-
of the Injection taken to prepare the Assay preparation, and
ted for Procedure: the relative standard deviation for repli-
A[f and As are the absorbances of the solutions from the As-
cate injections is not more than 3.0%.
say preparation and the Standard preparation, respectively.
Assay for citrate—
uL) of the Standard preparations and the Assay preparation
Mobile phase—Prepare a filtered and degassed 0.0375 N
into the chromatograph, record the chromatograms for about
sodium hydroxide solution. Make adjustments if necessary
16 minutes, and measure the responses for the major peaks.
Prepare a standard curve by plotting the conductivities of
Standard stock solution—Transfer 0.7776 g of trisodium
the Standard preparations versus their concentrations, in
citrate dihydrate to a 100-mL volumetric flask, dilute with
ug per mL. Determine the concentration, C, in ug per mL,
water to volume, filter, and refrigerate. This solution con-
of citrate in the Assay preparation by extrapolation from the
tains 5000 fig of citrate per mL (5000 ppm).
standard curve. Calculate the quantity, in mg per mL, of ci-
Standard preparations—Transfer 10 mL of Standard
trate in the volume of Injection taken by the formula:
stock solution to a 100-mL volumetric flask, dilute with
water to volume, and mix. Transfer 1.0, 2.0, and 4.0 mL
2
AG 50W-X8 (H+), available from Biorad.
of this solution to separate 100-mL volumetric flasks, add 3
DX-500, available from Dionex Corporation or equivalent source.
4
0.8 mL of hydrochloric acid to each flask, dilute with water HPIC IonPac AS5 or equivalent
5
HPIC IonPac AG5 or equivalent
Pharmacopeial Forum
0.025C(W), Erratum:
Assay, line 3 under Chromatographic system: Change "4.6-mm
in which S is the specific gravity of the Injection; and W\s x 25-cm column that contains 4-u.m packing L7" to: 4.0-mm x
25-cm column that contains 10-um packing L7.
the weight, in g, of the volume of Injection taken to prepare
the Assay preparation. AUSP26
BRIEFING
Ganciclovir, page 301 of PF 28(2) [Mar.-Apr. 2002]. A change

BRIEFING to the Definition is proposed to be consistent with the instructions
for the Assay preparation in the Assay.
Fluorodopa F 18 Injection, USP 25 page 753. It is proposed to
reinstate Identification test B that was previously official in USP 24 (PA7: S. Dressman) RTS—36737-1
because the test in USP 25 references a Radiochemical purity test
that was previously proposed but subsequently cancelled.
(RMI: F. Barletta) RTS—36521-1 Add the following:

A
Ganciclovir
Change to read: (Chemical structure to come)
Radionuclide identification (see Radioactivity (821))—
A: Its half-life, determined using a suitable detector system, is
between 105 and 115 minutes. C9H13N5O4 255.23
B: Radiochemical identity—Tho retention timo of tho major
peak in tho ohromatogram of tho Test solution oorrooponds, within 6//-Purin-6-one, 2-amino-l,9-dihydro-9-[[2-hydroxy-l-
+ 10%, to that in tho ohromatogram of tho Standard solution, aa
obtained in tho tost for Radiochemical purity. (hy droxymethy l)ethoxy ] methyl] -.
"Its gamma-ray spectrum is identical to that of a specimen 9-[[2-Hydroxy-l-(hydroxymethyl)ethoxy]methyl]gua-
of 18F in that it exhibits a major photopeak at 0.511 MeVand nine [82410-32-0]
possibly a sum peak of 1.022 MeV dependent on geometry

and detector efficiency. B1
» Ganciclovir contains not less than 98.0 percent
and not more than 102.0 percent of C9H13N5O4,
calculated on the
•previously, j
dried basis.
BRIEFING
Packaging and storage—Preserve in well-closed contain-
Flurbiprofen Sodium, USP 25 page 771. ers.
(PA2: J. Kelly) RTS—36519-1 USP Reference standards (11)—USP Ganciclovir RS.
USP Ganciclovir Related Compound A RS.
Identification—
A: Infrared Absorption (197K).
Pharmacopeial Forum
B: Ultraviolet Absorption (197U)— System suitability solution—Dissolve accurately weighed

Solution: 10 (j.g per mL. quantities of USP Ganciclovir RS and USP Ganciclovir Re-
Medium: methanol. lated Compound A RS in Mobile phase, sonicating if nec-
Water, Method I (921): not more than 6.0%. [NOTE—Gan- essary, to obtain a solution having a known concentration of
ciclovir is extremely hygroscopic] about 0.1 mg of each per mL.
Residue on ignition (281): not more than 0.1%. Standard preparation—Dissolve an accurately weighed
quantity of USP Ganciclovir RS, previously dried under va-
cuum at 80° for 3 hours, in Mobile phase, and dilute quan-
titatively, and stepwise if necessary, with Mobile phase to
Mobile phase, System suitability solution, and
0.22 mg per mL.
Test solution—Transfer about 5 mg 11 mg of Ganciclovir,
Assay preparation—Transfer about 11 mg of Ganciclovir,
previously dried under vacuum at 80° for 3 hours and accu-
and dilute with Mobile phase to volume, and mix.
rately weighed, to a 50-mL volumetric flask, dissolve in and
Procedure—Inject a volume (about 20 uL) of the Test so-
dilute with Mobile phase to volume, and mix.
lution into the chromatograph, record the chromatogram,
and measure the peak responses. Calculate the percentage
of each impurity in the portion of Ganciclovir taken by
tor and a 4.6-mm x 25-cm column that contains packing
the formula:
L9. The flow rate is about 1.5 mL per minute. The column
100(r,/r,), temperature is 40°. Chromatograph the System suitability
in which r, is the peak response for each impurity in the Test solution, and record the peak responses as directed for Pro-
solution, and rs is the sum of the responses of all the peaks: cedure: the relative retention times are about 0.9 for ganci-
not more than 0.5% of ganciclovir related compound A is clovir related compound A and 1.0 for ganciclovir; the
found, and not more than 1.5% of total impurities is found. resolution, R, between ganciclovir and ganciclovir related
Assay— compound A is not less than 1.4; the column efficiency is
Trifluoroacetic acid solution—Transfer about 0.5 mL of not less than 5000 theoretical plates; the tailing factor is
trifluoroacetic acid to a 1000-mL volumetric flask, dilute not more than 4-^t 1 -4; and the relative standard deviation
with water to volume, and mix. for replicate injections is not more than 1.0%.
Mobile phase—Prepare a filtered and degassed mixture of Procedure—Separately inject equal volumes (about 20
Trifluoroacetic acid solution and acetonitrile (1:1). Make uL) of the Standard preparation and the Assay preparation
adjustments if necessary (see System Suitability under into the chromatograph, record the chromatograms, and
Chromatography (621)). measure the responses for the major peaks. Calculate the
quantity, in mg, of C9H13N5O4 in the portion of Ganciclovir
Pharmacopeial Forum
in which C is the concentration, in mg per mL, of USP Gan-

BRIEFING
ciclovir RS in the Standard preparation; and rv and rs are
Hydrocortisone, USP 25 page 852. It is proposed to revise the
the peak responses obtained from the Assay preparation and analytical procedure in the Assay from normal phase to reverse
phase HPLC because the latter is more reproducible, robust, and
the Standard preparation, respectively. AUSP26 uses a much smaller quantity of toxic organic solvents to perform
the test. The validation was performed using a Luna C18 brand of
LI packing column. Typical retention times are about 5.5 minutes
for hydrocortisone and about 9.7 minutes for the internal standard,
propylparaben.
(PA 1: C. Anthony) RTS—35126-1
BRIEFING Change to read:

Assay—
Glutaral Concentrate, USP 25 page 806 and page 60 of PF Mobile solvent—Proparo a solution oontaining butyl ohlorido,
28(1) [Jan.-Feb. 2002]—See briefing under Benzethonium Chlo- water oaturatod butyl chloride, totrahydrofuran, mcthanol, and gla-
ride Concentrate. cial aootio aoid (95:95:11:7:6).
Internal standard solution—Proparo a solution of prodnisono in
water saturated ohloroform oontaining 0.06 mg por mL.
(NL: C. Bamstein) RTS—36765-1 Standard preparation—Diooolvo an aoouratoly woighod quantity
of USP Hydrooortisono RS in Internal standard solution to obtain
a solution having a known oonoontration of about 0.1 mg por mL.
Assay preparation—Transfer about 10 mg of Hydrooortiaono,
aoouratoly woighod, to a 100 mL volumotrio flask, add Internal
Add the following: standard solution to volume, and mix.
Procedure—Injoot oqual volumes of tho Standard preparation
•Labeling—Labol it to otato The label states that this article and the Assay preparation into a suitable high prossuro liquid ohro-
matograph (ooo Chrotnatography (634-)) equipped with a 254 nm
is not intended for direct administration to humans or ani- dotootor and a suitable rooordor and oapablo of providing column
prossuro up to about 1000 pai. Tho ohromatograph is fitted with a
mals. B1 3.9 mm x 30 om stainless stool oolumn oontaining packing L3. In
a suitable ohromatogram, tho resolution factor, R, is not loss than
3.0 botwoon tho poaks for hydrooortisono and tho internal standard:
Four roplioato injections of tho Standard preparation 3how a rola-
tivo standard deviation of not moro than 2.0%. Calculate tho quan-
tity, in mg, of Catftt»<>Q» in tho portion of Hydrooortisono taken by
the formula:
in whioh C i3 tho oonoontration, in mg por mL, of USP Hydrooor

tisono FiS in tho Standard preparation; and Ry and R^ are tho poak
BRIEFING rosponso ratios of the hydrooortisono poak and tho internal standard
poak obtained from tho Assay preparation and tho Standard prep-
Glycerin, USP 25 page 808. It is proposed to delete USP Hex- aration, respectively.
ylene Glycol RS from the monograph, because this Reference
Standard was used in the test for Chromatographic purity, which 'Mobile phase—Prepare a filtered and degassed mixture
has been deleted.
of water, acetonitrile, and methanol (50:25:25). Make ad-
(EMC: C. Sheehan) RTS—36537-1 justments if necessary (see System Suitability under
Chromatography(621)).
Diluent—Prepare a mixture of methanol and water (1:1).
Change to read:
USP Reference standards (11)—USP Glycerin RS. USP Hcxy Internal standard solution—Prepare a solution of propyl-
Icnc Glycol RS.
paraben in methanol having a concentration of about 1 mg
per mL.
Pharmacopeia! Forum
Standard stock solution—Dissolve an accurately weighed in which C is the concentration, in mg per mL, of USP Hy-
quantity of USP Hydrocortisone RS in methanol to obtain a drocortisone RS in the Standard preparation; and Rv and Rs
solution having a known concentration of about 1 mg per axe the ratios of the peak response of hydrocortisone to that
mL. of propylparaben obtained from the Assay preparation and
Standard preparation—Transfer 2.0 mL of Standard the Standard preparation, respectively. B1
stock solution and 2.0 mL of Internal standard solution to
a 50-mL volumetric flask, dilute with Diluent to volume,
and mix.
Assay preparation—Transfer about 50 mg of Hydrocorti-
sone, accurately weighed, to a 50-mL volumetric flask, dis-
solve in and dilute with methanol to volume, and mix.
BRIEFING
Transfer 2.0 mL of this solution and 2.0 mL of Internal stan-
Hydrogen Peroxide Concentrate, USP 25 page 865 and page
dard solution to a 50-mL volumetric flask, dilute with Dil- 65 of PF 28(1) [Jan.-Feb. 2002]—See briefing under Benzetho-
nium Chloride Concentrate. The new statement is proposed for
uent to volume, and mix. adoption in addition to the current Labeling requirement, which
was not meant to be removed.
packing LI. The flow rate is about 1 mL per minute. Chro- Change to read:
matograph the Standard preparation, and record the peak "Labeling—Label it to indicate the name and amount of any
added preservative.
responses as directed for Procedure: the relative retention Label it to state The label states that this article is not intended for
direct administration to humans or animals.-,
times are about 1.8 for propylparaben and 1.0 for hydrocor-
tisone; the resolution, R, between the hydrocortisone and
propylparaben peaks is not less than 9.0; the column effi-
ciency is not less than 3000 theoretical plates for hydrocor-
tisone; the tailing factor is not more than 1.2; and the relative
BRIEFING
2.0%.
Procedure—Separately inject equal volumes (about 10 Indocyanine Green, USP 25 page 904. As the current definition
does not adequately describe the article of commerce, it is pro-
uL) of the Standard preparation and the Assay preparation posed to change the rubric from "not less than 94.0 percent and
not more than 105.0 percent of C^H^^NaOgS^, calculated on
into the chromatograph, record the chromatograms, and the dried basis" to "not less than 89.0 percent and not more than
100.0 percent of C^H^N^NaOgS,, calculated on the dried basis."
In the absence of any significant adverse comment, it is proposed to
measure the responses for the major peaks. Calculate the implement these revisions via the Fourth Interim Revision An-
nouncement pertaining to USP 25-NF 20, with an official date
quantity, in mg, of C21H30O5 in the portion of Hydrocorti- of August 1,2002.
sone taken by the formula:
(GTB: I. DeVeau) RTS—36283-1
Pharmacopeial Forum
Change to read:
» Indocyanine Green contains not less than 91.0 per BRIEFING

cent and not moro than 105.0 porcont
Lactulose Concentrate, USP 25 page 983 and page 71 of PF
•89.0 percent and not more than 100.0 percent#4 28(1) [Jan.-Feb. 2002]. This monograph includes an erratum. In
of C43H47N2NaO6S2, calculated on the dried basis. It addition, see also the briefing under Benzethonium Chloride Con-
contains not more than 5.0 percent of sodium iodide, centrate for the Labeling revision.
calculated on the dried basis.
(PA4: A. Medjedovic; NL: C. Barnstein) RTS—36376-1;
36768-1
Change to read:
Assay—Dissolve a quantity of Indocyanine Green, equivalent to
about 100 mg of dried indocyanine green and accurately weighed,
in methanol, and dilute quantitatively and stepwise with methanol Erratum:
to obtain a solution containing about 2 fig per mL. Dissolve a quan- Related compounds, line 11 under Procedure: Change "and the
tity of USP Indocyanine Green RS, accurately weighed Standard solutions respectively: not more than 16% of galactose is
*and corrected for labeled purity, -4 found; not more than 12% of lactose is found; not more than 8% of
in methanol, and dilute quantitatively and stepwise with methanol epilactose is found; and not more than 1% of fructose is found." to:
to obtain a Standard solution having a known concentration of and the Standard solution, respectively: relative to lactulose, not
about 2 (Xg per mL. Concomitantly determine the absorbances of more than 16% of galactose is found, not more than 12% of lactose
both solutions in 1-cm cells at the wavelength of maximum absor- is found, not more than 8% of epilactose is found, and not more
bance at about 785 nm, with a suitable spectrophotometer, using than 1 % of fructose is found.
methanol as the blank. Calculate the quantity, in mg, of
C43H47N2NaO6S2 in the Indocyanine Green taken by the formula: Add the following:
5QC{AV/AS\ "Labeling—Label it to Qtato
in which Cis the concentration, in ug per mL, of USP Indocyanine
Green RS in the Standard solution, and Av and As are the absor- The label states that this article is not intended for direct ad-
bances of the solution of Indocyanine Green and the Standard so-
lution, respectively. ministration to humans or animals.B1
BRIEFING BRIEFING
Isosorbide Concentrate, USP 25 page 965 and page 71 of PF Lansoprazole Delayed-Release Capsules, page 1295 of P F
28(1) [Jan.-Feb. 2002]—See briefing under Benzethonium Chlo- 26(5) [Sept.-Oct. 2000]. On the basis of comments received, it is
ride Concentrate. proposed to make some changes for further clarification of the test
for Drug release.
Add the following:

•Labeling—Label it to otato The label states that this article
is not intended for direct administration to humans or ani-
mals. _,
Pharmacopeial Forum
Add the following: by employing UV absorption at the wavelength of maxi-

•Lansoprazole Delayed-Release mum absorbance at about 306 nm, using Acid stage medium
Capsules as the blank. Concomitantly determine the absorbance of the
Acid stage test solution in comparison with a solution of
USP Lansoprazole RS, having a known concentration
» Lansoprazole Delayed-Release Capsules con- equivalent to about 8% of the labeled amount of lansopra-
tain not less than 90.0 percent and not more than zole dissolved per 500 mL of Acid stage medium. A volume
110.0 percent of the labeled amount of lansopra- of methanol not to exceed 0.5% of the total volume of the
zole Standard solution may be used to dissolve USP Lansopra-
zole RS prior to dilution with Acid stage medium.
Packaging and storage—Store in a tight container at con-
Tolerances—Not more than 10% of the labeled amount of
trolled room temperature.
C16H14F3N3O2S is dissolved in 60 minutes.
USP Reference standards (11)—USP Lansoprazole RS.
BUFFER STAGE—
USP Lansoprazole Related Compound A RS.
Buffer concentrate—Transfer 65.4 g of monobasic so-
Identification—
dium phosphate, 28.2 g of sodium hydroxide, and 12 g of
A: Ultraviolet Absorption (197U)—
sodium dodecyl sulfate to a suitable container, and add en-
Medium: methanol.
ough water to dissolve. Dilute with water to 4 liters, and mix
Procedure—Powder a portion of Capsule contents
well.
equivalent to 5 mg of lansoprazole. Add 5 mL of methanol,
Blank solution—Prepare a mixture of Acid stage medium
shake well, and centrifuge. To 0.1 mL of the supernatant,
and Buffer concentrate (19:17). Adjust, if necessary, with
add 10 mL of methanol.
either phosphoric acid or sodium hydroxide to a pH of 6.8.
B: The retention time of the major peak in the chroma-
Test solution—Add 425 mL of Buffer concentrate to the
togram of the Assay preparation corresponds to that in the
remaining 475 mL of solution in each vessel from the Acid
chromatogram of the Standard preparation, as obtained in
stage. Adjust, if necessary, with either phosphoric acid or
the Assay.
sodium hydroxide to a pH of 6.8.
Drug release, Method A (724)—
ACID STAGE—
Time: 60 minutes.
Acid stage medium: 0.1 M N hydrochloric acid; 500 mL. Procedure—At tho end of 60 minutes, Determine the
Apparatus 2: 75 rpm. amount of C^H^F^NsC^S dissolved in filtered portions of
Time: 60 minutes. the Test solution, using the difference between the U ¥ ab-
Procedure—After-1 hour of operation in 0.1 M hydro sorbances at the wavelengths of about 286 nm and 650 nm,
chloric aoid,Withdraw a 25-mL aliquot and then proceed with Blank solution as the blank. Concomitantly determine
immediately as directed for Test solution in the Buffer stage the absorbances of the Test solution in comparison with the
leaving with the remaining 475 mL in the vessel for use in solution of USP Lansoprazole RS having a known concen-
the Buffer stage. Using tho 25 mL a filtered portion of the tration in tho Blank solution equivalent to about 70% of the
aliquot, determine the amount of C ^ H ^ N3O2S dissolved
Pharmacopeial Forum
labeled amount of lansoprazole dissolved in 900 mL of Loss on drying (731)—Dry about 1 g of the Capsule con-
Blank solution. An amount of methanol not to exceed 2% tents in vacuum over phosphorus pentoxide at a pressure not
of the total volume of the Standard solution may be used exceeding 5 mm of mercury at 60° for 5 hours: it loses not
to dissolve USP Lansoprazole RS prior to dilution with more than 5.0% of its weight.
Blank solution. Assay—
Tolerances—Not less than 80% (Q) of the labeled amount Diluent, Mobile phase, and Resolution solution—Prepare
of C16H14F3N3O2S is dissolved in 60 minutes. as directed in the Assay under Lansoprazole.
Uniformity of dosage units (905): meet the requirements. Internal standard solution—Dissolve an accurately
PROCEDURE FOR CONTENT UNIFORMITY— weighed quantity of 4'-ethoxyacetophenone in acetonitrile
Test solution—Transfer the contents of 1 Capsule to a to obtain a solution having a known concentration of about
100-mL volumetric flask, add 30 mL of 0.1 M sodium hy- 7.5 mg per mL.
droxide, and sonicate to disintegrate. Add 65 mL of aceto- Standard preparation—Dissolve an accurately weighed
nitrile, cool, and dilute with acetonitrile to volume. quantity of USP Lansoprazole RS in a mixture of 0.1 M so-
Centrifuge a portion of the suspension and pass through a dium hydroxide and acetonitrile (3:2) to obtain a solution
membrane filter having a 0.5-um or finer porosity. Quanti- having a known concentration of 3.0 mg per mL. Transfer
tatively dilute a volume of the filtrate with a mixture of ace- 25.0 mL of this solution and 5.0 mL of Internal standard
tonitrile and 0.1 M sodium hydroxide (7:3) to obtain a solution to a 50-mL volumetric flask, dilute with Diluent
solution containing about 0.012 mg of lansoprazole per mL. to volume, and mix. Dilute quantitatively with Diluent to
Procedure—Concomitantly determine the absorbances of obtain a solution having a known concentration of about
the Test solution and a solution of USP Lansoprazole RS in 0.1 mg of USP Lansoprazole RS per mL.
the same medium and having a known concentration of Assay preparation—Transfer the contents of not fewer
about 0.012 mg of lansoprazole per mL, in 1-cm cells, at than 10 Capsules, equivalent to about 300 mg of lansopra-
the wavelength of maximum absorbance at about 294 nm, zole, to a 300-mL conical flask containing 60.0 mL of 0.1 M
with a suitable spectrophotometer, using a mixture of aceto- sodium hydroxide, and sonicate until completely disinte-
nitrile and 0.1 M sodium hydroxide (7:3) as the blank. Cal- grated. Add 20.0 mL of acetonitrile and 20.0 mL of Internal
culate the quantity, in mg, of Ci6H14F3N3O2S in the Capsule standard solution, shake well, and centrifuge a portion of
taken by the formula: the suspension. Quantitatively dilute a volume of the super-
natant with Diluent to obtain a solution containing about 0.1
mg of lansoprazole per mL, and pass through a membrane
in which L is the labeled quantity of lansoprazole in the Cap-
filter having a 0.5-um or finer porosity.
sule; C is the concentration, in mg per mL, of USP Lanso-
prazole RS in the Standard solution; D is the concentration,
in mg per mL, of lansoprazole in the Test solution, based on
tor and a 4.6-mm x 25-cm column that contains 5-fim
the labeled quantity of lansoprazole per Capsule and the ex-
packing LI. The flow rate is about 1 mL per minute. Chro-
tent of dilution; and Av and As are the absorbances of the
matograph the Resolution solution, and record the peak re-
Pharmacopeial Forum
sponses as directed for Procedure: the resolution, R, be-

Percentage
tween the two major peaks is not less than 5. Chromato- (%, for
Concentration comparison
graph the Standard preparation, and record the peak Standard (ugRS with test
preparation Dilution per mL) specimen)
responses as directed for Procedure: the relative standard (Undiluted) 500
A 1.0
deviation for replicate injections is not more than 2.0%. B 5 in 10 250 0.5
C 1 in 5 100 0.2
D (Undiluted) 500 1.0
E 5 in 10 250 0.5
F 1 in 5 100 0.2
uL) of the Standard preparation and the Assay preparation
into the chromatograph, record the chromatograms, and Test preparation—Dissolve an accurately weighed quantity of
Mafenide Acetate in methanol to obtain a solution containing 50
measure the peak responses. Calculate the quantity, in mg, mg per mL.
Identification preparation—Quantitatively dilute a portion of the
of lansoprazole (CieH^FsNaC^S) in each Capsule taken by Test preparation with methanol to obtain a solution containing 500
ug per mL.
the formula: Ninhydrin solution—Dissolve 300 mg of trikotohydrindono hy
•ninhydrin_j
in 100 mL of butyl alcohol, add 3 mL of glacial acetic acid, and
mix.
in which L is the labeled quantity, in mg, of lansoprazole in Procedure—Apply separately 5 uL of the Test preparation, 5 uL
of the Identification preparation, and 5 uL of each Standard prep-
each Capsule taken; C is the concentration, in mg per mL, of aration to a suitable thin-layer chromatographic plate (see
Chromatography (621)) coated with a 0.25-mm layer of chroma-
USP Lansoprazole RS in the Standard preparation; D is the tographic silica gel mixture. Position the plate in a chromato-
graphic chamber, and develop the chromatograms in a solvent
concentration, in mg per mL, of lansoprazole in the Assay system consisting of a mixture of ethyl acetate, methanol, and iso-
propylamine (77:20:3) until the solvent front has moved about
preparation, based on the labeled quantity of lansoprazole three-fourths of the length of the plate. Remove the plate from
the developing chamber, mark the solvent front, and allow the sol-
in the Capsules taken and the extent of dilution; and Rv and vent to evaporate in warm, circulating air. Examine the plate under
short-wavelength UV light, and compare the intensities of any sec-
Rs are the peak response ratios obtained from the Assay ondary spots observed in the chromatogram of the Test preparation
at the RF value corresponding to those of the principal spots in the
preparation and the Standard preparation, respectively. B1 chromatograms of Standard preparations D, E, and F. Spray the
plate with the Ninhydrin solution, heat the plate at 105° for 5 min-
utes, and examine the plate. Compare the intensities of any second-
ary spots observed in the chromatogram of the Test preparation to
those of the principal spots in the chromatograms of Standard pre-
parations A, B, and C. No secondary spot, observed by both visua-
lizations, from the chromatogram of the Test preparation is larger
or more intense than the principal spots obtained from Standard
preparation B (0.5%) and Standard preparation E (0.5%), and
the sum of the intensities of all secondary spots obtained from
the Test preparation corresponds to not more than 1.0%.
BRIEFING
Mafenide Acetate, USP 25 page 1028—See briefing under

Bacitracin.
BRIEFING
Change to read:
Chromatographic purity— Methyldopa, USP 25 page 1120—See briefing under Bacitra-
Standard preparations—Dissolve USP Mafenide Acetate RS in cin.
methanol, mix to obtain Standard preparation A having a known
concentration of 500 ug per mL, dissolve USP 4-Formylbenzene-
sulfonamide RS in methanol, and mix to obtain Standard prepara- (BPC: M. Marques) RTS—36575
tion D having a known concentration of 500 ug per mL.
Quantitatively dilute portions of these solutions with methanol to
obtain Standard preparations having the following compositions:
Pharmacopeial Forum
Change to read: ocycline Hydrochloride, including the current USP Minocycline

Identification— Hydrochloride RS, provision is made to omit the preparation of
A: Infrared Absorption (197M). the Resolution solution if the presence of epiminocycline is evident
B: Ultraviolet Absorption (197U)— in the chromatogram of the Standard preparation, and that the re-
Solution: 40 ug per mL. quired resolution is achieved. The concentration of the Standard
Medium: 0.1 N hydrochloric acid. Absorptivities at 280 nm, cal- preparation and the Assay preparation is changed to 0.25 mg
culated on the anhydrous basis, do not differ by more than 3.0%. per mL, instead of 0.5 mg per mL, so that the same solution can
C: To 10 mg add 0.15 mL of a solution of trikotohydrindcno be used for both the test for Chromatographic purity and the Assay.

•ninhydririj,
in sulfuric acid (1 in 250): a dark purple color is produced within 5
to 10 minutes. Add 0.15 mL of water: the color changes to pale
brownish yellow.
Change to read:
Chromatographic purity—Calculate tho aroa percentage of each
peak (oxoopt tho oolvent peak) obgcrved in tho ohromatogram of
tho Assay preparation obtained in tho Assay: cpiminooyolino, if
present, haa a rotontion timo-of about 0.86 0.76 rolative to that of
minocyolino and oon3tituto3 not more than 1.2% of tho total aroa,
and tho sum of any othor oxtranoous poaka oonatitutoa not moro
than 2.0% of tho total aroa.
'Mobile phase, Resolution solution, Assay preparation,

BRIEFING
Methyldopa Tablets, USP 25 page 1122—See briefing under
Bacitracin. Assay.
Test solution 1—Transfer about 25 mg of Minooyolino

Hydrochloridc, accurately weighed, to a 100 mL volumotrio
flask, dilute with water to volume, and mix. Use the Assay
Change to read: preparation. Protect this solution from light, store in a re-
Identification—
A: To about 10 mg of finely ground Tablets add 3 drops of a frigerator, and use within 3 hours.
solution of trikotohydrindono hydrato
Test solution 2—Transfer 1.0 mL of Test solution 1 to a
•ninhydririj,
in sulfuric acid (1 in 250): a dark purple color is produced within 5 50-mL volumetric flask, dilute with water to volume, and
to 10 minutes. Add 3 drops of water: the color changes to pale
brownish yellow. mix. Protect this solution from light, store in a refrigerator,
B: To about 10 mg of finely ground Tablets add 2 mL of 0.1 N
sulfuric acid and 2 mL of Ferrous tartrate solution prepared as di- and use within 3 hours.
rected in the Assay, then add 0.25 mL of 6 N ammonium hydrox-
ide, and mix: a dark purple color is produced immediately. Test solution 3—Transfer 6.0 mL of Test solution 2 to a
10-mL volumetric flask, dilute with water to volume, and
mix. Protect this solution from light, store in a refrigerator,
and use within 3 hours.
uL) of Test solution 1, Test solution 2, and Test solution 3
BRIEFING
into the chromatograph, record the chromatograms, and
Minocycline Hydrochloride, USP 25 page 1158 and page 3022 measure the areas for all the peaks. Tho relative standard do
of PF 27(5) [Sept.-Oct. 2001]. Based on data and suggestions re-
ceived, several minor modifications of the proposed new liquid viation of tho minoeyclino peak responses for triplicate in
chromatographic procedures for Chromatographic purity and As-
say are presented for public review and comment. It has been de- jootions of Test solution'1 is not more than 2%, and for
monstrated that the Hypersil BDS C18 brand of base-deactivated
LI column performs as well as the Hypersil ODS brand of LI col-
umn and yields somewhat better separation of impurities. In view triplicate injootions of Test solution 2 and Test solution 3 it
of the fact that epiminocycline is a consistent component of Min-
is not moro than 5%. [NOTE—Record the chromatogram of
Pharmacopeial Forum
Test solution 1 for a period of time that is about 2.6 times the Standard preparation—Dissolve an accurately weighed quantity
of USP Minocycline Hydrochloride RS in water to obtain a solu-
retention time of minocycline.] Calculate the percentage of tion having a known concentration of about §QQ
•250 B 1
epiminocycline in the portion of Minocycline Hydrochlor- ug of minocycline (C23H27N3O7) per mL.
ide taken by the formula: "Use this solution within 3-hours: Protect the solution from
light, store in a refrigerator, and use within 3 hours.
\2rE1lrm,
Resolution solution—Proparo a solution in water containing 2
in which rEl is the average response of tho opiminooyolino mg of USP Minooyolino Hydroohlorido RS por mL. Transfer 5
mL of this oolution to a 25 mL volumotrioflask,heat on a atoam
peak in the ohromatograms peak response for epiminocy- bath for 60 minutoo, and cool. Dilute with water to volume, and
cline obtained from Test solution 1; and rm is the average •[NOTE—To be prepared if the chromatogram of the Stan-
of tho minooyolino peak responses rooponoo in tho ohroma dard preparation does not show a peak for epiminocycline
togramsohromatogram peak response for minocycline ob- at a retention time of about 0.7 in relation to the main peak
tained from Test solution 3. Not more than 1.2% is found. for minocycline.] Transfer 10 mg of USP Minocycline Hy-
Calculate the total percentage of impurities other than epi- drochloride RS to a 25-mL volumetric flask, add 20 mL of
minocycline in the portion of Minocycline Hydrochloride 0.2 M ammonium oxalate, and swirl to dissolve. Heat on a
taken by the formula: water bath at 60° for 180 minutes, and allow to cool. Dilute
with water to volume, and mix.B1
Assay preparation—Transfer an accurately weighed quantity of
in which rs is the sum of the responses of all impurity peaks Minocycline Hydrochloride, equivalent to about #0
other than epiminocycline in tho ohromatogram obtained "25
mg of minocycline (C23H27N3O7), to a 100-mL volumetric flask,
from Test solution 1; and rm is tho avorago of the peak re- add water to volume, and mix.
•Protect the solution from light, store in a refrigerator, and
sponse for minocycline in tho ohromatograms ohromato
use within 3 hours.B1
gram obtained from Test solution 2. Not more than 2.0%
of other impurities is found. Bl quid chromatograph is equipped with a 280-nm detector a 4.6 mm
)( 3 om guard column that oentaina 10 [im packing L7,
Change to read: and a 4.6-mm x 15 om
Assay—
Mobile phase—Proparo a ouitablo mixture of 0.2 M ammonium '25-cm.
oxalato, dimothylformamido, and 0.1 M diaodium othylonodiami
nototraaootato (550:250:200). Adjuat with 0.<1 M totrabutylammo
nium hydroxide? to a pH botwoon 6.2 and 6.5 for optimal roaolution, column that contains 5-um packing fe2
and filter through a membrane? filter (0.5 |xm or finer porooity). •LI ,
"Prepare a mixture of 0.2 M ammonium oxalate, 0.1 M 0.01 The flow rate is about 3
M edetate disodium, dimethylformamide, and tetrahydro- •1-5.,

mL per minute. Chromatograph the Standard preparation, and re-
furan (600:180:120:80). Adjust with 25% ammonia solution cord the peak responses as directed fox Procedure: the capacity fac-
tor, K, is not less than 6.2 5.9
ammonium hydroxide to a pH of TÔ? 7.2, and pass through
ana not more than 11.5; the tailing factor for the analyte peak is not
a filter having a 0.5-um or finer porosity. Make adjustments less than 0.9 and not more than 3
if necessary (see System Suitability under Chromatography , B1

and the relative standard deviation for replicate injections is not
<621». m more than 2.0%. Chromatograph
Pharmacopeial Forum
•[NOTE—If the chromatogram of the Standard preparation Packaging and storage—Preserve in light-resistant, her-
does not show a peak for epiminocycline at a retention time metic containers.
of about 0.7 in relation to the main peak for minocycline,
Labeling—Label it to state The label states that this article
chromatograph-,
is not intended for direct administration to humans or ani-
the Resolution solution and record the peak responses as directed
for Procedure: the relative retention times are about 0.8 0.76 mals.
-7-i .
for epiminocycline and 1.0 for minocycline; and the resolution, R, USP Reference standards (11)—USP Misoprostol RS.
between epiminocycline and minocycline is not less than 2.0 4.2.
USP Misoprostol Related Compound A RS. USP Misopros-
•4.6.].,
tol Related Compound B RS. USP Misoprostol Related
•20 Compound C RS.
uL) of the Standard preparation and the Assay preparation into the
chromatograph, record the chromatograms, and measure the re- Identification—
sponses for the major peaks. Calculate the quantity, in ug per
mg, of minocycline (C23H27N3O7), in the portion of Minocycline A: Ultraviolet Absorption (197U)—
Hydrochloride taken by the formula:
Solution 1: 1.6 mg per mL.
100(0 W)(ru/rs),
in which C is the concentration, in ug per mL, of minocycline Medium: a mixture of methanol and water (4:1). The so-
(C23H27N3O7) in the Standard preparation; W is the weight, in
mg, of Minocycline Hydrochloride taken; and rv and rs are the lution does not exhibit a maximum near 280 nm, when com-
peak responses obtained from the Assay preparation and the Stan-
dard preparation, respectively. pared to a blank solution containing hydroxypropyl
methylcellulose.
Solution 2: 0.08 mg per mL, prepared from Solution 1.
Medium: a 50% mixture of methanol and water (4:1) and
methanol and 1 N potassium hydroxide (4:1). After 30 min-
utes, the solution exhibits a maximum near 280 nm, when
BRIEFING compared to a blank solution containing hydroxypropyl
Misoprostol Dispersion, page 76 of PF 28(1) [Jan.-Feb. methylcellulose.
2002]—See briefing under Benzethonium Chloride Concentrate.
B: The retention time of the major peak in the chroma-
(NL: C. Bamstein) RTS—36769-1 togram of the Assay preparation corresponds to that in the
chromatogram of the Standard preparation, as obtained in
Add the following: the Assay.
•Misoprostol Dispersion Water, Methodic (921): not more than 1.5%, using a sam-
ple of 300 mg 40 to 110 mg.
» Misoprostol Dispersion is a mixture of Miso-
prostol and Hydroxypropyl Methylcellulose
Diluent, Phosphate buffer, and Mobile phase—Prepare as
(1:100). It contains not less than 9$& 90.0 percent directed in the Assay.
and not more than 105.0 110.0 percent of the la- Standard solution 1—Dissolve accurately weighed quan-
beled amount of misoprostol (C22H38O5). tities of USP Misoprostol Related Compound A RS, USP
Misoprostol Related Compound B RS, and USP Misopros-
Pharmacopeial Forum
tol Related Compound C RS in Mobile phase Diluent to ob- in the Test solution; and rv and rs are the peak areas obtained
tain a solution having known concentrations of about 0.1 jag from the Test solution and Standard solution 2, respectively:
of each USP Reference Standard per mL. not more than 0.3% of misoprostol related compound B is
Standard solution 2—Dissolve accurately weighed quan- found; not more than 0.5% of misoprostol related com-
tities of USP Misoprostol Related Compound A RS, USP pound A is found; and not more than 0.5% of misoprostol
Misoprostol Related Compound B RS, and USP Misopros- related compound C is found. Calculate the percentage of
tol Related Compound C RS in Diluent to obtain a solution any unknown impurities using the same formula, in which
having known concentrations of about 0.5, 0.3, and 0.5 (ig Cs is the concentration, in mg per mL, of USP Related Com-
per mL, respectively. pound C RS in Standard solution 2; rv is the peak response
System suitability solution—Dissolve accurately weighed of any unknown impurity obtained from the Test solution; rs
quantities of USP Misoprostol RS, USP Misoprostol Re- is the peak response of misoprostol related compound C ob-
lated Compound A RS, USP Misoprostol Related Com- tained from Standard solution 2; and the other term is as
pound B RS, and USP Misoprostol Related Compound C defined therein: not more than 0.5% of any unknown indi-
RS in a mixture of water and ioopropyl alcohol (4:1) Diluent vidual impurity is found; not more than 1.0% of total un-
to obtain a solution having concentrations of about 0.1 mg known impurities is found; and not more than 2.3% of
per mL, 0.5 ug per mL, 0.5 ug per mL, and 0.3 ug per mL, total impurities is found.
respectively. Assay—
Test solution—Use the Assay preparation. Diluent—Prepare a mixture of water and isopropyl alco-
Chromatographic system—Prepare as directed in the As- hol (73:27).
say. Chromatograph Standard solution 1, and record the Phosphate buffer—Transfer 1.36 g of monobasic potassi-
peak areas as directed for Procedure: the resolution, R, be- um phosphate to a 1000-mL volumetric flask, add 990 mL
tween misoprostol and misoprostol related compound C is of water, adjust with phosphoric acid to a pH of 3.0, dilute
not less than 0.9; and the relative standard deviation for re- with water to volume, and mix.
plicate injections is not less than 2.0%. Mobile phase—Prepare a filtered and degassed mixture of
Procedure—Separately inject equal volumes (about 100 Phosphate buffer and isopropyl alcohol (73:27). Make ad-
uL) of Standard solution 1, Standard solution 2, the System justments if necessary (see System Suitability under
suitability solution, and the Test solution into the chromato- Chromatography (621)).
graph, record the chromatograms, and measure the areas for Standard preparation—Dissolve an accurately weighed
the major peaks. Calculate the percentage of the relevant re- quantity of USP Misoprostol RS in a mixture of wator and
lated compound in the portion of Dispersion taken by the ioopropyl aloohol (1:1) Diluent to obtain a solution having a
formula: known concentration of about 0.1 mg of misoprostol per
\0,\00(Cs/CaXry/rs), mL.
in which Cs is the concentration, in mg per mL, of the rele-

vant USP Reference Standard in Standard solution 2; Cv is
the concentration, in mg per mL, of Misoprostol Dispersion
Pharmacopeial Forum
Assay preparation—Dissolve an accurately weighed Chromatographic purity, line 1 under Mobile phase: Change
"Prepare a mixture of 0.005 M sodium 1-octane sulfonate, aceto-
quantity of Misoprostol Dispersion in a mixture of water nitrile, and triethylamine (580:420:1)," to: Prepare a mixture of
water, acetonitrile, and triethylamine (580:420:1) containing
and isopropyl alcohol (75:25) Diluent to obtain a solution 0.005 M sodium 1-octane sulfonate,
Assay, line 1 under Mobile phase: Change "Prepare a mixture of
having a concentration of about 10 mg per mL. 0.005 M sodium 1-octane sulfonate, acetonitrile, glacial acetic
acid, and triethylamine (580:420:2:1)." to: Prepare a mixture of
Chromatographic system (see Chromatography (621))— water, acetonitrile, glacial acetic acid, and triethylamine
(580:420:20:1) containing 0.005 M sodium 1-octane sulfonate.
tor and a 4.6-mm x 15-cm column that contains packing
L7. The flow rate is about 1.5 mL per minute. Chromato-
graph the Standard preparation, and record the peak areas
as directed for Procedure: the relative retention time for
misoprostol is about 12 minutes.
BRIEFING
Neomycin and Polymyxin B Sulfates and Pramoxine Hydro-
uL) of the Standard preparation and the Assay preparation chloride Cream, USP 25 page 1214—See briefing under Bacitra-
into the chromatograph, record the chromatograms, and

measure the areas for the major peaks. Calculate the quan-
tity, in mg, of misoprostol (C22H38O5) in the portion of the
Dispersion taken by the formula: Change to read:
Identification—
A: Thin-Layer Chromatographic Identification Test (201)—
Test solution—Disperse a quantity of Cream, equivalent to about
25 mg of neomycin, with 20 mL of chloroform in a 60-mL separa-
in which Fis the volume, in mL, of solution used to prepare tor. Add 0.2 mL of 2.5 N hydrochloric acid, and shake. Allow the
layers to separate for about 30 minutes. Discard the lower chloro-
the Assay preparation; C is the concentration, in mg per mL, form layer, and centrifuge the upper aqueous layer. Use a portion of
the centrifuged aqueous layer.
of USP Misoprostol RS in the Standard preparation; and rv Standard solution—Dissolve suitable quantities of USP Neomy-
cin Sulfate RS and USP Polymyxin B Sulfate RS in 0.1 N hydro-
and rs are the peak areas obtained from the Assay prepara- chloric acid to obtain a solution containing the equivalent of about
3.5 mg of neomycin and 10,000 USP Polymyxin B Units per mL.
tion and the Standard preparation, respectively.B1 Developing solvent system—Dissolve 0.1 g of benzalkonium
chloride in a mixture of isopropyl alcohol, water, and ammonium
hydroxide (60:40:10).
Procedure—Proceed as directed in the chapter. Place the plate in
a chromatographic chamber saturated with Developing solvent sys-
tem, and develop the chromatogram. Dry the plate at 105° for about
10 minutes, spray with a solution of trikotohydrindono hydrate
•ninhydrin-j
in butyl alcohol (1 in 200), and heat the plate at 105° for about 15
minutes. The RF values of the two principal spots in the chromato-
gram obtained from the Test solution correspond to those of the two
BRIEFING principal spots in the chromatogram obtained from the Standard
solution.
Moricizine Hydrochloride, USP 25 page 1171. B: The retention time of the major peak in the chromatogram
(PA5: J. Esker) RTS—36337-1 of the Standard preparation, as obtained in the Assay for pramox-
ine hydrochloride.
Errata:
Identification, line 5 under test C: Change "0.25-cm" to: 0.25-
mm
Pharmacopeial Forum
Medium—Mix 125.0 mL of Buffer concentrate and 1 liter of

10% sodium lauryl sulfate solution, and dilute to 10 liters. Adjust
BRIEFING if necessary to a pH of 6.8; 900 mL.
Nifedipine Extended-Release Tablets, USP 25 page 1229 and Times: 3, 6, and 12 hours.
page 2746 of the First Supplement. It is proposed to add a Test 3 Determine the amount of nifedipine (Ci7Hi8N2O6) dissolved by
and a Test 4 to the test for Drug release in this monograph because employing the following method.
FDA has recently approved two new generic nifedipine extended- Mobile phase—Prepare a filtered and degassed mixture of ace-
release tablets. These two new products have different drug release tonitrile and water (70:30). Make adjustments if necessary (see
rates in vitro and do not comply with any of the current Drug re- System Suitability under Chromatography (621)).
lease tests. In the absence of any adverse comment, it is proposed Standard solution—Dissolve an accurately weighed quantity of
to implement this revision via the Fifth Interim Revision An- USP Nifedipine RS in methanol to obtain a solution having a
nouncement pertaining to USP 25-NF 20, with an official date known concentration of about 1.11 mg per mL. Dilute quantita-
of October 1, 2002. tively and stepwise with Dissolution Medium to obtain a solution
having a known concentration of 0.1 mg per mL.
(BPC: M. Marques) RTS—36597-1; 36177-1 equipped with a 350-nm detector and a 4.0-mm x 125-mm col-
umn that contains 3-um packing LI. The flow rate is about 1.5
mL per minute. The column is maintained at about 40°. Chromato-
graph the Standard solution, and record the peak responses as di-
rected for Procedure: the column efficiency is not less than 2000
Change to read: theoretical plates; the tailing factor is not more than 1.5; and the
Drug release (724)— relative standard deviation for replicate injections is not more than
Test 1: If the product complies with this test, the labeling indi- 2.0%.
cates that the product meets USP Drug Release Test 1. Procedure—Separately inject equal volumes (about 20 uL) of
Medium: water; 50 mL. filtered portions of the Standard solution and the solution under
Apparatus 7—Do not use the reciprocating disk, but use a 25-cm test into the chromatograph, record the chromatograms, and mea-
plexiglas rod, the perimeter of the Tablets being affixed to the rod sure the responses for the major peaks. Determine the amount of
with a water-insoluble glue. The solution containers are 25-mm test nifedipine (C17H18N2O6) dissolved.
tubes, 150 to 200 mm in length, and the water bath is maintained at Tolerances—The percentages of the labeled amount of nifedi-
37 ± 0.5°. pine (C16H18N2O6) released in vivo and dissolved at the times spe-
Times: 4, 12, and 24 hours. cified conform to Acceptance Table 1.
Diluting solution 1: a mixture of methanol and acetonitrile (1:1).
Diluting solution 2: a mixture of Diluting solution 1 and water Time (hours) Amount dissolved
(1:1). 3 between 10% and 30%
Standard solutions—Transfer about 50 mg of USP Nifedipine 6 between 40% and 65%
RS, accurately weighed, to a 100-mL volumetric flask, dissolve 12 not less than 80%
in 50 mL of Diluting solution 1, dilute with water to volume,
and mix to obtain a Standard stock solution. Quantitatively dilute
this Standard stock solution *Test 3: If the product complies with this test, the labeling
•with Diluting solution 2 - 5
to obtain solutions having known concentrations of 0.01 mg per indicates that it meets USP Drug Release Test 3.
mL, 0.05 mg per mL, and 0.20 mg per mL that are used at 4 hours,
12 hours, and 24 hours, respectively. FOR TABLETS LABELED TO CONTAIN 30 MG OF NIFEDIPINE—
Procedure—[NOTE—For the 4-hour time period, filter, deter-
mine the absorbance at 456 nm, and use this determination to cor- Phase 1:
rect for excipient interference at the other time periods.] Determine
the amount of C17H18N2O6 released at each 4-hour interval by em- Medium: 0.05 M phosphate buffer, pH 7.5.
ploying UV absorption at the wavelength of maximum absorbance
at about 338 nm, in 0.5-cm cells. Use test solutions that are suitably Apparatus 2: 100 rpm.
diluted, if necessary, with Diluting solution 1 and water to obtain a
final mixture of water, methanol, and acetonitrile (2:1:1) in com- Time: 1 hour.
parison with the appropriate Standard solution, using Diluting so-
lution 2 as the blank. Standard solution—Prepare a solution in Medium having
Tolerances—The cumulative percentages of the labeled amount
of nifedipine (C17H18N2O6), released in vivo and dissolved at the an accurately known concentration of about 0.034 mg of
times specified, conform to Acceptance Table 1.
USP Nifedipine RS per mL. If necessary, a volume of
4
methanol, not exceeding 10% of the final volume, can be
between 5% and 17%
12 between 43% and 80% used to help solubilize nifedipine.
24 not less than 80%
Test 2: If the product complies with this test, the labeling indi-
Procedure—[NOTE—After the run, take the Tablet out of
cates that it meets USP Drug Release Test 2. the dissolution vessel, adapt a sinker to it, and transfer the
Buffer concentrate—Transfer 330.9 g of dibasic sodium phos-
phate and 38 g of citric acid to a 1-liter volumetric flask, add water Tablet with the sinker to the dissolution vessel containing
to dissolve, add 10 mL of phosphoric acid, dilute with water to
volume, and mix. the Dissolution Medium for Phase 2.] Determine the amount
Pharmacopeial Forum
FOR TABLETS LABELED TO CONTAIN 60 MG OF NIFEDIPINE—

of C17H18N2O6 released in Phase 1 from UV absorbances at
the wavelength of maximum absorbance at about 238 nm Phase 1:
using filtered portions of the solution under test, in compar- Medium: 0.05 M phosphate buffer, pH 7.5.
ison with the Standard solution, using the Dissolution Med- Apparatus 2: 100 rpm.
ium as the blank. Time: 25 minutes.
Phase 2: Standard solution—Prepare a solution in Medium having
Medium: 0.5% sodium lauryl sulfate in simulated gastric an accurately known concentration of about 0.067 mg of
fluid without enzyme, pH 1.2; 900 mL. USP Nifedipine RS per mL. If necessary, a volume of
Apparatus 2: 100 rpm. methanol, not exceeding 10% of the final volume, can be
Times: 1, 4, 8, and 12 hours. used to help solubilize nifedipine.
Standard solution—Prepare a solution in Medium having Procedure—[NOTE—After the run, take the Tablet out of
an accurately known concentration of about 0.034 mg of the dissolution vessel, adapt a sinker to it, and transfer the
USP Nifedipine RS per mL. If necessary, a volume of Tablet with the sinker to the dissolution vessel containing
methanol, not exceeding 10% of the final volume, can be the Dissolution Medium for Phase 2.] Determine the amount
used to help solubilize nifedipine. of C17H18N2O6 released in Phase 1 from UV absorbances at
Procedure—Determine the amount of C 17 H 18 N 2 O 6 re- the wavelength of maximum absorbance at about 238 nm
leased in Phase 2 from UV absorbances at the wavelength using filtered portions of the solution under test, in compar-
of maximum absorbance at about 238 nm usingfilteredpor- ison with the Standard solution, using Dissolution Medium
tions of the solution under test, in comparison with the Stan- as the blank.
dard solution, using Dissolution Medium as the blank. Phase 2:
Tolerances—The cumulative percentages of the labeled Medium: 0.5% sodium lauryl sulfate in simulated gastric
amount of nifedipine (C 17 H lg N 2 O 6 ), released in vivo and fluid without enzyme, pH 1.2; 900 mL.
dissolved at the times specified, conform to Acceptance Ta- Apparatus 2: 100 rpm.
ble 1. Times: 1, 4, 8, and 12 hours.

Standard solution—Prepare a solution in Medium having
Time (hours) Amount dissolved an accurately known concentration of about 0.067 mg of

USP Nifedipine RS per mL. If necessary, a volume of
1 not more than 30%
methanol, not exceeding 10% of the final volume, can be
used to help solubilize nifedipine.
8 not less than 60%
Procedure—Determine the amount of C17H18N2O6 re-
leased in Phase 2 from UV absorbances at the wavelength
* For each dosage unit, add the amount dissolved in phos-
phate buffer, pH 7.5 from Phase 1 to the amount dissolved of maximum absorbance at about 238 nm usingfilteredpor-
at each time point in Phase 2.
tions of the solution under test, in comparison with the Stan-
dard solution, using Dissolution Medium as the blank.
Pharmacopeial Forum
Tolerances—The cumulative percentages of the labeled FOR TABLETS LABELED TO CONTAIN 30 MG OF NIFEDIPINE
amount of nifedipine (C17H18N2O6), released in vivo and

dissolved at the times specified, conform to Acceptance Ta-
blel.
Time (hours) Amount dissolved* 12 not less than 80%
1 not more than 30%

4 between 40% and 70% FOR TABLETS LABELED TO CONTAIN 60 MG OF NIFEDIPINE
8 not less than 70%
* For each dosage unit, add the amount dissolved in phos- 1 between 10% and 30%
phate buffer, pH 7.5 from Phase 1 to the amount dissolved
at each time point in Phase 2. 4 between 40% and 63%
Test 4: If the product complies with this test, the labeling •5
indicates that the product meets USP Drug Release Test 4.

Medium: 0.5% sodium lauryl sulfate in simulated gastric
fluid without enzyme, pH 1.2; 900 mL.
Times: 1, 4, and 12 hours.
Standard solution—Prepare a solution in Medium having BRIEFING
an accurately known concentration of about 0.067 mg of Paroxetine Tablets, page 3029 of PF 27(5) [Sept.-Oct. 2001].
USP Nifedipine RS per mL for Tablets labeled to contain It is proposed to revise the Definition to clarify that the Tablets are
made with paroxetine hydrochloride.
60 mg, and of about 0.034 mg of USP Nifedipine RS per
mL for Tablets labeled to contain 30 mg. If necessary, a vol-
ume of methanol, not exceeding 10% of the final volume,
Add the following:
can be used to help solubilize nifedipine.
Procedure—Determine the amount of C 17 H 18 N 2 O 6 re- •Paroxetine Hydroehloride Tablets
leased from UVabsorbances at the wavelength of maximum
absorbance at about 238 nm using filtered portions of the
» Paroxetine Mydrochloridc Tablets contain an
solution under test, in comparison with the Standard solu-
amount of paroxetine hydrochloride equivalent
tion, using Dissolution Medium as the blank.
Tolerances—The cumulative percentages of the labeled to not less than 90.0 percent and not more than
amount of nifedipine (C17H18N2O6), released at the times 110.0 percent of the labeled amount of paroxetine
specified, conform to Acceptance Table 1. hydrochloride
Pharmacopeial Forum
Packaging and storage—Preserve in well-closed contain- Determine the amount of C19H2oFN03--4iGi dissolved by
ers. employing the following method.
USP Reference standards (11)—USP Paroxetine Hydro- Buffer solution and Mobile phase—Prepare as directed in
chloride RS. the Assay.
Identification— Standard stock solution—Dissolve an accurately weighed
A: Infrared Absorption (197K)— quantity of USP Paroxetine Hydrochloride RS in an amount
Test specimen—Transfer an amount of finely powdered of methanol not exceeding 5% of the volume of the final
Tablets, equivalent to about 400 90 mg of paroxetine hydro solution, and dilute with Dissolution Medium to obtain a so-
ohlorido, to a suitable flask, add 100 mL of 0.1 N hydro- lution having a known concentration of about 0.63 mg per
chloric acid, and stir for 1 hour. Transfer the mixture to a mL.
separatory funnel, and add ammonium hydroxide until the Standard solution—Quantitatively dilute the Standard
solution is alkaline to litmus paper. Add 100 mL of ethyl stock solution with Dissolution Medium to obtain a solution
ether to the funnel, and shake for 2 minutes. Transfer the having a concentration estimated to correspond to that of the
organic layer into the necessary number of centrifuge tubes, filtered solution under test.
and centrifuge for 10 minutes. Recombine the clarified ex- Chromatographic system—Proceed as directed in the As-
tracts, add 1 drop of water and 0.5 mL of 0.1 N hydrochloric say, except to prepare the Standard preparation as directed
acid, stir, and evaporate to dryness under a stream of nitro- under Dissolution (^44-)? chromatograph the Standard solu-
gen. Dry the residue in an oven at 90° for 1 hour. tion.
B: The retention time of the major peak in the chroma- Procedure—Separately inject equal volumes (about 20
togram of the Assay preparation corresponds to that in the JIL) of a portion of the solution under test, previously passed
chromatogram of the Standard preparation, as obtained in through a suitable 0.45-um membrane filter, and the Stan-
the Assay. dard solution into the chromatograph, record the chromato-
C: Place a quantity of finely powdered Tablets, equiva- grams, and measure the responses for the major peaks.
lent to about 500 450 mg of paroxetine hydroohlorido, in a Calculate the quantity of C19H20FNO3—H€i dissolved based
stoppered flask. Add 100 mL of alcohol, and shake for 1 on the peak responses obtained from the solution under test
hour. Centrifuge about 20 mL of the mixture, and measure and the Standard solution.
the angular rotation of the supernatant at 20° (see Optical Tolerances—Not less than 80% (Q) of the labeled amount
Rotation (781)): the angular rotation is between -75° and of C19H20FNO3—MGi is dissolved in 60minutes.
-115°. Uniformity of dosage units (905): meet the requirements.

Dissolution (711)— PROCEDURE FOR CONTENT UNIFORMITY—
Medium: simulated gastric fluid without enzyme; 900 Buffer solution, Mobile phase, and Chromatographic sys-
mL. tem—Proceed as directed in the Assay.
Apparatus 2: 60 rpm. Standard solution—Use the Standard preparation, pre-
Time: 60 minutes. pared as directed in the Assay.
Pharmacopeia! Forum
Test solution—Place 1 Tablet in a suitable volumetric tion of this solution for 6 minutes. Transfer 20 mL of the
flask, and add a volume of a hydrochloric acid solution (7 supernatant to a 100-mL volumetric flask, dilute with
in 1000), equivalent to about 25% of the flask volume. Al- methanol to volume, and mix.
low the Tablet to disintegrate, dilute with methanol to vol- Chromatographic system (see Chromatography (621))—
ume, and mix to obtain a solution containing about 0.1 mg The liquid chromatograph is equipped with a 295-nm detec-
of paroxetine hydroohlorido per mL. Centrifuge a portion of tor and a 4.6-mm x 3.3-cm column that contains 3-um
the solution. packing L7. The flow rate is about 2.0 mL per minute. Chro-
Procedure—Proceed as directed in the Assay. Calculate matograph the Standard preparation, and record the peak
the quantity, in mg, of C19H2oFN03—HGl in the Tablet taken responses as directed for Procedure: the column efficiency
by the formula: is not less than 750 theoretical plates; the tailing factor is not
more than 4; and the relative standard deviation for replicate
of the Standard preparation and the Assay preparation into
in which Fis the volume of the flask used; rv and rs are the
the responses for the major peaks. Calculate the quantity, in
mg, of paroxetine hydroohlorido (C19H20FNO3—HGi) in the
dard solution, respectively; and the other terms are as de-
portion of Tablets taken by the formula:
fined therein.
Assay—
Buffer solution—Prepare a mixture of water, phosphoric
acid, and triethylamine (100:0.6:0.3).
1000C(329.37/365.83)(rl//r5),
Buffer solution and acetonitrile (7:3). Make adjustments if in which C is the concentration, in mg per mL, of USP Par-
necessary (see System Suitability under Chromatography oxetine Hydrochloride RS in the Standard preparation;
(621)). 329.37 and 365.83 are the molecular weights for paroxetine
Standard preparation—Dissolve an accurately weighed and paroxetine hydrochloride, respectively; and rând rs are
quantity of USP Paroxetine Hydrochloride RS in methanol, the peak responses obtained from the Assay preparation and
and dilute quantitatively, and stepwise if necessary, with the Standard preparation, respectively.ml
methanol to obtain a solution having a known concentration
Assay preparation—Weigh and finely powder not fewer
than 20 Tablets. Transfer an accurately weighed portion of
the powder, equivalent to about 100 mg of paroxetine fey-
droohlorido, to a 200-mL volumetric flask, dissolve in and
dilute with methanol to volume, and mix. Centrifuge a por-
Pharmacopeial Forum

the Standard solution and the solution under test into the chromato-
BRIEFING graph, record the chromatograms, and measure the responses for
the major peaks. Calculate the quantity, in mg, of phenytoin so-
Extended Phenytoin Sodium Capsules, USP 25 page 1372 dium (C15HnN2Na02) dissolved by the formula:
and page 3034 of PF 27(5) [Sept.-Oct. 2001]. It is proposed to (274.25/252.27)900C(r[//r5),
add a Test 2 and a Test 3 to the Dissolution test because the FDA
recently approved two new generic versions of Extended Pheny- in which 274.25 and 252.27 are the molecular weights of pheny-
toin Sodium Capsules. These two new products have different drug toin sodium and phenytoin, respectively; C is the concentration, in
release rates in vitro and do not comply with the current Dissolu- mg per mL, of USP Phenytoin RS in the Standard solution; and rv
tion test. In the absence of any adverse comment, it is proposed to and rs are the peak responses obtained from the solution under test
implement this revision via the Fifth Interim Revision Announce- and the Standard solution, respectively.
ment, pertaining to USP 25-NF20, with an official date of October Tolerances (for products labeled as 30-mg capsules)—The per-
1, 2002. centage of the labeled amount of C15H11N2NaO2 dissolved is not
more than 40% (Q) in 30 minutes, is 56% (£?') in 60 minutes,
(BPC: M. Marques) RTS—36197-1 and is not less than 65% (Q") in 120 minutes. The requirements
are met if the quantities dissolved from the Capsules tested con-
form to the accompanying Acceptance Table.
Acceptance Table
Add the following:
Number
^Packaging and storage—Preserve in tight, light-resistant Stage Tested Acceptance Criteria
6 Each unit is within the range between Q -
containers. Protect from moisture. Store at controlled room 15% and Q - 5%, is within the range Q
± 10%, and is not less than Q" + 5% at
temperature. AUSP26 the stated Times.
6 Average of 12 units (S[ + S2) is within the
Add the following: range between Q - 10% and Q, is within
the range Q' + 8%, and is not less than
"Labeling—When more than one Dissolution test is given, Q"; no unit is outside the range between Q
- 20% and Q + 10%, no unit is outside the
the labeling states the Dissolution test used only if Test 1 range Q ± 18%, and no unit is less than Q"
- 10% at the stated Times.
is not used..5 12 Average of 24 units (Si + S2 + S3) is within
the range between Q - 10% and Q, is within
Change to read: the range Q ± 8% and is not less than Q";
USP Reference standards {11 )—USP Phenytoin RS. USP Pheny- not more than 2 units are outside the range
toin Sodium RS between Q - 20% and Q + 10%, and no unit
is outside the range Q - 30% and Q + 20%;
A
USP Phenytoin Related Compound A RS. USP Phenytoin not more than 2 units are outside the range
Q + 18%, and no unit is outside the range
Related Compound B RS.AUSP26 Q + 25%; not more than 2 units are less
than Q" - 10%, and no unit is less than
Q" - 20% at the stated Times.
Change to read:
Test 1: If tho product complies with thia teat, tho labeling indi Tolerances (for products labeled as 100-mg capsules)—The per-
oatoo that it mocto USP Dissolution Test /.*, 5 centage of the labeled amount of C15HnN2NaO2 dissolved is not
Medium: water; 900 mL. more than 45% (Q) in 30 minutes, is 60% (Q1) in 60 minutes,
Apparatus 1: 50 rpm. and is not less than 70% (Q") in 120 minutes. The requirements
Times: 30, 60, and 120 minutes. are met if the quantities dissolved from the Capsules tested con-
Determine the amount of CI5H11N2NaO2 dissolved by employing form to the accompanying Acceptance Table.
methanol and water (7:3). Make adjustments if necessary (see Sys- Acceptance Table
tem Suitability under Chromatography (621)). Number
Standard solution—Prepare a solution of USP Phenytoin RS in Stage Tested Acceptance Criteria
methanol, and dilute with water to obtain a solution having a con-
centration similar to that of the solution under test. Each unit is within the range between Q -
Chromatographic system—The liquid chromatograph is 25% and Q - 5%, is equal to Q ± 20%,
equipped with a 229-nm detector and a 4.6-mm x 25-cm column and is not less than Q " + 5% at the stated
that contains packing LI. The flow rate is about 1 mL per minute. Times.
Chromatograph the Standard solution, and record the peak re-
sponses as directed for Procedure: the column efficiency is not less Average of 12 units (S] + S2) is within the
than range between Q - 20% and Q, is within
the range Q' + 15%, and is not less than
•3200^
. Q"; no unit is outside the range between Q
5
theoretical plates; the tailing factor is not more than 2.0; and the - 30% and Q + 10%, no unit is outside the
relativei standard deviation for replicate injections is not more than range Q' + 25%, and no unit is less than Q"
2.0%. - 10% at the stated Times.
Pharmacopeial Forum
Number Test 3: If the product complies with this test, the labeling
Stage Tested Acceptance Criteria
indicates that it meets USP Dissolution Test 3.
S3 12 Average of 24 units (S, + S 2 + S3) is within
the range between Q — 2 0 % and Q, is within
the range Q ± 1 5 % and is not less than Q";
not more than 2 units are outside the range
between Q - 3 0 % and Q + 10%, and no unit
is outside the range between Q - 4 0 % and Q
+ 2 0 % ; not more than 2 units are outside the
Times: 30, 60, and 120 minutes.
range Q + 2 5 % , and no unit is outside the
range Q + 3 5 % ; not more than 2 units are
Determine the amount of C 1 5 H n N 2 Na0 2 dissolved by
less than Q" - 10%, and no unit is less than
Q" - 2 0 % at the stated Times. employing the method described under Test 1.
Tolerances (for products labeled as 200-mg and 300-mg
capsules)—The percentage of the labeled amount of
*Test 2: If the product complies with this test, the labeling
C 15 H n N 2 Na0 2 dissolved is not more than 30% (Q) in 30
indicates that it meets USP Dissolution Test 2. Proceed as
minutes, is 50% (Q') in 60 minutes, and is not less than
directed in Test 1, except for the Tolerances.
60% (Q") in 120 minutes. The requirements are met if the
Tolerances (for products labeled as 100-mg capsules)—
quantities dissolved from the Capsules tested conform to the
The percentage of the labeled amount of Ci5HnN2NaO2 dis-
accompanying Acceptance Table.
solved is not more than 45% (Q) in 30 minutes, is 65% (Q')
in 60 minutes, and is not less than 70% (Q") in 120 minutes.
Acceptance Table
The requirements are met if the quantities dissolved from Number
Stage Tested Acceptance Criteria
the Capsules tested conform to the accompanying Accep-
S, 6 Each unit is within the range between Q
tance Table. - 20% and Q + 5%, is equal to Q - 20%
and Q + 25%, and is not less than Q" +
5% at the stated Times.
52 6 Average of 12 units (S{ + S2) is within the
Acceptance Table range between Q - 20% and Q, is within
Number the range of Q + 20%, and is not less
Stage Tested Acceptance Criteria than Q"; no unit is outside the range be-
tween Q - 2 5 % and Q + 10%, no unit is
Each unit is within the range between Q - outside the range Q ± 25%, and no unit
25% and Q - 5%, is equal to Q ± 20%, is less than Q" - 10% at the stated Times.
and is not less than Q" + 5% at the stated
Times. 53 12 Average of 24 units (S, + S2 + S3) is with-
Average of 12 units (St + S2) is within the in the range between Q - 20% and Q, is
range between Q - 25% and Q - 5%, is within the range of Q ± 20%, and is not
within the range of Q' - 20% and Q' + less than Q"; not more than 2 units are
10%, and is not less than Q"; no unit is out- outside the range between Q - 2 5 % and
side the range between Q - 30% and Q + Q + 10%, and no unit is outside the range
5%, no unit is outside the range Q - 25% Q - 2 5 % and Q + 15%; not more than 2
and Q + 20%, and no unit is less than Q" units are outside the range Q ± 25%;
- 10% at the stated Times and no unit is outside the range Q +
30%; not more than 2 units are less than
12 Average of 24 units (S, + S2 + S3) is within Q" — 10%; and no unit is less than Q" —
the range between Q - 25% and Q - 5%, is 20% at the stated Times.
within the range of Q - 20% and Q + 10%,
and is not less than Q"; not more than 2
units are outside the range between Q - •5
30% and Q + 5%; and no unit is outside
the range of Q - 40% and Q + 15%; not Change to read:
more than 2 units are outside the range Q Uniformity of dosage units {905): meet the requirements.
- 25% and Q + 20%, and no unit is outside
the range Q - 35% and Q + 25%; not more P R O C E D U R E FOR CONTENT UNIFORMITY—
than 2 units are less than Q" - 10%; and no
unit is less than Q" - 20% at the stated Phosphate buffer and Mobile phase, and Diluting solu
Times.
Hen—Proceed as directed in the Assay.
Pharmacopeial Forum
Standard solution—Dissolve an accurately weighed quantitatively, and stop wise if necessary, with Mobile phase
quantity of USP Phenytoin RS in methanol, and dilute quan- to obtain a solution having known oonoontrations of about 3
titatively, and stepwise if necessary, with Mobile phase to ug per mL for each Reference Standard.
obtain a solution having a known concentration of about Test solution—Use the Assay preparation.
0.5 mg per mL. Chromatographic system (see Chromatography (621))—
Test solution—Place one intact Capsule or one opened Prepare as directed in the Assay. Chromatograph the System
capsule with its contents in a suitable container, add approx- suitability Standard solution, and record the peak responses
imately 15 mL of Diluting solution, methanol, and place in a as directed for Procedure: the relative retention times are
shaking water bath at 37° for 30 minutes. Sonicate for 60 about 0.38 for phenytoin related compound A, 0.45 for phe-
minutes with occasional shaking. Dilute with Diluting solu- nytoin related compound B, and 1.0 for phenytoin; the reso-
Uen- methanol to volume, and mix. Dilute with Mobile lution, R, between phenytoin related compound B and
phase, if necessary, to obtain a final concentration of about phenytoin is not less than 8, and the resolution, R, between
0.5 mg per mL. phenytoin related compound A and phenytoin related com-
Chromatographic system—Proceed as directed in the As- pound B is not less than 1.5; the tailing factor for the phe-
say, except to chromatograph the Standard solution instead nytoin peak is not more than 2.0; and the relative standard
of the Standard preparation. deviation for the phonytoin peak for replicate injections is
Procedure—Proceed as directed in the Assay, except to in- not more than 2.0% determined from phenytoin, and Chro
ject the Standard solution and the Test solution instead of matograph tho Standard solution^ and rooord the peak re
the Standard preparation and the Assay preparation.AUSP26 gpon3O3 as directed for Procedure: the relative standard
deviation for replicate injections is not more than 5.0% de-
Add the following:
termined from cither peak phenytoin related compound A or
A
phenytoin related compound B.
Phosphate buffer and Mobile phase, and Diluting solu-
Hen—Proceed as directed in the Assay.
System suitability-Standard solution—Dissolve accurately
weighed quantities of USP Phenytoin RS, USP Phenytoin
responses for the major peaks. Calculate the quantity, in ug,
Related Compound A RS, and USP Phenytoin Related
of each phenytoin related compound in the portion of Cap-
Compound B RS in Mobile phase methanol, and dilute
sules taken by the formula:
quantitatively, and stepwise if necessary, with Mobile phase
methanol to obtain a solution having known concentrations
of about 60,1.5, and 1:5 ug 600,3, and 3 ug per mL, respec- in which C is the concentration, in ug per mL, of the appro-
tively. priate USP Reference Standard in the Standard solution;
Standard solution—Dissolve accurately weighed quanti and rv and rs are the peak responses for the corresponding
tioo of USP Phonytoin Related Compound A R.S and USP phenytoin related compound obtained from the Test solution
Phonytoin Related Compound B RS in methanol, and dilute
Pharmacopeial Forum
and the Standard solution, respectively: not more than 0.5%

BRIEFING
of phenytoin related compound A is found; and not more
Potassium Chloride Extended-Release Tablets, USP 25 page
than 1.0% of phenytoin related compound B is found. AUSP26 1405 and page 2749 of the First Supplement. Comments received
from a correspondent after the Dietary Supplements—-Non-Bota-
Change to read: nicals Expert Committee (DSN) had made a decision to go forward
Assay— with the proposed revisions to the Assay preparation in the Assay
Phosphate buffer—Prepare a solution of 0.05 M monobasic po- in this monograph indicated that the now official method would not
tassium phosphate in water, adjust with phosphoric acid to a pH of be applicable for certain preparations containing crystals coated
3.5, with waxy excipients. Data submitted by the correspondent indi-
A
cated that the revised method results in low recovery of the active
and mix.AUSP26 ingredient for these preparations and also that it is necessary to heat
the suspension as indicated in preparing the Assay preparation as
Mobile phase—Prepare a filtered and degassed mixture of specified in USP 25. Following a review of the data, the DSN Ex-
methanol and Phosphate buffer (11:9). Make adjustments if nec- pert Committee recommended reinstating the Assay preparation of
essary (see System Suitability under Chromatography (621)). USP 25 as Assay preparation 1 and, for those formulations con-
Diluting solution—Prepare a filtered mixture of methanol and taining crystals that are coated with hydrophobic polymers, the
water (11:0). DSN Expert Committee is proposing that the Assay preparation
A.USP26 made official in the First Supplement become Assay preparation
2. Also a proposed Labeling section is added to indicate with
Standard preparation—Dissolve an accurately weighed quantity which preparation the product complies. Other revisions are editor-
of USP Phenytoin RS in methanol, and dilute quantitatively, and ial in nature. In the absence of any significant adverse comments, it
stepwise if necessary, with Mobile phase to obtain a solution hav- is proposed to implement these revisions via the Fourth Interim
ing a known concentration of about 0.6 mg per mL. Revision Announcement, pertaining to USP25-NF20 with an offi-
Assay preparation—Transfer not fewer than 20 Capsules to a cial date of August 1, 2002.
ouitablo container, add about 150 mL of Diluting solution, and
homogenize. Tranafor thia solution to a 250 mL volumetric flask,
dilute with Diluting solution to volume, mix, and filter. (DSN: G. Giancaspro) RTS—36040-1
^Transfer the contents of 10 Capsules to a 250-mL volu-
metric flask. Add about 150 mL of methanol, and sonicate

Add the following:
for 20 minutes. Cool to room temperature, dilute with
•Labeling—The labeling states with which Assay prepara-
methanol to volume, mix, and filter.AaS7,^
Transfer an accurately measured portion of the filtered solution, tion the product complies, only if Assay preparation 1 is
equivalent to about 60 mg of phenytoin, to a 100-mL volumetric
flask, dilute with Mobile phase to volume, and mix. not used.04
quid chromatograph is equipped with a 229-nm detector and a 4.6- Change to read:
mm x 25-cm column that contains packing LI. The flow rate is Identification—A portion of the filtrate obtained as directed for
about 1 mL per minute. Chromatograph the Standard preparation, the
and record the peak responses as directed for Procedure: the col- *designated #4
umn efficiency is not less than 8000 6800 Assay preparation in the Assay meets the requirements of the tests
for Potassium (191) and for Chloride (191).
theoretical plates; the tailing factor is not more than 2.0; and the Change to read:
relative standard deviation for replicate injections is not more than
2.0%. Assay—NOTE—If noooggary, acoro nonaugar coated tablets first.
the Standard preparation and the Assay preparation into the chro- •[NOTES—If necessary, first score nonsugar-coated tablets.
matograph, record the chromatograms, and measure the responses
for the major peaks. Calculate the quantity, in mg, of phenytoin Retain a portion of the filtrate of either Assay preparation 1
sodium (C^HnNjNaOj) in the portion of Capsules taken by the for-
mula: or Assay preparation 2 for use in the test for Identifica-
(274.25/252.27)100C(r[//r.s.), tion.]^
in which 274.25 and 252.27 are the molecular weights of pheny- Potassium stock solution and Standard preparations—Prepare
toin sodium and phenytoin, respectively; C is the concentration, in as directed in the Assay under Potassium Chloride Oral Solution.
mg per mL, of USP Phenytoin RS in the Standard preparation; and Assay pivpupation—
rv and rs are the peak responses obtained from the Assay prepara-
tion and the Standard preparation, respectively. *Assay preparation 1—Place not fewer than 20 Tablets in
a suitable container with 400 mL of water, heat to boiling,
and boil for 20 minutes. Allow to cool, transfer the solution
to a 1000-mL volumetric flask, dilute with water to volume,
Pharmacopeial Forum
and mix. Filter, discarding the first 20 mL of the filtrate. Phenol, 2,6-bis(l-methylethyl).
Transfer an accurately measured volume of the subsequent 2,6-Diisopropylphenol [2078-54-8].
filtrate, equivalent to about 60 mg of potassium chloride, to
a 1000-mL volumetric flask, dilute with water to volume,
and mix. » Propofol contains not less than 98.0 percent and
Assay preparation 2 (For formulations containing crystals not more than 102.0 percent of C12H18O, calcu-
coated with hydrophobic polymers)—#4 lated on the anhydrous basis.
Place not fewer than 20 Tablets in a 2000-mL volumetric flask.
Add 1200 mL of a mixture of acetonitrile and water (1:1), and
shake by mechanical means, Packaging and storage—Preserve in tight containers.
* or stir using a magnetic bar..4
USP Reference standards (11)—C/SP Propofol RS. USP
Procedure—Proceed as directed in the Assay under Potassium
Chloride Oral Solution. Calculate the quantity, in mg, of potassium Propofol Resolution RS. USP 3,3'-5,5'-Tetraisopropyldiphe-
chloride (KC1) in each Tablet taken by the formula:
nol RS.
l.901(TC/D),
in which T is the labeled quantity, in mg, of potassium chloride in Identification, Infrared Absorption (197F).
each Tablet; D is the concentration, in ug per mL, of potassium
chloride in the Refractive index (831): between 1.5120 and 1.5160 at 20°.
*designated -4
Assay preparation, based on the labeled quantity per Tablet and the Bacterial endotoxins (85): [To come.]
extent of dilution; and the other terms are as defined therein.
Water, Method la (921): not more than 0.20%.
System suitability solution and Chromatographic sys
BRIEFING iem—Proceed as directed in the Assay.
Propofol, page 2774 of PF 27(4) [July-Aug. 2001]. This Test solution—Use tho Assay preparation.
monograph is being revised to include new methods to control
the impurities in Propofol. These methods not only offer better re- Proccdwc—Injoot equal volumes (about 0.5 uL) of tho
solution and thus more accurate assessment of the impurity content
but also utilize instrumentation that is commonly available in any System suitability solution and tho Test solution into the
laboratory. The gas-chromatographic procedure for the Chromato-
graphicpurity test is based on analyses performed with the T-WAX ohromatograph, record tho ohromatograms, and measure
brand of" G16 column. The typical retention time for propofol is
about 15 minutes. Limits in the Chromatographic purity test are all of tho poak responses. Calculate tho percentage of each
also revised. The liquid chromatographic procedure for the Limit
of3,3'-5,5'-Tetraisopropyldiphenol is based on analyses performed impurity in tho portion of Propofol takon by tho formula:
with a YMC-Pack ODS-A brand of LI column.

in whioh i\ is tho poak response for oach impurity obtained
from tho Test solution; and Pg ia the peak response for pro
Add the following:
pofol obtained from tho System suitability solution: not
'Propofol
moro than 0.3% of any individual impurity is found; and
(Chemical structure to come) not more than 1.0% of total impurities ia found.
CIIHIRO 178.27
Pharmacopeia! Forum
System suitability solution—Prepare a solution in diohlor in which ^ is the peak response for each impurity obtained
omothano containing 4 ug of 2 isopropylphonol and 4 mg of from the Test solution; and r9 is tho sum of the responses for
USP Propofol RS por mL. all the peaks; excluding that of tho solvent peak: not more
Test solution Dissolve 100 mg of Propofol in 100 mL of than 0.1% of any individual peak is found; and not more
diohloromothano, and mix? than 0.3% of total impurities is found.
Chromatographic system (ace Chmmatography (634-))— Resolution solution—Dissolve about 1000 mg of USP
The gas ohromatograph ia equipped with a flame ionization Propofol Resolution RS in 10.0 mL of methanol.
dotootor, a 0:25 mm x 30 m oolumn ooatod with a 0.15 Standard solution—Dissolve 50 mg of USP Propofol RS
mm phase G3, and a 0.53 mm x 5 m deactivated fused sil in 50.0 mL of methanol, and mix. Further dilute 5.0 mL of
ioa guard column: The carrier gag is helium; flowing at a rate this solution with methanol to 50.0 mL.
of about 1.7 mL por minute and maintained at about 20 psi. Test solution—Dissolve 1000 mg of Propofol in 10.0 mL
The detector temperature is maintained at 270°. The injector of methanol.
temperature is maintained at 38°; immediately after the in Chromatographic system (see Chromatography (621))—
jootion it is increased at a rate of 125° por minute to 270°; The gas chromatograph is equipped with a flame-ionization
and then it is maintained at 270° for 28 minutes. Initially the detector and a 0.53-mm x 30-m column coated with a 1.2-
temperature of the oolumn is equilibrated at 35° for 3 min um phase Gl 6. The carrier gas is helium, flowing at a rate of
utos; upon injootion it is inoroasod at a rate of 20° por minute about 8 mL per minute. The injection port and the detector
to 80°; it ia increased again at a rate of 6° por minute to 150°; temperatures are maintained at 250° and 300°, respectively.
it is increased again at a rate of 20° per minute to 270°; and The chromatograph is programmed as follows. Upon injec-
then it is maintained at 270° for 7 minutes. Chromatograph tion, the column temperature is maintained at 145° for 20
the System suitability solution, and rooord the peak re minutes; the temperature is increased at a rate of 5° per min-
sponseg as dirootod for Procedure: the relative retention ute to 200° and maintained at 200° for 5 minutes. Chromato-
times are about 0.8 for 2 isopropylphonol and 1.0 for propo graph the Resolution solution, and record the peak responses
fol; the tailing faotor for the 2 isopropylphonol peak is not as directed for Procedure: the retention time of propofol is
more than 2; the peak area for 2 isopropylphcnol is not loss between 14 and 16 minutes; the relative retention time is
than 0.085% and not more than 0.125% relative to propofol; about 0.18 for 2,6-diisopropylphenyl isopropylether, 1.0
and the relative standard deviation for replicate injections is for propofol and about 1.1 for 2-isopropyl-6-n-propylphe-
not more than 2.0%. nol; the resolution, R, between propofol and 2-isopropyl-
Proccdwe—Separately inject equal volumes (about 5 uL) 6-n-propylphenol is not less than 2. Chromatograph the
of the System suitability solution and the Test solution into Standard solution six times, and record the peak responses
the ohromatograph, rooord tho chromatograms; and measure as directed for Procedure: the column efficiency determined
all the peak responses. Calculate the percentage of each im from the propofol peak is not less than 5,000 theoretical
purity in the portion of Propofol taken by tho formula: plates; and the relative standard deviation for replicate injec-
tions is not more than 3.5%.
Pharmacopeial Forum
Procedure—Separately inject equal volumes (about 1.0 the peak responses for propofol and 3,3'-5,5'-tetraisopropyl-
uL) of the Resolution solution, the Standard solution, and diphenol. Calculate the percentage of 3,3'-5,5'-tetraisopro-
the Test solution into the chromatograph, record the chroma- pyldiphenol in the portion of Propofol taken by the formula:
tograms, and measure all of the peak responses. Calculate
the percentage of each impurity in the portion of Propofol
taken by the formula: in which rA and rs are the peak responses for 3,3'-5,5'-tetra-
isopropyldiphenol obtained from the Test solution and the
Standard solution, respectively: not more than 0.1% of
in which r, is the peak response for each impurity obtained 3,3'-5,5'-tetraisopropyldiphenol is found.
from the Test solution; and rs is the peak response for Pro- Limit of 2,6-diisopropylbenzoquinone—
pofol obtained from the Standard solution: not more than Sample solution: neat.
0.1% of 2,6-Diisopropylphenyl isopropylether is found; Procedure—Examine the portion of Propofol taken at 330
not more than 0.1% of each other individual impurity is nm using air as the blank (see Ultraviolet Absorption
found; and not more than 0.3% of total impurities is found. (197U). The absorbance of the Sample solution is not more
Limit of 3,3'-5,5'-tetraisopropyldiphenol— than 0.4 absorbance units (0.1%).
Mobile phase—Prepare a filtered and degassed mixture of Content of chloride (221)—Dissolve about 3 g of Propo-
acetonitrile, water, and methanol (50:40:10). fol, accurately weighed, in 60 mL of methanol, add 10 mL
Standard solution—Prepare a solution in Mobile phase of water and 20 mL of 2 N nitric acid, and titrate with 0.01 N
containing 2 ug per mL each of USP Propofol RS and silver nitrate, determining the endpoint potentiometrically
USP 3,3'-5,5'-Tetraisopropyldiphenol RS. (see Titrimetry (541)). Each mL of 0.01 N silver nitrate is
Test solution—Dissolve 500 mg of Propofol in 25.0 mL of equivalent to 35.45 mg of chloride: not more than 0.01%
Mobile phase. of chloride is found.
Chromatographic system (see Chromatography (621))— Assay—
The liquid chromatograph is equipped with a 270-nm detec- System suitability solution—Dissolve about 100 mg of
tor and a 4.6-mm x 15-cm column that contains packing USP Propofol RS and 10 mg of triethylamine in 5.0 mL
LI. The flow rate is about 1.5 mL per minute. Chromato- of dichloromethane, and mix.
graph the Standard solution six times, and record the peak Standard preparation—Dissolve 100 mg of USP Propo-
responses as directed for Procedure: the retention time of fol RS in 5.0 mL of dichloromethane, and mix.
propofol is between 8 and 11 minutes; the column effi-
Assay preparation—Dissolve 100 mg of Propofol in 5.0
ciency, based on the propofol peak, is not less than 6,000
mL of dichloromethane, and mix.
theoretical plates; and the relative standard deviation for re-
plicate injections for propofol and 3,3'-5,5'-tetraisopropyldi-
phenol peaks is not more than 15% each.
detector and a 0.25-mm x 30-m column coated with a 0.25-
Procedure—Separately inject equal volumes (about 20 um phase G49. The carrier gas is hydrogen, flowing at a rate
mL) of the Standard solution and the Test solution into of about 2 mL per minute and maintained at 10 psi; and the
Pharmacopeial Forum
split flow rate is about 10 mL per minute with a split flow brand of L34 column. The typical retention times for mannitol and
sorbitol are 8.8 and 14.3 minutes, respectively. Editorial style
ratio of 5:4. The injection port and the detector temperatures changes have also been made.
are maintained at 250° and 300°, respectively. The chro- (EMC: C. Sheehan; AMB: D. Porter) RTS—36749-2
matograph is programmed as follows. Initially the column
temperature is equilibrated at 60° for 2 minutes; upon injec- Change to read:
tion the temperature is increased at a rate of 10° per minute
» Sorbitol Solution is an aqueous solution containing?
to 150°; the temperature is increased again at a rate of 30° in each 100.0 g,
•
per minute to 270°; and is maintained at 270° for 5 minutes. •I
not less than 64.0 g
•percent,,
the peak responses as directed for Procedure: the relative of D-sorbitol (C6H14O6). The amounts of total sugars,
other polyhydric alcohols, and any hexitol anhydrides,
retention times are about 0.15 for triethylamine and 1.0 if detected, are not included in the requirements nor
for propofol; and the relative standard deviation for replicate •in.,
injections is not more than 2.0%. the calculated amount under Other Impurities.
Procedure—Separately inject equal volumes (about 0.5 Change to read:

Identification—
uL) of the Standard preparation and the Assay preparation A: To 3 mL of a 1 in 75 dilution of it in
into the chromatograph, record the chromatograms, and "Dissolve 1.4 g of Sorbitol Solution in 75 mL of water.
measure the responses for the major peaks. Calculate the Transfer 3 mL of this solution to_,
a 15-cm test tube, add 3 mL of freshly prepared catechol solution
quantity, in mg, of C12H18O, in the portion of Propofol taken (1 in 10), mix, add 6 mL of sulfuric acid, mix again, and gently heat
the rube in a flame for about 30 seconds: a deep pink or wine color
by the formula: appears.
in which C is the concentration, in mg per mL, of USP Pro- Delete the following:
"Specific gravity (S44-): not looo than 1.285.,,
pofol RS in the Standard preparation; and rv and rs are the
peak responses obtained from the Assay preparation and the
" Refractive index (S34-): botwoon 1.155 and 1.165 at 20°..,
Standard preparation, respectively. m ,
Add the following:
"Microbial limits (61)—The total aerobic microbial count
using the Plate Method is not more than 103 cfu per mL, and
the total combined molds and yeasts count is not more than
102 cfu per mL.,,,
Add the following:
BRIEFING
•pH (791): between 5.0 and 7.5, in a 14% (w/w) solution of
Sorbitol Solution, USP 25 page 1594 and page 3329 of PF
27(6) [Nov.-Dec. 2001]. The retention times for mannitol and sor- Sorbitol Solution in carbon dioxide-free water. m
bitol were inadvertently misstated in the briefing under Sorbitol So-
lution in PF 27(6). The chromatographic method in the Assay is Change to read:
based on analyses performed with the Aminex Fast Carbohydrate Residue on ignition (281): not more than 0.1%,
•calculated on the anhydrous basis, determined on a 2-g
portion, accurately weighed.,,
Pharmacopeial Forum
Delete the following: Procedure—Proceed as directed in the test for Nickel un-
"Chloride (324-)—A 2.0 g portion shows no moro chloride than
corresponds to 0.10 mL of 0.020 N hydroohlorio aoid der Mannitol. Not more than 1 ug per g, calculated on the
(0.0035%).M1
anhydrous basis, is found.B1
"Suifate (S34-)—A 1.37 g portion shows no more sulfato than cor Change to read:
roaponda to 0.10 mL of 0.020 N aulfuric acid (0.008S<)).,,1 Assay—
Mobile phase, Resolution solution, Standard preparation, and
Delete the following: Chromatographic system—Proceed as directed in the Assay under
"Arsenic, Method II (344-): 2.5 ppm., 1 Sorbitol (see NF monograph).
Assay preparation—Transfer an accurately weighed portion of
Delete the following: Solution, equivalent to about 0.21 g of sorbitol, to a 50 mL volu
metric flask, dilute with water to volume, and mix:
"Heavy metals, Method I
•Accurately weigh about 0.12 g of Sorbitol Solution, dis-
Change to read:
Reducing sugars—A10:0 g portion, accurately weighed, meets solve in and dilute with water to about 20 g. Accurately re-
the requirements of the tost for Reducing sugar's under Sorbitol.
Tho amount determined in thin tost is not included in the oaloulatod cord the final solution weight, and mix thoroughly. B1
amount under Other1 Impurities.
Procedure—Proceed as directed in the Assay under Sorbitol.
"To an amount of Sorbitol Solution, equivalent to 3.3 g on Calculate the quantity, in mg, of C^ti^Q^ in the portion of Solu
tion taken by the formula:
the anhydrous basis, add 3 mL of water, 20.0 mL of cupric
citrate TS, and a few glass beads. Proceed as directed in the in which C is tho concentration, in mg per mL, of USP Sorbitol RS
in tho Standard pwparation,
test for Reducing sugars under Mannitol, beginning with
"percentage of D-sorbitol (C6H14O6) in the portion of Sorbi-
"Heat so that boiling begins." Not less than 12.8 mL of
tol Solution taken by the formula:
0.05 N sodium thiosulfate VS is required, corresponding
to not more than 0.3% of reducing sugars, on the anhydrous
basis, as glucose. The amount determined in this test is not in which Cs is the concentration, in mg per g, of USP Sor-
included in the calculated amount under Other Impurities. B1 bitol RS in the Standard preparation; Cv is the concentra-
tion, in mg per g, of Sorbitol Solution in the Assay
Add the following:
preparation; ux
•Limit of nickel—
and rv and rs are the peak responses obtained from the Assay prep-
Test solution—Dissolve 20.0 g of Sorbitol Solution in di- aration and the Standard preparation, respectively.
luted acetic acid, and dilute with diluted acetic acid to 100.0
mL. Add 2.0 mL of a saturated ammonium pyrrolidine-
dithiocarbamate solution (containing about 10 g of ammo-
nium pyrrolidinedithiocarbamate per liter) and 10.0 mL of
methyl isobutyl ketone, and shake for 30 seconds. Protect
BRIEFING
from bright light. Allow the two layers to separate, and
Sulfasalazine Delayed-Release Tablets, USP 25 page 1630. In
use the methyl isobutyl ketone layer. accordance with the Definition of Delayed-Release Tablets and
with the general test chapter Disintegration (701), it is proposed
Blank solution—Prepare as directed for Test solution, ex- to change the time in the test for Disintegration from 15 minutes
to 60 minutes.
cept to omit the use of the Sorbitol Solution.
Standard solutions—Prepare as directed for Test solution, (BPC: M. Marques) RTS—21631-1
except to prepare three solutions by adding 0.5 mL, 1.0 mL,

and 1.5 mL of nickel standard solution TS.
Pharmacopeial Forum
Change to read:
Disintegration (701):44 BRIEFING
•60 B 1
minutes, determined as directed under Delayed-Release {enteric Tobramycin Inhalation Solution, page 1340 of PF 26(5)
coated) Tablets. [Sept.-Oct. 2000]. On the basis of additional comments and data
received on this proposed new monograph, several suggested mod-
ifications were considered. A suggestion was received to change
the Definition to omit the requirement that the Inhalation Solution
be nonpyrogenic, and in consonance with this, it was suggested
that the test for Bacterial endotoxins should be omitted. It was also
suggested that the requirement for using Waterfor Injection in pre-
paring the Inhalation Solution be eliminated, and to specify simply
that it is an "aqueous solution." It was further suggested that the
test for Paniculate matter be eliminated. The USP Expert Commit-
tee on Antibiotics, however, recognized that the prime indication
for clinical use of Tobramycin Inhalation Solution is in the treat-
BRIEFING ment of cystic fibrosis, in which cases the patients may have da-
maged lung tissue that would be receptive to the adverse effects
Thyroid, USP 25 page 1710. As the current histological test for of bacterial endotoxins and particulate matter. The Committee
Identification is not suitable for the modern manufacturing process therefore retained in the proposed new monograph the use of Water
of Thyroid, it is proposed to replace the histological test with an for Injection, the Bacterial endotoxins requirement, and the test for
HPLC test that is based upon the Assay. Interested parties are en- Particulate matter. It is proposed to change the Packaging and sto-
couraged to submit their comments on this proposal to the USP rage section by adding a requirement for foil over-wrapping, to re-
Expert Committee on Biotechnology and Natural Therapeutics flect the conditions needed to protect the tobramycin component
and Diagnostics. from light degradation and to prevent evaporative water loss. In
view of the fact that the article is a single-unit container, it is pro-
posed to specify a requirement for Uniformity of dosage units, in-
(BNT: I. DeVeau) RTS—36285-1 stead of Minimum fill. The latter test is applied to multiple-unit
containers. A new test for Osmolarity is proposed to complement
the test for Content of sodium chloride. An isocratic liquid chroma-
tographic procedure for Chromatographicpurity that would reduce
the analysis time from 60 minutes to 40 minutes was also sug-
Change to read: gested. The Expert Committee, however, decided to retain the gra-
Identification—Whon ouitably mountod and examined under a dient elution procedure for Chromatographic purity proposed in
microscope, it shows numorouo omooth to otriatod hyalino frag PF 26(5) because it yielded more impurity peaks and better resolu-
monts of oolloid of angular to irregular shape, which arcs colorloaa tion than the isocratic method.
to pale yellow in water mounta, brown in Mallory'a atain, and pink
in oosin oolution, oomo of thooo fragmonto containing granules,
minute vacuolos, oryatalloidal bodies, and oolla; numerous irrogu (PA7: W. Wright; AMB: D. Porter) RTS—33611-2; 33943-1;
lar fragments of follioular epithelium 3taining brown with Mai 36529-1
lory's otain, tho individual oollo moro or loss polygonal to
rounded angular or irregularly ouboidal, often with prominent nu
olei staining dark blue; their cytoplasm purplish with Delafiold's
homatoxylin TS; alondor, glistening segments of capillaries of clo Add the following:
soly undulate outline; numorous slender segments of nouraxons;
numoroua aggregates of particles of intercellular substance and
alondor, mostly straight, connective tissue fibers staining blue to
•Tobramycin Inhalation Solution
greenish blue with a mixture of Mallory'a stain and pho3photungg
tio aoid TS, tho bundlos of fibers often appearing reddish in Mai
lory's atain; few glistening fragments of blood vessels with serrated
or oronated ends as viewed in water mounts.
» Tobramycin Inhalation Solution is a sterile, non-
"The retention times of the peaks for liothyronine and le-
pyrogenic, preservative-free solution of Tobramy-
vothyroxine in the chromatogram of the Assay preparation
correspond to those in the chromatogram of the Standard cin in Water for Injection containing Sodium
preparation, as obtained in the Assay. m Chloride. It is prepared with the aid of Sulfuric
Acid or Sodium Hydroxide and contains, in each
mL, not less than 90.0 percent and not more than
110.0 percent of the labeled amount of tobramycin
Pharmacopeia! Forum
Packaging and storage—Preserve in low-density, poly- System suitability stock solution—Dissolve an accurately
ethylene, single-use ampules stored in light-resistant ie*l weighed quantity of USP Tobramycin RS in water to obtain
over pouches foil over-wrapped packaging, in a refrigerator. a solution having a known concentration of about 1.1 mg
USP Reference standards (11)—USP Endotoxin RS. USP per mL, and adjust with 1 N sulfuric acid to a pH of 6.0.
Tobramycin RS. System suitability solution 1—Dilute the System suitabil-
Absorbance—The absorbance of the Inhalation Solution ity stock solution quantitatively, and stepwise if necessary,
with water to obtain a solution having a known concentra-
determined at 410 nm is not more than Or4-0 0.24.
Bacterial endotoxins (85)—It contains not more than W
System suitability solution 2—Heat a portion of the Sys-
60 USP Endotoxin Units per mL.
tem suitability stock solution in a sealed glass ampul at
Sterility (71)—It meets the requirements when tested as di-
100° for 8 to 9 hours. Cool to room temperature, and dilute
rected for Membrane Filtration Method under Test Proce-
with water to obtain a solution having a known concentra-
dures.
Minimum fill {!$&): moots tho requirements.
Standard solution—Prepare a solution of about 55 mg of
Uniformity of dosage units (905): meets the requirements.
USP Tobramycin RS, accurately weighed, in 50 mL of a
pH (791): between 5.5 and 6.5. mixture of water and 1.0 N sulfuric acid (49:1). Dilute quan-
Particulate matter (788): meets the requirements for titatively, and stepwise if necessary, with water to obtain a
small-volume injections. solution having a concentration of about 1.1 ug per mL.
Osmolarity (785): between 150 and 200 mOsm per liter. Test solution—Transfer an accurately measured volume of
Chromatographic purity— Inhalation Solution, equivalent to about 240 mg of tobramy-
Solution A—Prepare a filtered and degassed mixture of cin, to a 50-mL volumetric flask, dilute with water to vol-
water, acetonitrile, and phosphoric acid (95:5:0.08). ume, and mix. Dilute quantitatively, and stepwise if
Solution B—Prepare a filtered and degassed mixture of necessary, with water to obtain a solution having a concen-
acetonitrile, water, and phosphoric acid (75:25:0.08). tration of about 192 jig per mL.
Mobile phase—Use variable mixtures of Solution A and Derivatization procedure—Proceed aa directed in the -As-
Solution B as directed for Chromatographic system. Make say under Tobramycin. Tho oolutions thus obtained aro Be-
adjustments if necessary (see System Suitability under rivatiscd system suitability solution 1, Dcrivatizcd system
Chromatography (621)). suitability solution 2, tho Dcrivatiscd standard preparation,
Blank solution—Use water. tho Dcrivatkcd test preparation, and tho Dcrivatiscd blank
2 ,4 -Dinitr ofl uorobenzene reagent and

Tris{hydroxymethyl)aminomethane reagent—Proceed as di- [NOTE—Heat all solutions at the same temperature and
rected in the Assay under Tobramycin. for the same duration as indicated. Move all flasks to and
from the 60° constant-temperature bath at the same time.]
To separate 50-mL flasks transfer 4.0 mL of System suitabil-
ity solution 1, 4.0 mL of System suitability solution 2, 4.0
mL of Standard solution, 4.0 mL of Test solution, and 4.0
Pharmacopeial Forum
mL of Blank solution. To each flask, add 1.0 mL of 2,4-Di- tern suitability solution 2, and rcoord tho peak responses as
nitrofluorobenzene reagent and 10 mL of TrisQiydroxy- dirootod for Procedure: tho relative retention times are about
methyl)aminomethane reagent, shake, and insert the 0.36 and 1.04 for unknown impurities, 0.66 for dooxyatrcp
stopper. Place the flasks in a constant-temperature bath at tamino kanosaminido, 0.73 and 0.74 for oarbamyl tobramy
60 + 2°, and heat for 50 + 5 minutes. Remove the flasks cin, 0.89 for noaminc, 0.94 for ncbraminc, 0.96 for
from the bath, and allow to stand for 10 minutes. Add ace- kanamyoin B, and 1.0 for tobramyoin; the resolution bo
tonitrile to about 2 mL below the 50-mL mark, allow to cool twoon tho dooxystroptamino kanosaminido peak and tho
to room temperature, dilute with acetonitrile to volume, and nearest peak; which has a signal to noiso ratio groator than
mix. The solutions thus obtained are Derivatized system 10^ is not loss than 1.0; tho resolution botwoon the nebra
suitability solution 1, Derivatized system suitability solution mine and kanamyoin B peaks is not I003 than 1.0; and tho
2, the Derivatized standard solution, the Derivatized test so- oapaoity faotor, Id, for tobramyoin is not loos than 15.5.
lution, and the Derivatized blank solution. Chromatograph Derivatized system suitability solution 2,
Chromatographic system (see Chromatography (621))— and record the peak responses as directed for Procedure:
The liquid chromatograph is equipped with a 365-nm detec- the capacity factor, k', determined from tobramy cin is not
tor and a 4.6-mm x 25-cm column that contains packing less than 15.5. Chromatograph Derivatized system suitabil-
L l l . The flow rate is about 1.2 mL per minute. The chro- ity solution 1, and use the chromatogram to locate the degra-
matograph is programmed as follows. dation peaks from comparison to Derivatized system
suitability solution 2 (deoxystreptamine kanosaminide and
nebramine will increase in response in Derivatized system
suitability solution 2 when viewed at a 1-10 mAbs unit or
(minutes) (%) Elution
0-5 mV unit full scale). Record the peak responses as direc-
0 79 21 equilibration ted for Procedure: the relative retention times are about 0.66
0-14 79-+66 21->34 linear gradient for deoxystreptamine kanosamininide, 0.94 for nebramine,
14-25 66-+30 34->70 linear gradient and 1.00 for tobramycin. For both the deoxystreptamine ka-
25-35 30 70 isocratic nosaminide and nebramine peaks, the nearest peak with a
35-40 30-»20 70->80 linear gradient signal-to-noise ratio of not less than 10 produces a resolu-
40-50 20^5 80->95 linear gradient tion, R, not less than or equal to 1.0
Chromatograph the Derivatized standard preparation, Procedure—Separately inject equal volumes (about 45
and rooord the peak responsesasdirected for Procedure: uL) of Derivatized system suitability solution 1, Derivatized
the capacity factor, k', for tobramyoin is not loss than system suitability solution 2, the Derivatized standard solu-
15.5; and tho relative standard deviation for replicate injoo tion, the Derivatized test solution, and the Derivatized blank
tiono is not more than 2.0%. Chromatograph Derivatized solution, record the chromatograms, and measure the peak
system suitability solution 7, and use tho chromatogram to responses, disregarding any peak corresponding to those ob-
locate any degradation peaks obtained from Derivatized sys tained from the Derivatized blank solution, and subtracting
tan suitability solution 2. Chromatograph Derivatized sys • the quantities of any such peaks found at the relative reten-
Pharmacopeial Forum
tion times of 0.66 and 0.94 from those found in the Deriva- Assay—
tized test solution. Calculate the quantity, in ug, of each im- Mobile phase, 2,4-Dinitrofluorobenzene reagent,
purity per mL of Inhalation Solution taken by the formula: Tris(hydroxymethyl)aminomethane reagent, Standard
preparation, Derivatization procedure, Resolution
(5000/16)CE(r,/rs),
solution, and Chromatographic system—Proceed as direc-
in which C is the concentration, in ug per mL, of USP To-
ted in the Assay under Tobramycin.
bramycin RS in the Standard solution; E is the tobramycin
Assay preparation—Transfer an accurately measured vol-
equivalent, in ug per mg, of USP Tobramycin RS; r, is the
ume of Inhalation Solution to a suitable volumetric flask,
peak area of any impurity obtained from the Derivatized test
and dilute quantitatively with water to obtain a solution hav-
solution; and rs is the peak area for tobramycin obtained
ing a concentration of about 200 ug per mL.
from the Derivatized standard solution: not more than
Procedure—Proceed as directed in the Assay under To-
0.25% of 0.3% of deoxystreptamine kanosaminide or any
bramycin. Calculate the quantity, in mg, of tobramycin
impurity with a relative retention time of &S6 0.66 is found;
(C18H37N5O9) in each mL of Inhalation Solution taken by
not more than 0.3% each of the impurity with a relative TO
the formula:
tcntion time of 1.04, dcoxy3troptaminc kanooaminidc;nca
mine, and nobramino is found; not more than 1.0% of {CE){L/D){rulrs),
oarbamyl tobramyoin ia found; not moro than 0.5% kanamy in which C, E, rv, and rs are as defined therein; L is the la-
oin B is found; and not more than 3.0% of total impurities is beled quantity, in mg, of tobramycin per mL in the Inhala-
found; not more than 0.4% of nebramine or any impurity tion Solution taken; and D is the concentration, in ug per
with a relative retention time of 0.94 is found; not more than mL, of tobramycin in the Assay preparation. mx
0.1% of any unknown impurity is found; not more than
0.2% of total unknown impurities is found; and not more
than 1.0% of total impurities is found. The relative standard
deviation for replicate injections of the Derivatized standard
solution is not more than 2.0%.
BRIEFING
Content of sodium chloride—Pipet 25 mL of Inhalation
Solution into a suitable container. Add between 70 and Triamterene Capsules, USP 25 page 1748. It is proposed to
add a Test 2 under Dissolution for those products that do not con-
100 mL of water. Add 10 mL of an acidic gelatin solution, tain surfactants in their formulation. A Labeling section has been
added to reflect this modification.
prepared by dissolving 2 g of gelatin and 50 mL of nitric Additionally, a manufacturer of triamterene capsules proposed
to delete Identification test B and to replace Identification test C
acid in 1000 mL of water. Titrate potentiometrically with with an HPLC identification by retention time. Review by the
PA5 Expert Committee agreed that identification by HPLC reten-
0.1 N silver nitrate VS using a suitable silver electrode: tion time and by UV were sufficiently discriminating techniques to
identify the characteristics inherent to triamterene in the product
not less than 90.0% and not more than 110.0% of the labeled without excessive testing requirements.
Also revisions are proposed in the Assay preparation and in the
amount of sodium chloride is found. Procedure of the Assay that address problems of incomplete re-
moval of capsule contents that have been reported to cause a nega-
Other requirements—It meets the requirements for the tive bias in the test results; and an editorial correction, which will
Identification tests under Tobramycin.
Pharmacopeial Forum
become official in USP 26-NF 21, is proposed to change acetic test, suitably diluted with Dissolution Medium, if necessary, in
acid to glacial acetic acid when preparing the Standard preparation comparison with a Standard solution having a known concentra-
and the Assay preparation. tion of USP Triamterene RS in the same Medium.
(BPC: M. Marques; PA5: J. Esker) RTS—21694; 21694-2 Ci 2 HjjN 7 is dissolved in 45 minutes.
'Test 2—If the product complies with this test, the label-
ing indicates that it meets USP Dissolution Test 2.
Add the following:
Medium: 1% w/v of polysorbate 20 in 0.1 N acetic acid;
"Labeling—When more than one Dissolution test is given,
900 mL.
the labeling states the Dissolution test used only if Test 1 is
not used.B1
Time: 120 minutes.
Change to read: Procedure—Proceed as directed under Test 1.
Identification-
Ac Ultraviolet Absorption (197U)—Transfer a portion of the
contents of the Capsules, equivalent to about 0.1 g of triamterene, Tolerances—Not less than 80% ( 0 of the labeled amount
to a 250-mL volumetric flask. Add 100 mL of methoxyethanol,
shake until dissolved, dilute with water to volume, and mix. Trans- of C 12 H n N 7 is dissolved in 120 minutes.B1
fer 5 mL of this solution to a 200-mL volumetric flask, add 5 mL of
formic acid, and dilute with water to volume. Prepare a solution of
USP Triamterene RS in the manner described above to obtain a Change to read:
Standard solution with a final concentration of about 10 ug per Assay—
mL. Determine the ultraviolet spectrum from 280 nm to 420 nm. Buffer solution and Mobile phase—Proceed as directed in the
B: The aolution of Capsules prepared for the Assay ohowo an Assay under Triamterene and Hydrochlorothiazide Tablets.
intense, bluish fluorescence. Standard preparation—Transfer about 50 mg of USP Triamter-
ene RS, accurately weighed, to a 100-mL volumetric flask. Add 10
"The retention time of the major peak in the chromatogram mL of acetonitrile, 10 mL of water, and 5 mL of
of the Assay preparation corresponds to that in the chroma- g A W ? / 2 5
acetic acid, sonicating for 3 minutes after each addition. Cool to
togram of the Standard preparation, as obtained in the As- room temperature, dilute with water to volume, and mix.
Assay preparation—Remove, as completely as possible, the
say.^ contents of not loss than
•
G1.—Dissolve a portion of tho Capsule oontonto, equivalent to 20 Capsules, combine the contents, and transfer an accurately
about 50 mg of triamterene, in 50 mL of methoxyethanol, mix, weighed portion of powder, equivalent to about 50 mg of triarnter
and filter. Use the filtrate aa tho toot solution. Prepare a Standard one, to a 100 mL volumetric flask.
solution containing 1 mg of USP Triamtorono RS per mL of moth
oxyothanoL Separately apply 2 pL of tho tost solution and 2 uL of "that which is in one dosage unit, to a 100-mL volumetric
tho Standard solution to a suitable thin layer ohromatographio plate
(see Chi'omatogi'aphy {€H)) coated with a 0.25 mm layer of ohro flask (Flask 1). To a separate 100-mL volumetric flask, add
matographio silioa gol mixture. Dry tho 3pot3 with a ourront of air.
Develop tho plate in a solvent systom consisting of a mixture of all 20 capsule shells (Flask 2). For each flask,B1
othyl aootato, aootio acid, and wator (8:1:1) until tho solvent front add 10 mL of acetonitrile, and sonicate for 10 minutes. Add 10 mL
has moved about thrco fourths of the length of tho plate. Remove of boiling water, sonicate for 5 minutes, and mix. Add 10 mL of
tho plate from tho developing chamber, mark tho solvent front, al g A C / ^ t f
low to dry. Locate tho spots under short wavelength and long wa acetic acid, sonicate for 10 minutes, and mix. Add 60 mL of water,
volongth ultraviolet light: tho intensity and tho Jfy value of tho mix, and allow to cool to room temperature. Dilute with water to
principal 3pot obtained from tho tost solution correspond to that volume, mix, and filter, discarding tho first 3 mL of tho filtrate.
from tho Standard solution.
"Dilute the contents of Flask 2 with water to volume, and
add 5.0 mL of the solution from Flask 2 to Flask 1. Dilute
Change to read:
Dissolution (711)— the contents of Flask 1 with water to volume, and mix. If
'Test 1—B1 necessary, quantitatively dilute with a solution of acetoni-
Medium: 0.1 N hydrochloric acid; 900 mL. trile, glacial acetic acid, and water (10:10:80) to obtain a fi-
Time: 45 minutes. nal concentration of about 0.5 mg per mL. Filter a portion of
Procedure—Determine the amount of C, 2 H,jN 7 dissolved by
employing UV absorption at the wavelength or maximum absor- this solution, discarding the first 3 mL of the filtrate.,{
bance at about 357 nm on filtered portions of the solution under
Pharmacopeial Forum

quid chromatograph is equipped with a 280-nm detector and a 3.9-
mm x 30-cm column that contains packing LI. The flow rate is BRIEFING
about 1 mL per minute. Chromatograph the Standard preparation,
and record the peak responses as directed under Procedure: the Crystallized Trypsin for Inhalation Solution, USP 25 page
tailing factor is not more than 2.0, and the relative standard devia- 1780 and page 2755 of the First Supplement. Deletion of this
tion for replicate injections is not more than 2.0%. monograph is proposed. Withdrawal of this monograph is recom-
Procedure—Separately inject equal volumes (about 10 uL) of mended by the Expert Committee on Nomenclature and Labeling
the Standard preparation and the Assay preparation into the chro- and the Expert Committee on Biotechnology and Natural Thera-
matograph, record the chromatograms, and measure the responses peutics and Diagnostics because it is reported that inhalation, as
of the major peaks. Calculate the quantity, in mg, of Cj 2 HjjN 7 in implied by the monograph title, is not intended for trypsin, a med-
the portion of Capsules taken by the formula: ication that may be applied topically. Moreover, there is no known
product for inhalation of trypsin commercially available, and
safety concerns have been expressed regarding the administration
of the substance by inhalation. Inasmuch as protection of the public
u health is at issue, deletion of the monograph at the earliest feasible
CV(rulrs),mx date, by an Interim Revision Announcement, is proposed. In the
absence of any significant adverse comment, it is proposed to im-
plement this revision via the Fifth Interim Revision Announcement
in which C is the concentration, in mg per mL, of USP Triamterene pertaining to USP 25-NF 20, with an official date of Oct. 1, 2002.
RS in the Standard preparation;
• V is the sample dilution volume, in mL, considering the (NL: C. Bamstein; BNT: I. DeVeau) RTS—36759-1
100-mL volume of the solution in Flask 1 and any subse-
quent dilution factor, if used;B1 Delete the following:
and rv and rs are the peak responses obtained from the Assay prep-
aration and the Standard preparation, respectively.
'Crystallized Trypsin for Inhalation
Solution
Former title: Cryotalligod Trypoin for Inhalation Aoroool
» Crystallized Trypsin for Inhalation Solution is pro

parod by cryodosiccation. It contains not loss than
90.0 poroont and not moro than 110.0 porcont of tho
BRIEFING
labolod potency of trypsin.
NOTE—Determine the suitability of tho substrates
Triamterene and Hydrochlorothiazide Tablets, USP 25 page and chock tho adjustment of tho spoctrophotomotor
1750 and page 2754 of the First Supplement. by performing tho Assay using USP Trypsin Crystal
lizod Reference Standard.
Change to read:
Packaging and storage—Preserve in
Errata:
Identification test B, line 6: Change "(Standard solution / ) " to: ainglo ao30 containers; preferably of Typo I glass, and avoid oxpo •
(Standard solution 2) sure to excessive heat.
Identification test B, line 12: Change "acetic acid," to: glacial "Storo at oontrollod room temperature^
acetic acid,
Assay, line 2 under Solvent mixture: Change "acetic acid" to: USP Reference standards (44-)—USP Trypsin Cryatalltcd RS.
glacial acetic acid Solubility test—Crystallized Trypain for Inhalation Solution con-
taining 500,000 USP Trypsin Units is aoluble in 10 mL of water
and in 10 mL of oaline TS.
Identification—Prepare a substrate oolution as follows. Transfer
85.7 mg of iVbonzoyl fe arginino ethyl eater hydrochlorido, suit
able for use in assaying crystallized trypsin (sec Note), to a 100
mL volumetric flank. Add 20 mL of 0.067 M Phosphate buffer,
pH 7.6, prepared ao dirootod in tho Assay under Crystallized Tryp
sin, add 1 mL of methyl rod mothylono bluo TS, and diluto with
water to volume. Mix 0.01 mL of thio solution with 0.01 mL of
a solution of Crystallized Trypgin for Inhalation Solution contain
ing 250,000 USP Units in 6 mL of saline on a spot plate: a purple
color is produood (distinction from chymotrypsin, which produces
no purple color within 3 minutes).
TTSSIIJ 1
Pharmacopeial Forum
0.06? M Phosphate buffer, pH 7.6 and Substrate solution Pro Change to read:
pare aa dirootod in tho Assay undor Crystallised Ttypsin. Assay—•
Ciystallised Trypsin solution—Dissolve? tho contents of 1 vial of Standard preparation—Transfer about 50 mg of USP Xylomo-
Cryatallizod Trypsin for Inhalation Solution in 10.0 mL of 0.0010 tazolino Hydroohlorido RS, aoouratoly woighod, to a 100 mL vol
N hydrochlorio aoid. Dilute this solution quantitatively with tho umotrio flask, add water to dissolve, diluto with wator to volume,
oamo diluto acid to obtain a solution containing 50 to 60 USP Tryp
oin Units per mL.
Pmccdurc—Proceed as directed in tho Assay undor Crystallized •Dissolve an accurately weighed quantity of USP Xylome-
tazoline Hydrochloride RS in water to obtain a solution hav-
ing a known concentration of about 0.5 mg per mL.Bl
Transfer 10.0 mL of this solution to a 125-mL separator, and pro-
ceed as directed under Assay preparation, beginning with "add 10
mL each of water and dilute hydrochloric acid (1 in 6), respec-
tively." The concentration of USP Xylometazoline Hydrochloride
RS in the Standard preparation is about 100 ug per mL.
Assay preparation—Transfer an accurately measured volume of
Nasal Solution, equivalent to about 5 mg of xylometazoline hydro-
chloride, to a 125-mL separator, add 10 mL each of water and di-
BRIEFING lute hydrochloric acid (1 in 6), respectively, and extract with three
10-mL portions of methylene chloride. Discard the methylene
Xylometazoline Hydrochloride Nasal Solution, USP 25 page chloride extracts, add 10 mL of sodium hydroxide solution (1 in
1816. To reduce the quantity of the USP Reference Standard 5) to the separator, and extract with three 15-mL portions of meth-
needed, it is proposed to revise the Standard solution in the test ylene chloride. Filter the combined extracts through glass wool
for Identification and the Standard preparation in the Assay. into a 50-mL volumetric flask, dilute with methylene chloride to
volume, and mix. [NOTE—Reserve a 25-mL portion of this solu-
tion for the Identification test.]
Procedure—Transfer 5.0 mL each of the Standard preparation
and the Assay preparation, to separate 10-mL volumetric flasks,
and evaporate in a water bath maintained at 40°, with the aid of
a stream of nitrogen, to dryness. Dissolve the residue in each flask
in 0.50 mL of dehydrated alcohol, and add 0.50 mL of dehydrated
Change to read: alcohol to a third 10-mL volumetric flask to provide the blank. To
Identification— each flask add 0.50 mL of sodium hydroxide solution (1 in 25),
Standard solution—Disaolvo 50 mg of USP Xylomotazolino swirl, to each add 5.0 mL of sodium nitroferricyanide solution (1
Hydroohlorido RS in 50 mL of water, in 200), and mix. After 10 minutes, accurately timed, add 1.0 mL
"Dissolve an accurately weighed quantity of USP Xylome- of a saturated solution of sodium bicarbonate to each flask, swirl,
and allow to stand for 10 minutes. Dilute each with water to vol-
tazoline Hydrochloride RS in water to obtain a solution hav- ume, mix, and allow to stand for 15 minutes. Concomitantly deter-
mine the absorbances of the solutions in 1-cm cells at the
ing a known concentration of about 1 mg per mL,B1 wavelength of maximum absorbance at about 565 nm, with a suit-
and proceed as directed for Test solution. able spectrophotometer, using the blank to set the instrument. Cal-
culate the quantity, in mg, of C 16 H 24 N 2 • HC1 in each mL of the
Test solution—Transfer 10 mL to a suitable separator, add 2 mL Nasal Solution taken by the formula:
of sodium carbonate solution (1 in 10), and extract with 10 mL of
chloroform, filtering the extract through anhydrous sodium sulfate.
Evaporate the chloroform extract on a steam bath to dryness, and
dissolve the residue in 1 mL of a mixture of chloroform and metha- in which C is the concentration, in jig per mL, of USP Xylometazo-
nol(l:l). line Hydrochloride RS in the Standard preparation; V is the vol-
Procedure—Apply separately 5-uL portions of the Test solution ume, in mL, of Nasal Solution taken; and Ay and As are the
and the Standard solution to a suitable thin-layer chromatographic absorbances of the solutions from the Assay preparation and the
plate coated with a 0.25-mm layer of chromatographic silica gel Standard preparation, respectively.
mixture (see Chromatography (621)). Allow the spots to dry,
and develop the chromatogram in a solvent system consisting of
a mixture of chloroform, methanol, and isopropylamine (92:3:3).
Remove the plate from the developing chamber, mark the solvent
front, and allow the solvent to evaporate. Spray the plate with p-
nitrobenzenediazonium tetrafluoroborate solution, prepared by
adding 250 mg to 5 mL of water, mixing, and filtering. Spray
the plate with sodium carbonate solution (1 in 10): the RF value
of the principal spot obtained from the Test solution corresponds
to that obtained from the Standard solution.
Pharmacopeial Forum
Change to read:
BRIEFING Tablet Binder
Acacia
Excipients, USP and NF Excipients, Listed by Category, NF Alginic Acid
20 page 2496 and page 447 of PF 26(2) [Mar.-Apr. 2000]. The Carboxymethylcellulose, Sodium
proposed revisions complement the proposed new monograph on Cellulose, Microcrystalline
Tapioca Starch, published under the In-Process Revision section in Dextrin
this number of PF. Ethylcellulose
Gelatin
Glucose, Liquid
(EMC) Guar Gum
Hydroxypropyl Methylcellulose
Methylcellulose
Polyethylene Oxide
Change to read: Povidone
Suspending and/or Viscosity-increasing Agent Starch, Pregelatinized
Acacia Syrup
Agar
Alginic Acid
Aluminum Monostearate "Tapioca Starch, j
Attapulgite, Activated
Attapulgite, Colloidal Activated Change to read:
Bentonite Tablet and/or Capsule Diluent
Bentonite, Purified Calcium Carbonate
Bentonite Magma Calcium Phosphate, Dibasic
Carbomer910 Calcium Phosphate, Tribasic
Carbomer 934 Calcium Sulfate
Carbomer 934P Cellulose, Microcrystalline
Carbomer 940 Cellulose, Powdered
Carbomer 941 Dextrates
Carbomer 1342 Dextrin
Carboxymethylcellulose Calcium Dextrose Excipient
Carboxymethylcellulose Sodium Fructose
Carboxymethylcellulose Sodium 12 Kaolin
Carrageenan Lactitol
Cellulose, Microcrystalline, and Carboxymethylcellulose Lactose
Sodium Mannitol
Dextrin Sorbitol
Gelatin Starch
Guar Gum Starch, Pregelatinized
Hydroxyethyl Cellulose Sucrose
Hydroxypropyl Cellulose Sugar, Compressible
Hydroxypropyl Methylcellulose Sugar, Confectioner's
Magnesium Aluminum Silicate
Methylcellulose
Pectin •Tapioca Starch, l
Polyethylene Oxide
Polyvinyl Alcohol Change to read:
Povidone Tablet Disintegrant
Propylene Glycol Alginate Alginic Acid
Silicon Dioxide Cellulose, Microcrystalline
Silicon Dioxide, Colloidal Croscarmellose Sodium
Sodium Alginate Crospovidone
Polacrilin Potassium
Sodium Starch Glycolate
"Tapioca Starch B1 Starch
Starch, Pregelatinized
Tragacanth
Xanthan Gum
'Tapioca Starch • l
Pharmacopeia! Forum
mm thick, with a large round-shaped, light brown spot (hi-

MONOGRAPHS (NF) lum). The seed coat is shiny, but only in fresh condition. The
space under the coat is totally filled with the shiny, massive
embryo and its large, pale yellow cotyledons lacking endo-
sperm.
Microscopic—The epidermis of the testa in surface view
has yellowish brown cells of fairly uniform size, with the
majority of cells rounded to polygonal, and a few that are
BRIEFING
square to obscurely triangular. The walls of these cells are
Horse Chestnut, page 3402 of PF 27(6) [Nov.-Dec. 2001];
Powdered Horse Chestnut, page 3404 of PF 27(6) [Nov.-Dec. considerably, but rather unevenly thickened, and lacking
2001]; Powdered Horse Chestnut Extract, page 3405 of P F
27(6) [Nov.-Dec. 2001]. These new monographs, which pre- pits. In sectional view, the cells are columnar, approximately
viously appeared in Pharmacopeial Previews, are now forwarded
to In-Process Revision. 3 to 4 times as high as they are wide, with the outer peri-
(DSN: G. Giancaspro) RTS—33621-1 clinal wall markedly thickened, uneven, and becoming thin-
ner towards the base; beneath the epidermis there are a few
Add the following: layers of small collenchymatously thickened cells with

small intercellular spaces; the greater part of the testa con-
•Horse Chestnut
sists of larger, loosely-packed parenchymatous cells form-
ing a spongy tissue; the walls are variably and unevenly
thickened, with intracellular and large circular spaces well
» Horse Chestnut consists of the dried seeds of
marked; the inner testa is a narrow zone, with ill-defined
Aesculus hippocastanum L. (Fam. Hippocastana-
and thinner-walled cells. All the parenchymatous cells of
ceae). It is harvested in the fall. It contains not less
the testa are darkly pigmented. The embryo has an outer
than 3.0 percent of triterpene glycosides, calcu-
layer of small colorless cells, almost square in sectional
lated on the dried basis as escin (C55Hg6O24). view, with outer and side walls thickened. In surface view,
Packaging and storage—Store in a well-closed, light-re- only the irregular and more or less polygonal lumens are dis-
sistant container, protected from moisture. cernible, giving a reticulate, pitted appearance. Cotyledons
Labeling—The label states the Latin binomial name- and, are moderately thickened and indistinctly pitted, having
following the official name, the part of the plant contained round to ovoid parenchymatous cells densely filled with
starch. Starch granules, mainly simple, are present in two
in the article.
size ranges: from 15 to 30 um and from 3 to 10 urn. The
USP Reference standards (11)—C/SP Escin RS.
largest granules vary from circular, ovoid, and bluntly poly-
gonal to pyriform, most of them with a well-marked cleft or
Macroscopic—Horse chestnut seeds are dense and hard,
stellate hilum, and lacking striations. The smaller starch
subspherical to oval, slightly flattened, and from 2 to 4 cm
in diameter. They have a dark brown seed coat from 1 to 1.5
Pharmacopeial Forum
granules are less variable, spherical to ovoid, with the hilum Extractable matter—Proceed as directed for Alcohol-Solu-
more often a point. Compound starch granules are very in- ble Extractives, Method 2 under Articles ofBotanical Origin
frequently found. (561), but use a mixture of methanol and water (8:2) instead
Thin-layer chromatographic identification test (201)— of alcohol: not less than 18.0% is found.
Test solution—Transfer about 1 g of the powdered plant Foreign organic matter (561): not more than 2.0%.
material to a screw-capped centrifuge tube, add 10 mL of Total ash (561): not more than 4.0%.
a mixture of alcohol and water (7:3), and heat on a steam
bath for 10 minutes. Centrifuge, and use the clear superna-
Heavy metals, Method III (231): not more than 20 ug per g.
tant.
Content of triterpene glycosides—
Solvent 1—Prepare a mixture of methanol and water
quantity of USP Escin RS in methanol to obtain a solution
(65:35).
having a known concentration of about 5 mg per mL.
Solvent 2—Use the lower phase of a mixture of 30 mL of
Developing solvent system—Use the upper phase of a
0.1 N hydrochloric acid, 20 mL of 1-propanol, and 50 mL of
mixture of 1-butanol, water, and glacial acetic acid
chloroform.
(50:40:10).
Reagent—Dissolve 75 mg of ferric chloride in 50 mL of
Spray reagent—Prepare a mixture of methanol, glacial
glacial acetic acid. Add 50 mL of sulfuric acid, while shak-
acetic acid, sulfuric acid, and/7-anisaldehyde (85:10:5:0.5).
ing and cooling. Prepare immediately before use.
Procedure—Develop the chromatogram to a length of not
Escin standard solutions—Dissolve an accurately
less than 15 cm, and dry the plate in a current of air. Spray
weighed quantity of USP Escin RS in glacial acetic acid,
the plate with Spray reagent, heat the plate at 100° for 5
shaking for 1 minute. Dilute quantitatively, and stepwise
minutes, and examine the plate under daylight: the chroma-
if necessary, to obtain solutions having known concentra-
togram obtained from the Test solution shows a blue-violet
tions of about 0.6, 0.4, and 0.2 mg per mL.
zone corresponding to escin, comparable in position and
Test solution—Accurately weigh 1.00 g of ground seeds,
color to the main zone in the chromatogram obtained from
and place in a 250-mL round-bottom flask. Add exactly 100
the Standard solution. Above this zone, the chromatogram
mL of Solvent 1, and weigh the filled flask with a precision
of the Test solution shows several narrow, brown to brown-
of ±0.1 g. Attach a condenser to the flask, reflux for 30
ish red zones that are less intense than the zone correspond-
minutes, and allow to cool. Adjust to the initial weight by
ing to escin.
adding Solvent 1 as needed, mix, and filter. Transfer 30.0
Microbial limits (2021)—It meets the requirements of the
mL of the filtrate to a round-bottom flask, and evaporate
tests for absence of Salmonella species and Escherichia
the solvents under vacuum. Dissolve the residue with 20
coli. The total aerobic microbial count does not exceed
mL of 0.1 N hydrochloric acid, and quantitatively transfer
106 per g, the total combined molds and yeast count does
with the aid of two additional 5-mL portions of 0.1 N hydro-
not exceed 104 per g, and the enterobacterial count is not chloric acid to a 250-mL separation funnel. Add 20 mL of 1-
more than 103 per g. propanol and 50 mL of chloroform, and shake vigorously
Loss on drying (731): not more than 10.0%. for 2 minutes. Separate the chloroform layer, and add Sol-
Pharmacopeial Forum
vent 2 to the upper phase remaining in the separation tunnel.

Shake vigorously for 2 minutes, and separate the chloroform BRIEFING
layer. Combine the chloroform layers in a round-bottom
Powdered Horse Chestnut, page 3404 of PF 27(6) [Nov.-Dec.
flask, and evaporate to dryness under vacuum. Evaporate 2001]—See briefing under Horse Chestnut.
the remaining solvents with the aid of a current of air. Wash (DSN: G. Giancaspro) RTS—33621-2
the residue with two 10-mL portions of ether,filter,wash the
filter with 10 mL of ether, and discard the ether filtrates. Add the following:
After evaporation of the residual ether, add to the residue
•Powdered Horse Chestnut
a 10-mL portion of glacial acetic acid, and pass through
the previously used dried filter into a 50-mL volumetric
flask. Repeat the addition of glacial acetic acid followed » Powdered Horse Chestnut is Horse Chestnut re-
by filtration two additional times, combining the filtrates
duced to a powder or very fine powder. It contains
in the volumetric flask. Wash the round-bottom flask with
not less than 3.0 percent of triterpene glycosides,
small quantities of glacial acetic acid, and filter into the vol-
calculated on the dried basis as escin (C55H86O24).
umetric flask. Dilute with glacial acetic acid to volume.
Procedure—Transfer 1 mL each of the Escin standard so- Packaging and storage—Preserve in well-closed, light-re-
lutions, the Test solution, and glacial acetic acid to separate sistant containers, protected from moisture.
test tubes with stoppers. Add 4.0 mL of Reagent to each Labeling—The label states the Latin binomial name and,
tube, cap the tubes, and place them in a water bath at 60° following the official name, the part of the plant from which
for 25 minutes, shaking occasionally. Measure the absor- the article was derived.
bances at 540 nm of the reacted Test solution and the reacted USP Reference standards (11)—USP Escin RS.
Escin standard solutions, using glacial acetic acid as the Botanic characteristics—Yellowish brown powder, odor-
blank. Plot the absorbances obtained from the reacted Escin less, with a somewhat mealy, disagreeably bitter, and linger-
standard solutions versus concentrations, in mg per mL, of ing taste. It shows numerous, different-sized fatty oil
USP Escin RS in the corresponding Escin standard solution. droplets that are free or within the thin-walled, colorless tis-
From the graphs so obtained, determine the concentration, sue of the cotyledons. Fragments of the testa consist of
C, in mg per mL, of triterpene glycosides as escin thick-walled pitted sclerenchymatous cells. The following
(C55H86O24) in the Test solution. Calculate the percentage are also present: pyriforrn, roundish or reniform larger indi-
of triterpene glycosides in the portion of Horse Chestnut ta-
vidual starch granules from 15 to 30 um in diameter, smaller
ken by the formula:
individual granules from 3 to 10 um, and only a few com-
(50/3)(C/FF), pounded granules consisting of 2 to 4 single grains that form

rows up to 45 urn in length. Many of the starch granules
in which C is the concentration, in mg per mL, of triterpene
have a bistellate or polystellate, but rarely simple, hilum.
glycosides in the Test solution as obtained above; and W is
the weight, in g, of Horse Chestnut taken to prepare the Test
solution.-.
Pharmacopeial Forum
Other requirements—It meets the requirements of the tests mixture used for preparation, the ratio of the starting crude
for Identification, Microbial limits, Loss on drying, Extrac- plant material to Powdered Extract, and the name and con-
table matter, Total ash, Pesticide residues, Heavy metals, tent of any added substance. It meets the requirements for
and Content of triterpene glycosides under Horse Chest- labeling under Botanical Extracts (565).
nut.-, USP Reference standards (11)—USP Escin RS.
Thin-layer chromatographic identification test (201)—
Standard solution, Developing solvent system, and Proce-
dure—Proceed as directed for Thin-layer chromatographic
identification test (201) under Horse Chestnut.
Test solution—To 10 mL of methanol, add a quantity of
BRIEFING
Powdered Extract equivalent to 25 mg of the labeled amount
Powdered Horse Chestnut Extract, page 3405 of PF 27(6) of triterpene glycosides, andshake. Allow to stand for 15
[Nov.-Dec. 2001]—See briefing under Horse Chestnut.
minutes before use.
Microbial limits (2021)—It meets the requirements of the
tests for absence of Salmonella species and Escherichia
Add the following:
coli. The total aerobic microbial count does not exceed
•Powdered Horse Chestnut Extract 104 per g, the total combined molds and yeasts count does
not exceed 102per g, and the count for enterobacteria does
not exceed 103 per g.
» Powdered Horse Chestnut Extract is prepared
Loss on drying (731): not more than 5.0%.
from Horse Chestnut by extraction with alcohol-
Heavy metals, Method II (231): not more than 20 ug per g.
water mixtures or methanol—water mixtures. The
Organic volatile impurities, Method VI (467): meets the
ratio of starting plant material to extract is be-
requirements.
tween 5:1 and 8:1. It contains not less than 90.0
Other requirements—It meets the requirements for Packa-
percent and not more than 110.0 percent of the la-
ging and Storage, Residual Solvents, and Pesticide Residues
beled amount of triterpene glycosides, calculated
in General Pharmacopeial Requirements for powdered ex-
on the dried basis as escin (C55H86O24). It may con-
tracts under Botanical Extracts (565).
tain suitable added substances. Content of triterpene glycosides—
Packaging and storage—Preserve in tight, light-resistant Solvent 1, Solvent 2, Reagent, and Escin standard solu-
containers, in a cool place. tions—Proceed as directed for Content of triterpene glyco-

sides under Horse Chestnut.
Labeling—The label states the Latin binomial name- and,
Test solution—Transfer an accurately weighed quantity of
following the official name, the part of the plant from which
Powdered Extract equivalent to about 50 mg of the labeled
the article was prepared. The label also indicates the content
content of triterpene glycosides into a 50-mL flask. Add 20
of triterpene glycosides, the extracting solvent or solvent
mL of 0.1 N hydrochloric acid, and shake for 5 minutes. Fil-
Pharmacopeial Forum
ter into a 250-mL separatory funnel with the aid of two ad- posed to avoid erroneous results obtained with samples having
concentrations significantly different from the concentration of
ditional 5-mL portions of 0.1 N hydrochloric acid. Proceed the Standard. In addition, editorial changes have been made.
as directed for Test solution in the test for Content oftriter- (DSB: G. Giancaspro) RTS—34977-1; 36302-1; 33232-1;
33295-1; 33879-1; 33977-1
pene glycosides under Horse Chestnut, starting with "Add
20 mL of 1-propanol and 50 mL of chloroform."
Add the following:
for Content of triterpene glycosides under Horse Chestnut. •Chondroitin Sulfate Sodium
Calculate the percentage of triterpene glycosides in the por-
tion of Powdered Extract taken by the formula:
(C14H19NO14SNa2),
5000(C/W),
Chondroitin sulfatc sodium A, chondroitin 4 sulfato^ go
in which C is the concentration, in mg per mL, of triterpene dium aalt [12678 07 8]
glycosides in the Test solution as obtained above; and W is Chondroitin oulfato oodium C, ohondroitin 6 sulfatOj GO
the weight, in mg, of Powdered Extract taken to prepare the dium aalt [12678 07 8]
Test solution.-. Sodium chondroitin sulfate [24967-93-9]
» Chondroitin Sulfate Sodium is the sodium salt

of the sulfated linear mucoporysaccharide glyco-
saminoglycan obtained from bovine, porcine, or
BRIEFING
avian cartilages of healthy and domestic animals
Chondroitin Sulfate Sodium, page 3059 of PF 27(5) [Sept-
Oct. 2001]. The test for Electrophoretic purity is included to com- used for food by humans. Chondroitin Sulfate So-
plement the test for Content of glycosaminoglycans by titration.
This test is intended to detect glycosaminoglycans other than chon- dium consists mostly of the sodium salt of the sul-
droitin as impurities. The electrophoretic procedure based on the
method from Volpi N. in Anal. Biochem. 1996, 240, 114-118, fate ester of 7V-acetylchondrosamine (2-
was validated to determine chondroitin related impurities using ni-
trocellose membranes from Millipore (Catalog No. HAHY 00010,
unsupported) and BIO-RAD (Catalog No. 162-0090, supported). acetamido-2-deoxy-P-D-galactopyranose) and D-
Mobilities of related compounds with respect to chondroitin sulfate
were: 0.85 for keratin sulfate, 0.70 for dermatan sulfate and hyal- glucuronic acid copolymer. These hexoses are al-
uronic acid, 0.55 for fast moving heparin and 0.00 for slow-moving
heparin. It is proposed to change the concentrations of the Standard ternately linked p-1,4 and (3-1,3 in the polymer.
solutions and the Test solution in the test for Electrophoretic purity
to improve the detection of impurities. With these modifications, The prevalent mucopolysaccharidos glycosami-
the method is reported to detect other glycosaminoglycans in con-
centrations of 1% or less. Therefore, a new limit for electrophoretic
impurities is proposed. A new limit in the test for Limit of proteins noglycans are designated chondroitin sulfate so-
is also proposed. According to data received by the USP, the pro-
posed value appears to better correlate with the new limit in the test dium A, containing iV-acetylchondrosamine-4-<9-
for Content of glycosaminoglycans (not less than 90% as changed
in PF 27(5) [Sept.-Oct. 2001]). The new test for Limit of protein sulfate, and chondroitin sulfate sodium C, con-
also accounts for the total mass balance considering the glycosami-
noglycan content and chlorides, sulfates, proteins, and electro- taining iV-acetylchondrosamme-6-<9-sulfate. It
phoretic impurities. In the test for Content of total
glycosaminoglycans it is proposed to eliminate the blank because
no inflection can be obtained with the phototrode in the absence of contains not less than 95.0 percent 90.0 percent
analyte. Interpolation of the three-level calibration curve is pro-
Pharmacopeial Forum
and not more than 105.0 percent of total mucopo Loss on drying (731)—Dry it at 105° for 4 hours: it loses
lysaccharidos glycosaminoglycans as chondroitin not more than 10.0% of its weight. [NOTE—Chondroitin
sulfate sodium, calculated on the dried basis. Sulfate Sodium is extremely hygroscopic once dried. Avoid
exposure to the atmosphere, and weigh promptly]
NOTE—Chondroitin sulfate sodium is extre-
Residue on ignition (281): between 20.0% and 30.0%, on
mely hygroscopic once dried. Avoid exposure to
the dried basis, omitting the addition of sulfuric acid.
the atmosphere and weigh promptly.
[NOTE—Retain a portion of tho residue for Identification
Packaging and storage—Preserve in tight containers, and
store at room temperature. Chloride (221)—A 0.10-g portion shows no more chloride
Labeling—Label it to indicate the species of the source than corresponds to 0.4 mL 0.7 mL of 0.020 N hydrochloric
from which the article was derived. acid: not more than 0.50% is found.
USP Reference standards (11)—USP Chondroitin Sulfate Sulfate (221)—Dissolve 200 mg in 40 mL of water. Add 10
Sodium RS. mL of a solution of cetylpyridinium chloride having a con-
Clarity and color of solution—Transfer 2.5 g of Chondroi- centration of about 30 mg per mL, mix, and pass through a
tin Sulfate Sodium to a 50-mL volumetric flask. Dissolve in filter. A 0.10 g 25-mL portion of the filtrate shows no more
and dilute with carbon dioxide-free water to volume, mix, sulfate than corresponds to 0.25 mL of 0.020 N sulfuric
and examine immediately. Measure the absorbance of this acid: not more than 0.24% is found.
solution at 420 nm in a 1-cm cell, using carbon dioxide-free Arsenic, Method II (£44-):-not more than 2 ug por g.
water as the blank: its absorbance is not greater than 0.35. Heavy metals, MethodII (231): 0.002%.
Identification— Organic volatile impurities, Method I (467): meets the re-
A: Infrared Absorption (197K)—Proceed as directed in quirements.
the chapter, except to record the spectrum from 3800 to Electrophoretic purity (see Electrophoresis (726))—ffe
1
1000 cm- .
B: The residue, as obtained from tho tost for Residue on 1 M Barium acetate buffer, pH 5.0—Dissolve about
ignition, is soluble in A solution containing 0.5 g in 10 mL 225.43 g of barium acetate, accurately woighod, in water,
of water «»4 meets the requirements of the test for Sodium and dilute with water to 900 mL. Adjust with acetic acid
(191) .and Sulfato (494-)? to a pH of 5.0, dilute with water to 1 liter, and mix.
Specific rotation (781S): between -20.0° and-30.0°. 0.4 M Barium acetate buffer, pH 5.0—Dissolve about
Test solution: 30 mg per mL. 90.17 g of barium acetate, accurately woighod, in water,
Microbial limits (2021)—The total bacterial count does and dilute with water to 900 mL. Adjust with acetic acid
not exceed 1000 per g, and the total combined molds and to a pH of 5.0, dilute with water to 1 liter, and mix.
yeasts count does not exceed 100 per g. It meets the require- Staining reagent: 0.08% azure A solution.
ments of the tests for absence of Clostridium species, Sal- Standard solution 1—Prepare a solution of USP Chon-
monella species, and Escherichia coli. droitin Sulfate Sodium RS in water having a known concen-
pH (791): between 5.5 and 7.5, in a solution (1 in 100). tration of 0.01 mg about 3 mg per mL.
Pharmacopeial Forum
Standard solution 2—Dilute 2 mL 1 mL of Standard so- Standard solution 3 remains red (pH buffering capacity),
lution 1 with water to 100 mL, and mix. and the band corresponding to Standard solution 2 is clearly
Standard solution 3—Prepare a solution containing 1.0 g visible at a mobility similar to the band obtained from Stan-
of phenol red TS in 100 mL water. dard solution 1. Any secondary band in the electrophero-
Test solution—Transfer about 50.0 mg 150 mg, accurately gram of the Test solution is not more intense than the
weighed, to a 50-mL volumetric flask, dissolve in and dilute band obtained from Standard solution 2. Not more than
with water to volume, and mix. Transfer 1.0 mL of tho solu 3% 1% of any individual impurity is found.
tion so obtained to a 100 mL volumetric- flask, dilute with Content Limit of protein—
water to volume, and mix. Standard solution—Transfer an accurately measured vol-
Procedure—Adhere a cellophane sheet to the top of a ume of 7 percent bovine serum albumin certified standard to
cooling plate of the electrophoretic equipment by means a suitable container, and dilute quantitatively and stepwise
of some water drops. Remove any air bubbles. Soak a cut with water to obtain a solution having a known concentra-
6- x 12-cm cellulose nitrate gel having a 0.45-um porosity tion of about 35 ug per mL.
in 0.4 M Barium acetate buffer, pH 5.0 for 5 minutes, and Test solution—Transfer an accurately weighed amount of
remove any excess solution between the filter paper and the Chondroitin Sulfate Sodium, equivalent to 100 mg 60 mg of
cellulose strip. Apply 10 uL each of Standard solution 1, the dried substance, to a 100-mL volumetric flask, dissolve
Standard solution 2, Standard solution 3, and the Test solu- in and dilute with water to volume, and mix.
tion as bands to the gel near the cathode. [NOTE—Back the Procedure—Add 2.0 mL of freshly prepared alkaline cup-
cellophane sheet with a plastic sheet for protection to pre- ric tartrate TS to test tubes containing 2.0 mL of water, 2.0
vent the gel from breaking; otherwise use a supported nitro- mL of the Test solution, or 2.0 mL of the Standard solution,
cellulose membrane, and place it on top of the cellophane and mix. After about 10 minutes, add 1.0 mL of Folin-Cio-
sheet.] Attach the strip to the support bridge of an electro- calteu phenol TS, prepared immediately before use, to each
phoresis chamber containing 1MBarium acetate buffer, pH test tube, and mix. After 30 minutes, measure the absor-
5.0 in each side of the chamber. Ensure that each end of the bance of each solution at 750 nm against the blank. The ab-
strip is in contact with 1 M Barium acetate buffer, pH 5.0.
sorbance of the Test solution is not greater than the
Connect the electrodes, close the cover, start the water cir-
absorbance of the Standard solution: not more than 3.5%
culation for gel cooling until the temperature of the plate is
6.0% of proteins is found, calculated on the dried basis.
about 10°, and apply a 20-mA current at about 330 V for 1
Content of total mueopolysaceharidcs glycosaminogly-
hour. Switch off the current, disconnect the electrodes, re-
cans—
move the plastic sheet, and immerse the gel in the Staining
Cetylpyridinium chloride solution—Prepare a solution of
reagent for 10 minutes. Wash with water to remove any un-
cetylpyridinium chloride in water having a concentration of
bound Staining reagent, and compare the bands: the band
about 1 mg per mL.
electropherogram obtained from the Test solution exhibits
Standard solution solutions—Transfer about 25 mg 30 mg
a major band that is similar in position and shape to the band
of USP Chondroitin Sulfate Sodium RS, accurately
obtained from Standard solution 1. The band obtained from
weighed, to a 25-mL volumetric flask. Dissolve in 6 mL
Pharmacopeial Forum
of water, add 1 mL of pH 7.2 phosphate buffer solution (see nium chloride solution. From a linear regression equation
Buffer Solutions under Solutions in the section Reagents, In- calculated using the volumes of Cetylpyridinium chloride
dicators, and Solutions), and dilute with water to volume, solution consumed, and the mass, in mg, of USP Chondroi-
quantitatively and step wise if necessary, to obtain a solution tin Sulfate Sodium RS, determine the mass of glycosamino-
three Standard solutions having known concentrations of glycans as chondroitin sulfate sodium in the aliquot of the
about 1 mg por-roL 1.2 mg per mL, 0.8 mg per mL, and Test solution taken. Calculate the percentage of total muoo
0.4 mg per mL, respectively. polysaooharidos glycosaminoglycans as chondroitin sulfate
Test solution—Transfer about 100 mg of dried Chondroi- sodium in the portion of Chondroitin Sulfate Sodium taken
tin Sulfate Sodium, accurately weighed, to a 100-mL volu- by the formula:
metric flask, dissolve in 30 mL of water, add 5 mL of pH 7.2
phosphate buffer solution (see Buffer Solutions under Solu-
tions in the section Reagents, Indicators, and Solutions), di-
2000(M/W),
lute with water to volume, and mix.
Procedure—Transfer 5 mL 5.0 mL of each Standard so- in which Fis tho equivalence factor, in mg por mL, ao oal
lution and the Test solution to four separate titration vessels, culatod abovo; V'v$ tho volume; in mL, of Cetylpyridinium
and add about 30 mL of water. Titrate with Cetylpyridinium chloride solution consumed by tho Test solution; M is the
chloride solution using a phototrodo to determine tho ond- mass of glycosaminoglycans in the aliquot of the Test solu-
point turbidimotrioally, at 420, 550, or 660 nnij with tho in tion; and W'\s the weight, in mg, of Chondroitin Sulfate So-
3trumont sot in transmittanoo mode at 70% for the- initial dium taken to prepare the Test solution.B1
solution. Perform a blank determination, and make any noo

osaary oorrootion. Determine tho equivalence factor, F, in
mg of USP Chondroitin Sulfato Sodium RS per mL of Cc
tylpyridinium chloride solution taken by tho formula:
BRIEFING
in whioh C ia tho oonoentration, in mg por mL, of USP Chondroitin Sulfate Tablets, page 3063 of PF 27(5) [Sept-
Oct. 2001]. Details for the Identification test are cross-referenced
Chondroitin Sulfato Sodium RS in tho Standard solution; to the test for Electrophoretic purity under Chondroitin Sulfate So-
dium. A cooling plate to 10° C is recommended because of diffu-
and Via tho volume, in mL, of Cetylpyridinium chloride so • sion of the spots and the explosive nature of nitrocelluose gel. In
the Procedure in the test for Content of chondroitin sulfate sodium,
lution oonsumed by the Standard solution. Ropoat tho pro it is proposed to delete the blank determination because no inflec-
tion can be obtained with the phototrode in the absence of analyte.
coduro, oxoopt to use 5.0 mL of tho Test solution instead of Interpolation of the three-level calibration curve is proposed to
avoid erroneous results obtained with samples having concentra-
tho Standard solution. Stir until a steady reading is obtained tions significantly different from the concentration of the Standard
solution. In addition, editorial changes have been made.
using a phototrode to determine the endpoint turbidimetri-
cally, either at 420 nm, 550 nm, or 660 nm. Set the instru- (DSB: G. Giancaspro) RTS—36302-2
ment to zero if absorbance is being monitored or not less

than 70% if transmittance is used. Titrate with Cetylpyridi-
Pharmacopeial Forum
Add the following: Procedure (see Elcctrophoresis(&6)) Soak a 6 x 10
•Chondroitin Sulfate Tablets cm nitrocellulose strip in 100 mL of 0.2 M Barium acetate

buffet' for 10 to 60 minutes:Remove the atrip using forceps,
taking care to only handle the outer edges. Place the strip
» Chondroitin Sulfate Tablets are prepared from between two absorbent pad3, and blot to remove 0x0003 so
Chondroitin Sulfate Sodium and contain not less lution: Attach the strip to the support bridge of an electro
than 90.0 percent and not more than 120.0 percent phorosis chamber containing 0.2 MBarium acetate buffer in
oaoh side of the ohambor. Ensure that each end of the strip is
of the labeled amount of chondroitin sulfate so-
in contact with 0.2 M Barium acetate buffer. Mark the ap
dium.
plication lino near the cathode end of the strip:
NOTE—Chondroitin sulfate sodium is extre-
Apply 1 uL of a solution of phenol rod TS in 0.2 M Bar
mely hygroscopic once dried. Avoid exposure to
ium acetate buffer (1 in 1000) as a spot. Adjacent to this;
the atmosphere and weigh promptly. apply 1 uL oaoh of the Test solutionand the Standard solu
tion as two otroaks, oaoh about 9 mm long. Attach tho oham
containers, and store at room temperature.
bor cover, and perform the oloctrophorosia at 300 V until the
USP Reference standards (U)—USP Chondroitin Sulfate phenol rod (yellow dyo) has moved about 2.5 om of tho
Sodium RS. lengthof the strip. NOTE—Movement of tho dyo takos about
Labeling—Label it to indicate the species of the source 40 minutes: Remove tho strip from the chamber, and blot tho
from which the chondroitin used to prepare the Tablets onds on paper towels. Stain tho gol with a 0.2% solution of
was derived. toluidino blue O in a mixture of alcohol, water, and acotio
Identification— aoid (50:49:1). The principal spot obtained from the Test so-
0.2 M Barium acetate buffer—Dissolve 25.51 g of barium lution has the same migration as the principal spot obtained
acetate in 400 mL of water. Adjust with a suitable volume of from the Standard solution.
glacial acetic acid, while stirring, to a pH of 5.0, dilute with Disintegration and dissolution (2040): meet the require-
water to volume, and mix; ments for Dissolution.
/ MBarium acetate buffer,pH 5.0; 0.4 MBarium acetate Medium: water; 900 mL.
buffer, pH 5.0; Staining reagent; and Procedure—Proceed Apparatus 2: 75 rpm.
as directed in Electrophoretic purity under Chondroitin Sul- Time: 60 minutes.
fate Sodium. Cetylpyridinium chloride solution, Standard solution, and
Standard solution—Use the Standard solution of middle Test solution—Prepare as directed in the test for Content of
concentration in the test for Content of chondroitin sulfate chondroitin sulfate sodium.
sodium.
Standard solution and Test solution—Prepare as directed
in the test for Content of chondroitin sulfate sodium.
Pharmacopeial Forum
Procedure—Proceed as directed in the test for Content of Procedure—Separately transfer 5.0 mL oaoh of the- of
chondroitin sulfate sodium, adjusting the volume of the ali- each Standard solution and the Test solution to separate ti-
quot if necessary. Calculate the quantity, in rng, of chondroi- tration vessels, and add about 30 mL of water to each. ^
tin sulfate sodium dissolved in the portion of Tablets taken trate with Cetylpyridinium chloride solution; using a
by the formula: phototrodo to determine the endpoint turbidimotrioally, at
420, 550, or 660 nm, with the instrument sot in transmit
900C,
tanco mode at 70% for the initial solution. Perform a blank
in which C is the concentration, in mg per mL, of chondroi- determination, and make any nooossary oorrootion. Calou
tin sulfate sodium in the solution under test. late the equivalence factor, F, in mg of USP Chondroitin
Tolerances—Not less than 75% of the labeled amount of Sulfato Sodium RS in each mL of Cetylpyridinium chloride
chondroitin sulfate sodium is dissolved in 60 minutes. solution taken by the formula:
Content of chondroitin sulfate sodium—
Cetylpyridinium chloride solution—Prepare a solution of in which C is the concentration, in mg per mL, of USP
cetylpyridinium chloride in water having a concentration of Chondroitin Sulfato Sodium RS in the Standard solution;
about 1 mg per mL and Vis tho volume, in mL, of Cetylpyridinium chloride so
Standard solutions—Transfer about 25 mg of USP Chon lution consumed by the Standard solution. Stir until a steady
droitin Sulfate Sodium RS, accurately weighed, to a 25 mL reading is obtained using a phototrode to determine the end-
volumetric- flask, and dissolve in 6 mL of water. Add 1 mL point turbidimetrically, either at 420, 550, or 660 nm. Set the
of pH 7.2 phosphate buffer solution (see Buffer Solutions instrument to zero if absorbance is being monitored or to not
under Solutions in the section Reagents*; Indicators, and So less than 70% if transmittance is used. From a linear regres-
lutions), and dilute with water to volume to obtain a solution sion equation calculated using the volumes of Cetylpyridi-
having a known oonoentration of about 1 mg per mL: Pre- nium chloride solution consumed, and the mass, in mg, of
pare as directed in the test for Content of total glycosamino- USP Chondroitin Sulfate Sodium RS, determine the mass of
glycans under Chondroitin Sulfate Sodium. chondroitin sulfate sodium in the aliquot of the Test solution
Test solution—Weigh and finely powder not fewer than 20 taken. Calculate the amount, in mg, of chondroitin sulfate
Tablets. Transfer an accurately weighed portion of the pow- sodium in the portion of Tablets taken by the formula:
der, equivalent to about 100 mg of chondroitin sulfate so- 2&FV20M,

dium, to a 100-mL volumetric flask, add 30 mL of water
in which F is tho oquivalonoo factor; in mg per mL, as oal
and 5 mL of pH 7.2 phosphate buffer solution (see Buffer
oulatod above; and V'm the volume, in mL, of Cctylpyridi
Solutions under Solutions in the section Reagents, Indica-
nium chloride solution consumed by M is the mass of
tors, and Solutions), and shake to suspend the powder in so-
Chondroitin Sulfate Sodium in the aliquot of the Test solu-
lution. Sonicate in a 65° water bath for 20 minutes. Remove
tion.-.
from the bath, stir with a magnetic stirrer for 5 minutes, di-
lute with water to volume, and centrifuge.
© 2002 The United States Pharmacopeial Convention, Inc. All Rights Reserved. '
Pharmacopeial Forum
and have the following: five green, hairy, subulate calyx

BRIEFING
teeth, one longer than the other four; petals united into a
Red Clover, page 3406 of PF 27(6) [Nov.-Dec. 2001]; Pow-
dered Red Clover, page 3409 of P F 27(6) [Nov.-Dec. 2001]; more or less campanulate tube, somewhat recurved, and col-
Powdered Red Clover Extract, page 3410 of PF 27(6) [Nov.-
Dec. 2001]; Red Clover Tablets, page 3411 of PF 27(6) [Nov.- orless with pinkish purple veins; diadelphous stamens; slen-
Dec. 2001]. These monographs have been previewed and are now
forwarded to In-Process Revision. The method for the Content of der style; a faintly aromatic, somewhat tea-like odor; and a
isoflavones has been validated using the Symmetry C18 brand of
LI column. Typical retention times are about 7.5, 9.9, 11.7, and sweetish, then slightly bitter taste.
13.3 minutes for diadzein, genistein, formononetin, and biochanin
A, respectively. Microscopic—Epidermis of calyx composed of polygonal
cells with faintly striated cuticle and occasional anomocytic
(DSB: G. Giancaspro) RTS—33247-1; 33301-1
stomata on the outer epidermis only; abundant, uniseriate,
covering trichomes with two small, thin-walled basal cells
Add the following:
and a thick-walled tapering end cell, up to 1 mm in length
•Red Clover
with a warty cuticle. Glandular trichomes are also present,
particularly on the lower epidermis, each with a one- or two-
celled stalk and a large, cylindrical head composed of sev-
» Red Clover consists of the dried inflorescence of
eral cells arranged in two rows. Epidermal cells of the cor-
Trifolium pratense L. (Fam. Fabaceae). It contains
olla, papillose at the tip, are elongated with slightly wavy
not less than 0.5 percent of isoflavones, calculated
walls and a strongly striated cuticle; vascular strands of cor-
on the dried basis as the sum of daidzein, genis- olla and calyx are surrounded by a crystal sheath containing
tein, formononetin, and biochanin A. prismatic crystals of calcium oxalate. The following are also
present: fibrous layer of anthers; subspherical pollen grains,
Packaging and storage—Store in a well-closed, light-re-
20 to 48 urn in diameter with smooth exine, three distinct
sistant container, protected from moisture.
pores, and three furrows; upper epidermal cells of leaflets
with sinuous and slightly beaded anticlinal walls; lower epi-
following the official name, the parts of the plant contained
dermis with sinuous to wavy walls; anomocytic stomata on
in the article.
both surfaces, but more frequent on the lower surface; abun-
USP Reference standards (11)—USP Formononetin RS.
dant covering trichomes on both surfaces and on the mar-
USP Powdered Red Clover Extract RS.
gins; and fibro-vascular strands surrounded by a crystal
sheath containing prismatic crystals of calcium oxalate.
Macroscopic—Red Clover inflorescences are ovoid with
Identification—
a rounded summit, mostly from 12 to 34 mm in length and
A: Thin-layer chromatographic identification test
width, usually on a very short stalk, shriveled, purplish, and
(201)-
more or less brown from drying, consisting of many papilio-
naceous flowers, crowded together and clothed at the base
with broad, pointed, pale green ciliate stipules with darker
veins. The flowers, which may or may not be accompanied
by diminutive trifoliate leaves, are up to 15 mm in length
Pharmacopeial Forum
Test solution—Transfer about 1 g of the powdered plant togram of the Standard solution, as obtained in the test for
material to a screw-capped centrifuge tube. Add 10 mL of Content ofisoflavones. Calculate the ratio of 5,7-dihydrox-
a mixture of methanol and water (6:4), heat in a steam bath yisoflavones to 7-hydroxyisoflavones by the formula:
for 10 to 15 minutes, cool, and filter. Apply 20 to 30 uL to
(B + G)/(D + F),
the plate in bands that are 2 cm in length.
in which B, G, D, and F are the percentages of biochanin A,
Standard solution—Transfer about 100 mg of USP Pow-
genistein, daidzein, and formononetin, respectively, as ob-
dered Red Clover Extract RS to a screw-capped centrifuge
tained in the test for Content ofisoflavones: the ratio is be-
tube. Add 1 mL of a mixture of alcohol and water (7:3), and
tween 0.1 and 10.
heat in a steam bath for 10 minutes. Centrifuge, and use the
clear supernatant. Apply 20 to 30 uL to the plate. Microbial limits (2021)—It meets the requirements of the
Developing solvent system—Use the upper phase of a tests for absence of Salmonella species and Escherichia
mixture of ethyl acetate, water, formic acid, and glacial ace- coli. The total aerobic microbial count does not exceed
tic acid (100:27:11:11). 106 per g, the total combined molds and yeast count does
Spray reagent A—Prepare a solution of 2-aminoethyl di- not exceed 104 per g, and the enterobacterial count is not
phenylborinate in methanol containing 10 mg per mL. more than 103 per g.
Spray reagent B—Prepare a solution of polyethylene gly- Loss on drying (731): not more than 12.0%.
col 4000 in alcohol containing 50 mg per mL. Foreign organic matter (561): not more than 2.0%.
Procedure—Develop the chromatogram to a length of not Total ash (561): not more than 10.0%.
less than 18 cm, and dry the plate in a current of air. Spray Acid-insoluble ash (561): not more than 2.0%.
the plate with Spray reagent A followed by Spray reagent B,
Water-soluble extractives, Method 2 (561): not less than
and examine the plate under UV light at 365 nm: the chro-
15.0%.
matogram obtained from the Test solution shows a blue zone
at an RF value of about 0.7 that corresponds in color and RF
Heavy metals (231): not more than 10 fig per g.
value to that in the chromatogram obtained from the Stan-
Content of isoflavones—
dard solution; one yellowish green zone at an RF value of
Solvent: a mixture of alcohol and water (1:1).
about 0.55 corresponding in color and RF value to that in
Solution A—Prepare a filtered and degassed mixture of
the chromatogram obtained from the Standard solution;
water and acetonitrile (75:25) containing 0.05% trifluoroa-
and one yellowish orange zone at an RF value of about
cetic acid.
0.50 corresponding in color and RF value to that in the chro-
matogram of the Standard solution. Other colored zones of Solution B—Use filtered and degassed acetonitrile con-
varying intensities may be observed in the chromatogram taining 0.05% trifluoroacetic acid.
obtained from the Test solution. Mobile phase—Use variable mixtures of Solution A and
Solution B as directed for Chromatographicsystem. Make
B: The chromatogram of the Test solution exhibits
peaks for daidzein, genistein, formononetin, and biochanin
A at retention times that correspond to those in the chroma-
Pharmacopeial Forum
Standard solution 1—Dissolve an accurately weighed

quantity of USP Powdered Red Clover Extract RS in 50 Time Solution A Solution B
times the weight of 2 N hydrochloric acid with shaking (minutes) (%) (%) Elution
for 1 minute and heating in a water bath for 30 minutes. Di- 0 100 0 equilibration
lute with Solvent to obtain a solution having a known con- 0-2 100 0 isocratic
centration of about 0.5 mg per mL. Filter through a 2-2.5 100^87 0->13 linear gradi-
membrane having a 0.45-um or finer porosity. ent
Standard solution 2—Dissolve an accurately weighed 2.5-7.5 87->80 13-+20 linear gradi-
quantity of USP Formononetin RS in a mixture of n-propa- ent
nol and water (1:1) with sonication. Dilute quantitatively, 7.5-7.8 80->73 20->27 linear gradi-
and stepwise if necessary, with the mixture of n-propanol ent
and water (1:1) to obtain a solution having a known concen- 7.8-8.0 73->55 27->45 linear gradi-
tration of about 0.1 mg per mL. Filter through a membrane ent
having a 0.45-um or finer porosity. 8.0-11.0 55->50 45->50 linear gradi-
Test solution—Accurately weigh approximately 2500 mg ent
of ground plant material, and place in a 120-mL flask with a 11.0-13.0 50^40 50^60 linear gradi-
stopper. Add exactly 100 mL of Solvent, close the flask, and ent
shake on an orbital or wrist-action shaker for not less than 13.0-15.0 40->26 60->74 linear gradi-
12 hours. Transfer 50.0 mL of this solution to a round-bot- ent
tom flask, and evaporate to dryness under vacuum. Add 15 15.0-16.0 26->0 74->100 linear gradi-
mL of 2 N hydrochloric acid, and heat in a water bath for 30 ent
minutes. Quantitatively transfer this solution with the aid of 16.0-18.1 0-»100 100->0 linear gradi-
about 15 mL of alcohol, to a 50-mL volumetric flask, and ent
dilute with Solvent to volume. Filter through a membrane 18.1-23.0 100 0 isocratic
having a 0.45-jj.m or finer porosity, discarding the first 4 Chromatograph Standard solution 1, and record the peak re-
mL of filtrate. sponses as directed for Procedure: the chromatograms ob-
Chromatographic system (see Chromatography (621))— tained are similar to the Reference Chromatogram provided
The liquid chromatograph is equipped with a 254-nm detec- with the USP Powdered Red Clover Extract RS; the tailing
tor and a 4.6-mm x 25-cm column that contains end- factor for formononetin is not more than 2.0; and the relative
packed 5-um packing LI. The flow rate is about 1.0 mL standard deviation for replicate injections of Standard solu-
per minute. The column temperature is maintained at 45°. tion 1 is not more than 2.0%.
The chromatograph is programmed as follows.
Pharmacopeial Forum
Procedure—Separately inject equal volumes (about 20 Add the following:

uL) of Standard solution 1, Standard solution 2, and the Test
•Powdered Red Clover
solution into the chromatograph, record the chromatograms,
and measure the areas of the analyte peaks. Identify the re-
tention times of the peaks corresponding to daidzein, genis- » Powdered Red Clover is Red Clover reduced to
tein, formononetin, and biochanin A by comparison of the a powder or very fine powder. It contains not less
chromatogram of Standard solution 1 with that obtained
than 0.5% of isoflavones, calculated on the dried
from the Reference Chromatogram. Separately calculate
basis as the sum of daidzein, genistein, formono-
the percentages of daidzein, geni stein, formononetin, and
netin, and biochanin A.
biochanin A in the portion of Red Clover taken by the for-
mula: Packaging and storage—Preserve in well-closed, light-re-
sistant containers, protected from moisture.
50F(CIW){rulrs),
in which F is the conversion factor for each analyte (0.97 for
following the official name, the parts of the plant from
daidzein, 1.13 for genistein, 1.00 for formononetin, and 1.05
for bioachanin A); C is the concentration, in mg per mL, of
USP Formononetin RS in Standard solution 2; W is the
weight, in g, of Red Clover taken to prepare the Test solu-
Botanic characteristics—Brownish red to greenish red;
tion; and rv and rs are the peak responses for formononetin
numerous long, sharp-pointed, unicellular, nonglandular
obtained from the Test solution and Standard solution 2, re-
hairs with thick, nonlignified walls, the latter somewhat
spectively. B1
roughened by slight centrifugal projections; smooth, nearly
spheroidal pollen grains from 20 to 48 urn in diameter; frag-
ments of epidermis with stomata, the latter from 13 to 23 um
in length; fragments containing sclerenchyma fibers with
adherent crystal fibers containing monoclinic prisms of cal-
BRIEFING
cium oxalate that are up to 21 um in length.
Other requirements—It meets the requirements of the tests
Powdered Red Clover, page 3409 of PF 27(6) [Nov.-Dec.
2001]—See briefing under Red Clover. for Identification, Microbial limits, Loss on drying, Total
(DSB: G. Giancaspro) RTS—33301-2; 33247-2 ash, Acid-insoluble ash, Water-soluble extractives, Pesti-
cide residues, Heavy metals, and Content of isoflavones un-
der Red Clover.-,
Pharmacopeial Forum
Standard solution, Developing solvent system, Spray

BRIEFING
reagent A, Spray reagent B, and Procedure—Proceed as di-
Powdered Red Clover Extract, page 3410 of PF 27(6) [Nov.
Dec. 2001]—See briefing under Red Clover. rected for Thin-layer chromatographic identification test
(201) under Red Clover.
Test solution—Shake a quantity of Powdered Extract,
equivalent to 25 mg of the labeled amount of isoflavones,
Add the following:
in 20 mL of methanol. Allow to stand for 15 minutes before
•Powdered Red Clover Extract use.
B: The chromatogram of the Test solution exhibits
peaks for daidzein, genistein, formononetin, and biochanin
» Powdered Red Clover Extract is prepared from
A at retention times that correspond to those in the chroma-
Red Clover by extraction with hydroalcoholic
togram of Standard solution A, as obtained in the test for
mixtures or other suitable solvents. The ratio of
Content of isoflavones. Calculate the ratio of 5,7-dihydrox-
plant material to extract is between 3:1 and 25:1. yisoflavones to 7-hydroxyisoflavones by the formula:
It contains not less than 90.0 percent and not more
(B + G)/(D + F),
than 110.0 percent of the labeled amount of isofla-
in which B, G, D, and F are the percentages of biochanin A,
vones, calculated on the dried basis as the sum of
genistein, daidzein, and formononetin, respectively, as ob-
daidzein, genistein, formononetin, and biochanin
tained in the test for Content of isoflavones: the ratio is be-
A. It may contain suitable added substances.
tween 0.1 and 10.0.
Packaging and storage—Preserve in tight, light-resistant Microbial limits (2021)—It meets the requirements of the
containers, in a cool place. tests for absence of Salmonella species and Escherichia
Labeling—The label states the Latin binomial name and, coli. The total aerobic microbial count does not exceed
following the official name, the part of the plant from which 104 per g, the total combined molds and yeasts count does
the article was prepared. The label also indicates the content not exceed 103 per g, and the enterobacterial count is not
of isoflavones, the extracting solvent or solvent mixture more than 103 per g.
used for preparation, and the ratio of the starting crude plant Loss on drying (731): not more than 5.0%.
material to Powdered Extract. It meets the requirements for Heavy metals, Method II (231): not more than 10 jig per g.
labeling under Botanical Extracts (565). Organic volatile impurities, Method VI (467): meets the
USP Reference standards (II)—USP Formononetin RS. requirements.
USP Powdered Red Clover Extract RS. Content of isoflavones—
Identification— Solvent, Solution A, Solution B, Standard solution 1,
A: Thin-layer chromatographic identification test Standard solution 2, and Chromatographic system—Pro-
(201)- ceed as directed under Red Clover.
Pharmacopeial Forum
Test solution—Transfer an accurately weighed quantity of

BRIEFING
Powdered Extract, equivalent to about 30 mg of the labeled
Red Clover Tablets, page 3411 of PF 27(6) [Nov.-Dec.
content of isoflavones, to a 250-mL volumetric flask. Add 2001]—See briefing under Red Clover.
15 mL of dehydrated alcohol, sonicate until dissolved, di-
lute with Solvent to volume, and mix. Transfer 50.0 mL of
this solution to a round-bottom flask, and evaporate to dry-
Add the following:
ness under vacuum. Add 15 mL of 2 N hydrochloric acid,
and heat in a water bath for 30 minutes. Quantitatively trans-
•Red Clover Tablets
fer the resulting solution with the aid of about 15 mL of al-
cohol to a 50-mL volumetric flask, and dilute with Solvent to
» Red Clover Tablets contain Powdered Red Clo-
volume. Centrifuge, or filter through a membrane having a
ver Extract. Tablets contain not less than 90.0 per-
0.45-um or finer porosity.
cent and not more than 110.0 percent of the
Procedure—Proceed as directed under Red Clover. Sepa-
rately calculate the percentage of each relevant isoflavone
labeled amount of Powdered Extract calculated
component in the portion of Powdered Extract taken by as isoflavones.
the formula:
containers.
in which Wis the weight, in g, of Powdered Extract taken to Labeling—The label states the Latin binomial name and,
prepare the Test solution; and the other terms are as defined following the official name, the article from which Tablets
therein. Calculate the percentage of isoflavones in the Pow- were prepared. The label also indicates the quantity, in mg,
dered Extract taken by adding the individual quantities cal- of Powdered Extract per Tablet. Label Tablets to indicate the
culated. content, in mg, of isoflavones per 100 mg of Powdered Ex-

tract.
Other requirements—It meets the requirements for Packa-
under Botanical Extracts (565).B1
Identification—The chromatogram of the Test solution ex-
hibits peaks for daidzein, genistein, formononetin, and bio-
chanin A at retention times that correspond to those in the
chromatogram of Standard solution 1, as obtained in the test
for Content of isoflavones. Calculate the ratio of 5,7-dihy-
droxyisoflavones to 7-hydroxyisoflavones by the formula:
(B + G)f(D + F),
Pharmacopeial Forum
in which B, G, D, and F are the contents of biochanin A, Solvent to volume. Pass 5 mL of the solution through a filter
genistein, daidzein, and formononetin, respectively, as ob- having a 0.45-um porosity, discarding the first 4 mL of the
tained in the test for Content of isoflavones: the ratio is be- filtrate. Collect the remaining 1 mL of filtrate for testing.
tween 0.1 and 10.0. Procedure—Proceed as directed in the test for Content of
Microbial limits (2021)—It meets the requirements of the isoflavones under Red Clover. Calculate the content of iso-
tests for absence of Salmonella species and Escherichia flavones, in mg, in the portion of Tablets taken by the for-
coli. The total aerobic microbial count does not exceed mula:
104 per g, the total combined molds and yeasts count does
not exceed 103 per g, and the enterobacterial count is not less
in which the terms are as defined therein.B1
than 103 per g.
Dissolution (2040)—[To come.]

Disintegration (2040): meet the requirements for disinte-
gration of botanical dosage forms.
Content of isoflavones— BRIEFING
Mobile phase, Solvent, Solution A, Solution B, Standard Dimethicone, NF 20 page 2543 and page 3338 of PF 27(6)
[Nov.-Dec. 2001]. It is proposed to specify the use of a germanium
solution 1, Standard solution 2, and Chromatographic sys- (Ge) sample trough in the Assay. The use of other crystal types,
such as the commonly used ZnSe, may not produce satisfactory
tem—Proceed as directed in the test for Content of isofla- results. USP has also received reports that successful measure-
ments were made with 60° and 45° angles.
vones under Red Clover.
Test solution—Weigh accurately not fewer than 20 Ta-
blets, and pulverize, using a mortar and pestle. Transfer an
accurately weighed quantity of the powder, equivalent to 40 Change to read:
mg of the labeled amount of isoflavones, to a 250-mL vol- Bacterial endotoxins (85)(where it is intended for use in coating
containers that come in contact with articles for parenteral use)—
umetric flask. Add 15 mL of water, shake to disperse the Mix 1.0 mL of Dimethicone with 4.0 mL of poly dimethylsiloKane
having a vigooaity of 0.65 oontistokoa,
powder, add 15 mL of dehydrated alcohol and about 200 A
polydimethylsiloxane viscosity 0.65 centistokes,. USP26
previously tested and shown to be negative for bacterial endotox-
mL of Solvent, and sonicate for 30 minutes. If dark particles ins, by mixing on a vortex mixer for 1 minute in an extraction tube.
Add 10 mL of water, and mix on a vortex mixer for not less than 60
are present in the bottom of the flask, sonicate again for an minutes. Allow the layers to separate, and use the lower aqueous
layer as the test specimen. It contains not more than 1.0 USP En-
additional 10 minutes or until they disappear. Cool to room dotoxin Unit per mL, equivalent to not more than 10 Endotoxin
Units per mL of the Dimethicone taken.
temperature, and dilute with Solvent to volume. Transfer
50.0 mL of the resulting solution to a round-bottom flask, Change to read:
Assay—Use an IR spectrophotometer with a resolution of 4 cm"1
and evaporate to dryness under vacuum. Add 15 mL of 2 and fitted with an accessory for attenuated total reflectance (see
Spectrophotometry and Light-Scattering (851))
N hydrochloric acid, and heat in a water bath for 30 minutes. "and a germanium (Ge) sample trough.^
Fill the trough of the accessory with Dimethicone, and record the
Quantitatively transfer this solution with the aid of about 15 spectrum between 4000 cm"1 and 700 cm"1. Clean the trough, fill it
with USP Polydimethylsiloxane RS, and record the spectrum as
mL of alcohol, to a 50-mL volumetric flask, and dilute with above. Clean the trough, and record the spectrum as above to ob-
tain a background spectrum. Examine the spectra in the range be-
tween 1300 cm"1 and 1200 cm"1, and calculate the absorbance of
Pharmacopeial Forum
the peak in each spectrum at about 1259 cm"1. Calculate the per- Identification: meet the requirements of Identification tests
centage of [-(CH^SiO—]_ in the Dimethicone taken by the formu-
la: A, B, and C under Ginger.
in which Av is the absorbance of the Dimethicone; As is the absor-
bance of USP Polydimethylsiloxane RS; and Ds and Dv are the not exceed 10,000 104 per g, and the total combined molds
specific gravities of the USP Polydimethylsiloxane RS and Di-
methicone, respectively. and yeasts count does not exceed 1000 103 per g. Capsules
meet the requirements of the tests for absence of Salmonella
species and Escherichia coli, and Staphylococcus auwus,
and the enterobacterial and ooliform count is not-loos-than
100 of oaoh not more than 102 per g.
BRIEFING
Medium: 0.1 N hydrochloric acid; 500 mL.
Ginger Capsules, page 2227 of PF 27(2) [Mar.-Apr. 2001]. Apparatus 2: 75 rpm.
Changes in the test for Microbial limits are proposed in accordance
with the current recommendations of the USP Expert Committee Time: 60 minutes.
on Analytical Microbiology. In addition, editorial changes have
been made. NOTE—In each dissolution vessel, place a number of
(DSB: G. Giancaspro) RTS—34805-1 Capsules equivalent to about 20 mg of the labeled amounts
of gingerols, gingerdiones, and shogaols.
Add the following: Mobile phase—Prepare as directed in the test for Content
of gingerols and gingerdiones under Ginger.
•Ginger Capsules
Standard stock solution—Use the Standard preparation,
prepared as directed in the test for Content of gingerols
» Ginger Capsules are prepared from Powdered
and gingerdiones under Ginger.
Ginger and contain not less than 90.0 percent
Standard solution—Transfer 1.0 mL of the Standard stock
and not more than 110.0 percent of the labeled solution to a 10-mL volumetric flask, and dilute with Med-
amount of gingerols, gingerdiones, and shogaols ium to volume to obtain a solution having a known concen-
and not less than 90.0 percent of the labeled tration of about 0.025 mg of USP Capsaicin RS per mL.
amount of volatile oil. Test solution—Transfer an aliquot of solution from each
dissolution vial to a suitable vial. Allow to stand for 5 min-
utes so the powder settles into the suspension, or centrifuge
ers at controlled room temperature.
to obtain a clear supernatant. Pass through a membrane filter
having a 0.45-um or finer porosity.
Chromatographic system—Proceed as directed in the test
for Content of gingerols and gingerdiones under Ginger. To
of gingerols, gingerdiones, and shogaols, in mg per Capsule
evaluate the system suitability requirements, use the Stan-
and the content of volatile oil, in uL per Capsule.
USP Reference standards (II)—USP Capsaicin RS. USP
Powdered Ginger RS.
Pharmacopeial Forum
dard preparation and the System suitability solution, pre- Test preparation—Carefully open not fewer than 20 Cap-
pared as directed in the test for Content ofgingerols andgin- sules, and transfer about 1.0 g of the powder, accurately
gerdiones under Ginger. weighed, to a glass-stoppered conical flask. Add 50 mL of
Procedure—Separately inject equal volumes (about 20 alcohol, insert a stopper into the flask, and macerate for 24
uL) of the Standard solution and the Test solution into the hours, shaking frequently during the first 8 hours, and then
chromatograph, and allow the Test solution to elute for not allowing to stand for 18 hours. Filter, and evaporate the sol-
less than three times the retention time of capsaicin. Record vent to dryness in a vacuum. Quantitatively transfer the con-
the chromatograms, and measure all of the peak responses. tents with the aid of methanol to a 10-mL volumetric flask,
Calculate the quantity, in mg, of 6-gingerol dissolved, G, add methanol to volume, and mix.
from each Capsule taken by the formula: Procedure—Proceed as directed in the test for Content of
gingerols and gingerdiones under Ginger. Calculate the
amounts, in mg, of gingerols, gingerdiones, and shogaols
in which C is the concentration, in mg per mL, of USP Cap- in the portion of the Capsules taken by the formula:
saicin RS in the Standard solution; N is the number of Cap-
\0C(rvlrs),
sules in each vessel; rv is the peak response for 6-gingerol
obtained from the Test solution; and rs is the peak response in which C is the concentration, in mg per mL, of USP Cap-
for capsaicin obtained from the Standard solution. Calculate saicin RS in the Standard preparation; rv is the sum of peak
the percentage of the relative amount of 6-gingerol dis- responses for gingerols, gingerdiones, and shogaols; and rs
solved by the formula: is the peak response for capsaicin obtained from the Stan-
dard preparation. Calculate the amount, in mg, of 6-ginger-
100(G/G0),
ol in the portion of Capsules taken by the formula:
in which Go is the content of 6-gingerol, in mg, in each Cap-
sule, as determined in the test for Content ofgingerols, gin-
gerdiones, and shogaols. in which rv is the peak response for 6-gingerol obtained
Tolerances—Not less than 60% of the labeled amount from the Test preparation; and the other terms are as defined
content of 6-gingerol (C17H26O4) is dissolved in 60 minutes. above.B1

Volatile oil content (561)—Weigh and finely powder a
quantity of Capsules, equivalent to about 100 g of powdered
ginger: not less than 1.4 mL per 100 g is found.
Content of gingerols, gingerdiones, and shogaols—

BRIEFING
Mobile phase, Standard preparation, System suitability
Powdered Kava Extract, page 783 of PF 26(3) [May-June
solution, and Chromatographic system—Proceed as direc- 2000]; Semisolid Kava Extract, page 784 of P F 26(3) [May-June
2000]; Kava Capsules, page 785 oi PF 26(3) [May-June 2000];
ted in the test for Content ofgingerols and gingerdiones un- Kava Tablets, page 787 of PF 26(3) [May-June 2000]. All of
these proposed monographs reference Kava that appeared on page
der Ginger. 100 of PF 28(1) [Jan.-Feb. 2002]. It is proposed to change the De-
finition to reflect the fact that excipients are used to prepare the
Powdered Extract. It is also proposed to remove the ratio of starting
Pharmacopeial Forum
816 IN-PROCESS REVISION Vol. 28(3) [ M a y - J u n e 2002]
crude plant material to Powdered Extract from the Definition be- starting crude plant material to Powdered Extract: It meets
cause of the variability introduced by the use of different amounts
of externally added excipients. It is proposed to change the rubric the requirements for labeling under Botanical Extracts
limits for the content of kavalactones from "not less than 30% of
kavalactones," to "not less than 90% and not more than 110% of (565).
the labeled amount of kavalactones," calculated as the sum of ka-
valactones, to reflect the different concentrations of kavalactones USP Reference standards {11)—USP Powdered Kava Ex-
found in the different powdered extracts currently marketed. Revi-
sion of the test for Microbial limits is proposed in accordance with tract RS. USP Kawain RS.
the current recommendations of the USP Expert Committee on
Analytical Microbiology. Identification—
(DSB: G. Giancaspro) RTS—36762-1 A: Thin-Layer Chromatographic Identification Test
(201)-
Add the following: Adsorbent, Standard solution, Developing solvent system,
•Powdered Kava Extract Spray reagent, and Procedure—Proceed as directed for

Identification test A under Kava.
Test solution—Add 10 mL of methylene chloride to 100
» Powdered Kava Extract is prepared from dried mg of Powdered Extract, and heat under reflux on a water
and comminuted Kava by extraction with alcohol, bath for about 10 minutes. Filter, and dilute with methylene
seme other suitable solvent, or a mixture of sol- chloride to 10.0 mL.
vents. The ratio of starting crude plant material B: The retention times of the relevant analytes in the
to Powdered Extract is between 6:1 and 20:1. It chromatogram of the Test solution correspond to those in
the chromatogram of Standard solution 2, as obtained in
contains not less than 30.0 percent of 90.0 percent
the test for Content of kavalactones.
and not more than 110% of the labeled amount of
kavalactones, calculated as the sum of methysti-
cin, dihydromethysticin, kawain, dihydrokawain,
and yeasts count does not exceed 1000 103 per g, the count
desmethoxyyangonin, and yangonin, on the dried for ooliformo does not oxoocd 1000 por g, the count for en-
basis. It may contains labeled added substances as terobacteria does not exceed 1000 103 per g, and it meets the
carriers. requirements of the tests for absence of Salmonella species
and Escherichia coli. Staphylococcus aurvus.
Loss on drying (731): not more than 7.0%.
containers.
following the official name, the part of the plant oontainod
requirements.
m from which the article was derived. The label also indi-
Solvent: dimethylformamide.
cates the content of kavalactones and the extracting solvent
or solvent mixture used for preparation, and tho ratio of tho Content of kavalactones—
Mobile phase, Extraction solvent, Standard solution 1,
Standard solution 2, Chromatographic system—Proceed
as directed for Content of kavalactones under Kava.
Pharmacopeial Forum
Add the following:

Test solution—Transfer about 125 mg of Powdered Ex-
tract, accurately weighed, to a 50-mL volumetric flask, di- "Semisolid Native Kava Extract
lute with Extraction solvent to volume, and sonicate for 60
minutes at room temperature. Decant, and pass through a » Somisolid Native Kava Extract is prepared from
0.45-um nylon membrane filter. dried and comminuted Kava extracted with alco-
Procedure—Proceed as directed under Kava, except to hol, or 3omo other suitable solvent or mixture of
calculate the percentage of methysticin, dihydromethysticin, solvents. The ratio of the starting crude plant ma-
kawain, dihydrokawain, desmethoxyyangonin, and yango-
terial to somisolid Native Extract is between -t^-4-
nin in the portion of Powdered Extract taken by the formula:
11:1 and 20:1. It contains not less than 50.0 per-
cent kavalactones, calculated as the sum of
in which Wis the weight, in mg, of the portion of Powdered methysticin, dihydromethysticin, kawain, dihy-
Extract taken; and the other terms are as defined therein. drokawain, desmethoxyyangonin, and yangonin,
Alcohol content, Method II (611): not more than 0.5%. on the anhydrous basis. It does not contain added
Other requirements—It meets the requirements for Packa- substances.
under Botanical Extracts (565).ml
containers.
of kavalactones, the extracting solvent or solvent mixture
BRIEFING used for preparation, and the ratio of starting crude plant ma-
Semisolid Kava Extract, page 784 of PF 26(3) [May-June terial to Somioolid Native Extract. It meets the requirements
2000]—See briefing under Powdered Kava Extract. According
to the definition for Semisolid Kava Extract, added substances for Labeling under Botanical Extracts (565).
are not permitted in this article, and there is a limit for residual sol-
vents, thus requiring solvents to be removed as completely as pos- USP Reference standards (11 )—USP Powdered Kava Ex-
sible. Consequently, this article does not meet the definition for
Semisolid Extracts as described under Botanical Extracts (565) tract RS. USP Kawain RS.
and it is therefore proposed to change the title of the monograph
to Native Kava Extract. It is also proposed to change the limits in Identification—
the test for Microbial limits to be consistent with current recom-
mendations from the USP Expert Committee on Analytical Micro- A: Thin-Layer Chromatographic Identification Test
biology.
(201)-
Adsorbent, Standard solution, Developing solvent system,
Spray reagent, and Procedure—Proceed as directed for
Pharmacopeial Forum
Test solution—Homogenize the Semisolid Native Extract Procedure—Proceed as directed for Content ofkavalac-
by heating in a water bath between 60° and 80°. Add 10 mL tones under Kava, except to calculate the percentage of
of methylene chloride to about 60 mg of the homogenized methysticin, dihydromethysticin, kawain, dihydrokawain,
Scmiaolid Native Extract, and heat under reflux on a water desmethoxyyangonin, and yangonin in the portion of Somi
bath for 10 minutes. Filter, transfer the filtrate to a 10-mL solid Native Extract taken by the formula:
volumetric flask, and dilute with methylene chloride to
10.0 mL.
in which W'\s the weight, in mg, of the portion of SomisolM
B: The retention times of the relevant analytes in the
Native Extract taken; and the other terms are as defined
chromatogram of the Test solution correspond to those in
therein.
the chromatogram of Standard solution 2, as obtained in
the test for Content ofkavalactones. Alcohol content, Method II (611): not more than 0.5%.
Microbial limits (2021)—The total bacterial count does Other requirements—It meets the requirements fox Packa-
not exceed 10,000 104 per g, the total combined molds ging and Storage, Residual Solvents, and Pesticide Residues
and yeasts count does not exceed 1000 103 per g, the coli under Botanical Extracts (565).B1
form count doos not cxcoodlOOO per g, the count for enter-
obacteria does not exceed 1000 103 per g, and it meets the
requirements of the tests for absence of Salmonella species
and Escherichia coli. Staphylococcus aurcus:
Water, Method I (921): not more than 5.0%.
BRIEFING
Kava Capsules, page 785 of PF 26(3) [May-June 2000]—See
Organic volatile impurities, Method IV (467): meets the briefing under Powdered Kava Extract. It is proposed to replace the
Medium in the test for Dissolution with a surfactant more appropri-
requirements. ate to the characteristics ofkavalactones. The procedure for the de-
terminative step in the test for Dissolution is being changed from
the UV method to a liquid chromatographic method similar to that
Solvent: dimethylformamide. in the test for Content ofkavalactones. A change in the Tolerances
in the test for Dissolution is also proposed. Revision of Microbial
Content of kavalactones— limits is proposed in accordance with the current recommendations
of the USP Expert Committee on Analytical Microbiology for bo-
Mobile phase, Extraction solvent, Standard solution 1, tanical articles.
Standard solution 2, and Chromatographic system—Pro-
(BNA: G. Giancaspro) RTS—30689-4
ceed as directed for Content of kavalactones unde Kava.
Test solution—Homogenize the Somisolid Native Extract
Add the following:
by heating in a water bath between 60° and 80°. Transfer H
Kava Capsules
about 75 mg of the homogenized Semisolid Native Extract,
accurately weighed, to a 50-mL volumetric flask, add Ex-
traction solvent to volume, and sonicate at room tempera-
» Kava Capsules are prepared from Powdered
ture until the Somisolid Native Extract is dissolved.
Kava Extract or Somisolid Native Kava Extract.
Decant, and pass through a 0.45-um nylon membrane filter.
They contain not less than 90.0 percent and not
Pharmacopeial Forum
more than 120.0 percent of the labeled amount of terobacteria does not exceed 4^0 102 per g. It meets the
kavalactones, calculated as the sum of methysti- requirements of the tests for absence of Salmonella species,
and Escherichia coli. and Staphylococcus aurcus:
cin, dihydromethysticin, kawain, dihydrokawain,
desmethoxyyangonin, and yangonin.
Medium: 0.1 N hydroohlorio aoid; 1% laurel sulfate; 900
Packaging and storage—Preserve in tight containers, pro- mL.
tected from moisture and light, and store at room tempera- Apparatus 2: 100 rpm.
ture. Time: 60 minutes.
Labeling—The label states the Latin binomial and, follow- Standard solution—Dilute tho corresponding Test sola
ing the official name, the article from which the Capsules tion, prepared as dirootod in Content of kavalactones, with
were prepared. The label also indicates the amount of Ex- Dissolution Medium to obtain a aolution having a known
tract, in mg per Capsule, and the content of kavalactones, concentration of kavalaotonoG.
in mg, per 100 mg of Extract. Blank solution—Proparo a mixture of all ingredients of tho
USP Reference standards (11)—USP Powdered Kava Ex- CapGuloSj oxoept tho kava extraot, in tho proportion uood to
tract RS. USP Kawain RS. manufacture tho Capsuloo: Transfer an aoouratoly weighed
Identification— portion of tho mixture-, equivalent to 4 Capsulo, to a 50
A: Thin-Layer Chromatographic Identification Test mL volumetric flask, add about 40 mL of mothanol, and
(201)- shako by mechanical moans for 10 minutes: Sonicate for
Adsorbent, Standard solution, Developing solvent system, about 5 minutes, dilute with mothanol to volume, and
Spray reagent, and Procedure—Proceed as directed for mix. Diluto with Medium by tho aamo faotor usod to dilute
Identification test A under Kava. tho Standard solution^
Test solution—Transfer an accurately weighed portion of Procedure—Determine tho amount of kavalactonos dia
the contents of the Capsules, equivalent to about 40 mg of solved by employing UV absorption at tho wavelength of
kavalactones, to a round-bottom flask, add 10 mL of meth- maximum absorbanoo at about 350 nm on filtered or ccntri
ylene chloride, and heat for 10 minutes on a waterbath under fugod portions of tho solution undor tost, suitably diluted
a reflux condenser. Filter, and dilute the filtrate with meth- with Dissolution Medium, if necessary, in oomparison with
ylene chloride to 10.0 mL. tho Standai«d solution; uoing tho Blank solution as tho blank:
B: The retention times of the relevant analytes in the Procedure—Determine the amount of kavalactones dis-
chromatogram of the Test solution correspond to those in solved, by employing the procedure set forth in the test
the chromatogram of the Standard solution, as obtained in for Content of kavalactones, making any appropriate adjust-
the test for Content of kavalactones. ments.
Microbial limits (2021)—The total bacterial count does Tolerances—Not less than 70% 75% of the labeled
not exceed 10;000 104 per g, the total combined molds amount of kavalactones is dissolved in 60 minutes.
3
and yeasts count does not exceed 1000 10 per g, tho ooli Weight variation (2091): meet the requirements
form count does not oxoood 100 per g, and the count for en-
Pharmacopeial Forum
Content of kavalactones—
Mobile phase, Extraction solvent, Standard solution 1, BRIEFING
Standard solution 2, and Chromatographic system—Pro- Kava Tablets, page 787 of PF 26(3) [May-June 2000]—See
briefing under Kava Capsules.
ceed as directed in the test for Content of kavalactones under
Kava. (BNA: G. Giancaspro) RTS—30689-1
Test solution 1 (for soft gelatin capsules)—Using a suit-

able cutting instrument, open not fewer than 20 Capsules, Add the following:
and transfer the contents to a suitable container. Mix to •Kava Tablets

homogenize, and transfer an accurately weighed portion
of the composite, equivalent to about 40 mg of kavalac-
tones, to a 50-mL volumetric flask, add about 40 mL of » Kava Tablets are prepared from Powdered Kava
methanol, shake by mechanical means for 10 minutes, and Extract or Somisolid Native Kava Extract. They
sonicate for about 5 minutes. Cool to room temperature, di- contain not less than 90.0 percent and not more
lute with methanol to volume, and mix. Pass through a 0.45- than 120.0 percent of the labeled amount of kava-
jim nylon membrane filter. lactones, calculated as the sum of methysticin, di-
Test solution 2 (for hard gelatin capsules)—Weigh accu-
hydromethysticin, kawain, dihydrokawain,
rately the contents of not fewer than 20 Capsules, and com-
desmethoxyyangonin, and yangonin, on the dried
posite using a mortar and a pestle. Transfer an accurately
basis.
weighed portion of the finely powdered material, equivalent
to about 40 mg of kavalactones, to a 50-mL volumetric Packaging and storage—Preserve in tight, light-resistant
flask, add about 40 mL of methanol, shake by mechanical containers, at room temperature.
means for 10 minutes, and sonicate for about 5 minutes. Labeling—The label states the Latin binomial namo and,
Cool to room temperature, dilute with methanol to volume, following the official name, the derivative from which the
and mix. Pass through a 0.45-um nylon membrane filter. article was prepared. The label also indicates the content
Procedure—Proceed as directed in the test for Content of of kavalaotonos Extract, in mg per Tablet, and the content,
kavalactones under Kava, except to separately calculate the in mg, of kavalactones in each 100 mg of Extract.
quantity, in mg, of methysticin, dihydromethysticin, ka- USP Reference standards (11)—USP Powdered Kava Ex-
wain, dihydrokawain, desmethoxyyangonin, and yangonin tract RS. USP Kawain RS.
in the portion of Capsules used to prepare Test solution 1
Identification—
or Test solution 2, taken by the formula:
50FC(rv/rs), (201)-
Adsorbent, Standard solution, Developing solvent system,
in which the terms are as defined therein. Calculate the
Spray reagent, and Procedure—Proceed as directed for
quantity of kavalactones in the portion of Capsules taken
by adding the individual amounts.B1
Pharmacopeial Forum
Test solution—Weigh and finely powder not fewer than 20 Test solution, prepared as directed in the test for Content of
Tablets. Transfer an accurately weighed portion of the pow- kavalactones, with Dissolution-Medium to obtain a solution
der, equivalent to about 40 mg of kavalactones, to a round- having a known concentration of kavalaotones.
bottomed flask, add 10 mL of methylene chloride, and heat Blank solution—Prepare a mixture of all the ingredients of
under reflux on a water bath for 10 minutes. Filter, transfer the Tablets, except the kava extract, in the proportion used to
the filtrate to a 10-mL volumetric flask, and dilute with manufacture the Tablets. Transfer an aoouratoly weighed
methylene chloride to 10.0 mL. portion of the powder, equivalent to 1 Tablet, to a 50 mL
B: The retention times of the relevant analytes in the volumotrioflaskând proceed as direotod for the preparation
chromatogram of the Test solution correspond to those in of the Standard solution.
the chromatogram of Standard solution 2, as obtained in Procedure—Determine the amount of kavalaotonos dis
the test for Content of kavalactones. solved by employing UV absorption at the wavelength of
Microbial limits (2021)—The total bacterial count does maximum absorbance at about 350 nm on filtered portions
not exceed 10,000 104 per g,the total combined molds and of the solution under tost, suitably diluted with Dissolution
3
yeasts count does not exceed 1000 10 per g, the ooliform Medium, if necessary, in comparison with the Standard so •
count does not oxoood 100 por g, the count for enterobacter- lution, using the Blank solution as the blank.
2
ia does not exceed 400 10 per g, and it meets the require- Procedure—Determine the amount of kavalactones dis-
ments of the tests for absence of Salmonella species and solved by employing the procedure set forth in the test for
Escherichia coli. and Staphylococcus aurcus. Content of kavalactones, making any appropriate adjust-
Disintegration and Dissolution (2040)— ments.
Medium: 0.1 N hydrochloric acid; 1% lauryl sulfate; 900 Tolerances—Not less than 75%70% 75% of the labeled
mL. amount of kavalactones, as determined in the test for Con-

Apparatus 2: 100 rpm. tent of kavalactones, is dissolved in 60 minutes.
Time: 60 minutes. Weight variation (2091): meet the requirements.
Standard solution—Weigh and finely powder not fewer Content of kavalactones—
than 20 Tablets of the batoh under tost, having a known oon Mobile phase, Standard solution 1, Standard solution 2,
tent of kavalaotonos: Transfer an accurately weighed portion and Chromatographic system—Proceed as directed in the
of the powder, equivalent to 1 Tablet, to a 50 mL volumetric test for Content of kavalactones under Kava.
flask, add about 40 mL of methanol, shake by mechanical Test solution—Weigh and finely powder not fewer than 20
moans for10 minutes, sonicate for about 5 minutes, dilute Tablets. Transfer an accurately weighed portion of the pow-
with mothanol to volume, and mix. Transfer 5:0 mL of this der, equivalent to about 40 mg of kavalactones, to a 50-mL
solution to a 100 mL volumetric flask, dilute with Medium volumetric flask, add about 40 mL of methanol, shake by
to volume, and mix. Filter a portion of this solution, discard mechanical means for 10 minutes, and sonicate for about
ing the first 10 mL of the filtrate. Dilute the corresponding 5 minutes. Cool to room temperature, dilute with methanol
to volume, and mix. Pass through a 0.45-um nylon mem-
brane filter.
Pharmacopeial Forum
Procedure—Proceed as directed in the test for Content of Identification—The retention time of the major peak in the
kavalactones under Kava. Separately calculate the quantity, chromatogram of the Test solution corresponds to that in the
in mg, of methysticin, dihydromethysticin, kawain, dihy- chromatogram of the Standard solution, as obtained in the
drokawain, desmethoxyyangonin and yangonin in the por- test for Content ofa-lipoic acid.
tion of Tablets taken by the formula: Disintegration and dissolution (2040)—
50FC(ru/rs), Medium: water; 900 mL.

Apparatus 1 (for hard gelatin capsules): 100 rpm.
in which the terms are as defined therein. Calculate the
Apparatus 2 (for soft gelatin capsules): 75 rpm.
quantity of kavalactones in the portion of Tablets taken by
lime: 60 minutes.
adding the individual quantities calculated.,j
Determine the amount of C8H14O2S2 dissolved by em-
ploying the following method.
directed in the test for Content ofa-lipoic acid.
quantity of USP a-Lipoic Acid RS in a mixture of acetoni-
BRIEFING
trile and water (1:1) to obtain a solution having a known
oc-Lipoic Acid Capsules, page 3412 of PF 27(6) [Nov.-Dec.
2001]; a-Lipoic Acid Tablets, page 3414 of P F 27(6) [Nov.- concentration of 1 mg per mL. Transfer 1 mL of this solu-
Dec. 2001]. These monographs have been previewed and are
now forwarded ioIn-Process Revision. The liquid chromatographic tion to a 50-mL volumetric flask, dilute with water to vol-
procedures in the test for Content ofa-lipoic acid are based on ana-
lyses performed with a (iBondapack C18 brand of column LI, 10 ume, and mix to obtain a solution having a known
microns. The typical retention time for oc-lipoic acid is about 7.5
minutes. concentration of about 0.02 mg per mL.
(DSN: G. Giancaspro) RTS—34283-1 Test solution—Withdraw a portion of the solution under

test, and filter, discarding the first portion of the filtrate.
Add the following: Transfer an accurately measured aliquot to a volumetric

flask, and dilute with water to volume to obtain a solution
•a-Lipoic Acid Capsules
having an expected concentration of about 0.02 mg ofa-li-
poic acid per mL.
» a-Lipoic Acid Capsules contain not less than Procedure—Separately inject equal volumes (about 50
the labeled amount of C8H14O2S2.
peak areas. Determine the amount of CgH14O2S2 dissolved
Packaging and storage—Preserve in well-closed contain- by the formula:
ers.
9QQCD{rvlrs),
USP Reference standards (11)—USP a-Lipoic Acid RS.
Pharmacopeia! Forum
in which C is the concentration of USP a-Lipoic Acid RS in first 5 mL of the filtrate. Transfer 5.0 mL of the remaining
the Standard solution; D is the dilution factor of the Test so- filtrate to a 100-mL volumetric flask, dilute with water to
lution; and rv and rs are the peak areas of a-lipoic acid ob- volume, and mix.
tained from the Test solution and the Standard solution, Chromatographic system (see Chromatography (621))—
respectively. The liquid chromatograph is equipped with a 220-nm detec-
Tolerances—Not less than 70% of the labeled amount of tor and a 3.9-mm x 30-cm column that contains packing
C8H14O2S2 is dissolved in 60 minutes. LI. The flow rate is about 1.5 mL per minute. Chromato-
Weight variation (2091): meet the requirements. graph the Standard preparation, and record the peak re-
sponses as directed for Procedure: the tailing factor for a-
Content of a-lipoic acid—
lipoic acid is not more than 1.2; the efficiency of the column
is not less than 1300 theoretical plates; and the relative stan-
0.025 M phosphoric acid and acetonitrile (62:38).
dard deviation for replicate injections is not more than 1.0%.
quantity of USP a-Lipoic Acid RS in acetonitrile, and dilute Procedure—Separately inject equal volumes (about 20
quantitatively, and stepwise if necessary, with acetonitrile to uL) of the Standard solution and the appropriate Test solu-
obtain a solution having a known concentration of 0.05 mg tion into the chromatograph, record the chromatograms, and
per mL. measure the responses for the major peaks. Calculate the
Test solution 1 (for hard gelatin capsules)—Empty and quantity, in mg, of a-lipoic acid in the portion of hard gel
mix thoroughly the contents of not fewer than 20 Capsules. capsules taken by the formula:
Transfer an accurately weighed portion of the powder, 2000C(rl//rs),

equivalent to about 100 mg of a-lipoic acid, to a suitable
in which C is the concentration, in mg per mL, of USP a-
container, add about 70 mL of a mixture of acetonitrile
Lipoic Acid RS in the Standard solution; and rv and rs are
and water (1:1), and shake for 45 minutes by mechanical
the peak responses of a-lipoic acid obtained from Test solu-
means. Transfer to a 100-mL volumetric flask, dilute with
tion 1 and the Standard solution, respectively. Calculate the
the mixture of acetonitrile and water (1:1) to volume, mix,
quantity, in mg, of a-lipoic acid in each soft gel capsule ta-
and filter a portion of this preparation, discarding the first 5
ken by the formula:
mL of the filtrate. Transfer 5.0 mL of the remaining filtrate
to a 100-mL volumetric flask, dilute with water to volume,
and mix. in which C is the concentration, in mg per mL, of USP a-
Test solution 2 (for soft gelatin capsules)—Using a suit- Lipoic Acid RS in the Standard solution; Nis the number of
able cutting instrument, open an accurately counted number capsules taken; and rv and rs are the peak responses of a-
of Capsules equivalent to about 500 mg of a-lipoic acid. lipoic acid obtained from Test solution 2 and the Standard
Transfer the contents and the shells to a suitable container solution, respectively.B1
with stopper, add 500.0 mL of a mixture of acetonitrile
and water (1:1), and shake for 45 minutes by mechanical
means. Filter a portion of this preparation, discarding the
Pharmacopeial Forum
Content of oc-lipoic acid—

BRIEFING
Mobile phase, Standard preparation, and
a-Lipoic Acid Tablets, page 3414 of PF 27(6) [Nov.-Dec. Chromatographic system—Prepare as directed for the test
2001]—See briefing under"a-Lipoic Acid Capsules.
for Content ofa-lipoic acid under a-Lipoic Acid Capsules.
Test solution—Proceed as directed for Test solution 1 (for
hard gelatin capsules) in the test for Content ofa-lipoic acid
Add the following:
under a-Lipoic Acid Capsules, except to use not fewer than
•a-Lipoic Acid Tablets 20Tablets.
Procedure—Proceed as directed in the test for Content of
a-lipoic acid under a-Lipoic Acid Capsules. Calculate the
» a-Lipoic Acid Tablets contain not less than 90.0
quantity, in mg, ofa-lipoic acid in the portion of Tablets ta-
percent and not more than 115.0 percent of the la- ken by the formula:
beled amount of C8H14O2S2.
2000C(rv/rs),
in which C, rv, and rs are as defined therein. B1
ers.
Labeling—Tablets that are coated are so labeled.
USP Reference standards (11)—USP a-Lipoic Acid RS.
Identification—The retention time of the major peak in the
chromatogram of the Test solution corresponds to that in the
chromatogram of the Standard solution, as obtained in the BRIEFING
test for Content ofa-lipoic acid. Maltitol Solution, NF 20 page 2576 and page 3340 of P F 27(6)
[Nov.-Dec. 2001]. The retention times for maltotriitol, maltitol,
Disintegration and dissolution (2040)— and sorbitol were inadvertently misstated in the briefing under
Maltitol Solution in PF 27(6). The chromatographic method in
Medium: water; 900 mL. the Assay is based on analyses performed with the Aminex Fast
Carbohydrate brand of L34 column. The typical retention times
Apparatus 2: 75 rpm. for maltotriitol, maltitol, and sorbitol are 6.8, 8.8, and 18 minutes,
respectively. In addition, changes are made to the Assay calculation
Time: 60 minutes. to reflect that the assay should be calculated on the "anhydrous"
basis instead of on an "as is" basis. Editorial style changes have
Determine the amount of C8H14O2S2 dissolved by em- also been made.
ploying the following method. (EMC: C. Sheehan; AMB: D. Porter) RTS—36749-3

Mobile phase, Standard solution, Test solution,
Chromatographic system, and Procedure—Proceed as di- Change to read:
rected for Disintegration and dissolution (2040) under a-Li-
» Maltitol Solution is an aqueous solution of a hydro
poic Acid Capsules. gonatod, partially hydrolyzod starch. It contains,
Tolerances—Not less than 70% of the labeled amount of •containing,ml
on the anhydrous basis, not less than 50.0 percent of D-
CgHI4O2S2 is dissolved in 60 minutes. maltitol (C12H24On) (w/w), and not more than 16.0
Weight variation (2091): meet the requirements. •8.O.,
Pharmacopeial Forum
percent of D-sorbitol (C6H14O6) (w/w). The amounts of

total sugars, other polyhydric alcohols, and any polyol Change to read:
anhydrides, if detected, are not included in the require- Residue on ignition (281): not more than 0.1%,
ments nor •calculated on the anhydrous basis, determined on a 2-g
•in B 1 portion, accurately weighed.B1
the calculated amount under Other Impurities.
Change to read: "Chloride (£24-)—A 1.5 g portion 3hows no more ohlorido than
Identification— corresponds to 0.10 mL of 0.020 N hydrochloric aoid (0.005%). , t
A:—Developing solxvnt—Prepare a mixture of n propyl aloo
hoi, othyl aootato, and wator (70:20:10). Delete the following:
Standard solution—Dissolve USP Maltitol RS in wator to obtain "Sulfatc (224-)—A 1.0 g portion shows no more oulfato than oor
a solution having a concentration of 2.5 mg per mL.
Test solution—Diluto Maltitol Solution with wator to obtain a roopondo to 0.10 mL of 0.020 N sulfurio aoid (0.010%). m
solution containing, on the anhydrous basis, about 2.5 mg of mal
titol per mL. Delete the following:
Pmccdmv—Apply 3oparatoly 2 uL oaoh of tho Standard solu "Heavy metals, Method II (534-):
tion and tho Test solution to a thin layer chromatographio plato (soo
Chminatogr-aphy (624-)) ooatod with a 0.25 mm layer of chroma Change to read:
tographio silica gel. Allow tho opots to dry, and develop the plate in Reducing sugars—Dilute 0.2 g with wator to 2 mL. Add 5 mL of
a developing chamber containing tho Dcwloping solvent until tho alkaline cuprio citrate TS. Heat for 5 minutoo in a boiling water
solvent front has moved about 17 cm. Romovo tho plato from tho bath: not more than a alight prooipitato is formod. Tho amount do
chamber, mark tho solvent front, and allow tho solvent to ovapo tormined in this tost is not inoludod in tho calculated amount under
rate. Spray tho plato with sodium metaperiodate solution (1 in 500), Other Impufitics.
air dry for 15 minutes, spray with a 1 in 50 solution of 4,4'totra
mothyldiaminodiphonylmothano in a mixture of aootono and gla "To an amount of Maltitol Solution, equivalent to 3.3 g on
oial aoetio aoid (4:1), and wait for 30 minutes to bring out tho
full color of tho spots: tho principal spot obtained from the Test the anhydrous basis, add 3 mL of water, 20.0 mL of cupric
solution corresponds in R? value and oolor to that obtainod from
the Standard solution. citrate TS, and a few glass beads. Proceed as directed in the
"Dissolve 1.4 g of Maltitol Solution in 75 mL of water. test for Reducing sugars under Mannitol, beginning with
Transfer 3 mL of this solution to a 15-cm test tube, add 3 "Heat so that boiling begins." Not less than 12.8 mL of
mL of freshly prepared catechol solution (1 in 10), and 0.05 N sodium thiosulfate VS is required, corresponding
mix. Add 6 mL of sulfuric acid, mix, and gently heat the to not more than 0.3% of reducing sugars, on the anhydrous
tube in a flame for about 30 seconds: a deep pink or wine basis, as glucose. The amount determined in this test is not
red color appears.,x included in the calculated amount under Other Impurities.mx

of the Assay preparation corresponds to that in the chromatogram Add the following:
"Limit of nickel—Proceed as directed in the test for Limit
Add the following:
of nickel under Sorbitol Solution. Not more than 1 ug per g,
•Microbial limits (61)—The total aerobic microbial count
calculated on the anhydrous basis, is found.. {
Change to read:
the total combined molds and yeasts count is not more than Assay—
Mobile phase—Use degassed water.
102cfu per mL.B1 Standard preparation—Dissolve accurately weighed quantities
of USP Maltitol RS and USP Sorbitol RS in water, and diluto quan
Add the following: titativoly with wator to obtain a solution having known concontra
tion3 of about 10.0 mg of maltitol and 1.6 mg of sorbitol por mL.
"pH (791): between 5.0 and 7.5, in a 14% (w/w) solution of
"to obtain a solution having known concentrations of about
Maltitol Solution in carbon dioxide-free water., 1
10 mg per g and 1.6 mg per g, respectively. B1
Change to read:
Assay preparation—Transfer about 1 g of Solution, accurately
Water, Method I (921): not more than 30.0%. woighod, to a 50 mL volumotrio flask, diluto with wator to volumo;
Pharmacopeia! Forum
•Accurately weigh about 0.4 g of Maltitol Solution, dis- concentration, in mg per g, of tho corrc-gpondinganalyto •
solve in and dilute with water to about 20 g. Accurately re- Maltitol Solution in the Assay preparation;^ oaloulated on
cord the final solution weight, and mix thoroughly. B1 tho anhydrous baaia; and B l
rv and rs are the peak responses of the corresponding analyte ob-
Chromatographic system (see Chromatography (621))—The li- tained from the Assay preparation and the Standard preparation,
quid chromatograph is equipped with a refractive index detector respectively
that is maintained at a constant temperature and a 9 mm x 30
em column that contains packing LI9. The column t&mporaturo "; and Wis the percentage obtained in the test for Water. ml
13 maintained at 85 1 0.5°,
"of about 35° and a 7.8-mm x 10-cm column that contains
packing L34. The column temperature is maintained at a
constant temperature of about 60°, controlled to within +
2°
ana the flow rate is about 0.5 mL per minute. Chromatograph the
Standard preparation, and record the peak responses as directed
for Procedure:
BRIEFING
"the relative retention times are about 0.38 for maltotriitol,
0.48 for maltitol, and 1.0 for sorbitol; B1 Monoethanolamine, NF 20 page 2585.
the tailing factor for maltitol
•and sorbitol B1
is not more than 1.2; and the relative standard deviation for repli-
cate injections is not more than 2.0%.
Procedure—Separately inject equal volumes (about 20 uL) Erratum:
•10 uL) B1 Assay, line 3: Change "a mixed indicator of bromocresol green
of the Assay preparation and the Standard preparation into the TS and methyl red TS (5 in 6)," to: a mixed indicator of 5 parts
chromatograph, record the chromatograms, and measure the re- bromocresol green TS and 6 parts methyl red TS for a total of
sponses for the major peaks. Tho olution pattern inoludoa a broad approximately 11 parts of solution,
band, starting from the void volume, that includes the higher mo
locular weight hydrogenated polyaaccharides, followed by 3 indi
vidual peaks representing maltotriitol, maltitol, and aorbitol. Tho
relative retention times arc about 0.45 for maltotriitol, 0.6 for mal
titol, and 1.0 for oorbitol. Separately calculate tho quantities, in mg,
of aorbitol and maltitol in tho portion of Solution taken by tho for
muia.
in which C is the concentration, in mg per mL, of tho appropriate

USP Reference Standard in tho Standard preparation BRIEFING
"Separately calculate the percentagesof maltitol and sorbi
Monosodium Glutamate, NF 20 page 2585—See briefing un-
tei, on the anhydrous basis, of D-maltitol and D-sorbitol in der Bacitracin.
the portion of Maltitol Solution taken by the formula:B1 (BPC: M. Marques) RTS—36575
Change to read:
Identification—
A: To 1 mL of a solution (1 in 30) add 1 mL of trikoto-
hydrindono hydrate TS
in which Cs is the concentration, in mg per g, of the appro- •ninhydrin TS B ,
and 100 mg of sodium acetate, and heat in a boiling water bath for
priate USP Reference Standard in the Standard prepara- 10 minutes: an intense, violet blue color is formed.
B: To 10 mL of a solution (1 in 10) add 5.6 mL of 1 N hydro-
tion;, oaloulatod on-tho anhydrous baoio Cv is the chloric acid: a white, crystalline precipitate of glutamic acid is
formed on standing. Precipitation is promoted by agitation. When
6 mL of 1 N hydrochloric acid is added to the turbid solution, the
glutamic acid dissolves on stirring.
Pharmacopeial Forum
C: It meets the requirements of the pyroantimonate precipitate saving time of analysis. Validation data was obtained using an HP-
test for Sodium{ 191). 1 brand capillary column of type Gl. Typical retention times are
given in the following table:
Eicosanol 10.3 min

Tetracosanol 13.4 min
Hexacosanol 15.1 min
Octacosanol 17.4 min
Cholesterol 17.8 min
Campesterol 19.4 min
Stigmasterol 19.9 min
Triacontanol 20.5 min
BRIEFING (3-Sitosterol 21.0 min
Stimagstanol 21.2 min
Poloxamer, NF 20 page 2593 and page 2805 of the First Sup-
plement.
Add the following:

Erratum:
Organic volatile impurities, line 2: Change "requirements." to: •Saw Palmetto Extract
requirements for chloroform, methylene chloride, and trichlor-
oethylene.
» Saw Palmetto Extract is obtained from commin-

uted Saw Palmettoby extraction with hydroalco-
holic mixtures or solvent hexane, or by
supercritical extraction with carbon dioxide. The
BRIEFING
ratio of starting crude plant material to Extract is
Polyethylene Glycol, NF 20 page 2595 and page 2805 of the between 8.0:1 and 14.3:1. The Extract contains
First Supplement.
95.0 percent of fatty acids and not less than 0.2
Erratum: percent and not more than 0.5 percent of sterols,
Organic volatile impurities, line 2: Change "requirements." to:
requirements for chloroform, methylene chloride, and trichlor- calculated on the anhydrous basis. The lipophilic
oethylene.
Extract contains not less than 0.15 percent and not
more than 0.35 percent of long-chain alcohols.
The hydroalcoholic Extract contains not less than
long-chain alcohols. It contains no added sub-
BRIEFING stances.
Saw Palmetto Extract, page 425 of PF 28(2) [Mar.-Apr.
2002]. It is proposed to replace the methodology for determination Labeling—The label states the Latin binomial and, follow-
of long chain alcohols and sterols. The new proposed method has
the advantage of simplified sample preparation avoiding the for- ing the official name, the part of the plant from which the
merly required thin-layer separation. In addition, long-chain alco-
hols and sterols are determined in the same chromatographic run, article was prepared. The label also indicates the content
Pharmacopeial Forum
of fatty acids and sterols and the ratio of the starting crude Heavy metals, Method II (231): 40 ug per g.
plant material to Extract. It meets the requirements for La- Organic volatile impurities, Method IV (467): meets the
beling under Botanical Extracts (565). requirements.
USP Reference standards (U)—USP Hexacosanol RS. Solvent: benzyl alcohol.
USP Methyl Caprate RS. USP Methyl Caproate RS. USP Content of fatty acids—
Methyl Caprylate RS. USP Methyl Laurate RS. USP Methyl Internal standard solution, Standard solution, and
LinoleateRS. USP Methyl Linolenate RS. USP Methyl Myr- Chromatographic system—Prepare as directed for Content
istate RS. USP Methyl Oleate RS. USP Methyl Palmitate RS. of fatty acids under Saw Palmetto.
USP Methyl Palmitoleate RS. USP Methyl Stearate RS. USP Test solution—Transfer about 100 mg of Extract, accu-
$-Sitosterol RS. rately weighed, to a pressure-proof, screw-capped vial,
Identification—The retention times of the 11 major peaks and add 3.0 mL of a solution of sulfuric acid in methanol
in the chromatogram of the Test solution correspond to those (5 in 100). Heat at 100° in an oil bath for 2 hours, shaking
in the chromatogram of the Standard solution, as obtained from time to time. Allow to cool, and add 1.0 mL of Internal
in the test for Content of fatty acids. standard solution, 10.0 mL of water, 1 g of sodium chloride,
The ratios of the concentration of lauric acid to the con- and 5 mL of hexanes. Shake well, allow the layers to sepa-
centration of the respective fatty acid are in the following rate completely, and use the hexanes layer. [NOTE—Store in
ranges. a refrigerator until ready to use.]
Procedure—Proceed as directed for Content of fatty acids
under Saw Palmetto. Calculate the percentage of each fatty
Fatty Acid Minimum Ratio Maximum Ratio
acid in the portion of Extract taken by the formula:
Capric 16
500(C/W)(Ru/Rs)(MA/ME),
Caproic 8.5 53 24
Caprylic 40 8.5 17.5 in which W is the weight, in mg, of Extract taken to prepare
Linoleic 6T6 5.0 43^16 the Test solution; and the other terms are as defined therein.
Linolenic 31.5 4S55 Content of long chain alcohols—
Myristic 2.2 2.8 Dcrivatizing reagent—Prepare a mixture of pyridino and
Oleic &6S0.60 1.15 N (trimothylailyl)imidazolo (1:1).
Palmitic 2.8 2^3.9 Internal standard solution I—Prepare a solution contain •
Stearic 44 14 26 ing 1.0 mg of oioosanol per mL of chloroform.
Internal standard solution 2—Prepare a solution contain
ing 1.0 mg of P oholootanol por mL of chloroform.
Iodine value (401): between 40 and 50.
Standard solution—Trangfcr an accurately weighed quan
Saponification value (401): between 210 and 250.
tity of USP Hcxaoooanol RS to a volumetric flaak, and dis
Unsaponifiable matter (401): between 1.8% and 3.5%. solve in and dilute with ohloroform to volume to obtain a
Water, Method I (921): not more than 3% is found in the solution having a known concentration of about 1 mg por
hydroalcoholic Extract.
Pharmacopeial Forum
mL: Transfer 1.0 mL of this solution to a screw capped vial, coated with a 0.25 mm layer of ohromatographio oilioa gol
add 1.0 mL of Internal standard solution 1, and ovaporato to mixture, previously dipped in 3 om of a solution prepared by
drynogg using a stream of nitrogen. Dissolve the rosiduo in dissolving 13 g of potassium hydroxide in 20 mL of water
1.0 mL of Dcrivatising reagent, and allow to atand for not and diluting with mothanol to 1000 mL. NOTE—Tho plato is
lcso than 15 minutes at room temperature. plaood vertically in tho potassium hydroxide solution so that
System suitability solution—Prepare a solution containing only tho application zono is treated. Allow tho plato to dry,
about 1 mg per mL each of totraoosanol, ootaooaanol, USP and hoat to 100° for 1 hour before use. It can bo stored in a
Hoxaoosanol RS, and triaoontanol. Continue ao dirootod for dosiooator containing oaloium ohlorido. Dovolop with a sol
Standard solution, beginning with "Transfer 1.0 mL of this vent consisting of a mixture of hoxanoo and other (7:3) until
solution to a screw capped vial." the solvent front ha3 moved 17 to 10 om. Keep the chamber
Test solution—Transfer about 5 g of Extract, accurately temperature botwoon 15° and 20°. Dry the plato with a our
weighed, to a 250 mL round bottom flask. Add 2.0 mL of rent of warm air, then spray with an alkaline solution of 2,7-
Internal standai'd solution 1 and 2.0 mL of Internal stan diohlorofluorosooin in alcohol (0.2 in 100). Examine tho
dard solution 2. Evaporate in vacuum at a temperature not plato under 366 nmUV light, and identify tho bands corre-
exceeding 50°. Add 50 mL of a solution prepared by dissol sponding to long ohain aloohols and to storols using tho
ving 130 g of potassium hydroxide in 200 mL of water and spots of oioo3anol and ft oholcstanol, respectively. Sorapo
diluting with mothanol to 1000 mL. Attach a condense^ and off the zones of silica gol corresponding to long ohain aloo
reflux on a water bath until a dear solution is obtained. Ro hols, and transfer to a tost tube. NOTE—Retain the plate for
flux for an additional 10 minutes, and cool by adding 50 mL preparing the Test solution in tho t03t for Content ofstcrols.
of water through the condenser: Quantitatively transfer to a Add 10 mL of warm chloroform^ and shako for two minutes
separation funnel, rinsing the flaak with a total of 50 mL of with several glass beads. Filter, and wash the filter with
water divided into small portions. Extraot with throe 80 mL chloroform; Evaporate tho oombinod filtrate and washings
portions of other, shaking for 30 seconds each time. NOTE— to dry ness in vacuum: Dissolve tho rosiduo by adding a
If an emulsion forms, eliminate it by adding small quantities few drops of aootono, and ovaporato in vaouum: Dry tho ro
of mothanol. Transfer the oombinod other layers into a so siduc in an oven at 105° for 15 minutes. Dissolve tho rosiduo
paration funnel, and wash with successive 50 mL portions in 0.2 mL of Dcrivatising reagent, and allow to stand for not
of water until a neutral washing is obtained. NOTE—!£-««• loss than 15 minutes at room temperature.
emulsion forms, eliminate it by adding small quantities of Chromatographicsystem! (soo Chromatogfaphy (€H))—
mcthanol. Pass the other extract through filter paper contain Tho gas chromatograph is equipped with a flamo ionization
ing anhydrous sodium sulfato, wash tho filter with 30 mL of dotootor, a split injection system with a 50:1 split ratio, and a
other, ovaporato to drynoss in vaouum, and dissolve the ro 0.32 mm x 20 m oapillary oolumn ooatod with a 0.2 to
siduo in 2.0 mL of chloroform. Separately apply 200 uL of 0.25 urn film of phase G27. Tho carrier gas is helium, flow
this solution, 20 uL of a solution of cicosanol in chloroform ing at a rate of about 1.5 mL per minute, and tho makeup gas
(1 in 100), and 20 uL of a solution of (3 oholcstanol in is flowing at a rate of 30 mL per minute: Tho oolumn torn
chloroform (lin 100) to a thin layer ohromatographic plato poraturo is programmed as follows. Initially it is increased
Pharmacopeial Forum
from 150° to 300° at a rate of 5° por minuto, thon maintained add 1.0 mL of Internal standard solution 2, and evaporate to
at 300° for 10 minutes. Tho injootion port and the dotootor drynoss using a stream of nitrogen. Dissolve tho residue in
are maintained at a temperature of 350°. Chromatograph the 4:0 mL of Dcrivatising reagent, and allow to stand for not
Standard solution System suitability solution, and record tho loss than 15 minutes at room temperature.
peak responses as directed for Pmccdurc: the relative rctcn System suitability solution—Prepare a solution containing
tion times are 1.00, 1.35; 1.50, 1.65, and 1:82 for oioooanol, about 1 mg per mL oaoh of oampostorol, stigmaotorol, and
totraoosanol; hoxaoosanol, octaoosanol, and triacontanol, re USP (3 Sitostorol RS. Continue as directed for Standard so
spootivoly; tho oolumn offioionoy is not loss than 200,000 lution; beginning with "Transfer 1.0 mL of this solution to a
thoorotioal plates determined from the oioooanol peak; and screw capped vial."
tho tailing factor is not more than 2.0. Test solution—Use tho plate retained from the Test solu-
Procedure—Separately injoot equal volumes (about 1 uL) tion in tho Content of long-chain alcohols tost, and sorapo
of tho Standard solution and the Test solution into the chro off tho zone of silica gel corresponding to stcrols: Proceed
matography record tho chromatograms, and measure tho re as directed for Test solution in tho tost for Content of long-
sponsos for the major peaks. Separately calculate tho chained alcohols beginning with "Add 10 mL of warm
percentages of tetraoosanol, hoxaoosanol, ootaoooanol, and ohloroform."
triaoontanol in the portion of Extract taken by tho formula: Chromatographic system—Prepare as directed in tho tost
fox Content of long chain alcohols. Chromatograph tho
Standard solution System suitability solution, and rooord
in whioh C is tho concentration; in mg por mLj of USP Hex
aoosanol RS in tho Standard solution; Wia the weight, in
retention times are 1.00, 1.05, 1.06, and 1.00 for ft cholos
mg, of Extract taken to prepare tho Test solution; R^ is tho
tanol, oamposterol, stigmastcrol, and ft sitosterol, rcspec
rosponso ratio of tho appropriate long ohain alcohol peak to
tivoly; tho oolumn offioionoy is not loss than 200,000
tho internal standard peak in tho ohromatogram of the Test
thoorotioal plates determined from tho P oholo3tanol peak;
solution; and Rg is the response ratio of tho hoxaoosanol
and tho tailing factor is not moro than 2.0.
peak to tho internal standard peak in tho chromatogram of
Procedure—Separately injeot equal volumes (about 1 uL)
tho Standard solution. Caloulato tho oontont of long ohain
of tho Standard solution and tho Test solution into the ohro-
alcohols by adding tho individual percentages.
matograph, rooord the ohromatograms, and measure tho re
Content of stcrols—
sponscs for tho major peaks. Separately calculate tho
Dcrivatising reagent, Internal standard solution 1, and percentages of campcstorol, 3tigmastorol, and ft sitostorol
Internal standard solution 2—Prepare as directed in the test in tho portion of Extract taken by the formula:
for Content of long chain alcohols.
Standard solution—Transfer an accurately weighed
amount of USP ft Sitostorol RS to a volumetric flask; and in whioh C is the concentration, in mg por mL, of USP ft
diasolvo in and dilute with ohloroform to volume to obtain Sitostcrol RS in tho Standard solution; Wis the weight, in
a solution having a known concentration of about 1 mg per mg, of the Extract taken to prepare the Test solution; R^
mL. Transfer 1.0 mL of this solution to a 3orcw capped vial, the response ratio of tho appropriate storol poak to tho inter
Pharmacopeial Forum
nal standard peak in tho ohromatogram of tho Test solution; able cartridge is Extrelut NT3, or an equivalent cartridge.]
and Rg ig the reoponso ratio of the [3 oitostorol peak to the Absorb the solution into the column under vacuum for 20
. internal otandard peak in tho ohromatogmm of tho Standai«d minutes until the column is not cold. Elute the analytes from
solution. Caloulato tho content of otorolo by adding tho indi the column with 90 mL of methylene chloride, and evapo-
vidual poroontagos. rate the eluate to dryness. Dissolve the residue in 1.0 mL of
Content of long chain alcohols and sterols— Derivatizing solution 2, and allow to stand for not less than
Derivatizing solution 1: a mixture of./v",0-bis(trimethylsi- 15 minutes at room temperature.
lyl)-acetamide, trimethylchlorosilane, and trimethylsilylimi- System suitability solution 1—Prepare a solution contain-
dazole (3:2:3). ing about 2 mg per mL each of tetracosanol, octacosanol,
Derivatizing solution 2: a mixture of Derivatizing solu- USP Hexacosanol RS, and triacontanol in chloroform.
tion 1, bis(trimethylsilyl)-trifluoroacetamide, and pyridine Mix 5.0 mL of this solution with 1.0 mL of Internal stan-
(1:1:1). dard solution. Evaporate about 0.75 mL of this solution to
Internal standard solution—Prepare a solution containing dryness using a stream of nitrogen. Dissolve the residue in
10 mg per mL of eicosanol and 5 mg per mL of cholesterol 1.0 mL of Derivatizing solution 2, and allow to stand for not
in chloroform. less than 15 minutes at room temperature.
Standard solution—Prepare a solution of USP Hexacosa- System suitability solution 2—Prepare a solution contain-
nol RS and USP P-Sitosterol RS in chloroform having a ing about 2 mg per mL each of campesterol, stigmasterol,
known concentration of about 0.75 mg and 1.4 mg per and USP (3-Sitosterol RS, and 0.37 mg per mL of stigmas-
mL, respectively. Mix 5.0 mL of this solution with 1.0 tanol. Mix 5.0 mL of this solution with 1.0 mL of the Inter-
mL of the Internal standard solution. Evaporate about nal standard solution. Evaporate about 0.75 mL of this
0.75 mL of this solution to dryness using a stream of nitro- solution to dryness using a stream of nitrogen. Dissolve
gen. Dissolve the residue in 1.0 mL of Derivatizingsolution the residue in 1.0 mL of Derivatizing solution 2, and allow
2, and allow to stand for not less than 15 minutes at room to stand for not less than 15 minutes at room temperature.
temperature. Chromatographic system (see Chromatography (621))—
Test solution—Transfer an accurately weighed quantity of The gas chromatograph is equipped with a flame-ionization
about 3.35 g of extract into a 50-mL, round-bottomed flask. detector, a split injection system, and a 0.2-mm x 25-m ca-
Add 1.0 mL of Internal standard solution, and evaporate pillary column coated with a 0.33-um thickness of phase
under vacuum at a temperature not exceeding 50°. Add 20 Gl. The chromatograph is programmed to maintain the col-
mL of a solution prepared by dissolving 130 g of potassium umn temperature at 200° for 3 minutes, then to increase the
hydroxide in 200 mL of water and diluting to 1000 mL with temperature from 200° to 300° at a rate of 10° per minute,
methanol. Attach a condenser, and reflux in a bath at 100° and to hold the final temperature for 35 minutes. The injec-
for 2 hours. Quantitatively transfer this solution to a 25-mL tion port and detector are both maintained at 325°. The car-
volumetric flask, and dilute with water to volume. Transfer a rier gas is helium, flowing at a rate of about of 0.5 mL per
3-mL portion to a cartridge containing diatomaceous earth minute, and the split ratio is 1:40. The make up gas flow is
capable of holding 3 mL of aqueous phase. [NOTE—A suit- 25 mL per minute. Chromatograph the System suitability so-
Pharmacopeial Forum
lution 1 as directed for Procedure: the relative retention Separately calculate the percentages of campesterol, stig-
times are about 0.89, 1.00, 1.15, and 1.36 for tetracosanol, masterol, P-sitosterol, and stigmastanol, respectively, in the
hexacosanol, octacosanol, and triacontanol, respectively; portion of Extract taken by the formula:
the column efficiency is not less than 200,000 theoretical
plates for the eicosanol peak; and the tailing factor for each
in which C is the concentration, in mg per mL, of P-sitoster-
relevant peak is not more than 2.0. Chromatograph the Sys-
ol in the Standard solution; W is the weight, in mg, of the
tem suitability solution 2 as directed for Procedure: the re-
Extract taken to prepare the Test solution; Rv is the ratio of
lative retention times are about 0.85, 0.92, 0.95, 1.00, and
the appropriate sterol peak to the internal standard in the
1.01 for cholesterol, campesterol, stigmasterol, P-sitosterol,
chromatogram of the Test solution; and Rs is the ratio of
and stigmastanol, respectively; the resolution, R, between P-
the P-sitosterol peak to the cholesterol internal standard in
sistosterol and stigmastanol is not less than 2; the column
the chromatogram of the Standard solution. Calculate the
efficiency is not less than 150,000 theoretical plates for
total content of sterols as a percentage by adding the indivi-
the cholesterol peak; and the tailing factor for each relevant
dual percentages.
peak is not more than 2.0.
Procedure—Separately inject equal volumes (about 1 uL) Alcohol content, Method II (611) (if present): not more
of the Standard solution and the Test solution into the chro- than 1% is found.
matograph, record the chromatograms, and measure the re- Other requirements—It meets the requirements of the tests
sponses for the major peaks. Identify the signals for Packaging and Storage, Microbial Limits [To come],
corresponding to the relevant analytes by comparison with and Pesticide Residues under Botanical Extracts (565).B1
the chromatograms obtained with System suitability solu-

tions 1 and 2. Separately calculate the percentages of tetra-
cosanol, hexacosanol, octacosanol, and triacontanol,
respectively, in the portion of Extract taken by the formula:
BRIEFING
in which C is the concentration of hexacosanol, in mg per Sesame Oil, NF 20 page 2614. Because of the difficulties ex-
perienced in obtaining the triglycerides currently used in the test
mL, in the Standard solution; Wis the weight, in mg, of the for Triglyceride composition, OOL (l,2-dioleoyl-3-linoleoyl-rac-
glycerol) and POL (l-palmitoyl-2-oleoyl-3-linoleoyl-rac-glycer-
Extract taken to prepare the Test solution; Rv is the ratio of ol), it is proposed to replace them with two alternative triglycer-
ides, OLL (l,2-dilinoleoyl-3-oleoyl-rac-glycerol) and PLL (1,2-
the appropriate long-chain alcohol peak to the eicosanol in- dilinoleoyl-3-palmitoyl-rac-glycerol).
ternal standard in the chromatogram of the Test solution;
and Rs is the ratio of the hexacosanol peak to the eicosanol
internal standard in the chromatogram of the Standard solu-.
tion. Calculate the total content of long-chain alcohols as a Change to read:
Identification—The peak responses for the eight major triglycer-
percentage by adding the individual percentages. ides, LLL, OLL, PLL, OOL, POL, OOO, SOL, and POO, elute
between 0 and about 40 minutes, in the order specified, and at re-
lative retention times of about 0.52, 0.62, 0.66, 0.75, 0.81, 0.92,
•0.55, 0.65, 0.69, 0.77, 0.82, 0.93, B1
Pharmacopeial Forum
0.97, and 1.0, respectively, as obtained in the chromatogram of the

Test solution in the test for Triglyceride composition. Triglyceride Relative Retention Time Composition (%)
LLL 7.0 to 19.0
Change to read:
Triglyceride composition— "0.55.,
Mobile phase—Prepare a filtered and degassed mixture of ace- OLL Q (J2 13.0 to 30.0
tonitrile and methylene chloride (60:40). Make adjustments if nec-
essary (see System Suitability under Chromatography (621)). PLL 5.0 to 9.0
NOTE—The fatty acid radicals are designated as linoleic (L),
oleic (O), palmitic (P), and stearic (S), and the common abbrevia- •0^69.i
tions for triglycerides used are as follows: trilinolein (LLL), 1,2- OOL 14.0 to 25.0
dilinoleoyl-3-oleoyl-rac-glycerol (OLL), 1,2-dilinoleoyl-3-palmi-
toyl-rac-glycerol (PLL), l,2-dioleoyl-3-linoleoyl-rac-glycerol "0.77.,
(OOL), l-palmitoyl-2-oleoyl-3-linoleoyl-rac-glycerol (POL), trio- POL 8.0 to 16.0
lein (OOO), l-linoleoyl-2-oleoyl-3-stearoyl-rac-glycerol (SOL), •0.82 B1
and l,2-dioleoyl-3-palmitoyl-rac-glycerol (POO). OOO 5.0 to 14.0
System suitability solution—Transfer about 30 mg each of OOL
•0-93.,
SOL 0.97 2.0 to 8.0
•OLL and PLL, B1 POO 1.0 2.0 to 8.0
accurately weighed, to a 10-mL volumetric flask, dissolve in and
dilute with Mobile phase to volume, and mix.
Test solution—Transfer about 200 mg of Oil, accurately
weighed, to a 10-mL volumetric flask, dilute with Mobile phase
to volume, and mix.
chromatograph is equipped with a refractive index detector and
two 4.6-mm x 25-cm columns in series that contain packing LI
and are maintained at a constant temperature botwoon 22° and 25°.
•ofabout30°.B1
The flow rate is about 1.0 mL per minute. Chromatograph the Sys-
tem suitability solution, and record the peak areas as directed for BRIEFING
Procedure: the relative retention times are about 0.93 for OOL
•OLL B , Sorbitol, NF 20 page 2625 and page 3342 of PF 27(6) [Nov.-
and 1.0 forPOirj Dec. 2001]. The retention times for mannitol and sorbitol were in-
advertently misstated in the briefing under Sorbitol in PF 27(6).
PT T The chromatographic method in the Assay is based on analyses
the resolution, R, between OOL and POL performed with the Aminex Fast Carbohydrate brand of L34 col-
•OLL and PLL B 1 umn. The typical retention times for mannitol and sorbitol are 8.8
is not less than 1.8; the relative standard deviation for replicate in- and 14.3 minutes, respectively. In addition, changes are made to
jections, determined from peak areas, is not more than 1.5%; and the Assay calculation to reflect that the assay should be calculated
the relative standard deviation for replicate injections, determined on the "anhydrous" basis instead of "in mg". For consistency, it is
from peak area ratios of OOL to POL, proposed to add a test for Microbial limits to the monograph. Be-
cause it is believed that no commercial polyol producers use the
•OLL to PLL, B , solvents specified in the test for Organic volatile impurities, it is
is not more than 2.2%. proposed to delete this test in favor of the ICH guidelines on resi-
Procedure—Inject about 20 uL of the Test solution into the dual solvents. Editorial style changes have also been made.
chromatograph, record the chromatogram, and measure the areas
for the eight major triglyceride peaks, eluting from 0 to about 40 (EMC: C. Sheehan; AMB: D. Porter) RTS—36749-1
minutes, with relative retention times stated in the table below and
in the order specified. Calculate the percentage of each of these
triglycerides in the portion of Oil taken by the formula:
\00(A/B), Change to read:
in which A is the peak area for each individual triglyceride; and B is
the sum of the areas of all the peaks, excluding the solvent peak. » Sorbitol contains not less than 91.0 percent and not
more than 100.5 percent of G^HUQ€—
•D-sorbitol,B1
calculated on the anhydrous basis. The amounts of
•total sugars,B1
other polyhydric alcohols, and any hexitol anhydrides,
if detected, are not included in the requirements, nor
•inB1
the calculated amount under Other Impurities.
Pharmacopeial Forum
minutes: tho woight of tho cuprous oxido dooa not oxoood 50

Add the following: fflg. Tho amount dotorminod in this toot io not inoludod in tho oal
eulatod amount under Other Impurities.
•Labeling—Sorbitol intended for use in preparing parent-
"Dissolve 3.3 g of Sorbitol in 3 mL of water with the aid of
eral dosage forms is so labeled.H1
gentle heat. Proceed as directed in the test for Reducing su-
Change to read:
USP Reference standards (11)— gars under Mannitol beginning with "Cool, and add 20.0
U
USP Endotoxin RS.ml mL of cupric citrate TS". Not less than 12.8 mL of 0.05
USP Sorbitol RS.
N sodium thiosulfate VS is required, corresponding to not
Add the following:
more than 0.3% of reducing sugars, as glucose. The amount
•Microbial limits (61)—The total aerobic count using the
determined in this test is not included in the calculated
Plate Method is not more than 103 cfu per g and the total
amount under Other Impurities. ul
combined molds and yeasts count is not more than 102 cfu
perg. B1 Delete the following:
"Total sugars—Plaoo 2.1 g in a 250 mLflaskfittedwith a ground
Add the following: glass joint, add 40 mL of approximately 0.1 N hydroohlorio aoid,
attach a reflux oondonoor, and reflux for A hours. Tranafor tho aolu
•pH (791): between 3.5 and 7.0, in a 10% (w/w) solution in tion to a 400 mL beaker, rinsing tho flaak with about 10 mL of
water, neutralize with 6 Noodium hydroxide, and proooed as diroo
carbon dioxide-free water.B1 ted in tho tost for Reducing sugars, beginning with "Add 50 mL of
alkaline ouprio tartrato TS": tho woight of tho ouprouo oxido does
Change to read: net oxoood 50 mg. Tho amount dotorminod in this teat is not in*
Water, Method I (921): not more than -k©%r eluded in tho ooloulatod amount undor Other Impurities. ul
•1.5%. m Add the following:
Change to read: "Limit of nickel—Proceed as directed in the test for Nickel

Residue on ignition (281): not more than 0.1%, under Mannitol. Not more than 1 ug per g is found.,,
•determined on a 1.5-g portion, accurately weighed. B1
"Organic volatile impurities, Method IV (46?): moots tho re
"Chloride (2S4-)—A 1.5 g portion shows no more ohlorido than quiromonts.jj
corresponds to 0.10 mL of 0.020 N hydrochloric aoid
(0.0050%).,! Add the following:
Delete the following: "Other requirements—If labeled for use in preparing par-
"Sulfate (324-)—A 1.0 g portion showa no moro sulfato than cor enteral dosage forms, it also meets the following require-
responds to 0.10 mL of 0.020 N oulfurio aoid (0.010%). m
ments.
"Arsenic, Method II (£44): Clarity and color of solution—Dissolve a 10.0-g portion
Delete the following: in carbon dioxide-free water, and dilute with carbon diox-
"Heavy metalo (334-)—Dioaolvo 2.0 g in 25 mL of wator: tho limit
ifl 0.001% . ide-free water to 100.0 mL: the solution is clear and color-
M1
Change to read: less.

Reducing sugars—Transfer 7 g; accurately weighed, to a 100 mL
boalcor with tho aid of 35 mL of wator, and mix. Add 50 mL of Bacterial endotoxins (85): not more than 4 USP Endotox-
alkaline euprio tartrato TS, cover the beaker, heat tho mixture at
auoh a rate that it oomo3 to a boil in approximately A minutes, in Units per g for parenteral dosage forms having a concen-
and boil for 2 minutes, accurately timod. Collect tho precipitated
ouprous oxide in a tared filtering "oruoiblo previously waohed sue tration of less than 100 g of sorbitol per liter and not more
oosaivoly with hot wator, with alcohol, and with other and then
dried at 105° for 30 minutes. Thoroughly waoh tho collected cu than 2.5 USP Endotoxin Units per g for parenteral dosage
prous oxide on the filtor with hot water, thon with 10 mL of aloo
hoi, and finally with 10 mL of ether, and dry at 105° for 30 forms having a concentration of 100 g or more of sorbitol
per liter.
Pharmacopeial Forum
Chloride (221)—A 1.5-g portion shows no more chloride of the Assay preparation and the Standard preparation into the
chromatograph, record the chromatograms, and measure the re-
than corresponds to 0.10 mL of 0.020 N hydrochloric acid. sponses for the major peaks. Calculate the quantity, in mg, of
G^tf^Q^, in the Sorbitol takon by the formula:
Not more than 0.0050% is found.
Sulfate (221)—A 1.0-g portion shows no more sulfate in which C is tho concentration, in mg por mL, of USP Sorbitol RS
in the Standardpivparation, and
than corresponds to 0.10 mL of 0.020 N sulfuric acid. Not
'por mL, of Calculate the percentage, on the anhydrous ba-
more than 0.01% is found.B1
sis, of D-sorbitol in the portion of Sorbitol taken by the for-
Change to read:
Assay— mula:
Mobile phase—Use degassed water.
Resolution solution—Dissolve mannitol and USP Sorbitol RS in [10,000(Q ICvXrv /^)]/(100 - W),
water to obtain a solution having concentrations of about 4.8 mg
per «ds
in which Cs is the concentration, in mg per mb; g, of USP
of each. Sorbitol RS in the Standard preparation; Cv is the concen-
Standard preparation—Dissolve an accurately weighed quan-
tity of USP Sorbitol RS in water, and dilute quantitatively with tration, in mg per mk? g, of Sorbitol in the Assay prepara-
•
tion; _j
to obtain a solution having a known concentration of about 4.8 mg
rv and rs are the peak responses obtained from the Assay prepara-
tion and the Standard preparation, respectively;
=••1 "and Wis the percentage obtained in the test for Water.B1
Assay preparation—Transfer about 0.24 g of Sorbitol, aocu
ratoly weighed, to a 50 mL volumetric flask, dissolve in 10 mL
of water, dilute with water to volumo, and mix.
"Dissolve about 0.10 g of Sorbitol, accurately weighed, in
water, and dilute with water to about 20 g. Accurately record
the final solution weight, and mix thoroughly. B1
Chromatographic system (see Chromatography (621))— The
liquid chromatograph is equipped with a refractive index detector BRIEFING
that is maintained at a constant temperature and a 7.8 mm H 30
cm oolumn that contains packing LI9. Tho oolumn temperature is
maintained at a temperature between 30° and 85°, controlled to Noncrystallizing Sorbitol Solution, NF20 page 2625 and page
within _h2° of tho selected temperature, and tho flow rate ia about 3344 of P F 27(6) [Nov.-Dec. 2001]. The retention times for mal-
0.2 mL por minute. titol, mannitol, and sorbitol were inadvertently misstated in the
briefing under Noncrystallizing Sorbitol Solution in PF 27(6).
"of about 35° and a 7.8-mm x 10-cm column that contains The chromatographic method in the Assay is based on analyses
performed with the Aminex Fast Carbohydrate brand of L34 col-
packing L34. The column temperature is maintained at a umn. The typical retention times for maltitol, mannitol, and sorbi-
tol are 6.8, 8.8, and 14.3 minutes, respectively. In addition, changes
constant temperature of about 50°, controlled within + are made to the Assay calculation to reflect that the assay should be
calculated on an "as is" basis instead of on the "anhydrous" basis.
2°, and the flow rate is about 0.7 mL per minute. m Editorial style changes have also been made.
Chromatograph the Standard preparation, and record the peak re-
sponses as directed for Procedure: the relative standard deviation (EMC: C. Sheehan; AMB: D. Porter) RTS—36749-4
for replicate injections is not more than 2.0%. Chromatograph the
Resolution solution, and record the peak responses as directed for
Procedure:
•the relative retention times are about 0.6 for mannitol and Change to read:
1.0 for sorbitol; and B1 » Noncrystallizing Sorbitol Solution is an aqueous so-

the resolution, R, between sorbitol and mannitol is not less than
2.0. lution of hydrogonatod, fully and partially hydrolyzod
Procedure— Separately inject equal volumes (about 20 uL) starches. It contains
•10 uL) B 1 "containing.!
Pharmacopeial Forum
not less than 45.0 percent of D-sorbitol (C 6 H I4 O 6 ) (w/ (Solution A): Dissolve 25 g of ouprio oulfato in hot water, and dilute
w). The amounts of total sugars, other polyhydric alco- with water to 200 mL. Combine this aolution with Solution A, and
mix for 30 minutes (Solution S). Dissolve 0.1 g of sodium hydrox
hols, and any hexitol anhydrides, if detected, are not ido in about 100 mL of water. Dissolve 3.4 g of potassium iodato
included in the requirements nor and 50 g of potassium iodide in this sodium hydroxide solution;
and dilute with water to 200 mL (Solution Q. Add Solution C to
•in., Solution B, and stir for at least 2 hours.
the calculated amount under Other Impurities. Procedure—Transfer about 30 g of Solution, aoouratoly
weighed, to a 300 mL conical flask. Adjust the volume of the solu
tion with water to 50 mL, and add 50.0 mL of Cuprie aulfatc iodide
Change to read: aolution. Connect a suitable condenser to the flask, heat on a hot
Identification— plate adjusted to bring the solution to a boil within 3 minutes, and
A: To 3 mL of a 1 in 75 dilution of it in gently reflux tho solution for 5 minutos. Romovo the flask from the
hot plate, and cool it in a water bath at 20° for 15 to 25 minutes. Do
•Dissolve 1.4 g of Noncrystallizing Sorbitol Solution in 75 not overoool. Slowly add 25 mL of 5 N sulfurio aoid, and swirl
gently to mix. NOTC—Foaming may occur when the 5 N 3ulfurio
mL of water. Transfer 3 mL of this solution to B 1 aoid is added. Titrate tho liberated iodino with 0.1 N sodium thio
a 15-cm test tube, add 3 mL offreshlyprepared catechol solution (1 sulfato VS to a pale green color. Add 1 mL of 3tarch TS, mix, and
in 10), mix, add 6 mL of sulfuric acid, mix again, and gently heat continue the titration to a pale green blue ondpoint. Perform a
the tube in a flame for about 30 seconds: a deep pink or wine-red blank determination (soo Titrimctry (544-)), and make any nee
color appears. ossary correction. Calculate tho titration difference, based on a
B: The retention time of the major peak in the chromatogram 30 g specimen weight, by tho formula:
of the Standard preparation, as obtained in the Assay. (30/ffQ(0.1/N)(£ S),
Delete the following: in which W is the weight, in g, of tho Solution taken, N is tho nor
•Specific gravity (S44-): not lcoa than 1.290.,j mality of the sodium thiosulfato VS, and B and S arc the volumes;
in mL, of sodium thiooulfato consumed in the blank and specimen
Delete the following: titrations, respectively. Tho titration difference is not more than
21.1 mL, corresponding to 0.21% reducing ougar3 (a3 dextrose);
•Refractive index (£34): between 1.157 and 1.167.,{ Tho amount determined in this tost is not inoludod in tho oaloulatod
amount under Other Impurities.
Add the following:
"To an amount of Noncrystallizing Sorbitol Solution,
"Microbial limits (61)—The total aerobic microbial count
equivalent to 3.3 g on the anhydrous basis, add 3 mL of
water, 20.0 mL of cupric citrate TS, and a few glass beads.
the total combined molds and yeasts count is not more than
Proceed as directed in the test for Reducing sugars under
102 cfu per mL.,!
Mannitol, beginning with "Heat so that boiling begins."
Add the following:
Not less than 12.8 mL of 0.05 N sodium thiosulfate VS is
•pH (791): between 5.0 and 7.5, in a 14% (w/w) solution of
required, corresponding to not more than 0.3% of reducing
Noncrystallizing Sorbitol Solution in carbon dioxide-free
sugars, on the anhydrous basis, as glucose. The amount de-
water.,,
termined in this test is not included in the calculated amount
Add the following:
under Other Impurities. B1
•Water, Method I (921): between 28.5% and 31.5%.B1
•Residue on ignition (281): not more than 0.1%, calculated •Limit of nickel—Proceed as directed in the test for Limit
on the anhydrous basis, determined on a 2-g portion, accu- of nickel under Sorbitol Solution. Not more than 1 ug per g,
rately weighed., j calculated on the anhydrous basis, is found.,2
Delete the following: Delete the following:

"Other requirements—It moots the requirements for Water, Rcai
due on ignition, Chloride, Sulfate, and Arsenic, under Sorbitol So
Change to read: lution, USP.m2
Reducing sugars—
Cuprie aulfatc iodide solution—Disaolvo 81 g of potaaaium oi
trato monohydrato, 92 g of potassium oxalato, and 71 g of potaooi
um oarbonato in hot water, and dilute with water to 600 mL
Pharmacopeial Forum
Change to read: Cv is the concentration, in mg per g, of Noncrystallizing

Assay—
Mobile phase—Uao filtered and dc-gasaod wator: Sorbitol Solution in the Assay preparation;, oaloulatod on
Standardpreparation—Tranofor an accurately woighod quantity
of about 30 mg of USP Sorbitol RS to a 1 mL volumetric flank, tho anhydrous baois;
dissolve in and dilute with wator to volume, and mix. •
Assay preparation—Tranofor about 2.0 g of Solution, accurately •l
woighod, to a 50 mL volumetric flaak, dilute with water to volume,
tttxCFTTiTzw and rv and rs are the peak responses obtained from the Assay
Resolution solution—Dissolve 1.5 mg of mannitol in 0.5 mL of
tho Standard preparation, and mix. preparation and the Standard preparation, respectively. m
Ghmmatographic system (aoo Chromatography (-634-)^—Tho li
quid ohromatograph is-cquippod with a refractive indo?c detector
maintained at 25°, a 4.6 mm x 3 cm guard column containing
packing L34, and a 7.8 mm x 10 cm analytical column containing
packing L31 and maintained at 85°. Tho flow rate is about 0.6 mL
per minute. Chromatograph tho Resolution solution, and record tho
peak responses ao directed undor Pmccdurc: tho relative retention
times are about 0.7 for mannitol and 1.0 for aorbitol, and tho roao
lution, R, between tho mannitol peak and tho aorbitol peak ia not
looo than 2.0. Chromatograph tho Standard preparation, and record
tho peak rcoponaoa as directed under Procedure: tho relative stan
dard deviation for replicate injections io not more than 2.0%.
BRIEFING
Procedure—Separately injoot equal volumes (about 20 uL) of
tho Standardpreparation and tho Assay preparation into tho ohro
matograph, record tho ehromatograma, and measure tho responses Starch, NF 20 page 2626 and page 952 of PF 26(4) [July-Aug.
for tho major poako. Caloulate tho quantity, in mg, of C^H^Q^-m 2000]. Because of harmonization efforts,Tapioca Starch, appeared
tho portion of Solution taken by tho formula: as a separate monograph in a previous Pharmacopeial Previews,
and references to Tapioca Starch under the Starch monograph were
deleted in that same issue of Pharmacopeial Previews. The
changes under Starch are now being forwarded to In-Process Re-
in which C io tho ooncontration, in mg per mL, of USP Sorbitol RS vision.
in tho Standard preparation, and r># and r^ are tho Sorbitol poak
responses obtained from tho Assay preparation and the Standai«d
preparation, respectively. (EMC: C. Sheehan) RTS—36525-1
'Mobile phase, Resolution solution, Standard

preparation, and Chromatographic system—Proceed as di-Change to read:
rected in the Assay under Sorbitol.
» Starch consists of the granules separated from the
Assay preparation—Accurately weigh about 0.20 g of mature grain of corn [Zea mays Linne (Fam. Grami-
neae)] or of wheat [Triticum aestivum Linne (Fam.
Noncrystallizing Sorbitol Solution, dissolve in and dilute Gramineae)], or from tubers of the potato [Solarium tu-
berosum Linne (Fam. Solanaceae)] or of tapioca [Man
with water to about 20 g. Accurately record the final solu-
ihot utilissima Pohl (Fam. Euphorbi Aooao)].
•
tion weight, and mix thoroughly. •I
NOTE—Starches obtained from different botanical
Procedure—Proceed as directed in the Assay under Sorbi- sources may not have identical properties with respect
tol. Calculate the percentage of D-sorbitol (C6H14O6) in the to their use for specific pharmaceutical purposes, e.g.,
as a tablet-disintegrating agent. Therefore, types of
portion of Noncrystallizing Sorbitol Solution taken by the starch should not be interchanged unless performance
equivalency has been ascertained.
formula:
Change to read:
Corn starch—Polygonal, rounded or spheroidal granules up to
in which Q i s the concentration, in mg per g, of USP Sorbi- about 35 um in diameter and usually having a circular or sev-
eral-rayed central cleft.
tol RS in the Standard preparation;, calculated on the anhy Wheat starch—Two distinct types of granules are simple lenticu-
lar large granules 20 to 25 um or up to 50 um in diameter, and
drouo basis; small spherical granules 5 to 10 um in diameter. Striations are
faintly marked and concentric.
Potato starch—Simple granules, irregularly ovoid or spherical,
30 to 100 um in diameter, and subspherical granules 10 to 35 um in
diameter. Striations are well marked and concentric.
Pharmacopeial Forum
Tapioca starch—Sphorioal granuloo with one truncated oido, ty Identification—

pioally 5 urn to 35 urn in diamotor, typically having a oiroular or
aovoral rayed central olofto. A: Suspend 1 g of Tapioca Starch in 50 mL of water,
boil for 1 minute, and cool: a thin, cloudy mucilage is
Change to read: formed.
pH (791)—Prepare a slurry by weighing 20.0 g ± 100 mg of
Starch, transferring to a suitable nonmetallic container, and adding B: To 10 mL of the mucilage obtained in Identification
100 mL of water. Agitate continuously at a moderate rate for 5 min-
utes, then stop agitation, and immediately determine the pH to the tQStA add 0.04 mL each of iodine and potassium iodide TS:
nearest 0.1 unit: the pH, determined potentiometrically, is between
4.5 and 7.0 for Corn starch, Tapioca staivh, a reddish violet to dark blue color is produced, which disap-
and Wheat starch, and is between 5.0 and 8.0 for Potato starch. pears on heating and reappears on cooling.
Microbial limits (61)—It meets the requirements of the test
for absence of Escherichia coli. The total aerobic microbial
count does not exceed 1000 per g, and the total combined
molds and yeasts count does not exceed 100 per g.
pH (791)—Weigh 20.0 + 0.1 g of Tapioca Starch, transfer
BRIEFING to a suitable nonmetallic container, and add 100 mL of water
Tapioca Starch, page 952 of PF 26(4) [July-Aug. 2000]. This to obtain a slurry. Agitate continuously at a moderate rate for
new monograph, which previously appeared in Pharmacopeial
Previews, is now forwarded to In-Process Revision. For clarifica- 5 minutes, then stop agitation, and immediately determine
tion, it is proposed to modify the existing Test preparation in the
test for Iron (241). the pH: between 4.5 and 7.0.
(EMC: C. Sheehan) RTS—36525-2 Loss on drying (731)—Dry it at 130° for 90 minutes: it

loses not more than 16.0% of its weight.
Add the following: Residue on ignition (281): not more than 0.6%, determined
•Tapioca Starch on a 1.0-g specimen.
Iron (241): 0.002%, the Test preparation being prepared as
follows. Shake 0.75 g 0.25 g of Tapioca Starch with 15 mL
» Tapioca Starch consists of the starch granules of 0.1 N hydrochloric acid, and filter. Use 10 mL of this so-
separated from the tubers of tapioca (cassava) lution as the Test preparation.
[Manihot utilissima Pohl (Fam. Euphorbiaceae)]. Limit of oxidizing substances—Transfer 4.0 g of Tapioca
Starch to a glass-stoppered, 125-mL conical flask, and add
50.0 mL of water. Insert the stopper, and swirl for 5 minutes.
ers.
Decant into a glass-stoppered, 50-mL centrifuge tube, and
Botanic characteristics—Examine Tapioca Starch under a
centrifuge to clarify. Transfer 30.0 mL of the clear superna-
microscope, using not less than 20 x magnification and
tant liquid to a glass-stoppered, 125-mL conical flask. Add 1
using glycerin as the mounting agent: it appears as spherical
mL of glacial acetic acid and 0.5 to 1.0 g of potassium io-
granules with one truncated side, typically having a 5- to 35-
dide. Insert the stopper, swirl, and allow to stand for 25 to 30
um diameter and having circular or several-rayed central
minutes in the dark. Add 1 mL of starch TS, and titrate with
clefts.
0.002 N sodium thiosulfate VS to the disappearance of the
Pharmacopeia! Forum
starch-iodide color. Perform a blank determination, and

BRIEFING
make any necessary correction (see Titrimetry (541)). Each
Purified Stearic Acid, NF 20 page 2628—See briefing under
mL of 0.002 N sodium thiosulfate is equivalent to 34 jig of Stearic Acid.
oxidant, calculated as hydrogen peroxide. Not more than 1.4
mL of 0.002 N sodium thiosulfate is required: not more than
0.002% of oxidizing substances is found.
Limit of sulfur dioxide—Mix 20 g of Tapioca Starch with Change to read:

Iodine value (401): not more than 1.5.
200 mL of water until a smooth suspension is obtained, and
•Proceed as directed in Method I except to use 35 mL of
filter. To 100 mL of the clear filtrate add 3 mL of starch TS,
chloroform., j
and titrate with 0.010 N iodine solution to the first perma-
nent blue color. Not more than 1.7 mL is consumed: not
more than 0.005% of sulfur dioxide is found..,

GENERAL CHAPTERS
General Tests and Assays
BRIEFING
General Requirements for
Stearic Acid, NF 20 page 2627 and page 583 of PF 28(2)
[Mar.-Apr. 2002]; Purified Stearic Acid, NF 20 page 2628. In
Tests and Assays
the test for Iodine value, the amount of sample used depends on
the sample's expected Iodine Value (see Fats and Fixed Oils
(401)). For substances such as Stearic Acid that have an expected
Iodine Value of <5, 3.000 + 0.001 g of sample are required for the
test. Because there are problems with dissolving a sample of this
size, it is proposed to increase the volume of chloroform used in the
test from 10 mL to 35 mL to facilitate solution of the sample.
BRIEFING
(11) Reference Standards, USP 25 page 1836, page 2756 of
the First Supplement, page 8060 of P F 20(5) [Sept.-Oct. 1994],
page 3212 of P F 22(6) [Nov.-Dec. 1996], page 4500 of P F
23(4) [July-Aug. 1997], page 4849 of PF 23(5) [Sept.-Oct.
Change to read: 1997], page 5180 of PF 23(6) [Nov.-Dec. 1997], page 5965 of
Iodine value (401): not more than 4. PF 24(2) [Mar.-Apr. 1998], page 6925 of PF 24(5) [Aug.-Sept.
1998], page 7511 of PF 25(1) [Jan.-Feb. 1999], page 7876 of
"Proceed as directed in Method I except to use 35 mL of PF 25(2) [Mar.-Apr. 1999], page 8222 of PF 25(3) [May-June
1999], page 8561 of PF 25(4) [July-Aug. 1999], page 8893 of
chloroform.-, PF 25(5) [Sept-Oct. 1999], page 9222 of PF 25(6) [Nov.-Dec.
1999], page 218 of P F 26(1) [Jan.-Feb. 2000], page 471 of P F
26(2) [Mar.-Apr. 2000], page 793 of P F 26(3) [May-June
PF 26(5) [Sept-Oct 2000], page 1606 of PF 26(6) [Nov.-Dec.
2000], page 1832 of P F 27(1) [Jan.-Feb. 2001], page 2268 of
PF 27(2) [Mar.-Apr. 2001], page 2594 of P F 27(3) [May-June
Pharmacopeial Forum
PF 27(5) [Sept.-Oct. 2001], page 3348 of PF 27(6) [Nov.-Dec. Add the following:
2001], page 111 of P F 28(1) [Jan.-Feb. 2002], and page 433 of A
PF 28(2) [Mar.-Apr. 2002]. USP Ganciclovir Related Compound A RS [Chomical
(HDQ) RTS—33247-4; 33301-4; 33621-1; 34280-1; 35901- name to oomo;][(RS)-2-Amino-9-(2,3-dihydroxy-propoxy-

2; 36289-1; 36417-1; 36751-1; 36761-1; 36777-1
methyl)-l,9-dihydro-purin-6-one]—Dry portion in vacuum
at 80° for 3 hours before using. Keep container tightly
Add the following: closed and protected from light.AUSW(J
•USP Alendronate Sodium RS—Do not dry. This is the Add the following:
A
trihydrate form of alendronate sodium. B1 USP Glucosamine Hydrochloride RS—Dry portion at
Change to read: 105° for 2 hours. Keep container tightly closed. Protect from
USP Aspartic Acid RS.
A
—Do not dry. Store at room temperature.AUyP2(5
Add the following:
A
Change to read: USP Glutamic Acid RS—Do not dry. Store at room tem-
USP Betaine Hydrochloride RS.
perature. Al/5W5
A
—Do not dry. Keep container tightly closed.AUS.,>2(5
Change to read:
USP L-Histidine RS—Dry portion at 105° for 3 hours before
Add the following: using. Keep container tightly closed. "Starting with Lot G label
*USP Carbidopa Related Compound A RS—See USP 3-O- as: Do not dry before using. Keep container tightly closed.#3
Methylcarbidopa RS. (C,,H16N2O4<>240.26)—Do not dry. Keep
container tightly closed. Protect from light.-3 Add the following:
A
Change to read: USP Hydrocodone Bitrartrate Bitartrate Related Com-
USP Chlorpheniramine Maleate RS—Dry portion at 105° for 3
houro beforo uoing. pound A RS—[To come.]A[/^p25
"Do not dry. Bl Add the following:
Keep container tightly closed. Protect from light. "Starting with
Lot M label as: Do not dry. Keep container tightly closed. Protect A
USP Insulin Lispro—[To come.] Aas . W(5
from light.#3
Add the following:
Change to read:
USP Clorsulon RS—Dry portion in vacuum at 100° for 4 hours "USP Maltose RS—Do not dry; determine the water con-
before using. Keep container tightly closed.
^Protect from light.AUS.W5
tent titrimetrically at the time of use for quantitative ana-
lyses. Keep container tightly closed.,j
•USP Powdered Red Clover Extract RS—[To come.] m A
USP Mangafodipir Trisodium [manganese(II) dipyri-
Add the following: doxal diphosphate; Mn(II)DPDP]—[To come.]AUS.P2(j
A
USP Doxazosin Mesylate RS—Do not dry.AUSP26 Add the following:
Add the following: A
USP Mangafodipir Related Compound A RS [manga-
•USP Escin RS—[To come.]B1 nese(II) dipyridoxal monophosphate; Mn(II)DPMP]—[To
Add the following:
•USP Formononetin RS—[To come.]B1
Pharmacopeial Forum
Add the following:

A
Add the following:
USP Mangafodipir Related Compound B RS [mangane- A
USP Ramipril Related Compound A RS [1 [2 [[1
se(II) dipyridoxal diphosphate mono overalkylated;
(2S,3aS,6aS)-1 -[(5)2-[[(5) 1 -(methoxycarbonyl)-3-phenyl-
Mn(II)DPDP-MOA)]—[To come.]AUSM(,
propyljamino]-1 -oxopropyl]-octahydrocyclopenta[6]py r-
Add the following:
A
role-2-carboxylic acid] (C 22 H 30 N 2 O 5 <>402.48)—Do not
USP Mangafodipir Related Compound C RS [manga-
dry. Keep container tightly closed. AUSp26
nese(II) dipyridoxal diphosphate; Mn(III)DPDP-MOA)]—
Add the following:
[To come.]AC/5p26
A
USP Ramipril Related Compound B RS [(2S,3aS,6s£)-
Change to read:
USP Metoprolol Tartrate RS—Dry portion in vacuum at 60° for l-[(iS)2-[[(5)l-(methylethoxy)carbonyl-3-phenylpropyl]a-
4 houro boforo using.
mino]-l-oxopropyl]-octahydrocyclopenta[6]pyrrole-2-car-
Keep container tightly closed. Protect from light. "Starting with
Lot H-l label as: Keep container tightly closed. Protect from boxylic acid] (C 24 H 34 N 2 O 5 -0- 430.54)-Do not dry. Keep
light..3
container tightly closed.AW.«<5
Add the following:
A
Add the following:
USP Norgestimate RS—Dry a portion at 105° for 3 hours.
A
USP Ramipril Related Compound C RS [(2S,3aS,6aS)-
Keep containers tightly closed. AUSP26
1 -[(iS)2-[[(5) 1 -ethoxycarbonyl-3-cyclohexyl propyl]amino]-
Change to read:
USP Potassium Sucrose Octasulfate RS NOTE—Sucrosofate Po- l-oxopropyl]-octahydrocyclopenta[Z)]pyrrole-2-carboxylic
tassium is USAN [oc-D-glucopyranoside, l,3,4,6-tetra-O-sulfo-|3-
D-fructofuranosyl, tetrakis (hydrogen sulfate), octapotassium salt, acid] (C23H38N2O5 <> 422.56)—Do not dry. Keep container
heptahydrate] (C 12 H 14 K 8 O 35 S 8 • 7H2O <> 1113.65
A tightly closed.AUSP26
l4\3.64AUSP26
• CAS-76578-81-9). (anhydrous C 12 H 14 K 8 O 35 S 8 Add the following:
AC/5P2i A
USP Ramipril Related Compound D RS [ethyl (25)2-
<> CAS-73264-44-5)—Do not dry; determine the water content ti-
trimetrically when used for quantitative analyses. Keep container [(3S,5aS,8aS, 9aS)-3-methyl-1,4-dioxodecahydro-IH-cy-
tightly closed and store in a freezer. Allow to equilibrate to ambient
temperature before opening. clopenta[e]p)m:olo[l,2-a]pyrazin-2-yl]-4-phenyl-butanoate]
Change to read:
USP Procainamide Hydrochloride RS—Dry portion at 105° for (C 23 H 30 N 2 O 4 <> 398.50)—Do not dry. Keep container
4 hours before using. Keep container tightly closed.
tightly closed.AMSM(f
•Material is hygroscopic. B 1
Change to read:
USP Rifabutin RS—Do not dry before using. Keep container
Add the following: tightly closed.
•USP Propofol Resolution Solution RS—[To come.]B1 "Store in a freezer.-,
"Starting with Lot G label as: Do not dry before using. Keep con-
tainer tightly closed. Store in a freezer.-3
Pharmacopeia! Forum

A
USP Scopoletin RS—Do not dry. Store at -20°.AUSP26 •USP 3,3-5,5-TetraisopropyldiphenoI RS—[To
Add the following: come.]B1
A
USP P-Sitosterol RS—Do not dry. Store at room temper- Change to read:
USP Torsemide (Form 1) RS
ature. AUSP26 A
RS—(Form \)AVSP26
Add the following: Do not dry before using. Keep container tightly closed. Protect
A
USP Terazosin Hydrochloride RS—[To come] Use from light. # 3
without drying; correct for moisture, determined by drying Add the following:
A
a separate portion in vacuum at 105° for 3 hours. Keep con- USP Valsartan RS—Do not dxy.AVSP26
tainer tightly closed and protected from light.AUSP26 Add the following:
A
Add the following: USP Valsartan Related Compound A RS [(R) N ([V
A
USP Terazosin Related Compound A RS [l-(4-amino- (l#totrazolo 5 yl)biphcnyl 4 yl]mothyl)valino] [(i?)-A^-va-
6,7-dimethoxy-2-quinazolinyl)piperazine, dihydrochloride] leryl-A^-([2'-(l//-tetrazole-5-yl)biphen-4-yl]methyl)valine]
(C 14 H 19 N 5 O 2 • 2HC1 <> 289.34 362.25) [To oomo.] Do (C24H29N5O3 <> 4^r§3- 435.52)—Do not dry. AUSP26
not dry. Correct for water, determined titrimetrically before Add the following:
A
use. Store with desiccant in a cold place. Keep container USP Valsartan Related Compound B RS [(5)-iV-butyryl-
tightly closed and protected from light. A^-([2'-(l//-tetrazole-5-yl)biphenyl-4-yl]methyl)-valine]

AUSP26
Add the following: (C23H27N5O3 O 421.50 421.49)—Do not dry. AUSP26

A
USP Terazosin Related Compound E B RS [l-(4-hy- Add the following:
A
droxy-6,7-dimethoxy-2-quinazolinyl))-4-[(tetrahydro-2-fur- USP Valsartan Related Compound C RS [(S)-iV-valeryl-
anyl)carbonyl]piperazine] (C 1 9 H 2 4 N 4 O 5 <0> 388.-13 7/-([2'-(l//-tetrazole-5-yl)biphenyl-4-yl]methyl)valine ben-
388.42)— [To como.] Do not dry. Keep container tightly zyl ester] (C 3 1 H 3 5 N 5 O 3 <> 526.65 525.64)—Do not
closed and protected from light.AUSp26

Add the following:
A
USP Terazosin Related Compound F C R S [l,4-bis(4-
amino-6,7-dimethoxy-2-quinazolinyl)piperazine, dihy-
drochloride] (C 24 H 28 N 8 O 4 - 2HC1 <• 492.54 565.45)—fFe
oomo:] Do not dry. Keep container tightly closed and pro-
tected from li
Pharmacopeial Forum
Physical Tests and

Determinations
peak maximum
BRIEFING
Fig. 2. Asymmetrical chromatographic peak.
These tests are performed by collecting data from replicate in-
(621) Chromatography, USP 25 page 1982, page 2758 of the jections of standard or other solutions as specified in the individual
First Supplement, and page 3352 of P F 27(6) [Nov.-Dec. 2001]. It monograph. The specification of definitive parameters in a mono-
is proposed to add to the list of packings in the Chromatographic graph does not preclude the use of other suitable operating condi-
Reagents section of this chapter. Packing L53 is used in the pro- tions (see Procedures under Tests and Assays in the General
posed liquid chromatographic procedure in the tests for Dissolu- Notices). Adjuotmonta of operating conditions to moot ayatom suit
tion, Uniformity of dosage units, and Limit of phosphate and in ability roquiromont3 may bo noooaoary:
the Assay under Alendronate Sodium Tablets, appearing elsewhere
in this number of PF. A
If adjustments of operating conditions to meet system suit-
(PA4: A. Medjedovic) RTS—34280-1 ability requirements are necessary, each of the following is
the maximum specification that can be considered, unless
otherwise directed in the monograph. Adjustments are per-
Change to read: mitted only when Reference Standards suitable standards

(including Reference Standards) are available for all a«a-
lytca compounds used in the suitability test and are used
SYSTEM SUITABILITY
System suitability tests are an integral part of gas and liquid to show that the adjustments have improved the quality of
chromatographic methods. They are used to verify that the resolu-
tion and reproducibility of the chromatographic system are ade- the chromatography in meeting system suitability require-
quate for the analysis to be done. The tests are based on the
concept that the equipment, electronics, analytical operations, ments. Adjustments to chromatographic systems performed
and samples to be analyzed constitute an integral system that can
be evaluated as such. in order to comply with system suitability requirements are
The resolution, R, [NOTE—All terms and symbols are defined in not to be made to compensate for column failure or to cir-
the Glossary of Symbols.] is a function of column efficiency, N, and
is specified to ensure that closely eluting compounds are resolved
from each other, to establish the general resolving power of the sys- cumvent replacing a deteriorated column.
tem, and to ensure that internal standards are resolved from the
drug. Column efficiency may be specified also as a system suitabil- pH of Mobile Phase (HPLC)—The pH of the aqueous
ity requirement, especially if there is only one peak of interest in
the chromatogram; however, it is a less reliable means to ensure buffer used in the preparation of the mobile phase can be
resolution than direct measurement. Column efficiency is a mea-
sure of peak sharpness, which is important for the detection of trace adjusted to within + 0.2 units of the value or range speci-
components.
fied.
Replicate injections of a Standard preparation used in the assay
or other standard solution are compared to ascertain whether re- Concentration of Salts in Buffer (HPLC)—The con-
quirements for precision are met. Unless otherwise specified in
the individual monograph, data from five replicate injections of
the analyte are used to calculate the relative standard deviation, centration of the salts used in the preparation of the aqueous
SR, if the requirement is 2.0% or less; data from six replicate injec-
tions are used if the relative standard deviation requirement is more buffer used in the mobile phase can be adjusted to within
than 2.0%.
+10%, provided the permitted pH variation (see above)
The tailing factor, T, a measure of peak symmetry, is unity for
perfectly symmetrical peaks and its value increases as tailing be- is met.
comes more pronounced (see Fig. 2). In some cases, values less
than unity may be observed. As peak asymmetry increases, integra-
tion, and hence precision, becomes less reliable.
Pharmacopeial Forum
Ratio of Components in Mobile Phase (HPLC) Tho Detector Wavelength of UV-Visible Detector
amount of tho minor The following adjustment limits apply (HPLC)—Deviations from the wavelengths specified in
to minor components of the mobile phase (specified at 50% the method are not permitted. The procedure specified by
or less). The amount(s) of these component(s) can be ad- the detector manufacturer, or another validated procedure,
justed by + 30% relative or + 2 % absolute (i.e., in relation is to be used to verify that error in the detector wavelength
to the total mobile phase), whichever is larger. However, the is, at most, ± 3 nm.
change in any component cannot exceed ± 10% absolute, Column Length (GC, HPLC): can be adjusted by as
nor can the final concentration of any component be reduced much as ± 70%.
to zero. Examples of adjustments for binary and ternary Column Inner Diameter (GC, HPLC): can be adjusted
mixtures are given below. by as much as ± 35% 50%.
Binary Mixtures— Film Thickness (Capillary GC): can be adjusted by as
SPECIFIED RATIO OF 50:50—Thirty percent of 50 is 15% much as -50% to +100%.
absolute, but this exceeds the maximum permitted change of Particle Size (HPLC): can be reduced by as much as
+10% absolute in either component. Therefore, the mobile 50%.
phase ratio may be adjusted only within the range of 40:60 Flow Rate (GC, HPLC): can be adjusted by as much as
to 60:40. ±50%.
SPECIFIED RATIO OF 95:5—Thirty percent of 5 is 1.5% ab- Injection Volume (GC, HPLC): can be reduced as far as
solute. However, because adjustments up to + 2% absolute is consistent with accepted precision and detection limits. It
are allowed, the ratio may be adjusted within the range of may be increased to as much as twice the volume specified,
93:7 to 97:3. provided there are no adverse effects on factors such as
SPECIFIED RATIO OF 2:98—Thirty percent of 2 is 0.6% ab- baseline, peak shapes, resolution, linearity, and retention
solute. In this case an absolute adjustment of + 2% is not times.
allowed because it would reduce the amount of the first Column Temperature (HPLC): can be adjusted by as
component to zero. Therefore the maximum allowed adjust- much as +20°. Column thermostating is recommended to
ment is within the range of 1.4:98.6 to 2.6:97.4. improve control and reproducibility of retention time.
Ternary Mixtures— Column Temperature (GC): can be adjusted by as much
SPECIFIED RATIO OF 60:35:5—For the second component, as + 2%, in terms of absolute temperature.
30% of 35 is 10.5% absolute, which exceeds the maximum Oven Temperature Program (GC)—Adjustment of
permitted change of +10% absolute in any component. temperatures is permitted as stated above. For the times spe-
Therefore the second component may be adjusted only cified for the temperature to be maintained or for the tem-
within the range of 25% to 45% absolute. For the third com- perature to be changed from one to another, an adjustment
ponent, 30% of 5 is 1.5% absolute. Since + 2 % absolute is of up to ± 20% is permitted.A[/5.W(5
permitted and provides more flexibility, the third component Unless otherwise directed in the monograph, system suitability
parameters are determined from the analyte peak.
may be adjusted within the range of 3% to 7% absolute. In To ascertain the effectiveness of the final operating system, it
should be subjected to suitability testing. Replicate injections of
all cases, a sufficient quantity of the first component is used the standard preparation required to demonstrate adequate system
precision may be made before the injection of samples or may be
to give a total of 100%. interspersed among sample injections. System suitability must be
Pharmacopeial Forum
demonstrated throughout the run by injection of an appropriate L17—Strong cation-exchange resin consisting of sulfonated
control preparation at appropriate intervals. The control prepara- cross-linked styrene-divinylbenzene copolymer in the hydrogen
tion can be a standard preparation or a solution containing a known form, 7 to 11 um in diameter.
amount of analyte and any additional materials useful in the control LI 8—Amino and cyano groups chemically bonded to porous
of the analytical system, such as excipients or impurities. When- silica particles, 3 to 10 um in diameter.
ever there is a significant change in equipment or in a critical re- L19—Strong cation-exchange resin consisting of sulfonated
agent, suitability testing should be performed before the injection cross-linked styrene-divinylbenzene copolymer in the calcium
of samples. No sample analysis is acceptable unless the require- form, about 9 um in diameter.
ments of system suitability have been met. Sample analyses ob- L20—Dihydroxypropane groups chemically bonded to porous
tained while the system fails silica particles, 5 to 10 um in diameter.
A L21—A rigid, spherical styrene-divinylbenzene copolymer, 5 to
system suitability AUS . m 10 urn in diameter.
requirements are unacceptable. L22—A cation-exchange resin made of porous polystyrene gel
with sulfonic acid groups, about 10 um in size.
L23—An anion-exchange resin made of porous polymethacry-
Change to read: late or polyacrylate gel with quaternary ammonium groups, about
10 um in size.
L24—A semi-rigid hydrophilic gel consisting of vinyl polymers
with numerous hydroxyl groups on the matrix surface, 32 to 63 um
CHROMATOGRAPHIC REAGENTS in diameter.5
L25—Packing having the capacity to separate compounds with
The following list of packings (L), phases (G), and supports (S) a molecular weight range from 100-5000 (as determined by poly-
is intended to be a convenient reference for the chromatographer. ethylene oxide), applied to neutral, anionic, and cationic water-so-
[NOTE—Particle sizes given in this listing are those generally pro- luble polymers. A polymethacrylate resin base, cross-linked with
vided. Where other, usually finer, sizes are required, the individual polyhydroxylated ether (surface contained some residual carboxyl
monograph specifies the desired particle size. Within any category functional groups) was found suitable.
of packings or phases listed below, there may be a wide range of L26—Butyl silane chemically bonded to totally porous silica
columns available. Where it is necessary to define more specifi- particles, 5 to 10 um in diameter.
cally the chromatographic conditions, the individual monograph L27—Porous silica particles, 30 to 50 um in diameter.
so indicates.] L28—A multifunctional support, which consists of a high pur-
ity, 100 A, spherical silica substrate that has been bonded with an-
ionic exchanger, amine functionality in addition to a conventional
reversed phase C8 functionality.
Packings L29—Gamma alumina, reverse-phase, low carbon percentage
by weight, alumina-based polybutadiene spherical particles, 5
Ll—Octadecyl silane chemically bonded to porous silica or um in diameter with a pore volume of 80 A.
ceramic micro-particles, 3 to 10 um in diameter. L30—Ethyl silane chemically bonded to totally porous silica
L2—Octadecyl silane chemically bonded to silica gel of a con- particles, 3 to 10 urn in diameter.
trolled surface porosity that has been bonded to a solid spherical L31—A strong anion-exchange resin-quaternary amine bonded
core, 30 to 50 um in diameter. on latex particles attached to a core of 8.5-um macroporous parti-
L3—Porous silica particles, 5 to 10 um in diameter. cles having a pore size of 2000 A and consisting of ethylvinylben-
L4—Silica gel of controlled surface porosity bonded to a solid zene cross-linked with 55% divinylbenzene.
spherical core, 30 to 50 um in diameter. L32—A chiral ligand-exchange packing-L-proline copper com-
L5—Alumina of controlled surface porosity bonded to a solid plex covalently bonded to irregularly shaped silica particles, 5 to
spherical core, 30 to 50 um in diameter. 10 um in diameter.
L6—Strong cation-exchange packing-sulfonated fluorocarbon L33—Packing having the capacity to separate proteins by mo-
polymer coated on a solid spherical core, 30 to 50 um in diameter. lecular size over a range of 4,000 to 400,000 Da. It is spherical,
L7—Octylsilane chemically bonded to totally porous silica par- silica-based, and processed to provide pH stability.
ticles, 3 to 10 um in diameter. L34—Strong cation-exchange resin consisting of sulfonated
L8—An essentially monomolecular layer of aminopropylsilane cross-linked styrene-divinylbenzene copolymer in the lead form,
chemically bonded to totally porous silica gel support, 10 um in about 9 um in diameter.
diameter. L35—A zirconium-stabilized spherical silica packing with a hy-
L9—10-um irregular or spherical, totally porous silica gel hav- drophilic (diol-type) molecular monolayer bondedphase having a
ing a chemically bonded, strongly acidic cation-exchange coating. pore size of 150 A.
L10—Nitrile groups chemically bonded to porous silica parti- L36—A 3,5-dinitrobenzoyl derivative of L-phenylglycine cova-
cles, 3 to 10 um in diameter. lently bonded to 5-um aminopropyl silica.
Lll—Phenyl groups chemically bonded to porous silica parti- L3 7—Packing having the capacity to separate proteins by mo-
cles, 5 to 10 um in diameter. lecular size over a range of 2,000 to 40,000 Da. It is a polymetha-
L12—A strong anion-exchange packing made by chemically crylate gel.
bonding a quaternary amine to a solid silica spherical core, 30 to L38—A methacrylate-based size-exclusion packing for water-
50 um in diameter. soluble samples.
L13—Trimethylsilane chemically bonded to porous silica parti- L39—A hydrophilic polyhydroxymethacrylate gel of totally
cles, 3 to 10 um in diameter. porous spherical resin.
L14—Silica gel 10 um in diameter having a chemically bonded, L40—Cellulose tris-3,5-dimethylphenylcarbamate coated por-
strongly basic quaternary ammonium anion-exchange coating. ous silica particles, 5 to 20 um in diameter.
L15—Hexylsilane chemically bonded to totally porous silica L41—Immobilized a j-acid glycoprotein on spherical silica par-
particles, 3 to 10 um in diameter. ticles, 5 um in diameter.
L16—Dimethylsilane chemically bonded to porous silica parti- L42—Octylsilane and octadecylsilane groups chemically
cles, 5 to 10 um in diameter. bonded to porous silica particles, 5 um in diameter.
5
Available as Fractogel TSK-HW-40F and distributed by Merck and Co.
Pharmacopeial Forum
L43—Pentafluorophenyl groups chemically bonded to silica "L53—An anion-exchange resin consisting of a rigid, sphe-
particles, 5 to 10 (xm in diameter.
L44—A multifunctional support, which consists of a high pur- rical styrene-divinylbenzene copolymer with trimethylam-
ity, 60 A, spherical silica substrate that has been bonded with a ca-
tionic exchanger, sulfonic acid functionality in addition to a monium groups at a loading of about 2 mEq per g, 3 to
conventional reversed phase C8 functionality.
L45—Beta cyclodextrin bonded to porous silica particles, 5 to 20 um in diameter. 14 B1
10 urn in diameter.
L46—Polystyrene/divinylbenzene substrate agglomerated with
quaternary amine functionalized latex beads, 10 (am in diameter.
L47—High-capacity anion exchange microporous substrate,
fully functionalized with trimethlyamine groups, 8 um in dia- Phases
meter.6
L48—Sulfonated, cross-linked polystyrene with an outer layer Gl—Dimethylpolysiloxane oil.
of submicron, porous, anion-exchange microbeads, 15 um in dia- G2—Dimethylpolysiloxane gum.
meter. G3—50% Phenyl-50% methylpolysiloxane.
G4—Diethylene glycol succinate polyester.
A G5—3-Cyanopropylpolysiloxane.
L49—Amylose tris-3,5-dimethylphenylcarbamate-coated,
G6—Trifluoropropylmethylpolysiloxane.
porous, spherical, silica particles, 5 to 10 um in diame- G7—50% 3-Cyanopropyl-50% phenylmethylsilicone.
G8—80% Bis(3-cyanopropyl)-20% 3-cyanopropylphenylpoly-
,10 siloxane (percentages refer to molar substitution).
ter •A.USP26
G9—Methylvinylpolysiloxane.
G10—Polyamide formed by reacting a C 36 dicarboxylic acid
A
L50—A strong cation exchange resin made of porous sil- with l,3-di-4-piperidylpropane and piperidine in the respective
mole ratios of 1.00:0.90:0.20.
ica with sulfopropyl groups, 5 to 10 um in diameter.n ALUSP26 Gl 1—Bis(2-ethylhexyl) sebacate polyester.
G12—Phenyldiethanolamine succinate polyester.
G13—Sorbitol.
G14—Polyethylene glycol (av. mol. wt. of 950 to 1050).
"L51—A reversed-phase packing made by coating a thin Gl5—Polyethylene glycol (av. mol. wt. of 3000 to 3700).
G16—Polyethylene glycol compound (av. mol. wt. about
layer of polybutadiene on to spherical porous zirconia par- 15,000). A high molecular weight compound of polyethylene gly-
col with a diepoxide linker. Available commercially as Polyethy-
ticles, 3 to 10 um in diameter. 12 B2 lene Glycol Compound 20M, or as Carbowax 20M, from suppliers
of chromatographic reagents.
G17—75% Phenyl-25% methylpolysiloxane.
G18—Polyalkylene glycol.
•L52—Multifunction resin with reversed-phase retention G19—25% Phenyl-25% cyanopropyl-50% methylsilicone.
G20—Polyethylene glycol (av. mol. wt. of 380 to 420).
and strong anion-exchange functionalities. The resin con- G21—Neopentyl glycol succinate.
G22—Bis(2-ethylhexyl) phthalate.
sists of ethylvinylbenzene, 55% cross-linked with divinyl- G23—Polyethylene glycol adipate.
G24—Diisodecyl phthalate.
benzene copolymer, 3 to 15 um in diameter, and a surface G25—Polyethylene glycol compound TPA. A high molecular
weight compound of a polyethylene glycol and a diepoxide that
area not less than 350 m2 per g. Substrate is coated with qua- is esterified with terephthalic acid. Available commercially as Car-
bowax 20M-TPA from suppliers of chromatographic reagents.
ternary ammonium functionalized latex particles consisting G26—25% 2-Cyanoethyl-75% methylpolysiloxane.
G27—5% Phenyl-95% methylpolysiloxane.
of styrene cross-linked with divinylbenzene.1312 G28—25% Phenyl-75% methylpolysiloxane.
G29—3,3'-Thiodipropionitrile.
G30—Tetraethylene glycol dimethyl ether.
G31—Nonylphenoxypoly(ethyleneoxy)ethanol (av. ethyl-
eneoxy chain length is 30); Nonoxynol 30.
G32—20% Phenylmethyl-80% dimethylpolysiloxane.
G33—20% Carborane-80% methylsilicone.
G34—Diethylene glycol succinate polyester stabilized with
phosphoric acid.
G35—A high molecular weight compound of a polyethylene
glycol and a diepoxide that is esterified with nitroterephthalic acid.
Available as CarboPac MAI and distributed by Dionex Corporation. G36—1% Vinyl-5% phenylmethylpolysiloxane.
10
Available as Chiralpak AD from Chiral Technologies, Inc., 730 Spring- G37—Polyimide.
dale Drive, P. O. Box 564, Exton, PA 19341. G38—Phase Gl containing a small percentage of a tailing inhib-
" Available as TSK IC SW Cation from TosoHaas. itor.6
12 G39—Polyethylene glycol (av. mol. wt. about 1500).
Available as Zirchrom PBD, manufactured by ZirChrom Separations, G40—Ethylene glycol adipate.
Inc., distributed by Alltech, www.Alltechweb.com. G41—Phenylmethyldimethylsilicone (10% phenyl-substituted).
13
Available as OmniPac PAX-500 and distributed by Dionex Corporation.
14 6
Available as PRP-X100 from Hamilton Company (www.hamiltoncom- A suitable grade is available commercially as "SP2100/0.1% Carbowax
pany.com). 1500" from Supelco, Inc., Supelco Park, Bellefonte, PA 16823.
Pharmacopeial Forum
G42—35% phenyl-65% dimethylpolysiloxane (percentages re-

fer to molar substitution). BRIEFING
G43—6% cyanopropylphenyl-94% dimethylpolysiloxane (per-
centages refer to molar substitution). (776) Optical Microscopy, USP 25 page 2040 and page 229 of
G44—2% low molecular weight petrolatum hydrocarbon grease PF26(1) [Jan.-Feb. 2000]. The proposed revision in the introduc-
and 1 % solution of potassium hydroxide. tion of the general test chapter is intended to clarify the role of
G45—Divinylbenzene-ethylene glycol-dimethylacrylate. sieve analysis in particle size analysis. Sieve analysis is not neces-
G46—"14% Cyanopropylphenyl-86% methylpolysiloxane.B1 sarily considered the preferred method of analysis of particles in
G47—Polyethylene glycol (av. mol. wt. of about 8000). excess of 75 um. Instrumental methods, e.g., electrozone sensing
G48—Highly polar, partially cross-linked cyanopolysiloxane. and laser diffraction, have reportedly supplanted sieve analysis to a
large extent. The proposed new section, Limit Test of Particle Size
by Microscopy, is based primarily on the corresponding test 2.9.13
in the European Pharmacopoeia but with an added statement pro-
Supports viding guidance for the preparation of a homogeneous test sample
suspension. The degree of accuracy for the measurement of the
suspension medium has been modified to a more realistic value.
NOTE—Unless otherwise specified, mesh sizes of 80 to 100 or, In the section, Number of Particles to Characterize, the reference
alternatively, 100 to 120 are intended. to ASTM E20-85 is deleted as it is no longer in publication.
S1A—Siliceous earth for gas chromatography has been flux-cal-
cined by mixing diatomite with Na2CO3 flux and calcining above
900°. The siliceous earth is acid-washed, then water-washed until (ETM: J. Lane) RTS—36557-1; 36991-04
neutral, but not base-washed. The siliceous earth may be silanized
by treating with an agent such as dimethyldichlorosilane7 to mask
surface silanol groups.
S1AB—The siliceous earth as described above is both acid- and Change to read:
base-washed.7 Optical microscopy for particle characterization can generally be
SIC—A support prepared from crushed firebrick and calcined applied to particles in the size range between 0.5 and 100 um. The
or burned with a clay binder above 900° with subsequent acid- lower limit is imposed by the resolving power of the microscope.
wash. It may be silanized. The characterization of smaller particles can often be accomplished
by means of electron optical imaging techniques such as those de-
SINS—The siliceous earth is untreated. scribed under Scanning Electron Microscopy (1181) where practi-
S2—Styrene-divinylbenzene copolymer having a nominal sur- cal image resolution approaches 0.01 urn. The upper limit is less
face area of less than 50 m2 per g and an average pore diameter definite and is determined by the increased difficulty associated
of 0.3 to 0.4 um. with the characterization of larger particles, compared with siovo
S3—Copolymer of ethylvinylbenzene and divinylbenzene hav- analyaia. For partiolos in 0x0033 of 75 urn, the proforrod method
ing a nominal surface area of 500 to 600 m2 per g and an average of particle- size- analysis is by uso of siovo analyoio.
pore diameter of 0.0075 um.
S4—Styrene-divinylbenzene copolymer with aromatic -O and "Particle size distribution by use of analytical sieving (see
—N groups, having a nominal surface area of 400 to 600 m2 per g
and an average pore diameter of 0.0076 um. Particle Size Distribution Estimation by Analytical Sieving
S5—40- to 60-mesh, high-molecular weight tetrafluorethylene
polymer. (786)) may be performed where the majority of the particles
S6—Styrene-divinylbenzene copolymer having a nominal sur-
face area of 250 to 350 m2 per g and an average pore diameter are larger than about 75 um, although it can be used for
of 0.0091 um.
S7—Graphitized carbon having a nominal surface area of 12 m2 some powders having smaller particle sizes where the meth-
perg.
S8—Copolymer of 4-vinyl-pyridine and styrene-divinylben- od can be validated. H1
zene. Often stereo-microscopy can be a useful aid with larger particles,
S9—A porous polymer based on 2,6-diphenyl-p-phenylene yet it is not as definitive. Optical microscopy is particularly useful
oxide. for characterizing particles that are not spherical. This method may
S10—A highly polar cross-linked copolymer of acrylonitrite also serve as a base for the calibration of faster and more routine
and divinylbenzene. methods that may be developed.
Sll—Graphitized carbon having a nominal surface area of 100
m2 per g modified with small amounts of petrolatum and polyethy-
lene glycol compound.8 Add the following:
S12—Graphitized carbon having a nominal surface area of 100
m2 per g. •Limit Test of Particle Size by Microscopy—Unless
otherwise specified in the individual monograph, use the
following method. Weigh a suitable quantity of the powder
to be examined (for example, 10 to 100 mg), and suspend it
in 4&Q 10 mL of a suitable medium in which the powder
does not dissolve, adding, if necessary, a wetting agent. A
7
Unless otherwise specified in the individual monograph, silanized support
is intended. homogeneous suspension of particles can be achieved by
8
Commercially available as SP1500 on Carbopack B from Supelco.
Pharmacopeial Forum
matching the density of the medium and the particles, and

by providing adequate agitation. Introduce a portion of the Xa2 » r +1-96 + Win - 3
homogeneous suspension into a suitable counting cell, and
and
scan under a microscope an area corresponding to not less
than 10 (ig of the powder to be examined. Count all the par-
ticles having a maximum dimension greater than the pre-
scribed size limit. The size limit and the permitted number
of particles exceeding the limit are stated in the mono- In general, a larger sample must be acquired to obtain a good
estimate of the standard deviation or distribution of the population.
graph.. , For the example population described above, if the mean particle
diameter was 50 urn, only 61 particles would have to be measured
to obtain an uncertainty of 10% in the diameter (e.g., d — 50 + 5
Change to read: urn), but about 200 particles would have to be measured to obtain a
Number of Particles to Characterize—The number of particles similar confidence of +10% in the standard deviation (e.g., 18.3 <
characterized must be sufficient to ensure an acceptable level of s < 22.3).
uncertainty in the measured parameter. Successively higher magni- For a material that conforms more closely to a log normal dis-
fication may be necessary to ensure proper dispersion of the speci- tribution, the logarithm of the individual particle diameters can be
men. An estimate of the number of particles, n, to be measured that computed, and the mean and the standard deviation of the log par-
will provide an acceptable level of uncertainty in the mean particle ticle diameter directly substituted in the above equations. The anti-
diameter can be obtained from the statistical theory of normal po- logs correspond to the geometric mean and geometric standard de-
pulations. For a sufficiently large population (n > 30), the uncer- viation, respectively. Additional information on partiolo size moa
tainty in the estimate for the mean particle diameter, d, is given in 3uromont, sample size, and data analysis is available, for example-,
the formula: in ASTM E20 85.
d±zc
WnF
in which zc corresponds to the desired confidence coefficient and s

REAGENTS, INDICATORS,
is the standard deviation of the test specimen. For n > 30, zc is about
1.96 at the 95% confidence level. Other confidence coefficients can
be obtained from reference books on statistics, and, if necessary,
AND SOLUTIONS
small population statistics can be similarly applied. From this equa-
tion, it can be seen that the uncertainty in the measured diameter
decreases as the number of particles increases. As an example, to
obtain an uncertainty of + 5 um in a specimen that has a standard
deviation of 20 um would require that 61 particles be accurately
measured.
An estimate of the uncertainty in the standard deviation of a spe-
cimen can be obtained in a similar fashion. The standard deviation
Reagent Specifications
of the population, S, is estimated to lie in the interval:
< a < A—
U2 BRIEFING
dl-10-Camphorsulfonic Acid, USP 25 page 2290.

where s is the standard deviation of the specimen, and Xa a °d Xb
are the confidence coefficients obtained from the x2 distribution, x
2 2 can
a and Xb be obtained from standard statistics references or
approximated by the following expressions at the 95% confidence Erratum:
level where Xa a n ^ Xb represent the 97.5 and 2.5 percentile va-
lues, respectively: Melting range, line 1: Change "decomposes about 199°" to: de-
composes at about 199°
Pharmacopeial Forum
Add the following:

BRIEFING •Dicyclohexyl, C12H22—166.3 [92-51-3]—Use a suitable
Cesium Chloride. This new reagent is used to prepare the Ce- grade..!
sium chloride solution in the tests for Limit of calcium, Limit of
aluminum, and Content of magnesium under Talc, which appears
elsewhere in this number of PF. It is also used to prepare the Ce-
sium chloride solution in the test for Content of gadolinium under
Gadopentetate Dimeglumine Injection.
BRIEFING
l,2-Dilinoleoyl-3-oleoyl-rac-glycerol. Because of the difficul-
ties experienced in obtaining the current System suitability solution
triglyceride, OOL (l,2-dioleoyl-3-linoleoyl-rac-glycerol), required
Add the following: under Chromatographic system for Sesame Oil, it is proposed to
use the alternative triglyceride, OLL (l,2-dilinoleoyl-3-oleoyl-
•Cesium Chloride, CsCl—168.36 [7647-17-8]—A white rac-glycerol), in its place.
powder. Very soluble in water; freely soluble in methanol;
practically insoluble in acetone. Use a suitable grade.ml
Add the following:

•l,2-Dilinoleoyl-3-oleoyl-rac-glycerol, C57H100O6-
BRIEFING 881.4 [2190-21-8]—Use a suitable grade. 1 0 4 m
Cyclohexylmethanol, page 7582 of PF 25(1 )[Jan.-Feb. 1999].

This reagent is used as a specified component of the Related com-
pounds test for Benzyl Alcohol, appearing elsewhere in this PF.
(HDQ: M. Marques) RTS—36744-1 BRIEFING
l,2-Dilinoleoyl-3-palmitoyl-rac-glycerol. Because of the diffi-

culties experienced in obtaining the current System suitability solu-
Add the following: tion trygliceride, POL (l-palmitoyl-2-oleoyl-3-linoleoyl-rac-
glycerol), required under Chromatographic system for Sesame
•Cyclohexylmethanol, C7H14O—114.2 [100-49-2]—Use a Oil, it is proposed to use the alternative triglyceride, PLL (1,2-di-
linoleoyl-3-palmitoyl-rac-glycerol), in its place.
suitable grade.B1
Add the following:

BRIEFING
•l,2-Dilinoleoyl-3-palmitoyl-rac-glycerol, C55H98O6-
Dicyclohexyl, page 7582 of P F 25(1) [Jan.-Feb. 1999]. This
reagent is used as a specified component of the Related compounds 855.4 [2190-15-0]—Use a suitable grade. 104 B1
test for Benzyl Alcohol, appearing elsewhere in this PF.
BRIEFING
l,2-Dioleoyl-3-linoleoyl-rac-glycerol, USP 25 page 2300. This

reagent is being deleted and replaced with OLL (l,2-dilinoleoyl-3-
oleoyl-rac-glycerol) because of the difficulties experienced in ob-
Pharmacopeial Forum
taining the current System suitability solution tryglyceride, OOL Add the following:
(l,2-dioleoyl-3-linoleoyl-rac-glycerol), required under Chromato-
graphic system for Sesame Oil. "Glucose, C6H12O6—180.2—Use a suitable grade. A
(HDQ: M. Marques) RTS—36677-4 white crystalline powder, with a sweet taste. Freely soluble
in water; sparingly soluble in alcohol.B1

"1,2 Dioleoyl 3 linoleoyl rac glyecrol, ^ t t m ^ — $ $ 9 A
[65390 75 2]—Cloar, very faintly yellow oiT Uao a ouitablo
gruel o.^ j BRIEFING
Hexamethylenetetramine. This new reagent is used as a spe-

cified component of Clarity of solution in the monographs for Ci-
tric Acid, Anhydrous and Citric Acid, Monohydrate, which appear
in the Harmonization section of this PF.
BRIEFING
Ethylbenzene, page 7582 of PF 25(1) [Jan.-Feb. 1999]. This
reagent is used as a specified component of the Related compounds
test for Benzyl Alcohol, appearing elsewhere in this PF.
Add the following:
•Hexamethylenetetramine, C6H12N4—140.2 [100-97-
0]—Use a suitable grade. A colorless, crystalline powder.
Add the following:
Very soluble in water., j
•Ethylbenzene, C8H10—106.2 [100-41-4]—Use a suitable
grade. m
BRIEFING
Hydroxy Naphthol Blue, page 3366 of P F 27(6) [Nov.-Dec.

BRIEFING 2001]. It is proposed to add the percentage of concentration of this
compound in the mixture with sodium chloride.
Glucose. This new reagent is used as a specified component of
Total protein in the monograph for Wheat Starch, which appears in (HDQ: M. Marques) RTS—36138-1
the Harmonization section of this PF.

Add the following:
"Hydroxy Naphthol Blue {l-(2-Naphtholazo-3,6-disul-

fonic Acid)-2-naphthol-4-sulfonic acid, disodium salt),
C20H12N2O11S3Na2— 598.50—Deposited on crystals of so-
dium chloridein the concentration of about l%.Use ACS re-
agent grade. B1
Pharmacopeia! Forum
Ninhydrin—Soc Trikotohydrindcno Hydrato:

• C9H4O3 H2O—178.14—Use ACS reagent grade. B1
BRIEFING
Lanthanum Oxide. This new reagent is used to prepare the

Lanthanum chloride solution in the tests for Limit of calcium
and Content of magnesium under the Talc monograph previewed
in this number of PF.
BRIEFING
Nitric Acid, Lead-Free. This new reagent is used to prepare the
Test stock solution in the tests for Limit of calcium, Limit of alumi-
num, and Content of magnesium under the Talc monograph pre-
Add the following: viewed in this number of PF. It is also used to prepare the
Diluent in the Limit of lead test for Bismuth Subcarbonate (USP
•Lanthanum Oxide, La2O3—325.82 [7572-57-5]—An al- monograph).
most white, amorphous powder, practically insoluble in
water. It dissolves in dilute solutions of mineral acids and
absorbs atmospheric carbon dioxide. Use Atomic Absorp-

Add the following:
tion Spectroscopy grade.ml
•Nitric Acid, Lead-Free—Use ACS reagent grade.
Lead—To 100 g add 0.1 g of anhydrous sodium car-
bonate and evaporate to dryness. Dissolve the residue in
BRIEFING water, heating slightly, and dilute to 50.0 mL with the same
Monoethanolamine, USP 25 page 2313. solvent. Determine the lead content by atomic absorption
spectrophotometry (see Spectrophotometry and Light-Scat-
tering (851)) measuring the absorbance at 283.3 nm or
217.0 nm using a lead hollow-cathode lamp and an air-acet-
Erratum:
Assay, line 3: Change "a mixed indicator of bromocresol green ylene flame. It contains not more than 0.1 ppm of
TS and methyl red TS (5 in 6)" to: a mixed indicator of 5 parts
bromocresol green TS and 6 parts methyl red TS for a total of lead (Pb). m
approximately 11 parts of solution
BRIEFING
BRIEFING
l-Palmitoyl-2-oleoyI-3-linoleoyl-rac-glycerol, USP 25 page
Ninhydrin, USP 25 page 2314. It is proposed to update the in- 2315. This reagent is being deleted and replaced with PLL (1,2-di-
formation regarding this reagent to harmonize with the correspond- linoleoyl-3-palmitoyl-rac-glycerol) because of the difficulties ex-
ing monograph in the ACS Reagent Chemicals Specifications, 9lh perienced in obtaining the current System suitability solution
ed. Ninhydrin will replace its synonym triketohydrindene hydrate triglyceride, POL (l-palmitoyl-2-oleoyl-3-rac-glycerol), required
throughout all of USP-NF. Other affected reagents are Ninhydrin under Chromatographic system for Sesame Oil.
TS, Triketohydrindene Hydrate, and Triketohydrindene Hydrate
TS, appearing elsewhere in this PF. See also briefing under Baci- (HDQ: M. Marques) RTS—36677-5
tracin.
(HDQ: M. Marques) RTS—36575
Pharmacopeial Forum

"l Palmitoyl 2 olcoyl 3 linoleoyl-rae glyecrol, G^H™O,—
857.4 [15S7 93 5]—Clear, oolorlooa liquid. Use a suitabl BRIEFING
Triketohydrindene Hydrate TS, USP 25 page 2348. It is pro-

posed to delete this entry. See briefings under Bacitracin and Nin-
hydrin.
(HDQ: M. Marques) RTS—36575

BRIEFING
Triketohydrindene Hydrate, USP 25 page 2335. It is proposed Delete the following:

to delete this entry. See briefings under Bacitracin and Ninhydrin.
"Triketohydrindene Hydrate TS (Ninydrin TS)—Diaoolvo 200
(HDQ: M. Marques) RTS—36575 mg of trikotohydrindono hydrate in wator to mako 10 mL. Prepare
thio oolution froah.-.

"Triketohydrindene Hydrate {Ninydnn), CÛ^-^
178*14—Whito to brownish white oryotalo or eryotallino powder. REFERENCE TABLES
Soluble in water and in aloohol; slightly soluble in ether and in
chloroform. When heated above 100°, it becomes rod. Store it pro-
tooted from light.
Melting mngc (?4ty—between 210° and 215°, with dooom

position, determined in a bath preheated at 220°.
Residue on ignition (Reagent toot):—negligible, from 100 mg.
Sensitiveness—Prepare a solution of 10 mg of aminoaootio BRIEFING
aoid in 25 mL of water. To 1 mL of thio oolution add a solution
of 50 mg of sodiumaootate in 2 mL of wator, then add 0.2 mL
of a solution of 5 mg of trikotohydrindono hydrate in 1 mL of Container Specifications for Capsules and Tablets, USP 25 page
wator, and boil tho mixture for 1 to 2 minutes: a violet color is pro 2357, page 2798 of the First Supplement, page 836 of PF 26(3)
dueod, and it booomoo intense on standing for a few minutes: B l [May-June 2000], page 1133 of P F 26(4) [July-Aug. 2000], page
1383 ofPF26(5) [Sept.-Oct. 2000], page 1906 ofPF27(l) [Jan.-
Feb. 2001], page 2280 of PF 21 {2) [Mar.-Apr. 2001], page 2597 of
PF 27(3) [May-June 2001], page 2838 of P F 27(4) [July-Aug.
2001], page 3118 of P F 27(5) [Sept.-Oct. 2001], page 3374 of
Test Solutions PF 27(6) [Nov.-Dec. 2001], and page 115 of PF 28(1) [Jan.-
Feb. 2002].
(HDQ) RTS—30418-1; 33295-3; 33448-7; 34883-1
BRIEFING
The following table is provided as a reminder for the pharmacist
Ninhydrin TS, USP 25 page 2346. It is proposed to add the in- engaged in the typical dispensing situation who already is ac-
structions to prepare this test solution. See briefings under Bacitra- quainted with the Packaging and storage requirements set forth
cin and Ninhydrin. in the individual monographs. It lists the capsules and tablets that
are official in the United States Pharmacopeia and indicates the re-
levant tight (T), well-closed (W), and light-resistant (LR) specifi-
(HDQ: M. Marques) RTS—36575 cations applicable to containers in which the drug that is
repackaged should be dispensed.
This table is not intended to replace, nor should it be interpreted
as replacing, the definitive requirements stated in the individual
Change to read: monographs.
Ninhydrin TS Uoo Trikotohydrindono Hydrato TS.
•Dissolve 200 mg of ninhydrin in water to make 10 mL.
Prepare this solution fresh.ml
© 2002 The United States Pharmacopeial Convention, Inc. Alt Rights Reserved
Pharmacopeial Forum
[Sept.-Oct. 1995], page 4533 of P F 23(4) [July-Aug 1997], page

4874 of PF 23(5) [Sept.-Oct. 1997], page 5310 of PF 23(6) [Nov.-
Container Specifications for Capsules and Tablets Dec. 1997], page 7017 of P F 24(5) [Sept.-Oct. 1998], page 7930
of PF 25(2) [Mar.-Apr. 1999], page 8282 of P F 25(3) [May-June
Container 1999], page 8589 of PF25(4) [July-Aug. 1999], page 8917 of PF
Monograph Title Specification 25(5) [Sept-Oct 1999], page 9254 of PF 25(6) [Nov.-Dec. 1999],
page 250 of PF 26(1) [Jan.-Feb. 2000], page 504 of PF 26(2)
[Mar.-Apr. 2000], page 837 of PF 26(3) [May-June 2000], page
Add the following: 1135 of PF26(4) [July-Aug. 2000], page 1385 of PF26(5) [Sept-
"Cyanocobalamin Co 58 Capsules W, LRB1 Oct. 2000], page 1623 of P F 26(6) [Nov.-Dec. 2000], page 1907
of PF 27(1) [Jan.-Feb. 2001], page 2281 of PF 27(2) [Mar.-Apr.
Add the following: 2001], page 2601 of PF 27(3) [May-June 2001], page 2839 of P F
"Fluoxetine Tablets TBl 27(4) [July-Aug. 2001], page 3120 ofPF27(5) [Sept-Oct. 2001],
page 3374 of P F 27(6) [Nov.-Dec. 2001], page 116 of PF 28(1)
Add the following: [Jan.-Feb. 2002], and page 554 of P F 28(2) [Mar.-Apr. 2002].
•Glucosamine Tablets T, LR B 1
Add the following: (HDQ) RTS—24017-1; 30743-1; 31970-1; 32474-1; 35018-

1; 36456-1; 36456-2; 36496-1; 36496-3; 36496-4; 36525-2;
•Glucosamine and Chondroitin Sulfate 36797-1
T, LR B l
Tablets
Add the following: WB1
•oc-Lipoic Acid Capsules Change to read:
Metoprolol Succinate: White to off-white powder. Freely solu-
Add the following: ble in water; and in propylono glyool; slightly soluble; in aloohol
WB1
"a-Lipoic Acid Tablets and in aalino TS.
Add the following: •soluble in methanol; sparingly soluble in alcohol; slightly
"Norgestimate and Ethinyl Estradiol
soluble in isopropyl alcohol. B1
WB1
Tablets
Add the following:
Add the following: T, LR_, "Tapioca Starch: Irregular, angular, white to pale yellow
•Red Clover Tablets
masses or fine powder. Insoluble in cold water and in alco-
hol. NF category: Suspending and/or viscosity-increasing
agent; tablet binder; tablet and/or capsule diluent; tablet dis-
BRIEFING
integrant.B1
USP25 page 2363, page 3037 of PF 18(2) [Mar.-Apr. 1992], page
6597 of P F 19(6) [Nov.-Dec. 1993], page 1250 of P F 21(5)
Pharmacopeial Forum
Items from Earlier Numbers of PF that Have Not Yet Acetic Acid Irrigation—See PF Vol. 27, No. 3, page 2501.
Appeared in a Supplement, and are Therefore Candidates Acetic Acid Otic Solution—See PF Vol. 27, No. 3, page 2501.
for Subsequent Supplements. Acetohexamide—See PF Vol. 27, No. 3, page 2501.
Acetohexamide Tablets—See PF Vol. 27, No. 3, page 2501.
Acetylcholine Chloride—See PF Vol. 27, No. 3, page 2502.
GENERAL NOTICES AND REQUIREMENTS Acetylcholine Chloride for Ophthalmic Solution—See PF Vol. 27,
"Official" and "Official Articles"—See PF Vol. 28, No. 2, page No. 3, page 2502.
240. Acetylcysteine—See PF Vol. 27, No. 3, page 2503.
Preservation, Packaging, Storage, and Labeling—See PF Vol. 28, Acetylcysteine Solution—See PF Vol. 27, No. 3, page 2503.
No. 2, page 242. Acetylcysteine and Isoproterenol Hydrochloride Inhalation Solu-
tion—See PF Vol. 27, No. 3, page 2503.
USP MONOGRAPHS Acyclovir—See PF Vol. 27, No. 3, page 2503.
Acyclovir Capsules—See PF Vol. 27, No. 3, page 2503.
Acebutolol Hydrochloride—See PF Vol. 27, No. 3, page 2493. Acyclovir for Injection—See PF Vol. 27, No. 3, page 2503.
Acebutolol Hydrochloride Capsules—See PF Vol. 28, No. 1, page Acyclovir Ointment—See PF Vol. 27, No. 3, page 2504.
Acepromazine Maleate—See PF Vol. 27, No. 3, page 2493. Acyclovir Tablets—See PF Vol. 27, No. 3, page 2504.
Acepromazine Maleate Injection—See PF Vol. 27, No. 3, page Adenine—See PF Vol. 27, No. 3, page 2504.
2494. Adenosine—See PF Vol. 27, No. 3, page 2504.
Acepromazine Maleate Tablets—See PF Vol. 27, No. 3, page 2494. Adenosine Injection—See PF Vol. 27, No. 3, page 2504.
Acetaminophen—See PF Vol. 27, No. 3, page 2494. Alanine—See PF Vol. 27, No. 5, page 2973.
Acetaminophen Capsules—See PF Vol. 27, No. 3, page 2494. Albendazole—See PF Vol. 27, No. 3, page2505.
Acetaminophen for Effervescent Oral Solution—See PF Vol. 27, Albendazole Oral Suspension—See PF Vol. 27, No. 3, page 2505.
No. 3, page 2495. Albendazole Tablets—See PF Vol. 27, No. 3, page 2505.
Acetaminophen Oral Solution—See PF Vol. 27, No. 3, page 2494. Albumin Encapsulated Octafluoropropane Microspheres for Injec-
Acetaminophen Oral Suspension—See PF Vol. 27, No. 3, page tion—See PF Vol. 27, No. 4, page 2688.
2495. Albuterol—See PF Vol. 27, No. 3, page 2505.
Acetaminophen Suppositories—See PF Vol. 27, No. 3, page 2495. Albuterol Sulfate—See PF Vol. 27, No. 3, page 2506.
Acetaminophen Tablets—See PF Vol. 27, No. 3, page 2495. Albuterol Tablets—See PF Vol. 27, No. 3, page 2506.
Acetaminophen and Aspirin Tablets—See PF Vol. 27, No. 3, page Alclometasone Dipropionate—See PF Vol. 27, No. 3, page 2506.
2495. Alclometasone Dipropionate Cream—See PF Vol. 27, No. 3, page
Acetaminophen, Aspirin, and Caffeine Tablets—See PF Vol. 27, 2507.
No. 3, page 2495. Alclometasone Dipropionate Ointment—See PF Vol. 27, No. 3,
Acetaminophen and Caffeine Tablets—See PF Vol. 27, No. 3, page page 2507.
2496. Alcohol—See PF Vol. 27, No. 3, page 2507.
Capsules Containing at Least Three of the Following—Acetamino- Dehydrated Alcohol—See PF Vol. 27, No. 3, page 2507.
phen and Salts of Chlorpheniramine, Dextromethorphan, and Dehydrated Alcohol Injection—See PF Vol. 27, No. 3, page 2507.
Pseudoephedrine—See PF Vol. 27, No. 3, page 2496. Rubbing Alcohol—See PF Vol. 27, No. 3, page 2507.
Oral Powder Containing at Least Three of the Following—Aceta- Alcohol in Dextrose Injection—See PF Vol. 27, No. 3, page 2508.
minophen and Salts of Chlorpheniramine, Dextromethor- Alendronate Sodium—See PF Vol. 27, No. 4, page 2688.
phan, and Pseudoephedrine—See PF Vol. 27, No. 3, page Alendronate Sodium Tablets—See PF Vol. 28, No: 1, page 33.
2496. Alfentanil Hydrochloride—See PF Vol. 28, No. 2, page 244.
Oral Solution Containing at Least Three of the Following—Acet- Alfentanil Injection—See PF Vol. 27, No. 3, page 2508.
aminophen and Salts of Chlorpheniramine, Dextromethor- Allantoin—See PF Vol. 27, No. 5, page 2973.
phan, and Pseudoephedrine—See PF Vol. 27, No. 6, page Allopurinol Tablets—See PF Vol. 27, No. 3, page 2508.
3241. Allyl Isothiocyanate—See PF Vol. 27, No. 3, page 2509.
Tablets Containing at Least Three of the Following—Acetamino- Alprazolam— See PF Vol. 27, No. 3, page 2509.
phen and Salts of Chlorpheniramine, Dextromethorphan, and Alprazolam Tablets—See PF Vol. 27, No. 3, page 2509.
Pseudoephedrine—See PF Vol. 27, No. 3, page 2496. Alprostadil—See PF Vol. 28, No. 2, page 245.
Acetaminophen and Codeine Phosphate Capsules—See PF Vol. Altretamine—See PF Vol. 27, No. 3, page 2514.
27, No. 3, page 2496. Altretamine Capsules—See PF Vol. 27, No. 3, page 2514.
Acetaminophen and Codeine Phosphate Oral Solution—See PF Potassium Alum—See PF Vol. 27, No. 3, page 2515.
Acetaminophen and Codeine Phosphate Oral Suspension—See PF page 2515.
Vol. 27, No. 3, page 2497. Alumina and Magnesia Tablets—See PF Vol. 27, No. 3, page
Acetaminophen and Codeine Phosphate Tablets—See PF Vol. 27, 2515.
No. 5, page 2973. Alumina, Magnesia, and Calcium Carbonate Oral Suspension—
Acetaminophen, Dextromethorphan Hydrobromide, Doxylamine See PF Vol. 27, No. 6, page 3241.
Succinate, and Pseudoephedrine Hydrochloride Oral Solu- Alumina, Magnesia, and Calcium Carbonate Tablets—See PF Vol.
tion—See PF Vol. 27, No. 3, page 2499. 27, No. 3, page 2515.
Acetaminophen and Diphenhydramine Citrate Tablets—See PF Alumina, Magnesia, Calcium Carbonate, and Simethicone Ta-
Vol. 27, No. 3, page 2499. blets—See PF Vol. 27, No. 6, page 3241.
Acetaminophen, Diphenhydramine Hydrochloride, and Pseudo- Alumina and Magnesium Carbonate Oral Suspension—See PF
ephedrine Hydrochloride Tablets—See PF Vol. 27, No. 3, Vol. 27, No. 6, page 3242.
page 2499. Aluminum Phosphate Gel—See PF Vol. 27, No. 6, page 3242.
Acetaminophen and Pseudoephedrine Hydrochloride Tablets— Amantadine Hydrochloride Oral Solution—See PF Vol. 28, No. 2,
See PF Vol. 27, No. 3, page 2500. page 250.
Acetazolamide—See PF Vol. 27, No. 3, page 2500. Amantadine Hydrochloride Syrup—See PF Vol. 28, No. 2, page
Acetazolamide for Injection—See PF Vol. 27, No. 3, page 2500. 251.
Acetazolamide Tablets—See PF Vol. 27, No. 3, page 2501. Amiloxate—See PF Vol. 27, No. 5, page 2975.
Glacial Acetic Acid—See PF Vol. 27, No. 3, page 2501.
Pharmacopeial Forum
Aminocaproic Acid Oral Solution—See PF Vol. 28, No. 2, page Brompheniramine Maleate and Pseudoephedrine Sulfate Oral So-
251. lution—See PF Vol. 28, No. 2, page 256.
Aminocaproic Acid Syrup—See PF Vol. 28, No. 2, page 252. Brompheniramine Maleate and Pseudoephedrine Sulfate Syrup—
7-Aminodesacetoxycephalosporanic Acid—See PF Vol. 26, No. 6, See PF Vol. 28, No. 2, page 258.
page 1534. Bromodiphenhydramine Hydrochloride and Codeine Phosphate
6-Aminopenicillanic Acid—See PF Vol. 27, No. 1, page 1745. Syrup—See PF Vol. 27, No. 5, page 2980.
Aminopentamide Sulfate—See PF Vol. 27, No. 1, page 1748. Bromodiphenhydramine Maleate Elixir—See PF Vol. 28, No. 2,
1748. Bumetanide—See PF Vol. 27, No. 5, page 2982.
Aminopentamide Sulfate Tablets—See PF Vol. 27, No. 1, page Bupropion Hydrochloride—See PF Vol. 27, No. 4, page 2708.
1748. Bupropion Hydrochloride Tablets—See PF Vol. 27, No. 3, page
Aminophylline Rectal Solution—See PF Vol. 27, No. 1, page 2521.
1748. Bupropion Hydrochloride Extended-Release Tablets—See PF Vol.
Aminophylline Tablets—See PF Vol. 27, No. 4, page 2701. 27, No. 5, page 2982.
Ferric Ammonium Citrate—See PF Vol. 27, No. 2, page 2117. Butabarbital Sodium—See PF Vol. 27, No. 6, page 3253.
Ferric Ammonium Citrate for Oral Solution—See PF Vol. 27, No. Butabarbital Sodium Elixir—See PF Vol. 28, No. 2, page 259.
2, page 2118. Butabarbital Sodium Oral Solution—See PF Vol. 28, No. 2, page
Amoxicillin Capsules—See PF Vol. 28, No. 1, page 36. 259.
Amoxicillin Tablets—See PF Vol. 28, No. 1, page 36. Calcium Acetate—See PF Vol. 27, No. 6, page 3254.
Amoxicillin for Oral Suspension—See PF Vol. 27, No. 6, page Calcium Acetate Tablets—See PF Vol. 27, No. 6, page 3254.
3243. Calcium Ascorbate—See PF Vol. 27, No. 6, page 3255.
Amphetamine Sulfate—See PF Vol. 27, No. 3, page 2518. Calcium Carbonate—See PF Vol. 27, No. 6, page 3255.
Ampicillin Tablets—See PF Vol. 27, No. 2, page 2118. Calcium Carbonate and Magnesia Tablets—See PF Vol. 27, No. 6,
Arginine Hydrochloride—See PF Vol. 27, No. 6, page 3244. page 3256.
Arginine Hydrochloride Injection—See PF Vol. 27, No. 6, page Calcium Carbonate Oral Suspension—See PF Vol. 27, No. 6, page
3244. 3255.
Aspartic Acid—See PF Vol. 28, No. 2, page 252. Calcium Carbonate Tablets—See PF Vol. 27, No. 6, page 3255.
Atenolol Tablets—See PF Vol. 28, No. 1, page 38. Calcium Chloride—See PF Vol. 27, No. 6, page 3256.
Atenolol and Chlorthalidone Tablets—See PF Vol. 27, No. 6, page Calcium Citrate—See PF Vol. 27, No. 6, page 3257.
3244. Calcium Glubionate Syrup—See PF Vol. 27, No. 6, page 3257.
Atovaquone—See PF Vol. 26, No. 1, page 134. Calcium Gluceptate—See PF Vol. 27, No. 6, page 3257.
Atovaquone Oral Suspension—See PF Vol. 26, No. 1, page 137. Calcium Gluceptate Injection—See PF Vol. 27, No. 6, page 3257.
Atracurium Besylate—See PF Vol. 27, No. 5, page 2975. Calcium Gluconate—See PF Vol. 27, No. 6, page 3258.
Atracurium Besylate Injection—See PF Vol. 26, No. 2, page 403. Calcium Gluconate Injection—See PF Vol. 27, No. 6, page 3258.
Azithromycin—See PF Vol. 27, No. 6, page 3245. Calcium Gluconate Tablets—See PF Vol. 27, No. 6, page 3258.
Barium Sulfate—See PF Vol. 28, No. 1, page 38. Calcium Hydroxide—See PF Vol. 27, No. 6, page 3258.
Barium Sulfate Paste—See PF Vol. 25, No. 4, page 8479. Calcium Hydroxide Topical Solution—See PF Vol. 27, No. 6, page
Barium Sulfate Suspension—See PF Vol. 28, No. 1, page 38. 3259.
Barium Sulfate for Suspension—See PF Vol. 28, No. 1, page 39. Calcium Lactate—See PF Vol. 27, No. 6, page 3259.
Benazepril Hydrochloride—See PF Vol. 28, No. 1, page 39. Calcium Lactate Tablets—See PF Vol. 27, No. 6, page 3259.
Benazepril Hydrochloride Tablets—See PF Vol. 28, No. 1, page Calcium Lactobionate—See PF Vol. 27, No. 6, page 3260.
39. Calcium Levulinate—See PF Vol. 27, No. 6, page 3260.
Benazepril Tablets—See PF Vol. 27, No. 6, page 3250. Calcium and Magnesium Carbonates Tablets—See PF Vol. 27, No.
Benzethonium Chloride Concentrate—See PF Vol. 28, No. 1, page 6, page 3256.
41. Calcium Pantothenate—See PF Vol. 27, No. 6, page 3260.
Benzethonium Chloride Topical Solution—See PF Vol. 27, No. 5, Calcium Pantothenate Tablets—See PF Vol. 27, No. 6, page 3260.
page 2979. Dibasic Calcium Phosphate—See PF Vol. 27, No. 6, page 3261.
Benzylpenicilloyl Polylysine Concentrate—See PF Vol. 28, No. 1, Calcium Polycarbophil—See PF Vol. 28, No. 2, page 260.
page 42. Calcium Saccharate—See PF Vol. 27, No. 6, page 3261.
Betamethasone Oral Solution—See PF Vol. 28, No. 2, page 253. Carbamazepine Extended-Release Tablets—See PF Vol. 27, No. 6,
Betamethasone Syrup—See PF Vol. 28, No. 2, page 254. page 3261.
Betamethasone Valerate—See PF Vol. 27, No. 5, page 2980. Carboprost Tromethamine—See PF Vol. 27, No. 5, page 2988.
Betaxolol Tablets—See PF Vol. 27, No. 4, page 2703. Carboprost Tromethamine Injection—See PF Vol. 27, No. 5, page
Bismuth Citrate—See PF Vol. 27, No. 2, page 2118. 2990.
Bismuth Subsalicylate Magma—See PF Vol. 28, No. 1, page 43. Urea C 13—See PF Vol. 26, No. 2, page 410.
Bisoprolol Fumarate—See PF Vol. 26, No. 4, page 982. Urea C 13 for Oral Solution—See PF Vol. 26, No. 2, page 412.
Bisoprolol Fumarate Tablets—See PF Vol. 26, No. 4, page 983. Urea C 14 Capsules—See PF Vol. 27, No. 2, page 2126.
Bisoprolol Fumarate and Hydrochlorothiazide Tablets—See PF Cefaclor—See PF Vol. 27, No. 3, page 2523.
Vol. 26, No. 4, page 985. Cefaclor Extended-Release Tablets—See PF Vol. 27, No. 2, page
Brinzolamide—See PF Vol. 27, No. 4, page 2703. 2126.
Brinzolamide Ophthalmic Suspension—See PF Vol. 27, No. 4, Cefazolin Ophthalmic Solution—See PF Vol. 28, No. 2, page 261.
page 2705. Cefepime Hydrochloride—See PF Vol. 27, No. 5, page 2991.
Bromodiphenhydramine Hydrochloride Elixir—See PF Vol. 28, Cefepime for Injection—See PF Vol. 27, No. 5, page 2994.
No. 2, page 254. Cefpodoxime Proxetil—See PF Vol. 28, No. 1, page 44.
Bromodiphenhydramine Hydrochloride Oral Solution—See PF Cefpodoxime Proxetil for Oral Suspension—See PF Vol. 28, No.
Vol. 28, No. 2, page 255. 1, page 48.
Brompheniramine Maleate Elixir—See PF Vol. 28, No. 2, page Cefpodoxime Proxetil Tablets—See PF Vol. 28, No. 1, page 49.
255. Cellulose Sodium Phosphate—See PF Vol. 27, No. 6, page 3263.
Brompheniramine Maleate Oral Solution—See PF Vol. 28, No. 2, Chloral Hydrate Oral Solution—See PF Vol. 28, No. 2, page 261.
page 256. Chloral Hydrate Syrup—See PF Vol. 28, No. 2, page 262.
Pharmacopeial Forum
Chlordiazepoxide and Amitriptyline Hydrochloride Tablets—See Diethylcarbamazine Citrate—See PF Vol. 27, No. 1, page 1775.
PF Vol. 27, No. 6, page 3263. Diethylcarbamazine Citrate Tablets—See PF Vol. 27, No. 1, page
Chlorhexidine Gluconate Oral Rinse—See PF Vol. 27, No. 1, page 1777.
1765. Diflorasone Diacetate—See PF Vol. 27, No. 5, page 3003.
Chlorhexidine Gluconate Solution—See PF Vol. 27, No. 5, page Digoxin Elixir—See PF Vol. 28, No. 2, page 279.
2996. Digoxin Injection—See PF Vol. 28, No. 2, page 279.
Chlorothiazide Sodium for Injection—See PF Vol. 28, No. 1, page Digoxin Oral Solution—See PF Vol. 28, No. 2, page 279.
51. Digoxin Tablets—See PF Vol. 28, No. 2, page 281.
Chloroxylenol—See PF Vol. 27, No. 6, page 3264. Dihydroergotamine Mesylate—See PF Vol. 24, No. 1, page 5562.
Chlorpheniramine Maleate Oral Solution—See PF Vol. 28, No. 2, Dihydroergotamine Mesylate Injection—See PF Vol. 24, No. 1,
page 262. page 5564.
Chlorpheniramine Maleate Syrup—See PF Vol. 28, No. 2, page Diloxanide Furoate—See PF Vol. 27, No. 1, page 1778.
263. Dimenhydrinate Oral Solution—See PF Vol. 28, No. 2, page 281.
Chlorpheniramine Maleate Tablets—See PF Vol. 27, No. 6, page Dimenhydrinate Syrup—See PF Vol. 28, No. 2, page 282.
3265. Dinoprostone—See PF Vol. 28, No. 1, page 56.
Cholestyramine for Oral Suspension—See PF Vol. 28, No. 1, page Diphenhydramine Hydrochloride Elixir—See PF Vol. 28, No. 2,
51. page 282.
Sodium Chromate Cr 51 Injection—See PF Vol. 28, No. 2, page Diphenhydramine Hydrochloride Oral Solution—See PF Vol. 28,
264. No. 2, page 283.
Ciclopirox Olamine—See PF Vol. 28, No. 2, page 265. Divalproex Sodium Delayed-Release Tablets—See PF Vol. 28,
Cimetidine Tablets—See PF Vol. 28, No. 1, page 52. No. 2, page 284.
Ciprofloxacin Ophthalmic Ointment—See PF Vol. 27, No. 6, page Dobutamine in Dextrose Injection—See PF Vol. 27, No. 2, page
3266. 2140.
Citric Acid—See PF Vol. 25, No. 3, page 8114. Dolasetron Mesylate—See PF Vol. 26, No. 4, page 1017.
Clomiphene Citrate—See PF Vol. 27, No. 5, page 2997. Dolasetron Mesylate Injection—See PF Vol. 25, No. 4, page 8493.
Clomipramine Hydrochloride—See PF Vol. 27, No. 3, page 2529. Dolasetron Mesylate Tablets—See PF Vol. 26, No. 1, page 145.
Clomipramine Hydrochloride Capsules—See PF Vol. 28, No. 1, Doxazosin Mesylate—See PF Vol. 28, No. 2, page 286.
page 52. Doxazosin Mesylate Tablets—See PF Vol. 28, No. 2, page 289.
Clonazepam—See PF Vol. 25, No. 3, page 8120. Doxylamine Succinate Oral Solution—See PF Vol. 28, No. 2, page
Clonazepam Tablets—See PF Vol. 28, No. 1, page 54. 291.
Clonidine Transdermal System—See PF Vol. 28, No. 2, page 265. Doxylamine Succinate Syrup—See PF Vol. 28, No. 2, page 292.
Clorazepate Dipotassium Tablets—See PF Vol. 28, No. 1, page 54. Dyphylline Elixir—See PF Vol. 28, No. 2, page 292.
Clorsulon—See PF Vol. 28, No. 2, page 269. Dyphylline Oral Solution—See PF Vol. 28, No. 2, page 292.
Clozapine—See PF Vol. 25, No. 6, page 9129. Dyphylline and Guaifenesin Elixir—See PF Vol. 28, No. 2, page
Cocaine and Tetracaine Hydrochlorides and Epinephrine Topical Dyphylline and Guaifenesin Oral Solution—See PF Vol. 28, No. 2,
Solution—See PF Vol. 28, No. 2, page 270. page 294.
Cycloserine—See PF Vol. 27, No. 5, page 2998. Edetate Disodium—See PF Vol. 27, No. 6, page 3277.
Cycloserine Capsules—See PF Vol. 27, No. 5, page 2998. Emedastine Difumarate—See PF Vol. 27, No. 1, page 1782.
Cyclosporine Capsules—See PF Vol. 27, No. 4, page 2721. Emedastine Ophthalmic Solution—See PF Vol. 27, No. 1, page
Cyproheptadine Hydrochloride Oral Solution—See PF Vol. 28, 1782.
No. 2, page 271. Enalapril Maleate Tablets—See PF Vol. 28, No. 2, page 295.
Cyproheptadine Hydrochloride Syrup—See PF Vol. 28, No. 2, Ephedrine Sulfate Oral Solution—See PF Vol. 28, No. 2, page 297.
page 272. Ephedrine Sulfate Syrup—See PF Vol. 28, No. 2, page 296.
Danazol—See PF Vol. 27, No. 6, page 3269. Ergoloid Mesylates Tablets—See PF Vol. 28, No. 1, page 59.
Desogestrel—See PF Vol. 27, No. 4, page 2728. Erythromycin Ointment—See PF Vol. 28, No. 2, page 297.
Desogestrel and Ethinyl Estradiol Tablets—See PF Vol. 27, No. 6, Estradiol—See PF Vol. 27, No. 2, page 2141.
page 3270. Estropipate Tablets—See PF Vol. 27, No. 6, page 3280.
Dexchlorpheniramine Maleate Oral Solution—See PF Vol. 28, No. Etodolac Capsules—See PF Vol. 27, No. 2, page 2143.
2, page 272. Etoposide—See PF Vol. 27, No. 5, page 3004.
Dexchlorpheniramine Maleate Syrup—See PF Vol. 28, No. 2, page Etoposide Capsules—See PF Vol. 27, No. 5, page 3004.
273. Felodipine—See PF Vol. 27, No. 2, page 2144.
Dexchlorpheniramine Maleate Tablets—See PF Vol. 28, No. 2, Felodipine Extended-Release Tablets—See PF Vol. 27, No. 1, page
page 273. 1782.
Dextroamphetamine Sulfate—See PF Vol. 27, No. 3, page 2533. Fenoldopam Mesylate Injection—See PF Vol. 27, No. 1, page
Dextroamphetamine Sulfate Elixir—See PF Vol. 28, No. 2, page 1785.
274. Ferric Sulfate—See PF Vol. 27, No. 2, page 2144.
Dextroamphetamine Sulfate Oral Solution—See PF Vol. 28, No. 2, Ferrous Gluconate Elixir—See PF Vol. 28, No. 2, page 297.
page 274. Ferrous Gluconate Oral Solution—See PF Vol. 28, No. 2, page
Dextroamphetamine Sulfate Tablets—See PF Vol. 28, No. 2, page 297.
276. Ferumoxides Injection—See PF Vol. 27, No. 3, page 2543.
Dextromethorphan Hydrobromide Oral Solution—See PF Vol. 28, Ferumoxsil Oral Suspension—See PF Vol. 27, No. 6, page 3281.
No. 2, page 276. Finasteride—See PF Vol. 27, No. 2, page 2144.
Dextromethorphan Hydrobromide Syrup—See PF Vol. 28, No. 2, Finasteride Tablets—See PF Vol. 27, No. 2, page 2144.
page 277. Fluorodopa F 18 Injection—See PF Vol. 26, No. 1, page 155.
Diatrizoate Meglumine and Diatrizoate Sodium Solution—See PF Fluoxetine Capsules—See PF Vol. 27, No. 2, page 2150.
Vol. 27, No. 6, page 3273. Fluoxetine Tablets—See PF Vol. 27, No. 6, page 3283.
Dicyclomine Hydrochloride Oral Solution—See PF Vol. 28, No. 2, Flurandrenolide Cream—See PF Vol. 27, No. 2, page 2152.
page 278. Flurandrenolide Ointment—See PF Vol. 27, No. 2, page 2154.
Dicyclomine Hydrochloride Syrup—See PF Vol. 28, No. 2, page Fluoxymesterone—See PF Vol. 28, No. 1, page 59.
279. Fosphenytoin Sodium—See PF Vol. 27, No. 6, page 3285.
Pharmacopeial Forum
Fosphenytoin Sodium Injection—See PF Vol. 27, No. 6, page Lansoprazole Delayed-Release Capsules—See PF Vol. 26, No. 5,
3287. page 1295.
Furosemide Oral Solution—See PF Vol. 28, No. 1, page 59. Lamivudine—See PF Vol. 27, No. 1, page 1796.
Gabapentin—See PF Vol. 27, No. 5, page 3004. Letrozole—See PF Vol. 27, No. 6, page 3313.
Gabapentin Capsules—See PF Vol. 28, No. 2, page 298. Letrozole Tablets—See PF Vol. 28, No. 1, page 71.
Gadodiamide—See PF Vol. 27, No. 2, page 2163. Levocarnitine—See PF Vol. 28, No. 1, page 71.
Gadodiamide Injection—See PF Vol. 27, No. 2, page 2163. Levonorgestrel—See PF Vol. 27, No. 3, page 2565.
Gadoteridol—See PF Vol. 27, No. 2, page 2163. Levothyroxine Sodium Oral Powder—See PF Vol. 27, No. 6, page
Gadoteridol Injection—See PF Vol. 27, No. 2, page 2164. 3313.
Ganciclovir—See PF Vol. 28, No. 2, page 301. Levothyroxine Sodium Tablets—See PF Vol. 28, No. 2, page 312.
Ganciclovir for Injection—See PF Vol. 27, No. 5, page 3009. Lincomycin Hydrochloride Soluble Powder—See PF Vol. 28, No.
Gemfibrozil—See PF Vol. 27, No. 6, page 3289. 1, page 73.
Glutaral Concentrate—See PF Vol. 28, No. 1, page 60. Lincomycin Hydrochloride Syrup—See PF Vol. 28, No. 2, page
Glyburide Tablets—See PF Vol. 28, No. 1, page 60. 313.
Glycerin—See PF Vol. 27, No. 5, page 3010. Lincomycin Oral Solution—See PF Vol. 28, No. 2, page 313.
Graftskin—See PF Vol. 27, No. 6, page 3290. Lithium Citrate Syrup—See PF Vol. 28, No. 2, page 314.
Guaifenesin Oral Solution—See PF Vol. 28, No. 2, page 302. Lithium Oral Solution—See PF Vol. 28, No. 2, page 314.
Guaifenesin Syrup—See PF Vol. 28, No. 2, page 303. Magnesium Carbonate, Citric Acid, and Potassium Citrate for Oral
Guaifenesin and Codeine Phosphate Oral Solution—See PF Vol. Solution—See PF Vol. 26, No. 4, page 1050.
28, No. 2, page 303. Mangafodipir Trisodium—See PF Vol. 28, No. 2, page 315.
Guaifenesin and Codeine Phosphate Syrup—See PF Vol. 28, No. Mangafodipir Trisodium Injection—See PF Vol. 28, No. 2, page
2, page 306. 320.
Haloperidol—See PF Vol. 27, No. 6, page 3300. Mannitol—See PF Vol. 27, No. 5, page 3017.
Heparin Sodium—See PF Vol. 25, No. 6, page 9153. Mannitol Injection—See PF Vol. 28, No. 1, page 73.
Hydralazine Hydrochloride Oral Solution—See PF Vol. 28, No. 2, Mecamylamine Hydrochloride—See PF Vol. 28, No. 2, page 321.
page 306. Mecamylamine Hydrochloride Tablets—See PF Vol. 28, No. 2,
Hydroxyzine Hydrochloride Oral Solution—See PF Vol. 28, No. 2, page 322.
page 307. Medroxyprogesterone Acetate—See PF Vol. 27, No. 2, page 2172.
Hydroxyzine Hydrochloride Syrup—See PF Vol. 28, No. 2, page Megestrol Acetate Oral Suspension—See PF Vol. 27, No. 6, page
308. 3314.
Hydrochlorothiazide—See PF Vol. 28, No. 1, page 60. Meperidine Hydrochloride Oral Solution—See PF Vol. 28, No. 2,
Hydrocodone Bitartrate—See PF Vol. 28, No. 1, page 63. page 323.
Hydrocodone Bitartrate and Acetaminophen Tablets—See PF Vol. Meperidine Hydrochloride Syrup—See PF Vol. 28, No. 2, page
27, No. 6, page 3301. 323.
Hydrocortisone Acetate Ophthalmic Suspension—See PF Vol. 27, Mephenytoin—See PF Vol. 27, No. 2, page 2174.
No. 6, page 3302. Mephenytoin Tablets—See PF Vol. 27, No. 2, page 2174.
Hydrocortisone Valerate Ointment—See PF Vol. 27, No. 2, page Mephobarbital Tablets—See PF Vol. 26, No. 1, page 178.
2165. Meropenem—See PF Vol. 27, No. 1, page 1801.
Hydrogen Peroxide Concentrate—See PF Vol. 28, No. 1, page 65. Meropenem for Injection—See PF Vol. 27, No. 1, page 1801.
Hydromorphone Hydrochloride Tablets—See PF Vol. 26, No. 5, Mesalamine Rectal Suspension—See PF Vol. 27, No. 6, page
page 1291. 3315.
Hydroxyzine Hydrochloride Tablets—See PF Vol. 27, No. 6, page Metaproterenol Sulfate Oral Solution—See PF Vol. 28, No. 2, page
3302. 324.
Idarubicin Hydrochloride—See PF Vol. 27, No. 6, page 3302. Metaproterenol Sulfate Syrup—See PF Vol. 28, No. 2, page 325.
Indinavir Sulfate—See PF Vol. 27, No. 2, page 2165. Methdilazine Hydrochloride Oral Solution—See PF Vol. 28, No. 2,
Insulin Lispro—See PF Vol. 28, No. 1, page 66. page 325.
Insulin Lispro Injection—See PF Vol. 28, No. 1, page 69. Methdilazine Hydrochloride Syrup—See PF Vol. 28, No. 2, page
Inulin—See PF Vol. 27, No. 6, page 3303. 326.
Iodixanol—See PF Vol. 27, No. 6, page 3303. Methenamine Elixir—See PF Vol. 28, No. 2, page 326.
Iodixanol Injection—See PF Vol. 27, No. 6, page 3311. Methenamine Oral Solution—See PF Vol. 28, No. 2, page 327.
Iodoform—See PF Vol. 27, No. 2, page 2170. Methenamine Tablets—See PF Vol. 28, No. 2, page 328.
Iohexol Injection—See PF Vol. 28, No. 2, page 308. Methadone Hydrochloride Oral Solution—See PF Vol. 28, No. 1,
Iopromide Injection—See PF Vol. 27, No. 2, page 2170. page 74.
Ioxaglic Acid—See PF Vol. 27, No. 6, page 3312. Methylprednisolone Acetate for Rectal Suspension—See PF Vol.
Ipecac Oral Solution—See PF Vol. 28, No. 2, page 308. 27, No. 5, page 3022.
Ipecac Syrup—See PF Vol. 28, No. 2, page 310. Methyltestosterone—See PF Vol. 28, No. 1, page 74.
Iron Sucrose Injection—See PF Vol. 27, No. 5, page 3012. Miconazole Nitrate—See PF Vol. 25, No. 2, page 7838.
Isoamyl Methoxycinnamate—See PF Vol. 27, No. 5, page 3017. Miconazole Nitrate Cream—See PF Vol. 26, No. 5, page 1302.
Isoflupredone Acetate—See PF Vol. 27, No. 4, page 2749. Milrinone—See PF Vol. 27, No. 2, page 2175.
Isoflupredone Acetate Injectable Suspension—See PF Vol. 27, No. Minocycline Hydrochloride—See PF Vol. 27, No. 5, page 3022.
4, page 2751. Misoprostol—See PF Vol. 26, No. 5, page 1304.
Isoflurane—See PF Vol. 26, No. 1, page 172. Misoprostol Dispersion—See PF Vol. 28, No. 1, page 76.
Isoniazid Oral Solution—See PF Vol. 28, No. 2, page 310. Misoprostol Tablets—See PF Vol. 26, No. 5, page 1310.
Isoniazid Syrup—See PF Vol. 28, No. 2, page 311. Morphine Sulfate—See PF Vol. 28, No. 2, page 328.
Isosorbide Concentrate—See PF Vol. 28, No. 1, page 71. Morphine Sulfate Suppositories—See PF Vol. 28, No. 2, page 328.
Ivermectin—See PF Vol. 27, No. 1, page 1790. Myrrh—See PF Vol. 28, No. 1, page 78.
Kanamycin Sulfate—See PF Vol. 27, No. 6, page 3312. Nabumetone—See PF Vol. 27, No. 5, page 3024.
Ketoconazole Oral Suspension—See PF Vol. 28, No. 2, page 311. Nabumetone Tablets—See PF Vol. 26, No. 5, page 1315.
Ketorolac Tromethamine—See PF Vol. 27, No. 6, page 3313. Naloxone Hydrochloride—See PF Vol. 28, No. 2, page 329.
Lactulose Concentrate—See PF Vol. 28, No. 1, page 71. Naltrexone Hydrochloride—See PF Vol. 28, No. 2, page 329.
Lansoprazole—See PF Vol. 26, No. 5, page 1293.
Pharmacopeial Forum
Nandrolone Decanoate Injection—See PF Vol. 28, No. 2, page Promethazine Hydrochloride Syrup—See PF Vol. 28, No. 2, page
330. 349.
Neomycin Sulfate, Isoflupredone Acetate, and Tetracaine Hydro- Propofol—See PF Vol. 27, No. 4, page 2774.
chloride Ointment—See PF Vol.27, No. 4, page 2758. Propoxyphene Hydrochloride—See PF Vol. 28, No. 2, page 350.
Neomycin Sulfate, Isoflupredone Acetate, and Tetracaine Hydro- Propoxyphene Napsylate—See PF Vol. 28, No. 2, page 352.
chloride Topical Powder—See PF Vol. 27, No. 4, page 2760. Pseudoephedrine Hydrochloride Extended-Release Capsules—See
Nifedipine Capsules—See PF Vol. 28, No. 1, page 78. PF Vol. 27, No. 6, page 3323.
Nizatidine—See PF Vol. 27, No. 6, page 3319. Pseudoephedrine Hydrochloride Oral Solution—See PF Vol. 28,
Norethindrone Acetate and Ethinyl Estradiol Tablets—See PF Vol. No. 2, page 354.
27, No. 6, page 3320. Pseudoephedrine Hydrochloride Syrup—See PF Vol. 28, No. 2,
Norgestimate—See PF Vol. 28, No. 2, page 331. page 355.
Norgestimate and Ethinyl Estradiol Tablets—See PF Vol. 28, No. Pseudoephedrine Hydrochloride Tablets—See PF Vol. 28, No. 2,
l,page 79. page 356.
Octisalate—See PF Vol. 27, No. 5, page 3027. Pseudoephedrine Hydrochloride Extended-Release Tablets—See
Octocrylene—See PF Vol. 27, No. 5, page 3028. PF Vol. 28, No. 1, page 85.
Octyl Salicylate—See PF Vol. 27, No. 5, page 3028. Pseudoephedrine Hydrochloride, Carbinoxamine Maleate, and
Oxybutynin Chloride—See PF Vol. 26, No. 6, page 1561. Dextromethorphan Hydrobromide Oral Solution—See PF
Oxybutynin Chloride Oral Solution—See PF Vol. 28, No. 2, page Vol. 27, No. 2, page 2196.
334. Pyrantel Pamoate Oral Suspension—See PF Vol. 27, No. 6, page
Oxybutynin Chloride Syrup—See PF Vol. 28, No. 2, page 336. 3325.
Oxycodone Hydrochloride—See PF Vol. 28, No. 1, page 84. Pyrethrum Extract—See PF Vol. 26, No. 1, page 202.
Oxycodone and Acetaminophen Capsules—See PF Vol. 27, No. 6, Pyridostigmine Bromide Oral Solution—See PF Vol. 28, No. 2,
page 3320. page 356.
Water O 15 Injection—See PF Vol. 27, No. 2, page 2182. Pyridostigmine Bromide Syrup—See PF Vol. 28, No. 2, page 357.
Paclitaxel—See PF Vol. 28, No. 2, page 336. Ramipril—See PF Vol. 28, No. 2, page 357.
Paclitaxel Injection—See PF Vol. 27, No. 3, page 2572. Ranitidine Oral Solution—See PF Vol. 28, No. 2, page 360.
Paromomycin Oral Solution—See PF Vol. 28, No. 2, page 341. Repaglinide—See PF Vol. 27, No. 6, page 3325.
Paromomycin Sulfate Syrup—See PF Vol. 28, No. 2, page 342. Repaglinide Tablets—See PF Vol. 26, No. 5, page 1333.
Paroxetine Hydrochloride—See PF Vol. 27, No. 4, page 2763. Reserpine Elixir—See PF Vol. 28, No. 2, page 362.
Paroxetine Tablets—See PF Vol. 27, No. 5, page 3029. Reserpine Oral Solution—See PF Vol. 28, No. 2, page 362.
Penicillamine Capsules—See PF Vol. 27, No. 5, page 3031. Rifampin Oral Suspension—See PF Vol. 28, No. 2, page 363.
Pentobarbital Elixir—See PF Vol. 28, No. 2, page 342. Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Hydrochlor-
Pentobarbital Oral Solution—See PF Vol. 28, No. 2, page 342. ide Tablets—See PF Vol. 27, No. 5, page 3041.
Pentazocine and Naloxone Hydrochlorides Tablets—See PF Vol. Rimantadine Hydrochloride—See PF Vol. 24, No. 2, page 5927.
28, No. 1, page 84. Rimantadine Hydrochloride Tablets—See PF Vol. 24, No. 2, page
Pentoxifylline—See PF Vol. 26, No. 2, page 432. 5929.
Pentoxifylline Extended-Release Tablets—See PF Vol. 27, No. 2, Saquinavir Capsules—See PF Vol. 27, No. 2, page 2197.
Pergolide Mesylate—See PF Vol. 26, No. 4, page 1060. Saw Palmetto Capsules—See PF Vol. 26, No. 6, page 1571.
Pergolide Tablets—See PF Vol. 25, No. 2, page 7845. Saw Palmetto Extract—See PF Vol. 26, No. 6, page 1567.
Phenobarbital Elixir—See PF Vol. 28, No. 2, page 343. Secobarbital Elixir—See PF Vol. 28, No. 2, page 364.
Phenobarbital Oral Solution—See PF Vol. 28, No. 2, page 344. Secobarbital Oral Solution—See PF Vol. 28, No. 2, page 364.
Phenylpropanolamine Hydrochloride—See PF Vol. 26, No. 6, Senna Oral Solution—See PF Vol. 28, No. 2, page 365.
page 1562. Senna Syrup—See PF Vol. 28, No. 2, page 365.
Phenyltoloxamine Dihydrogen Citrate—See PF Vol. 27, No. 6, Sevoflurane—See PF Vol. 27, No. 3, page 2577.
page 3321. Shark Liver Oil—See PF Vol. 26, No. 6, page 1643.
Phenytoin Sodium—See PF Vol. 27, No. 5, page 3031. Simethicone—See PF Vol. 28, No. 2, page 366.
Extended Phenytoin Sodium Capsules—See PF Vol. 27, No. 5, Sodium Acetate—See PF Vol. 27, No. 6, page 3328.
page 3034. Sodium Butyrate—See PF Vol. 27, No. 2, page 2197.
Chromic Phosphate P 32 Suspension—See PF Vol. 27, No. 6, page Sodium Chloride Ophthalmic Ointment—See PF Vol. 27, No. 6,
3323. page 3329.
Potassium Gluconate Elixir—See PF Vol. 28, No. 2, page 345. Sodium Hypochlorite Topical Solution—See PF Vol. 28, No. 2,
Potassium Gluconate Oral Solution—See PF Vol. 28, No. 2, page page 366.
345. Sodium Phosphates Rectal Solution—See PF Vol. 27, No. 1, page
Povidone—See PF Vol. 22, No. 6, page 3163. 1816.
Praziquantel—See PF Vol. 28, No. 1, page 84. Sodium Sulfide Topical Gel—See PF Vol. 28, No. 2, page 366.
Prazosin Hydrochloride Capsules—See PF Vol. 28, No. 2, page Somatropin—See PF Vol. 25, No. 4, page 8540.
346. Somatropin for Injection—See PF Vol. 25, No. 4, page 8551.
Prednisolone—See PF Vol. 27, No. 5, page 3036. Sorbitol Solution—See PF Vol. 27, No. 6, page 3329.
Prednisolone Acetate—See PF Vol. 27, No. 5, page 3037. Sotalol Hydrochloride—See PF Vol. 26, No. 4, page 1068.
Prednisolone Oral Solution—See PF Vol. 28, No. 2, page 346. Sotalol Hydrochloride Tablets—See PF Vol. 27, No. 1, page 1816.
Prednisolone Syrup—See PF Vol. 28, No. 2, page 347. Stanozolol Tablets—See PF Vol. 28, No. 2, page 367.
Probenecid Tablets—See PF Vol. 28, No. 2, page 347. Streptomycin Injection—See PF Vol. 28, No. 1, page 86.
Procainamide Hydrochloride Tablets—See PF Vol. 28, No. 2, page Streptomycin for Injection—See PF Vol. 28, No. 1, page 86.
347. Streptomycin Sulfate—See PF Vol. 28, No. 1, page 87.
Progesterone Injection—See PF Vol. 27, No. 5, page 3038. Sulfadimethoxine Oral Suspension—See PF Vol. 27, No. 2, page
Progesterone Vaginal Suppositories—See PF Vol. 28, No. 2, page 2198.
348. Sulfadimethoxine Soluble Powder—See PF Vol. 27, No. 2, page
Promethazine Hydrochloride Oral Solution—See PF Vol. 28, No. 2198.
2, page 348. Sulfadimethoxine Tablets—See PF Vol. 27, No. 2, page 2198.
Sulindac—See PF Vol. 25, No. 5, page 8879.
Pharmacopeial Forum
Sulindac Tablets—See PF Vol. 25, No. 5, page Triprolidine and Pseudoephedrine Hydrochlorides Tablets—See
Sulisobenzone—See PF Vol. 27, No. 5, page 3044. PF Vol. 28, No. 2, page 394.
Sunflower Oil—See PF Vol. 27, No. 4, page 2779. Urofollitropin—See PF Vol. 27, No. 2, page 2207.
Sutilains—See PF Vol. 27, No. 2, page 2199. Urofollitropin for Injection—See PF Vol. 27, No. 5, page 3045.
Sutilains Ointment—See PF Vol. 27, No. 2, page 2201. Valproic Acid Oral Solution—See PF Vol. 28, No. 2, page 395.
Sucralfate—See PF Vol. 28, No. 2, page 367. Valproic Acid Syrup—See PF Vol. 28, No. 2, page 396.
Sucralfate Tablets—See PF Vol. 28, No. 2, page 369. Valrubicin—See PF Vol. 26, No. 5, page 1346.
Tacrine Capsules—See PF Vol. 26, No. 2, page 444. Valrubicin Intravesical Solution—See PF Vol. 26, No. 1, page 211.
Tacrine Hydrochloride—See PF Vol. 26, No. 5, page 1337. Valsartan—See PF Vol. 28, No. 2, page 396.
Taurine—See PF Vol. 27, No. 6, page 3331. Valsartan Capsules—See PF Vol. 28, No. 2, page 399.
Terazosin Hydrochloride—See PF Vol. 28, No. 2, page 369. Valsartan and Hydrochlorothiazide Tablets—See PF Vol. 27, No.
Terbutaline Sulfate—See PF Vol. 26, No. 3, page 752. 4, page 2780.
Terbutaline Sulfate Inhalation Aerosol—See PF Vol. 26, No. 3, Vancomycin—See PF Vol. 27, No. 4, page 2783.
page 753. Vancomycin Hydrochloride—See PF Vol. 27, No. 4, page 2784.
Terbutaline Sulfate Injection—See PF Vol. 26, No. 3, page 756. Vancomycin Injection—See PF Vol. 27, No. 4, page 2784.
Terbutaline Sulfate Tablets—See PF Vol. 26, No. 3, page 757. Vancomycin for Injection—See PF Vol. 27, No. 4, page 2785.
Terpin Hydrate Elixir—See PF Vol. 28, No. 2, page 374. Vancomycin Hydrochloride for Injection—See PF Vol. 27, No. 4,
Terpin Hydrate Oral Solution—See PF Vol. 28, No. 2, page 375. page 2786.
Terpin Hydrate and Codeine Elixir—See PF Vol. 28, No. 2, page Sterile Vancomycin Hydrochloride—See PF Vol. 27, No. 4, page
375. 2786.
Terpin Hydrate and Codeine Oral Solution—See PF Vol. 28, No. 2, Vecuronium Bromide—See PF Vol. 27, No. 5, page 3053.
page 376. Verteporfin—See PF Vol. 27, No. 3, page 2585.
Testolactone Tablets—See PF Vol. 27, No. 6, page 3332. Verteporfin for Injection—See PF Vol. 27, No. 3, page 2587.
Tetracycline Hydrochloride Oral Suspension—See PF Vol. 28, No. Vinorelbine Tartrate—See PF Vol. 27, No. 5, page 3054.
2, page 378. Sterile Water for Injection—See PF Vol. 27, No. 4, page 2787.
Theophylline Oral Solution—See PF Vol. 27, No. 5, page 3044. Purified Water—See PF Vol. 27, No. 5, page 3057.
Theophylline Sodium Glycinate Elixir—See PF Vol. 28, No. 2, Xylazine—See PF Vol. 27, No. 5, page 3057.
page 378. Zidovudine Capsules—See PF Vol. 27, No. 5, page 3058.
Theophylline Sodium Glycinate Oral Solution—See PF Vol. 28, Zileuton—See PF Vol. 27, No. 6, page 3335.
No. 2, page 378.
Theophylline Syrup—See PF Vol. 27, No. 1, page 1819. EXCIPIENTS
Thiamine Hydrochloride Elixir—See PF Vol. 28, No. 2, page 379. USP and NF Excipients, Listed by Category—See PF Vol. 26, No.
Thiamine Hydrochloride Injection—See PF Vol. 28, No. 2, page 2, page 447.
380.
Thiamine Hydrochloride Oral Solution—See PF Vol. 28, No. 2, GENERAL CHAPTERS
page 380.
Thiamine Mononitrate Elixir—See PF Vol. 28, No. 2, page 381.
Thiamine Mononitrate Oral Solution—See PF Vol. 28, No. 2, page General Tests and Assays
381.
Thyroid Tablets—See PF Vol. 28, No. 1, page 88. General Requirements for Tests and Assays
Tiagabine Hydrochloride—See PF Vol. 26, No. 4, page 1076.
Tobramycin Inhalation Solution—See PF Vol. 26, No. 5, page I) Injections—See PF Vol. 28, No. 2, page 430.
1340. II) USP Reference Standards—See PF Vol. 22, No. 6, page 3212;
Tolazamide—See PF Vol. 27, No. 6, page 3333. PF Vol. 23, No. 4, page 4500; PF Vol. 24, No. 2, page 5965;
Torsemide—See PF Vol. 28, No. 2, page 382. PF Vol. 24, No. 5, page 6925; PF Vol. 25, No. 2, page 7876;
Triamcinolone Diacetate Oral Solution—See PF Vol. 28, No. 2, PF Vol. 25, No. 3, page 8222; PF Vol. 25, No. 4, page 8561;
page 383. PF Vol. 25, No. 5, page 8893; PF Vol. 26, No. 1, page 218; PF
Triamcinolone Diacetate Syrup—See PF Vol. 28, No. 2, page 384. Vol. 26, No. 2, page 471; PF Vol. 26, No. 6, page 1606; PF
Triazolam—See PF Vol. 28, No. 2, page 385. Vol. 27, No. 1, page 1832; PF Vol. 27, No. 5, page 3071; PF
Tricitrates Oral Solution—See PF Vol. 28, No. 2, page 385. Vol. 27, No. 6, page 3348; PF Vol. 28, No. 1, page 111; and
Trichlorfon—See PF Vol. 26, No. 6, page 1576. PF Vol. 28, No. 2, page 433.
Trifluoperazine Hydrochloride Syrup—See PF Vol. 28, No. 2, page (13) Concordance of Foreign Pharmacopeial Tests and Assays—
385. See PF Vol. 24, No. 1, page 5612.
Trifluoperazine Oral Solution—See PF Vol. 28, No. 2, page 385.
Trihexyphenidyl Hydrochloride Elixir—See PF Vol. 28, No. 2, Apparatus for Tests and Assays
page 386. (41) Weights and Balances—See PF Vol. 26, No. 6, page 1607.
Trihexyphenidyl Hydrochloride Oral Solution—See PF Vol. 28,
No. 2, page 387. Microbiological Tests
Trimeprazine Oral Solution—See PF Vol. 28, No. 2, page 388.
Trimeprazine Tartrate Syrup—See PF Vol. 28, No. 2, page 389. (55) Biological Indicators—Resistance Performance Tests—See
Trimethoprim—See PF Vol. 28, No. 2, page 389. PF Vol. 27, No. 4, page 2807.
Triprolidine Hydrochloride Oral Solution—See PF Vol. 28, No. 2, 61) Microbial Limit Tests—See PF Vol. 27, No. 2, page 2269.
page 390. 62) Microbiological Procedures for Absence of Objectionable
Triprolidine Hydrochloride Syrup—See PF Vol. 28, No. 2, page Microorganisms—See PF Vol. 27, No. 2, page 2269.
391. (71) Sterility Tests—See PF Vol. 26, No. 4, page 1102.
Triprolidine Hydrochloride Tablets—See PF Vol. 28, No. 2, page
392. Biological Tests and Assays
Triprolidine and Pseudoephedrine Hydrochlorides Oral Solution— (85) Bacterial Endotoxins Test—See PF Vol. 28, No. 2, page 435.
See PF Vol. 28, No. 2, page 392.
Triprolidine and Pseudoephedrine Hydrochlorides Syrup—See PF Chemical Tests and Assays
Vol. 28, No. 2, page 394.
Pharmacopeial Forum
LIMIT TESTS L-Aspartic Acid—See PF Vol. 27, No. 6, page 3363.

(191) Identification Tests—General—See PF Vol. 27, No. 6, page Azure A—See PF Vol. 27, No. 5, page 3115.
3349. Bacterial Alkaline Protease Preparation—See PF Vol. 28, No. 2,
(281) Residue on Ignition—See PF Vol. 28, No. 1, page 112. page 552.
Bromelain—See PF Vol. 28, No. 2, page 552.
OTHER TESTS AND ASSAYS Branched Polymeric Sucrose—See PF Vol. 27, No. 6, page 3363.
4-(Butylamino)benzoic Acid—See PF Vol. 28, No. 2, page 553.
(381) Elastomeric Closures for Injections—See PF Vol. 26, No. 4, Butyrolactone—See PF Vol. 22, No. 6, page 3248.
page 1108. Canada Balsam—See PF Vol. 27, No. 2, page 2278.
(563) Biological and Chemical Identification of Articles of Bota- Carmine—See PF Vol. 27, No. 2, page 2278.
nical Origin—See PF Vol. 28, No. 2, page 435. m-Chlorobenzoic Acid—See PF Vol. 26, No. 4, page 1132.
(565) Botanical Extracts—See PF Vol. 28, No. 2, page 451. 1-Chloronaphthalene—See PF Vol. 27, No. 6, page 3364.
(581) Vitamin D Assay—See PF Vol. 26, No. 4, page 1111. 0.5 M Copper Sulfate Solution—See PF Vol. 26, No. 5, page 1382.
Cupric Nitrate—See PF Vol. 27, No. 6, page 3364.
Physical Tests and Determinations Cyclohexylmethanol—See PF Vol. 25, No. 1, page 7582.
(625) Clarity and Degree of Opalescence of Liquids—See PF Vol. Deoxyadenosine Triphosphate—See PF Vol. 27, No. 6, page 3364.
Deoxycytidine Triphosphate—See PF Vol. 27, No. 6, page 3364.
26, No. 6, page 1616. Deoxyguanosine Triphosphate—SeePF Vol. 27, No. 6, page 3364.
(627) Degree of Color of Liquids—See PF Vol. 26, No. 6, page Deoxyribonucleic Acid Polymerase—See PF Vol. 27, No. 6, page
1617.
643 Total Organic Carbon—See PF Vol. 27, No. 6, page 3356. 3365.
645 Water Conductivity—See PF Vol. 27, No. 5, page 3076. Deoxythymidine Triphosphate—See PF Vol. 27, No. 6, page 3365.
661 Containers—See PF Vol. 28, No. 2, page 453. Dextran, High Molecular Weight—See PF Vol. 27, No. 5, page
671 Containers—Permeation—See PF Vol. 28, No. 2, page 456. 3115.
724 Drug Release—See PF Vol. 27, No. 6, page 3358. Dibutylammonium Phosphate—See PF Vol. 26, No. 4, page 1132.
776 Optical Microscopy—See PF Vol. 26, No. 1, page 229. Dicyclohexyl—See PF Vol. 25, No. 1, page 7582.
795 Pharmacy Compounding—See PF Vol. 28, No. 2, page 458. Dicyclohexyl Phthalate—See PF Vol. 26, No. 2, page 504.
905 Uniformity of Dosage Units—See PF Vol. 27, No. 3, page Diethylpyrocarbonate—See PF Vol. 27, No. 6, page 3365.
2595. 2,7-Dihydroxynapthalene—See PF Vol. 21, No. 3, page 823.
N,N-Dimethyldodecylamine-N-oxide—See PF Vol. 27, No. 4,
General Information page 2837.
2,5-Dimethylphenol—See PF Vol. 27, No. 6, page 3364.
(1010) Analytical Data—Interpretation and Treatment—See PF 1,4-Dimethylpiperazine—See PF Vol. 27, No. 1, page 1903.
Vol. 27, No. 5, page 3086. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl Tetrazolium Bro-
(1035) Biological Indicators for Sterilization—See PF Vol. 27, No. mide—See PF Vol. 27, No. 6, page 3365.
4, page 2820. Dimethyltin Dibromide—See PF Vol. 25, No. 3, page 8280.
(1047) Biotechnology-Derived Articles—Tests—See PF Vol. 27, Dioleoylglycerol—See PF Vol. 26, No. 6, page 1622.
No. 2, page 2277. Racemic Epinephrine—See PF Vol. 23, No. 4, page 4529.
(1116) Microbiological Evaluation of Clean Rooms and Other Escin—See PF Vol. 27, No. 4, page 2837.
Controlled Environments—See PF Vol. 25, No. 3, page 8264. 17a-Estradiol—See PF Vol. 27, No. 2, page 2278.
(1118) Monitoring Devices—Time, Temperature, and Humidity— Ether, Peroxide-Free—See PF Vol. 27, No. 6, page 3365.
See PF Vol. 26, No. 2, page 481. Ethidium Bromide—See PF Vol. 27, No. 6, page 3366.
(1119) Near-Infrared Spectrophotometry—See PF Vol. 27, No. 5, 4'-Ethoxyacetophenone—See PF Vol. 26, No. 5, page 1382.
page 3101. Ethylbenzene—See PF Vol. 25, No. 1, page 7582.
(1141) Packaging, Storage, and Distribution of Pharmacopeial Ar- Fast Green FCF—See PF Vol. 27, No. 2, page 2278.
ticles—See PF Vol. 26, No. 2, page 493. FD&C Blue No. 1—See PF Vol. 28, No. 1, page 115.
(1146) Packaging Practice—Repackaging a Single Solid Oral 9-Fluorenylmethyl Chloroformate—See PF Vol. 25, No. 5, page
Drug Product into a Unit-Dose Container—See PF Vol. 28, 8916.
No. 2, page 467. Formamide, Anhydrous—See PF Vol. 27, No. 5, page 3115.
(1151) Pharmaceutical Dosage Forms—See PF Vol. 26, No. 2, L-Glutamic Acid—See PF Vol. 27, No. 6, page 3366.
page 499. L-Glutamine—See PF Vol. 27, No. 6, page 3366.
(1160) Pharmaceutical Calculations in Prescrition Compound- Guanidine Isothiocyanate—See PF Vol. 27, No. 6, page 3366.
ing—See PF Vol. 28, No. 2, page 476. Heptafluorobutyric Acid—See PF Vol. 26, No. 4, page 1132.
(1186) Shipping and Storage of Labile Preparations—See PF Vol. L-Histidine Hydrochloride Monohydrate—See PF Vol. 27, No. 6,
28, No. 2, page 495. page 3366.
(1191) Stability Considerations in Dispensing Practice—See PF Hydroxy Naphthol Blue—See PF Vol. 27, No. 6, page 3366.
Vol. 28, No. l,page 112. Hypoxanthine—See PF Vol. 27, No. 6, page 3367.
(1206) Sterile Drug Products for Home Use—See PF Vol. 28, No. Indole—See PF Vol. 25, No. 4, page 8586.
2, page 498. Indole-3-carboxylic Acid—See PF Vol. 25, No. 4, page 8586.
(1207) Sterile Product Packaging—Integrity Evaluation—See PF Iodoethane—See PF Vol. 24, No. 6, page 7327.
Vol. 27, No. 5, page 3111. Isoferulic Acid—See PF Vol. 27, No. 4, page 2837.
2-Isopropylphenol—See PF Vol. 27, No. 4, page 2838.
REAGENTS, INDICATORS, AND SOLUTIONS Linoleic Acid—See PF Vol. 27, No. 6, page 3367.
a-Lipoic Acid—See PF Vol. 27, No. 6, page 3367.
Reagent Specifications Manganese Dioxide—See PF Vol. 27, No. 6, page 3367.
Agarose—See PF Vol. 27, No. 6, page 3363. Manganese Dioxide, Activated—See PF Vol. 27, No. 6, page
Ammonia Water, Stronger—See PF Vol. 27, No. 6, page 3363. 3367.
Ammonium Formate—See PF Vol. 25, No. 4, page 8586. Mercurous Nitrate—See PF Vol. 27, No. 6, page 3368.
Ammonium Pyrrolidinedithiocarbamate—See PF Vol. 27, No. 5, Methyl Benzenesulfonate—See PF Vol. 24, No. 4, page 6591.
page 3115. 3-Methyl-2-benzothiazolinone Hydrazone Hydrochloride—See
Aniline Sulfate—See PF Vol. 27, No. 2, page 2277. PF Vol. 25, No. 3, page 8280.
Methyl Green—See PF Vol. 27, No. 2, page 2279.
Pharmacopeia! Forum
l-Methylpiperazine—See PF Vol. 27, No. 1, page 1903. Nickel Standard Solution TS—See PF Vol. 27, No. 5, page 3117.
N-Methylpyrrolidine—See PF Vol. 27, No. 5, page 3116. Perchloric Acid TS—See PF Vol. 27 No. 1, page 1905.
Monooleoylglycerol—See PF Vol. 26, No. 6, page 1622. Potassium Iodide and Starch TS—See PF Vol. 27, No. 6, page
Morin—See PF Vol. 25, No. 3, page 8280. 3373.
1-Naphthylamine—See PF Vol. 27, No. 5, page 3116. Potassium Thiocyanate TS—See PF Vol. 27, No. 5, page 3118.
Nickel Chloride Hexahydrate—See PF Vol. 26, No. 5, page 1382.
Nickel(II) Sulfate Heptahydrate—See PF Vol. 27, No. 5, page Volumetric Solutions
3116. Edetate Disodium, Twentieth-Molar (0.05 M)—See PF Vol. 27,
n-Nonylamine—See PF Vol. 27, No. 6, page 3368. No. 6, page 3373.
Nonylphenol Polyoxyethylene Ether—See PF Vol. 27, No. 6, page Lead Perchlorate, Hundredth Molar (0.01 M)—See PF Vol. 28, No.
3368. 2, page 553.
Oligo-deoxythymidine—See PF Vol. 27, No. 6, page 3368.
Pentadecanoic Acid Methyl Ester—See PF Vol. 26, No. 6, page Reagent Footnotes
1622.
2-Pentanone—See PF Vol. 26, No. 4, page 1132. Footnote 43—See PF Vol. 28, No. 2, page 553.
o-Phenan thro line Monohydrochloride Monohydrate—See PF Vol. Footnote 46—See PF Vol. 28, No. 2, page 553.
27, No. 1, page 1904. Footnote 78—See PF Vol. 28, No. 2, page 553.
Phenol Red, Sodium—See PF Vol. 27, No. 6, page 3368. Footnote 85—See PF Vol. 26, No. 4, page 1133.
Phenoxyacetic Acid—See PF Vol. 27, No. 1, page 1904. Footnote 87—See PF Vol. 26, No. 5, page 1383.
Phenylacetic Acid—See PF Vol. 27, No. 1, page 1904. Footnote 93—See PF Vol. 27, No. 3, page 2597.
Polyoxyethylene (20) Sorbitan Monolaurate—See PF Vol. 27, No. Footnote 96—See PF Vol. 27, No. 5, page 3118.
Polysaccharide Molecular Weight Standards—See PF Vol. 27, No. Footnote 98—See PF Vol. 27, No. 5, page 3118.
Propionaldehyde—See PF Vol. 24, No. 6, page 7328. Footnote 100—See PF Vol. 27, No. 6, page 3374.
(-)-Pseudoephedrine—See PF Vol. 23, No. 5, page 4872. Footnote 101—See PF Vol. 27, No. 6, page 3374.
Putrescine Dihydrochloride—See PF Vol. 27, No. 6, page 3369. Footnote 102—See PF Vol. 27, No. 6, page 3374.
Reverse Transcriptase—See PF Vol. 27, No. 6, page 3369. Footnote 103—See PF Vol. 28, No. 2, page 554.
Ribonuclease Inhibitor—See PF Vol. 27, No. 6, page 3369. Footnote 104—See PF Vol. 28, No. 2, page 554.
Silver Chloride, Granular Reagent—See PF Vol. 26, No. 5, page
1383. REFERENCE TABLES
Sodium Iodate—See PF Vol. 27, No. 6, page 3369. Container Specifications for Capsules and Tablets—See PF Vol.
Tetrahydrofuran, Peroxide-Free—See PF Vol. 27, No. 6, page 28, No. 1, page 115.
3369. Description and Relative Solubility of USP and NF Articles—See
l,l,4,4-Tetraphenyl-l,3-butadiene—See PF Vol. 26, No. 6, page PF Vol. 23, No. 4, page 4533; PF Vol. 23, No. 5, page 4874;
1623. PF Vol. 23, No. 6, page 5310; PF Vol. 24, No. 5, page 7017;
Thionine Acetate—See PF Vol. 27, No. 2, page 2279. PF Vol. 25, No. 2, page 7930; PF Vol. 25, No. 3, page 8282;
Thymidine—See PF Vol. 27, No. 6, page 3369. PF Vol. 25, No. 4, page 8589; PF Vol. 25, No. 5, page 8917;
Toluidine Blue—See PF Vol. 27, No. 2, page 2280. PF Vol. 25, No. 6, page 9254; PF Vol. 26, No. 1, page 251; PF
Toluidine Blue O—See PF Vol. 27, No. 2, page 2280. Vol. 26, No. 2, page 504; PF Vol. 26, No. 2, page 505; PF Vol.
a,a,a-Trifluoro-p-cresol—See PF Vol. 27, No. 3, page 2596. 26, No. 3, page 837; PF Vol. 26, No. 5, page 1385; PF Vol. 26,
Trimethyltin Bromide—See PF Vol. 25, No. 3, page 8281. No. 6, page 1623; PF Vol. 27, No. 1, page 1907; PF Vol. 27,
Trioleoylglycerol—See PF Vol. 26, No. 6, page 1623. No. 2, page 2281; PF Vol. 27, No. 5, page 3120; PF Vol. 27,
Tris(hydroxymethyl)arninornethane Acetate—See PF Vol. 27, No. No. 6, page 3374; PF Vol. 28, No. 1, page 116; and PF Vol.
5, page 3117. 28, No. 2, page 554.
Tris(hydroxymethyl)aminomethane Hydrochloride—See PF Vol.
27, No. 6, page 3370. GENERAL NOTICES AND REQUIREMENTS
N-Tris(hydroxymethyl)methylglycine—See PF Vol. 27, No. 5,
page 3117. "Official" and "Official Articles"—See PF Vol. 28, No. 1, page
L-Tyrosine Disodium—See PF Vol. 27, No. 6, page 3370.
Water, HPLC Grade—See PF Vol. 28, No. 1, page 115.
Vinyl Acetate—See PF Vol. 21, No. 2, page 466. NF MONOGRAPHS
2-Vinylpyridine—See PF Vol. 26, No. 2, page 504. Corn Syrup—See PF Vol. 28, No. 2, page 403.
l-Vinyl-2-pyrrolidone—See PF Vol. 22, No. 6, page 3249. High Fructose Corn Syrup—See PF Vol. 28, No. 2, page 408.
Zinc Sulfate Heptahydrate—See PF Vol. 26, No. 2, page 504. Acetyltributyl Citrate—See PF Vol. 27, No. 5, page 3058.
Acetyltriethyl Citrate—See PF Vol. 27, No. 5, page 3058.
Indicator and Test Papers Myristyl Alcohol—See PF Vol. 27, No. 3, page 2589.
Hydroxy Naphthol Blue Indicator—See PF Vol. 27, No. 6, page Benzalkonium Chloride Solution—See PF Vol. 27, No. 5, page
3370. 3059.
Hydroxy Naphthol Blue Trituration—See PF Vol. 27, No. 6, page Benzyl Alcohol—See PF Vol. 27, No. 4, page 2790.
3370. Butylated Hydroxyanisole—See PF Vol. 27, No. 3, page 2590.
Thiazole Yellow Paper—See PF Vol. 27, No. 5, page 3117. Calcium Silicate—See PF Vol. 27, No. 6, page 3337.
Calcium Sulfate—See PF Vol. 27, No. 6, page 3337.
Test Solutions Caprylocaproyl Macrogolglycerides—See PF Vol. 26, No. 2, page
448.
Buffer Solutions—See PF Vol. 27, No. 6, page 3371. Carbomer 941—See PF Vol. 27, No. 6, page 3338.
Cupric Citrate TS—See PF Vol. 27, No. 5, page 3117. Carbomer Copolymer—See PF Vol. 27, No. 2, page 2219.
Ferroin TS—See PF Vol. 27 No. 1, page 1905. Carbomer Interpolymer—See PF Vol. 27, No. 2, page 2222.
Iodine, Diluted TS—See PF Vol. 27, No. 6, page 3372. Carboxymethylcellulose Sodium 12—See PF Vol. 26, No. 6, page
Mercuric-Potassium Iodide TS, Alkaline—See PF Vol. 27, No. 6, 1577.
page 3372.
Pharmacopeial Forum
Cellulose Acetate Butyrate—See PF Vol. 25, No. 2, page 7861. Kava Capsules—See PF Vol. 26, No. 3, page 785.
Cetostearyl Alcohol—See PF Vol. 26, No. 6, page 1350. Kava Tablets—See PF Vol. 26, No. 3, page 787.
Chamomile—See PF Vol. 27, No. 5, page 3059. Lauroyl Macrogolglycerides—See PF Vol. 26, No. 2, page 456.
Chondroitin Sulfate Sodium—See PF Vol. 27, No. 5, page 3059. Licorice—See PF Vol. 26, No. 5, page 1363.
Chondroitin Sulfate Tablets—See PF Vol. 27, No. 5, page 3063. Linoleoyl Macrogolglycerides—See PF Vol. 26, No. 2, page 457.
Copovidone—See PF Vol. 24, No. 5, page 6891. oc-Lipoic Acid—See PF Vol. 27, No. 6, page 3338.
Purified Cotton Filler—See PF Vol. 26, No. 1, page 213. Magnesium Aluminometasilicate—See PF Vol. 28, No. 2, page
Dextrin—See PF Vol. 28, No. 2, page 411. 411.
Dimethicone—See PF Vol. 27, No. 6, page 3338. Magnesium Aluminosilicate—See PF Vol. 28, No. 2, page 414.
Echinacea angustifolia—See PF Vol. 26, No. 6, page 1578. Maltitol Solution—See PF Vol. 27, No. 6, page 3340.
Powdered Echinacea angustifolia—See PF Vol. 26, No. 6, page Milk Thistle—See PF Vol. 28, No. 2, page 414.
1583. Powdered Milk Thistle—See PF Vol. 28, No. 2, page 417.
Powdered Echinacea angustifolia Extract—See PF Vol. 26, No. 6, Powdered Milk Thistle Extract—See PF Vol. 28, No. 2, page 417.
page 1583. Milk Thistle Capsules—See PF Vol. 28, No. 2, page 420.
Echinacea pallida—See PF Vol. 26, No. 6, page 1585. Milk Thistle Tablets—See PF Vol. 28, No. 2, page 422.
Powdered Echinacea pallida—See PF Vol. 26, No. 6, page 1588. Mono- and Di-glycerides—See PF Vol. 27, No. 5, page 3065.
Powdered Echinacea pallida Extract—See PF Vol. 26, No. 6, page Myristyl Alcohol—See PF Vol. 28, No. 2, page 424.
1588. Nettle—See PF Vol. 28, No. 1, page 105.
Echinacea purpurea Root—See PF Vol. 26, No. 6, page 1590. Powdered Nettle—See PF Vol. 28, No. 1, page 108.
Powdered Echinacea purpurea—See PF Vol. 26, No. 6, page 1593. Powdered Nettle Extract—See PF Vol. 28, No. 1, page 109.
Powdered Echinacea purpurea Extract—See PF Vol. 26, No. 6, Oleic Acid—See PF Vol. 26, No. 5, page 1366.
page 1594. Oleoyl Macrogolglycerides—See PF Vol. 26, No. 2, page 459.
Eleuthero—See PF Vol. 26, No. 6, page 1596. Purified Rayon Filler—See PF Vol. 26, No. 1, page 216.
Powdered Eleuthero—See PF Vol. 26, No. 6, page 1598. Saw Palmetto Extract—See PF Vol. 28, No. 2, page 425.
Powdered Eleuthero Extract—See PF Vol. 26, No. 6, page 1599. St. John's Wort—See PF Vol. 26, No. 2, page 460.
Ethylcellulose—See PF Vol. 25, No. 2, page 7866. Powdered St. John's Wort—See PF Vol. 25, No. 2, page 7876.
Garlic Delayed-Release Tablets—See PF Vol. 28, No. 1, page 89. Powdered St. John's Wort Extract—See PF Vol. 26, No. 2, page
Ginger Capsules—See PF Vol. 27, No. 2, page 2227. 463.
Ginkgo—See PF Vol. 27, No. 2, page 2229. Sodium Starch Glycolate—See PF Vol. 22, No. 6, page 3202.
Powdered Ginkgo Extract—See PF Vol. 27, No. 2, page 2233. Sorbitol—See PF Vol. 27, No. 6, page 3342.
Ginkgo Capsules—See PF Vol. 27, No. 2, page 2238. Noncrystallizing Sorbitol Solution—See PF Vol. 27, No. 6, page
Ginkgo Tablets—See PF Vol. 27, No. 2, page 2240. 3344.
American Ginseng—See PF Vol. 27, No. 2, page 2243. Stearoyl Macrogolglycerides—See PF Vol. 26, No. 2, page 467.
Powdered American Ginseng—See PF Vol. 27, No. 2, page 2247. Sucrose—See PF Vol. 22, No. 6, page 3206.
Powdered American Ginseng Extract—See PF Vol. 27, No. 2, page Sunflower Oil—See PF Vol. 27, No. 4, page 2803.
2247. Sugar-Free Suspension Structured Vehicle—See PF Vol. 28, No. 2,
Asian Ginseng Capsules—See PF Vol. 26, No. 3, page 775. page 428.
Asian Ginseng Tablets—See PF Vol. 27, No. 2, page 2254. Suspension Structured Vehicle—See PF Vol.28, No. 2, page 429.
Goldenseal—See PF Vol. 27, No. 2, page 2255. Tributyl Citrate—See PF Vol. 27, No. 5, page 3067.
Powdered Goldenseal—See PF Vol. 27, No. 2, page 2257. Triethyl Citrate—See PF Vol. 27, No. 5, page 3068.
Powdered Goldenseal Extract—See PF Vol. 27, No. 2, page 2258. Valerian Capsules—See PF Vol. 27, No. 1, page 1825.
Hawthorn Leaf with Flower—See PF Vol. 26, No. 5, page 1357. Xanthan Gum Solution—See PF Vol. 28, No. 2, page 429.
Powdered Hawthorn Leaf with Flower—See PF Vol. 26, No. 5,
page 1362. NUTRITIONAL SUPPLEMENTS
Glucosamine Hydrochloride—See PF Vol. 28, No. 1, page 92.
Glucosamine Potassium Sulfate—See PF Vol. 28, No. 1, page 94. USP MONOGRAPHS
Glucosamine Sodium Sulfate—See PF Vol. 28, No. 1, page 95.
Glucosamine Tablets—See PF Vol. 28, No. 1, page 97. Calcium and Vitamin D with Minerals Tablets—See PF Vol. 27,
Glucosamine and Chondroitin Sulfate Tablets—See PF Vol. 28, No. 2, page 2283.
No. 1, page 98.
Hydroxypropyl Beta Cyclodextrin—See PF Vol. 24, No. 6, page GENERAL CHAPTERS
7284. (2040) Disintegration and Dissolution of Nutritional Supple-
Isopropyl Myristate—See PF Vol. 26, No. 5, page 1362. ments—See PF Vol. 26, No. 3, page 838.
Kava—See PF Vol. 28, No. 1, page 100. (2750) Manufacturing Practices for Nutritional Supplements—See
Powdered Kava—See PF Vol. 28, No. 1, page 104. PF Vol. 28, No. 2, page 534.
Powdered Kava Extract—See PF Vol. 26, No. 3, page 783.
Semisolid Kava Extract—See PF Vol. 26, No. 3, page 784.
Pharmacopeial Forum
(Canceled proposals may be republished at any time in a future number of Pharmacopeial Forum.)
[PF 2%{\}-PF 28(6)]
Title and Proposal Vol. No. Page(s)
USP Monographs
Alcohol (Monograph reproduced from Pharmeumpa) 22 6 3021
Dehydrated Alcohol (Monograph reproduced from 22 6 3024
Pharmeuropa)
Citric Acid (Monograph reproduced from 25 3 8114
Pharmeuropa)
USP Reference standards, Clarity of
solution, Color of solution, Identification
(subsections A B C D)
Fluorodopa F 18 Injection—pH, Chemical purity, 26 1 155
Radiochemical purity, Specific activity,
USP Reference standards, Enantiomeric
purity
fGlycerin 27 5 3010
Definition (Proposed IRA)
fNitrofurantoin Extended-Release Capsules 25 5 8853
Paclitaxel (new) 27 2 2183
•fPhenylpropanolamine Hydrochloride Extended- 24 2 5787
Release Capsules—Drug release
(subsection Test 2)
fPhenylpropanolamine Hydrochloride Extended- 24 2 5788
Release Tablets—Drug release
(subsection Test 2)
(I) Injections—Packaging 27 5 3068
Content variation of single-dose
injections containing 30 mL or less
(II) USP Reference Standards— 25 3 8222
USP 6-Fluoro-D,L-dopa RS , USP
Tinidazole RS, USP Tinidazole Related
Compound A RS, USP Saquinavir Related
Compound A RS
(13) Concordance of Foreign 24 1 5612
Pharmacopeial Tests and Assays (new)
(281) Residue on Ignition— 27 2 2269
Introduction
Procedure
(381) Elastomeric Closures for 24 5 6988
Injections—Introduction
Physicochemical Tests (subsections
Apparatus Preparation and Extraction,
Testing, Footnote, Interpretation,
Table I )
NF Monographs
Ethylcellulose—Definition, Identification 25 2 7866
(subsections ABC), Labeling, Limit of
acetaldehyde, Limit of chloride, Organic
volatile impurities, Assay
(Harmonization)
fNew cancellations in 28(3)
HARMONIZATION
This section contains monographs or chapters undergoing harmonization by the Pharmacopeial Discussion Group (PDG).
The PDG consists of the United States Pharmacopeia (USP), the European Pharmacopoeia (EP), and the Japanese Pharma-
copoeia (JP). The process of harmonization is composed of several steps (Stages).
item. The PDG distributes the work by consensus among the three participating pharmacopeias. Harmonization may be car-
ried out retrospectively for existing monographs or chapters, or prospectively for new monographs or chapters.
experts, and staff.
Stage 5: Consensus
A. Provisional
B. Final
Adopted items are published by the three pharmacopeias in their Supplements or, where applicable, in a new edition of their
Pharmacopeias.
region.
Pharmacopeia! Forum
866 HARMONIZATION Vol. 28(3) [May-June 2002]
HARMONIZATION 865
IN-PROCESS 867
Carboxymethylcellulose Sodium 867
Citric Acid 872
MONOGRAPHS (NF) 879
Benzyl Alcohol 879
Corn Starch 882
Potato Starch 885
Wheat Starch 888
(1216) Tablet Friability 891
Description and Relative Solubility of Harmonization Articles 892
Corn Starch 892
Potato Starch 892
Wheat Starch 893
PREVIEWS 893
(267) Porosimetry by Mercury Intrusion 893
(429) Light Diffraction Measure of Particle Size 895
(616) Bulk Density and Tapped Density 901
(943) X-Ray Diffraction Solids 905
(1111) Microbial Contamination Limits for Non-sterile Products 916
Pharmacopeial Forum
Vol. 28(3) [May-June 2002] HARMONIZATION 867
1439-94, Degree of Substitution, Method B. The calculation

MONOGRAPHS (USP) has been modified to provide the percentage of sodium. Table
2 is used in determining the degree of substitution.
(12) Sodium chloride, Sodium glycolate, and Sodium sulfate—The
primary impurities in the manufacture of Carboxymethylcel-
lulose Sodium are sodium chloride and sodium glycolate. The
Japanese Pharmacopoeia has indicated that there is also at
least one manufacturer's process with sodium sulfate as an
impurity.
BRIEFING
The test procedures for sodium chloride and sodium glyco-
late are taken from the NF monograph for Carboxymethylcel-
Carboxymethylcellulose Sodium, USP 25 page 316. The Uni- lulose Sodium 12 and are essentially the same as those
ted States Pharmacopeia is the coordinating pharmacopeia for the described in ASTM Standard D 1439-94. The test procedure
international harmonization of compendial standards for the sub- for sodium sulfate is taken from the JP.
ject article. The revisions presented in this proposal, which repre- The United States Code of Federal Regulations requires
sents the OFFICIAL INQUIRY STAGE 4 draft in the CMC sodium (cellulose gum) to have a minimum purity of
harmonization process, reflect those changes suggested by industry 99.5% (calculated on the dry basis). Because manufacturers
and also incorporates comments and suggestions made by EP and worldwide have demonstrated the ability to meet this require-
JP. The harmonized monograph sections proposed for the USP ment, the proposed limit for all three impurities combined is
monograph have been editorially styled. not more than 0.5%.
Changes from the current USP monograph include the follow-
ing:
(1) Definition—The official USP position is that if there are any (EMC: J. Lane) RTS—36747-2
additives in an article, they must be specified in the Definition.
Because no additives are allowed in this article, none are men-
tioned. In response to a request from EP, the limit for sodium
content is changed from not less than 6.5% and not more than
9.5% to not less than 6.0% and not more than 12.0%. Because Change to read:
there is no health or safety issue involved in reducing the low-
er limit to 6.0%, the recommended specification for sodium is •Carboxymethylcellulose Sodium
6.0% to 12.0%.
(2) Packaging and storage—No change.
(3) Labeling—The labeling is strengthened with a requirement to Cellulose, carboxymethyl ether, sodium salt
indicate the nominal viscosity of solutions of stated concen-
trations at 25° and the degree of substitution, which may be Carmellose Sodium
given as a range.
(4) USP Reference standards—A reference standard is added to
comply with the added Identification test.
(5) Identification—A new definitive Identification test based on
IR spectroscopy replaces existing Identification tests A and B. » Carboxymethylcellulose Sodium is the sodium
(6) Viscosity—A modified test method is proposed. Formulas for
calculating the Carboxymethylcellulose Sodium mass, in g, salt of a carboxymethyl ether of cellulose. It con-
necessary to make 240 g of test solution, and for calculating
the required amount of distilled water are provided, as well as tains not less than 6.0 percent and not more than
a reference table listing the spindle and speed. The prepara-
tion of the solution and the procedure is described in ASTM 12.0 percent of sodium (Na), calculated on the
Standard D 1439-94, Standard Test Methods for Sodium Car-
boxymethylcellulose. The requirement is not less than 65%
and not more than 135% of the nominal value stated on the dried basis.
label.
(7) pH—Limits of 6.0 to 8.5 are recommended. The current spe- Packaging and storage—Preserve in a tight container.
cification for a 1% solution is 6.0 to 8.0 in the EP and JP and
6.5 to 8.5 in the USP. Some consideration was given to redu- Labeling—Label it to indicate (1) the nominal viscosity of
cing the lower end of the specification to 5.0, but it was
decided that this was nearing the specification of the acid form
of CMC (Carmellose in the JP) where the pH specification is solutions of stated concentrations at 25°, and (2) degree of
3.5 to 5.0.
(8) Loss on drying—No change. substitution (may be stated as a range).
(9) Heavy metals—The working group decided to keep this test as
a general indicator of fitness for use. Wet digestion is specified USP Reference standards (U)—USP Carboxymethylcel-
because of a concern over the loss of heavy metals during
ignition. The sample size has been changed from 1.0 g to lulose Sodium RS.
2.0 g.
(10) Organic volatile impurities—This test has been omitted from Identification—Transfer, while stirring, about 1.0 g of
the Harmonization draft, because it most likely will not be a
harmonized attribute. This test will, however, remain in the powdered Carboxymethylcellulose Sodium, accurately
USP monograph.
(11) Degree of substitution—The method selected is the Degree of weighed, to a beaker containing 100 mL of water, stir to pro-
substitution test shown in the current NF monograph for Car-
boxymethylcellulose Sodium 12 and in ASTM Standard D
Pharmacopeial Forum
duce a uniform dispersion, and continue stirring until a clear pH (791): between 6.0 and 8.5 in a solution (1 in 100).
solution is produced (about 2 hours). Use this solution for Loss on drying (731)—Dry it at 105° for 3 hours: it loses
the following tests. not more than 10.0% of its weight.
A: The infrared absorption spectrum of a dried film of it Heavy metals, Method III (231): 20 jag per g, using a 2.0-g
matches that of a similar preparation of USP Carboxy- specimen and submitting it to wet digestion after adding 1.0
methylcellulose Sodium RS. mL of Standard Lead Solution to the Standard preparation.
B: A portion of the solution responds to the tests for So- Degree of substitution—Transfer about 200 mg of Carbox-
dium (191). ymethylcellulose Sodium, accurately weighed and pre-
Viscosity (911)—Determine the viscosity in a water solu- viously dried at 105° for 3 hours, to a glass-stoppered,
tion at the concentration stated on the label. Using the value 250-mL conical flask, add 75 mL of glacial acetic acid, con-
for Loss on drying, calculate the mass of Carboxymethylcel- nect the flask to a water-cooled condenser, and reflux gently
lulose Sodium required to make 240 g of test solution using on a hot plate for 2 hours. Cool, transfer the solution to a
the following formula: 250-mL beaker with the aid of 50 mL of glacial acetic acid,
and titrate with 0.1 N perchloric acid in dioxane VS while
M= 240,4/(100 -B),
stirring with a magnetic stirrer. Determine the endpoint po-
in which A is the desired concentration of the solution and B tentiometrically, using a silver electrode and a mercurous
is the percentage obtained in the Loss on drying test. Calcu-
sulfate electrode having a potassium sulfate bridge and stir-
late the required volume of distilled water required by the
ring constantly. Record the amount, in mL, of 0.1 N perchlo-
formula:
ric acid in the 0- to 700-mV range, and continue the titration
F=240-M,
to a few mL beyond the endpoint. Plot the titration curve,
in which Mis the mass, in g, of Carboxymethylcellulose So- and read the volume, in mL, of 0.1 N perchloric acid at
dium; Fis the volume, in mL, of distilled water; and Mis the the inflection point. Each mL of 0.1 N perchloric acid is
mass, in g, of Carboxymethylcellulose Sodium in the test equivalent to 2.299 mg of sodium (see Table 2).
solution. Transfer the required volume of water to a wide- Sodium chloride—Transfer about 5 g of Carboxymethyl-
mouth glass jar that is approximately 64 mm (2.5 inches) cellulose Sodium, accurately weighed, to a 250-mL beaker,
in diameter and 152 mm (6 inches) tall. Position the stirrer add 50 mL of water and 5 mL of 30% hydrogen peroxide,
in the jar, leaving a minimal clearance between the stirrer and heat on a steam bath for 20 minutes, stirring occasion-
and the bottom of the jar. While stirring, slowly add the Car- ally to ensure hydration. Cool, add 100 mL of water and 10
boxymethylcellulose Sodium. Adjust the stirring speed to mL of nitric acid, and titrate, while stirring constantly, with
approximately 900 ± 1 0 0 rpm, and mix for 2 hours in a 0.05 N silver nitrate VS, determining the endpoint potentio-
constant-temperature bath at 25°. Immediately measure metrically, using a silver electrode and a mercurous sulfate
the viscosity with an LV-type rotational viscometer using electrode with a potassium sulfate bridge. Calculate the per-
the spindle and speed indicated in Table 1. Allow the spindle centage of sodium chloride (NaCl) in the Carboxymethyl-
to rotate for 3 minutes before taking the reading. The visc- cellulose Sodium taken by the formula:
osity is not less than 65.0% and not more than 135.0% of the
nominal value stated on the label. - b)W\,
Pharmacopeia! Forum
in which 584.4 is the equivalence factor for sodium chlo- move from the bath, and cool. To each flask, add 5.0 mL of
ride; Fis the volume, in mL, of silver nitrate; TV is the nor- 2,7-dihydroxynaphthalene TS, mix, add an additional 15
mality of silver nitrate; b is the percentage obtained from the mL, and mix again. Cover the mouth of each flask with a
Loss on drying test, determined separately; and W is the small piece of aluminum foil, place the flasks upright in a
weight, in g, of the Carboxymethylcellulose Sodium taken. boiling water bath for 20 minutes, remove from the bath,
Sodium chloride is not more than 0.64%. cool, dilute with sulfuric acid to volume, and mix. Deter-
Sodium glycolate— mine the absorbance of each solution at 540 nm with a suit-
Test solution—Transfer about 500 mg of Carboxymethyl- able spectrophotometer against the Blank, and prepare a
cellulose Sodium, accurately weighed, to a 100-mL beaker, standard curve using the absorbances obtained from the
moisten thoroughly with 5 mL of glacial acetic acid, add 5 Standard solutions. From the standard curve and the absor-
mL of water, and stir with a glass rod to ensure proper hy- bance of the test specimen, determine the weight (w), in mg,
dration (about 15 minutes). Slowly add 50 mL of acetone of glycolic acid in the specimen, and calculate the percen-
while stirring, add 1 g of sodium chloride, and stir for sev- tage of sodium glycolate in the specimen taken by the for-
eral minutes to ensure the complete precipitation of carbox- mula:
ymethylcellulose. Filter through a soft, open-textured paper, 12.9w/[(100 - b)W],

previously wetted with a small amount of acetone, collect
in which 12.9 is the g molecular mass of sodium glycolate
the filtrate in a 100-mL volumetric flask, and use an addi-
per g (molecular mass of glycolic acid) x 10, b is the %
tional 30 mL of acetone to facilitate the transfer of solids
Loss on drying, W is the weight, in mg, of the specimen,
and to wash the filter cake. Dilute the filtrate with acetone
and w is the weight, in mg, of glycolic acid from the stan-
to volume, and mix.
dard curve.
Standard solutions—Transfer 100 mg of glycolic acid,
Sodium sulfate—
previously dried overnight in a desiccator at room tempera-
Test solution—Dissolve 0.5 g of Carboxymethylcellulose
ture and accurately weighed, to a 100-mL volumetric flask,
Sodium, accurately weighed, in 50 mL of water. To 10 mL
dissolve in water, dilute with water to volume, and mix. Use
of this solution, add 1 mL of hydrochloric acid, shake well,
this stock solution within 30 days. Transfer 1.0-mL, 2.0-mL,
heat to produce aflocculentprecipitate, cool, and centrifuge.
3.0-mL, and 4.0-mL portions of the stock solution, respec-
Separate the supernatant, and wash the precipitate with three
tively, to separate 100-mL volumetric flasks. To each flask,
10-mL portions of water, centrifuging each time and com-
add water to make 5 mL, add 5 mL of glacial acetic acid,
bining the washings with the supernatant. Dilute with water
dilute with acetone to volume, and mix.
to 50 mL, transfer 10 mL to a Nessler tube, and dilute with
Blank—Transfer 2.0 mL of a solution in acetone contain-
water to 50 mL.
ing 5% of glacial acetic acid and 5% water to a flask.
Control solution—Transfer 0.40 mL of 0.001 N sulfuric
Procedure—Transfer 2.0 mL of Test solution and 2.0 mL
acid to a second Nessler tube, add 1 mL of dilute hydro-
of each Standard solution to separate 25-mL volumetric
chloric acid, and add water to make 50 mL.
flasks. Place the uncovered flasks in a boiling water bath
for 20 minutes, accurately timed, to remove the acetone, re-
Pharmacopeial Forum
Procedure—If the Test solution is not perfectly clear after Table 1. Viscosity Measurement of Carboxymethyl-
acidification, filter the Test solution and the Control solution cellulose Sodium Using an LV-Type Rotational Visc-
through a filter paper that gives a negative test for sulfate. ometer
Add 2 mL of barium chloride TS to each solution, mix well,
Labeled Spindle Speed Factor Maximum
and allow to stand for 10 minutes. Compare the white tur-
Viscosity No. (rpm) Reading
bidity produced by viewing downward or transversely
(cps.)
against a black background. The Test solution shows no
more turbidity than the Control solution. Sodium sulfate is 15 or 1 60 1 100
not more than 0.96%. more and
Assay—Assay is defined as 100 - (% sodium glycolate). less than
The limit is not less than 99.5%. 51
50 or 2 60 5 500
more and
less than
201
200 or 2 30 10 1,000
more and
less than
901
750 or 3 30 40 4,000
more and
less than
3200
2500 or 4 30 200 20,000

more and
less than
12000
Pharmacopeial Forum
Table 2. Degree of Substitution (D.S.) corresponding to Percent Sodium (% Na)f
D.S. %Na D.S. %Na D.S. %Na D.S. %Na D.S. %Na
0.38 4.5 0.63 6.8 0.88 8.7 1.13 10.3 1.38 11.6
0.39 ' 4.6 0.64: - *6>£ 0.89 8.8 - {'L14 # ,;IO.3 * ^1.319= 1 ILT, -
0.40 4.7 0.65 7.0 0.90 8.8 1.15 10.4 1.40 11.7
0.41 , 4,8 < W.66 \ •7.1 0.91 - 8 . 9 '• ^ i.i6": -'• I O J • : XM „ "•/1*E8-:
0.42 4.9 0.67 7.1 0.92 9.0 1.17 10.5 1.42 11.8
1
0.43 " 5$ '^ 0.68 •* • 12 ; , 0.93 9.0 " - : 118 1016 ' t;43- ••.' 1 1 . 9 - - - ;
0.44 5.1 0.69 7.3 0.94 9.1 1.19 10.6 1.44 11.9
0.45 v 5.2 o ' O.70 7.4 ; ' 0.95 ' 912. .-" 1.20 ' '- 1G.7 - .1.45 : f2.0^V '
0.46 5.3 0.71 7.5 0.96 9.2 1.21 10.7 1.46 12.0
0.47 5.4. * " ,0,72 " 7.5 ,. 0.97 " 9.3 t.22 10.8 1:47" '
0.48 5.5 0.73 7.6 0.98 9.4 1.23 10.9 1.48 12.1
0.49' * 5.6" - 0.74 * 7.7 ; ' 0.99 ' - "9.4 - s - 1,24 10.9 ' . 1.49*"' -
0.50 5.7 0.75 7.8 1.00 9.5 1.25 11.0 1.50 12.2
0.51 . 5.8 - 0.76 *. -7.8-' . . ' WSiV- -' 9,6 ' I -L26" : 1 1 . 0 *"• ^'51^ \
0.52 5.9 0.77 7.9 1.02 9.6 1.27 11.1 1.52 12.3
0.53 6.0 0.78. 8,0 - 1.03-- * 9.7/ 1J28 " 7 * ir:Lu^r K^3 * -:> 12.4 "^
0.54 6.0 0.79 8.1 1.04 9.7 1.29 11.2 1.54 12.4
1
0.55 ' 61 /:•. 0.80" 8 . 1 " . • 1.05 - 3.S ;1.30 . 11.2 ,f- 1.55" • -• $2&l?&
0.56 6.2 0.81 8.2 1.06 9.9 1.31 11.3 1.56 12.5
J
. 0.57 63 . '" 0.82 . ' -8.3 1.07 9.9 : 1.32: , - 11.3 * 4.-57T^
0.58 6.4 0.83 8.4 1.08 10.0 1.33 11.4 1.58 12.6
1
0.5,9 ' 6.5 .. 0.84 ' '8.4 1.09 10.1 • "1.34 - • 1 1 . 4 - * *i:s9 .. .£2;6 J y"',
; v
0,60 6.6 0.85 8.5 1.10 10.1 1.35 11.5 1.60 12.7
0.61 • 6.7 •'. 0:86 * 8.6,,, 111 ,10.2 ...!• 1.36 • -11.5 •
0.62 6.7 0.87 8.6 112 10.2 1.37 11.6
t % Na = (28.74 D.S.)/(2.026 + D.S.)
Pharmacopeial Forum
Assay—Place about 3 g of Citrio Aoid in a tarod flask, and woigh

accurately. Diaaolvo in 10 mL of wator, add phonolphthaloin TS,
and titrate with 1 N sodium hydroxide VS. Each mL of 1 N sodium
BRIEFING hydroxide is equivalent to 61.01 mg of C^H^Q^T, J
Citric Acid, USP 25 page 430. It is proposed to delete the

monograph. See briefings under Citric Acid, Anhydrous and Citric
Acid, Monohydrate.
(EMC: J. Lane) RTS—36456

BRIEFING
m
Citric Acid
Citric Acid, Anhydrous. The European Pharmacopoeia is the
the compendial standards for the Citric Acid, Anhydrous mono-
graph, as part of the process of international harmonization of
monographs and general analytical methods of the European, Japa-
nese, and United States pharmacopeias. The following monograph,
which represents the ADOPTION STAGE 6 document, is based on
the corresponding monograph for Citric Acid, Anhydrous that was
prepared by the European Pharmacopoeia. The European Pharma-
192 12 copoeia draft was based in part on comments from the Japanese
1,2,3 Propanetricarboxylio aoid, 2 hydroxy . Pharmacopoeia and the United States Pharmacopeia in response
Citrio aoid [77 92 9]. to the Provisional Harmonized Text Stage 5A and 5B drafts pre-
Monohydrato 24444 [5949 29 I]. pared by the European Pharmacopoeia. The current USP mono-
graph for Citric Acid will be replaced with two separate
monographs for Citric Acid, Anhydrous and Citric Acid, Monohy-
drate.
» Citric Acid is anhydrous or contains ono moloculo of Differences between the European Pharmacopoeia Adoption
wator of hydration. It contains not loss than 99.5 por Stage 6 document and the current USP monograph include the fol-
cent and not moro than 100.5 percent of C^HÔ?, cal lowing:
culatod on the anhydrous basis. (1) Definition—Changed to include only Citric Acid, Anhydrous,
as to conform to the individual monograph for Citric Acid,
Packaging and storage—Preserve in tight containers. Anhydrous.
Labeling—Label it to indicate whether it is anhydrous or hydrous. (2) Labeling—The indication of anhydrous or hydrous is deleted,
Identification—A solution responds to the tests for Citrate (4-94-)? as to conform to the individual monograph for Citric Acid,
Anhydrous. A requirement that the label indicate where it is
Water, Method I (934-): not moro than 0.5% (anhydrous form) and intended for use in dialysis solutions is added.
not moro than 8.8% (hydrous form). (3) USP Reference standards—A Citric Acid reference standard
Readily earbonizablo substances—Transfer 1.0 g, powdorod for to be used with the Identification test is added.
tho tost, to a 22—x 175 mm tost tube previously rinsod with 10 mL (4) Clarity of solution—This test is added in order to conform
of sulfurio aoid TS and allowed to drain for 10 minutes. Add 10 mL with EP standards.
of sulfurio aoid TS, agitato until solution is oomploto, and immorso (5) Color ofsolution—This test is added in order to conform with
in a wator bath at 90 + 1° for 60 + 0.5 minutes, kooping tho lovol EP standards.
of the aoid below tho lovol of the water during tho entire period- (6) Identification—The test for Citrate is deleted and a more de-
Cool tho tubo in running wator, and transfer tho aoid to a color finitive infrared absorption test is added.
comparison tubo: the oolor of the aoid is not darker than that of a (7) Water—The standard for this test is increased from 0.5% to
similar volume of Matching Fluid K (see Color and Achwmicity 1.0% in order to conform with EP standards.
(6£4-)) in a matching tubo, tho tubes being observed vertically (8) Residue on ignition—The standard for this test is increased
against a white background- from 0.05% to 0.1% in order to conform with JP standards.
(9) Readily carbonizable substances—No change.
Residue on ignition (S&4-): not more than 0.05%. (10) Sulfate—The test procedure is changed to a quantitative test
Sulfate To 10 mL of a solution (1 in 100) add 1 mL of barium in order to conform to EP standards.
chloride TS to which has boon added 1 drop of hydrochloric aoid: (11) Arsenic—This test is deleted because the Heavy metals test
no turbidity is produced. sufficiently accounts for arsenic.
Arsenic, Method I (344-)T- (12) Heavy metals—No change.
Heavy metals (S2 (13) Limit of oxalic acid—The test procedure is changed to a quan-
Limit of oxalate—Noutralizo 10 mL of a solution (1 in 10) with 6 titative test in order to conform to EP standards.
N ammonium hydroxide, add 5 drops of 3 N hydroohlorio aoid, (14) Limit of aluminum—This test is added in order to conform
cool, and add 2 mL of oaloium chloride TS: no turbidity is pro with EP standards concerning usage in dialysis. This require-
ment is similar to the Limit of aluminum in the USP Calcium
Organic volatile impurities, Method IV (462): moots tho require Acetate monograph.
(15) Organic volatile impurities—No change.
Pharmacopeial Forum
(16) Assay—The sample size is decreased from 3 g in 40 mL of Primary opalescent suspension—[NOTE—This suspen-
water to 0.55 g in 50 mL of water. The amount of Citric Acid
that is equivalent to 1 mL of 1 N sodium hydroxide is changed sion is stable for 2 months, provided it is stored in a glass
from 64.04 mg to a more accurate 64.03 mg.
container free from surface defects. The suspension must
(EMC: J. Lane) RTS—36456-2 not adhere to the glass and must be well mixed before
use.] Transfer 25.0 mL of Hydrazine sulfate solution to
Add the following: the Hexamethylenetetramine solution in the 100-mL glass-

stoppered flask. Mix, and allow to stand for 24 hours.
•Citric Acid, Anhydrous
Opalescence standard—[NOTE—This suspension should
(Chemical structure to come) not be used beyond 24 hours after preparation.] Transfer
C6H8O7 192.13 15.0 mL of the Primary opalescent suspension to a 1000-
1,2,3-Propanetricarboxylic acid, 2-hydroxy-. mL volumetric flask, dilute with water to volume, and mix.
Citric acid [77-92-9]. Reference suspensions—Transfer 5.0 mL of the Opales-

cence standard to a 100-mL volumetric flask, dilute with
water to volume, and mix to obtain Reference suspension
» Anhydrous Citric Acid contains not less than A. Transfer 10.0 mL of the Opalescence standard to a sec-
ond 100-mL volumetric flask, dilute with water to volume,
and mix to obtain Reference suspension B.
C6H8O7, calculated on the anhydrous basis.
Test solution—Dissolve 2.0 g of Citric Acid in about 5 mL
Packaging and storage—Preserve in tight containers. of water, dilute with water to 10 mL, and mix.
Labeling—Where it is intended for use in dialysis solu- Procedure—Transfer a sufficient portion of the Test solu-
tions, it is so labeled. tion to a test tube of colorless, transparent, neutral glass with
USP Reference standards (11)—USP Citric Acid RS. a flat base and an internal diameter of 15 to 25 mm to obtain
Clarity of solution—[NOTE—The Test solution is to be a depth of 40 mm. Similarly transfer portions of Reference
compared to Reference suspension A in diffused daylight suspension A, Reference suspension B, and water to separate
5 minutes after preparation of Reference suspension A.] matching test tubes. Compare the Test solution, Reference
Hydrazine sulfate solution—Transfer 1.0 g of hydrazine suspension A, Reference suspension B, and water in diffused
sulfate to a 100-mL volumetric flask, dissolve in and dilute daylight, viewing vertically against a black background (see
with water to volume, and mix. Allow to stand for 4 to 6 Visual Comparison under Spectrophotometry and Light-
hours before use. Scattering (851)). [NOTE—The diffusion of light must be
Hexamethylenetetramine solution—Transfer 2.5 g of such that Reference suspension A can readily be distin-
Hexamethylenetetramine to a 100-mL glass-stoppered flask, guished from water, and that Reference suspension B can
add 25.0 mL of water, insert the glass stopper, and mix to readily be distinguished from Reference suspension A.]
dissolve. The Test solution shows the same clarity as that of water.
Pharmacopeia! Forum
Color of solution— Bacterial endotoxins test (85)—If intended for use in the
Standard stock solutions—Prepare three solutions, A, B, manufacturing of parenteral dosage forms, without a further
and C, containing, respectively, the following parts of ferric appropriate procedure for the removal of bacterial endotox-
chloride CS, cobaltous chloride CS, cupric sulfate CS, and ins, not more that 0.5 I.U. of endotoxin per milligram.
dilute hydrochloric acid (10 g/L): Water, Method I (921): not more than 1.0%.
^—2.4:0.6:0:7.0 Residue on ignition (281): not more than 0.1 %, determined
5—2.4:1.0:0.4:6.2 on 1.0 g.
C—9.6:0.2:0.2:0 Readily carbonizable substances—Transfer 1.0 g, pow-
Standard solutions—[NOTE—Prepare the Standard solu- dered for the test, to a 22- x 175-mm test tube previously
tions immediately before use.] Transfer 2.5 mL of Standard rinsed with 10 mL of sulfuric acid TS and allowed to drain
stock solution A to a 100-mL volumetric flask, dilute with for 10 minutes. Add 10 mL of sulfuric acid TS, agitate until
dilute hydrochloric acid (10 g/L) to volume, and mix to ob- solution is complete, and immerse in a water bath at 90° +
tain Standard solution A. Transfer 2.5 mL ofStandard stock 1° for 60 ± 0.5 minutes, keeping the level of the acid below
solution B to a 100-mL volumetric flask, dilute with dilute the level of the water during the entire period. Cool the tube
hydrochloric acid (10 g/L) to volume, and mix to obtain in running water, and transfer the acid to a color-comparison
Standard solution B. Transfer 0.75 mL of Standard stock so- tube: the color of the acid is not darker than that of a similar
lution C to a 100-mL volumetric flask, dilute with dilute hy- volume of Matching Fluid K (see Color and Achromicity
drochloric acid (10 g/L) to volume, and mix to obtain (631)) in a matching tube, the tubes being observed verti-
Standard solution C. cally against a white background.
Test solution—Use the Test solution prepared in the Sulfate—
Clarity of solution test.
Standard sulfate solution A—To 181 mg of dibasic potas-
Procedure—Transfer a sufficient portion of the Test solu-
sium sulfate in a 100-mL volumetric flask, add a few mL of
tion to a test tube of colorless, transparent, neutral glass with
30 percent alcohol, swirl to dissolve, dilute with 30 percent
a flat base and an internal diameter of 15 to 25 mm to obtain
alcohol to volume, and mix. Immediately before use, trans-
a depth of 40 mm. Similarly transfer portions of Standard
fer 10.0 mL of this solution to a 1000-mL volumetric flask,
solution A, Standard solution B, and Standard solution C
dilute with 30 percent alcohol to volume, and mix. This so-
to separate matching test tubes. Compare the Test solution,
lution contains 10 ug of sulfate per mL.
Standard solution A, Standard solution B, and Standard so-
Standard sulfate solution B—To 181 mg of dibasic potas-
lution C in diffused daylight, viewing vertically against a
sium sulfate in a 100-mL volumetric flask, add a few mL of
white background (see Visual Comparison under Spectro-
water, swirl to dissolve, dilute with water to volume, and
photometry and Light-Scattering (851)). The Test solution
mix. Immediately before use, transfer 10.0 mL of this solu-
is not more intensely colored than Standard solutions A,
tion to a 1000-mL volumetric flask, dilute with water to vol-
B, and C.
ume, and mix. This solution contains 10 |ig of sulfate per
Identification, Infrared Absorption (197K).
mL.
Pharmacopeial Forum
Citric acid solution—Dissolve 2.0 g of Citric Acid in acid, dilute with water to volume, and mix. Immediately be-
about 10 mL of water, dilute with water to 30 mL, and mix. fore use, transfer 1.0 mL of this solution to a 100-mL volu-
Procedure—To 4.5 mL of Standard sulfate solution A add metric flask, dilute with water to volume, and mix.
3 mL of a barium chloride solution (1 in 4), shake, and allow pH 6.0 acetate buffer—Dissolve 50 g of ammonium ace-
to stand for 1 minute. To 2.5 mL of the resulting suspension, tate in 150 mL of water, adjust with glacial acetic acid to a
add 15 mL of the Citric acid solution and 0.5 mL of 5 N pH of 6.0, dilute with water to 250 mL, and mix.
acetic acid, and mix (Test solution). Prepare the Standard Test solution—Dissolve 20.0 g of Citric Acid in 100 mL
solution in the same manner, except use 15 mL of Standard of water, and add 10 mL of pH 6.0 acetate buffer. Extract
sulfate solution B instead of the Citric acid solution: any tur- this solution with successive portions of 20, 20, and 10
bidity produced in the Test solution after 5 minutes standing mL of a 0.5% solution of 8-hydroxyquinoline in chloro-
is not greater than that produced in the Standard solution form, combining the chloroform extracts in a 50-mL volu-
(0.015%). metric flask. Dilute the combined extracts with chloroform
Heavy metals (231): 0.001%. to volume, and mix.
Limit of oxalic acid—Prepare a citric acid solution by dis- Standard solution—Prepare a mixture of 2.0 mL of Stan-
solving 800 mg of Citric Acid in 4 mL of water. Add 3 mL dard aluminum solution, 10 mL of pH 6.0 acetate buffer,
of hydrochloric acid and 1 g of granular zinc, boil for 1 min- and 98 mL of water. Extract this mixture as described for
ute, and allow to stand for 2 minutes. Transfer the superna- the Test solution, dilute the combined extracts with chloro-
tant to a test tube containing 0.25 mL of a phenylhydrazine form to volume, and mix.
hydrochloride solution (1 in 100), and heat to boiling. Cool Blank solution—Prepare a mixture of 10 mL of pH 6.0
rapidly, transfer to a graduated cylinder, and add an equal acetate buffer and 100 mL of water. Extract this mixture
volume of hydrochloric acid and 0.25 mL of a potassium as described for the Test solution, dilute the combined ex-
ferricyanide solution (1 in 20). Shake, and allow to stand tracts with chloroform to volume, and mix.
for 30 minutes (Test solution). Concomitantly prepare a Procedure—Determine the fluorescence intensities of the
control solution in the same manner, except use 4 mL of Test solution and the Standard solution in a fluorometer set
an oxalic acid solution containing 0.10 mg per mL, equiva- at an excitation wavelength of 392 nm and an emission wa-
lent to 0.0714 mg of anhydrous oxalic acid per mL, instead velength of 518 nm, using the Blank solution to set the in-
of the citric acid solution: any pink color produced in the strument to zero. The fluorescence of the Test solution does
Test solution is not more intense than that produced in the not exceed that of the Standard solution (0.2 jig per g).
control solution (0.036%). Organic volatile impurities, Method IV (467): meets the
requirements.
Limit of aluminum (where it is labeled as intended for use
in dialysis)— Assay—Place about 0.550 g of Citric Acid in a tared flask,
Standard aluminum solution—To 352 mg of aluminum and weigh accurately. Dissolve in 50 mL of water, add 0.5
potassium sulfate in a 100-mL volumetric flask, add a few mL of phenolphthalein TS, and titrate with 1 N sodium hy-
mL of water, swirl to dissolve, add 10 mL of diluted sulfuric droxide VS. Each mL of 1 N sodium hydroxide is equiva-
lent to 64.03 mg of C6H8O7.B1
Pharmacopeia! Forum
Add the following:

BRIEFING
•Citric Acid, Monohydrate
Citric Acid, Monohydrate. The European Pharmacopoeia is
the coordinating pharmacopeia for the international harmonization
of the compendial standards for the Citric Acid, Monohydrate (Chemical structure to come)
monograph, as part of the process of international harmonization
of monographs and general analytical methods of the European, C6H8O7H2O
Japanese, and United States pharmacopeias. The following mono- 210.14
graph, which represents the ADOPTION STAGE 6 document, is
based on the corresponding monograph for Citric Acid, Monohy- 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, monohy-
drate that was prepared by the European Pharmacopoeia. The Eur-
opean Pharmacopoeia draft was based in part on comments from drate [5949-29-1].
the Japanese Pharmacopoeia and the United States Pharmacopeia
in response to the Provisional Harmonized Text Stage 5A and 5B
drafts prepared by the European Pharmacopoeia. The current USP
monograph for Citric Acid will be replaced with two separate
monographs for Citric Acid, Anhydrous and Citric Acid, Monohy-
drate. » Monohydrate Citric Acid contains one molecule
Differences between the European Pharmacopoeia Adoption of water of hydration. It contains not less than
Stage 6 document and the current USP monograph for Citric Acid
include the following:
(1) Definition—Changed to include only Citric Acid, Monohy- 99.5 percent and not more than 100.5 percent of
drate, as to conform to the individual monograph for Citric
Acid, Monohydrate. C6H8O7, calculated on the anhydrous basis.
(2) Labeling—The indication of anhydrous or hydrous is deleted,
as to conform to the individual monograph for Citric Acid,
Monohydrate. A requirement that the label indicate where it Packaging and storage—Preserve in tight containers.
is intended for use in dialysis solutions is added.
(3) USP Reference standards—A Citric Acid reference standard Labeling—Where it is intended for use in dialysis solu-
to be used with the Identification test is added.
(4) Clarity of solution—This test is added in order to conform tions, it is so labeled.
with EP standards.
(5) Color of solution—This test is added in order to conform with USP Reference standards {U)—USP Citric Acid RS.
EP standards.
(6) Identification—The test for Citrate is deleted and a more de- Clarity of solution—[NOTE—The Test solution is to be
finitive infrared absorption test is added.
(7) Water—The standard for this test is changed from not more compared to Reference suspension A in diffused daylight
than 8.8% to a range of 7.5% to 9.0% in order to conform with
EP standards.
5 minutes after preparation of Reference suspension A.]
(8) Residue on ignition—The standard for this test is increased
from 0.05% to 0.1% in order to conform with JP standards. Hydrazine sulfate solution—Transfer 1.0 g of hydrazine
(9) Readily carbonizable substances—No change.
(10) Sulfate—The test procedure is changed to a quantitative test sulfate to a 100-mL volumetric flask, dissolve in and dilute
in order to conform to EP standards.
(11) Arsenic—This test is deleted because the Heavy metals test with water to volume, and mix. Allow to stand for 4 to 6
sufficiently accounts for arsenic.
(12) Heavy metals—No change. hours before use.
(13) Limit of oxalic acid—The test procedure is changed to a quan-
titative test in order to conform to EP standards. Hexamethylenetetramine solution—Transfer 2.5 g of
(14) Limit of aluminum—This test is added in order to conform
with EP standards concerning usage in dialysis. This require- Hexamethylenetetramine to a 100-mL glass-stoppered flask,
ment is similar to the Limit of aluminum in the USP Calcium
Acetate monograph. add 25.0 mL of water, insert the glass stopper, and mix to
(16) Assay—The sample size is decreased from 3 g in 40 mL of dissolve.
water to 0.55 g in 50 mL of water. The amount of Citric Acid
that is equivalent to 1 mL of 1 N sodium hydroxide is changed Primary opalescent suspension—[NOTE—This suspen-
from 64.04 mg to a more accurate 64.03 mg.
sion is stable for 2 months, provided it is stored in a glass
not adhere to the glass and must be well mixed before
Pharmacopeial Forum
use.] Transfer 25.0 mL of Hydrazine sulfate solution to the 5—2.4:1.0:0.4:6.2

Hexamethylenetetramine solution in the 100-mL glass-stop- C—9.6:0.2:0.2:0
pered flask. Mix, and allow to stand for 24 hours. Standard solutions—[NOTE—Prepare the Standard solu-
Opalescence standard—[NOTE—This suspension should tions immediately before use.] Transfer 2.5 mL of Standard
not be used beyond 24 hours after preparation.] Transfer stock solution A to a 100-mL volumetric flask, dilute with
15.0 mL of the Primary opalescent suspension to a 1000- dilute hydrochloric acid (10 g/L) to volume, and mix to ob-
mL volumetric flask, dilute with water to volume, and mix. tain Standard solution A. Transfer 2.5 mL of Standard stock
Reference suspensions—Transfer 5.0 mL of the Opales- solution B to a 100-mL volumetric flask, dilute with dilute
cence standard to a 100-mL volumetric flask, dilute with hydrochloric acid (10 g/L) to volume, and mix to obtain
water to volume, and mix to obtain Reference suspension Standard solution B. Transfer 0.75 mL ofStandard stock so-
A. Transfer 10.0 mL of the Opalescence standard to a sec- lution Cto a 100-mL volumetric flask, dilute with dilute hy-
ond 100-mL volumetric flask, dilute with water to volume, drochloric acid (10 g/L) to volume, and mix to obtain
and mix to obtain Reference suspension B. Standard solution C.
Test solution—Dissolve 2.0 g of Citric Acid in about 5 mL Test solution—Use the Test solution prepared in the
of water, dilute with water to 10 mL, and mix. Clarity of solution test.
Procedure—Transfer a sufficient portion of the Test solu- Procedure—Transfer a sufficient portion of the Test solu-
tion to a test tube of colorless, transparent, neutral glass with tion to a test tube of colorless, transparent, neutral glass with
a flat base and an internal diameter of 15 to 25 mm to obtain a flat base and an internal diameter of 15 to 25 mm to obtain
a depth of 40 mm. Similarly transfer portions of Reference a depth of 40 mm. Similarly transfer portions of Standard
suspension A, Reference suspension B, and water to separate solution A, Standard solution B, and Standard solution C
matching test tubes. Compare the Test solution, Reference to separate matching test tubes. Compare the Test solution,
suspension A, Reference suspension B, and water in diffused Standard solution A, Standard solution B, and Standard so-
daylight, viewing vertically against a black background (see lution C in diffused daylight, viewing vertically against a
Visual Comparison under Spectrophotometry and Light- white background (see Visual Comparison under Spectro-
Scattering (851)). [NOTE—The diffusion of light must be photometry and Light-Scattering (851)). The Test solution
such that Reference suspension A can readily be distin- is not more intensely colored than Standard solutions A,
guished from water, and that Reference suspension B can B, and C.
readily be distinguished from Reference suspension A.] Identification, Infrared Absorption {197K).
The Test solution shows the same clarity as that of water. Bacterial endotoxins test (85)—If intended for use in the
Color of solution— manufacturing of parenteral dosage forms, without a further
Standard stock solutions—Prepare three solutions, A, B, appropriate procedure for the removal of bacterial endotox-
and C, containing, respectively, the following parts of ferric ins, not more than 0.5 I.U. of endotoxin per milligram.
chloride CS, cobaltous chloride CS, cupric sulfate CS, and Water, Method I (921): between 7.5% and 9.0%.
dilute hydrochloric acid (10 g/L): Residue on ignition (281): not more than 0.1%, determined
^—2.4:0.6:0:7.0 on 1.0 g.
Pharmacopeial Forum
Readily carbonizable substances—Transfer 1.0 g, pow- sulfate solution B instead of the Citric acid solution: any tur-
dered for the test, to a 22- x 175-mm test tube previously bidity produced in the Test solution after 5 minutes standing
rinsed with 10 mL of sulfuric acid TS and allowed to drain is not greater than that produced in the Standard solution
for 10 minutes. Add 10 mL of sulfuric acid TS, agitate until (0.015%).
solution is complete, and immerse in a water bath at 90° ± Heavy metals (231): 0.001%.
1° for 60 ± 0.5 minutes, keeping the level of the acid below Limit of oxalic acid—Prepare a citric acid solution by dis-
the level of the water during the entire period. Cool the tube solving 800 mg of Citric Acid in 4 mL of water. Add 3 mL
in running water, and transfer the acid to a color-comparison of hydrochloric acid and 1 g of granular zinc, boil for 1 min-
tube: the color of the acid is not darker than that of a similar ute, and allow to stand for 2 minutes. Transfer the superna-
volume of Matching Fluid K (see Color and Achromicity tant to a test tube containing 0.25 mL of a phenylhydrazine
(631)) in a matching tube, the tubes being observed verti- hydrochloride solution (1 in 100), and heat to boiling. Cool
cally against a white background. rapidly, transfer to a graduated cylinder, and add an equal
Sulfate— volume of hydrochloric acid and 0.25 mL of a potassium
Standard sulfate solution A—To 181 mg of dibasic potas- ferricyanide solution (1 in 20). Shake, and allow to stand
sium sulfate in a 100-mL volumetric flask, add a few mL of for 30 minutes (Test solution). Concomitantly prepare a
30 percent alcohol, swirl to dissolve, dilute with 30 percent control solution in the same manner, except use 4 mL of
alcohol to volume, and mix. Immediately before use, trans- an oxalic acid solution containing 0.10 mg per mL, equiva-
fer 10.0 mL of this solution to a 1000-mL volumetric flask, lent to 0.0714 mg of anhydrous oxalic acid per mL, instead
dilute with 30 percent alcohol to volume, and mix. This so- of the citric acid solution: any pink color produced in the
lution contains 10 ug of sulfate per mL. Test solution is not more intense than that produced in the
Standard sulfate solution B—To 181 mg of dibasic potas- control solution (0.036%).
sium sulfate in a 100-mL volumetric flask, add a few mL of Limit of aluminum (where it is labeled as intended for use
water, swirl to dissolve, dilute with water to volume, and in dialysis)—
mix. Immediately before use, transfer 10.0 mL of this solu- Standard aluminum solution—To 352 mg of aluminum
tion to a 1000-mL volumetric flask, dilute with water to vol- potassium sulfate in a 100-mL volumetric flask, add a few
ume, and mix. This solution contains 10 jig of sulfate per mL of water, swirl to dissolve, add 10 mL of diluted sulfuric
mL. acid, dilute with water to volume, and mix. Immediately be-
Citric acid solution—Dissolve 2.0 g of Citric Acid in fore use, transfer 1.0 mL of this solution to a 100-mL volu-
about 10 mL of water, dilute with water to 30 mL, and mix. metric flask, dilute with water to volume, and mix.
Procedure—To 4.5 mL of Standard sulfate solution A add pH 6.0 acetate buffer—Dissolve 50 g of ammonium ace-
3 mL of a barium chloride solution (1 in 4), shake, and allow tate in 150 mL of water, adjust with glacial acetic acid to a
to stand for 1 minute. To 2.5 mL of the resulting suspension, pH of 6.0, dilute with water to 250 mL, and mix.
add 15 mL of the Citric acid solution and 0.5 mL of 5 N Test solution—Dissolve 20.0 g of Citric Acid in 100 mL
acetic acid, and mix (Test solution). Prepare the Standard of water, and add 10 mL of pH 6.0 acetate buffer. Extract
solution in the same manner, except use 15 mL of Standard this solution with successive portions of 20, 20, and 10
Pharmacopeia! Forum
mL of a 0.5% solution of 8-hydroxyquinoline in chloro-

form, combining the chloroform extracts in a 50-mL volu-
MONOGRAPHS (NF)
metric flask. Dilute the combined extracts with chloroform
to volume, and mix.
Standard solution—Prepare a mixture of 2.0 mL of Stan-

dard aluminum solution, 10 mL of pH 6.0 acetate buffer,
and 98 mL of water. Extract this mixture as described for
the Test solution, dilute the combined extracts with chloro- BRIEFING
form to volume, and mix. Benzyl Alcohol, NF 20 page 2514 and page 2855 of PF 27(4)
[July-Aug. 2001]. The European Pharmacopoeia is the coordinat-
Blank solution—Prepare a mixture of 10 mL oipH 6.0 ing pharmacopeia for the international harmonization of the com-
pendial standards for Benzyl Alcohol, as part of the process of
acetate buffer and 100 mL of water. Extract this mixture international harmonization of monographs and general analytical
methods of the European, Japanese, and United States pharmaco-
as described for the Test solution, dilute the combined ex- peias. The following draft monograph represents the ADOPTION
STAGE 6 draft, which has been accepted by the members of the
tracts with chloroform to volume, and mix. Pharmacopeial Discussion Group. Proposed changes to the current
NF monograph include the following:
Procedure—Determine the fluorescence intensities of the (1) Definition—The lower limit is changed from 97.0 percent to
98.0 percent based on the argument that this quality is easily
Test solution and the Standard solution in a fluorometer set obtainable and that the tight limits of the Related compounds
test justify a tighter limit for the Assay.
at an excitation wavelength of 392 nm and an emission wa- (2) Packaging and storage—No change.
(3) Labeling—Requirements for injectable dosage forms are
velength of 518 nm, using the Blank solution to set the in- added.
(4) USP Reference standards—A new reference standard for ben-
strument to zero. The fluorescence of the Test solution does zyl alcohol is added to comply with the proposed IR test.
(5) Clarity ofsolution—This test is added because of the possible
not exceed that of the Standard solution (0.2 ug per g). use of benzyl alcohol in parenteral dosage forms.
(6) Color of solution—This test is added because of the possible
Organic volatile impurities, Method IV (467): meets the use of benzyl alcohol in parenteral dosage forms.
(7) Identification—In light of comments received, the use of in-
requirements. frared absorption spectrophotometry is adopted for this test.
(8) Specific gravity—This test has been deleted from the mono-
Assay—Place about 0.550 g of Citric Acid in a tared flask, graph and added to the Benzyl Alcohol entry under Descrip-
tion and Solubility.
and weigh accurately. Dissolve in 50 mL of water, add 0.5 (9) Peroxide value—This test is added to conform to EP stan-
dards.
mL of phenolphthalein TS, and titrate with 1 N sodium hy- (10) Refractive index—The lower limit is changed to reflect EP
standards.
droxide VS. Each mL of 1 N sodium hydroxide is equiva- (11) Acidity—Minor editorial changes are made.
(12) Residue on ignition—This test is deleted. Inorganic com-
lent to 64.03 mg of C6H8O7.B1 pounds are not likely to be present since distillation proce-
dures are used during the production of this substance.
(13) Limit of nonvolatile residue—The sample weight is increased
from 2 g to 10 g to ensure greater accuracy.
(14) Halogenated compounds and halides—This test is deleted.
The GC method adequately controls benzyl chloride, and in-
organic halogenated compounds are not likely to be present
since distillation procedures are used during the production
of this substance.
Pharmacopeial Forum
(15) Related compounds—The Benzaldehyde test is renamed as anot adhere to the glass and must be well mixed before
Related compounds test. The test is revised to specify a G16
column based on analyses performed with a DB-Wax column, use.] Transfer 25.0 mL of Hydrazine solution to the Methe-
to reduce solution volumes, and to widen the limits for the
impurities under test. namine solution in the 100-mL glass-stoppered flask. Mix,
(17) Assay—The phenolphthalein solution preparation is changed and allow to stand for 24 hours.
to conform to EP methods.
Opalescence standard—[NOTE—This suspension should
not be used beyond 24 hours after preparation.] Transfer
15.0 mL of the Primary opalescent suspension to a 1000-
Change to read:
mL volumetric flask, dilute with water to volume, and mix.
•Benzyl Alcohol Reference suspensions—Transfer 5.0 mL of the Opales-
20024-26 cence standard to a 100-mL volumetric flask, dilute with
C7H8O 108.14 water to volume, and mix to obtain Reference suspension
Benzenemethanol. 1. Transfer 10.0 mL of the Opalescence standard to a sec-
Benzyl alcohol [100-51-6]. ond 100-mL volumetric flask, dilute with water to volume,
and mix to obtain Reference suspension 2.
Test solution—Dissolve 2.0 g of Benzyl Alcohol in 60 mL
» Benzyl Alcohol contains not less than 98.0 per-
of water, and mix.
cent and not more than 100.5 percent Procedure—Transfer a sufficient portion of the Test solu-
Packaging and storage—Preserve in tight containers, and tion to a test tube of colorless, transparent, neutral glass with
prevent exposure to light. a flat base and an internal diameter of 15 mm to 25 mm, to

obtain a depth of 40 mm. Similarly transfer portions of Ref-
Labeling—Where Benzyl Alcohol is intended for use in the
erence suspension 1, Reference suspension 2, and water to
manufacture of injectable dosage forms, it is so labeled.
separate matching test tubes. Compare the Test solution,
USP Reference standards (11 )—USP Benzyl Alcohol RS.
Reference suspension 1, Reference suspension 2, and water
Clarity of solution—[NOTE—The Test solution is to be
in diffused daylight, viewing vertically against a black back-
compared to Reference suspension 1 in diffused daylight 5
ground (see Visual Comparison under Spectrophotometry
minutes after preparation of Reference suspension 1.]
and Light-Scattering (851)). [NOTE—The diffusion of light
Hydrazine solution—Transfer 1.0 g of hydrazine sulfate
must be such that Reference suspension 1 can readily be dis-
to a 100-mL volumetric flask, dissolve in and dilute with
tinguished from water, and that Reference suspension 2 can
water to volume, and mix. Allow to stand 4 to 6 hours be-
readily be distinguished from Reference suspension 1.] The
fore use.
Test solution shows the same clarity as that of water.
Methenamine solution—Transfer 2.5 g of methenamine to
Color of solution—
a 100-mL glass-stoppered flask, add 25.0 mL of water, in-
Test solution—Use the Test solution prepared in the test
sert the glass stopper, and mix to dissolve.
for Clarity of solution.
Primary opalescent suspension—[NOTE—This suspen-
sion is stable for 2 months, provided it is stored in a glass
Pharmacopeial Forum
Procedure—Transfer a sufficient portion of the Test solu- Dicyclohexyl solution—Transfer 2.0 g of dicyclohexyl to
tion to a test tube of colorless, transparent, neutral glass with a 10-mL volumetric flask, dissolve in and dilute with Test
a flat base and an internal diameter of 15 mm to 25 mm, to solution to volume, and mix. Transfer 1.0 mL of this solu-
obtain a depth of 40 mm. Similarly transfer a portion of tion to a 10-mL volumetric flask, dilute with Test solution to
water to a separate matching test tube. Compare the color volume, and mix.
of the Test solution with that of water in diffused daylight, Standard solution 1—Transfer 750 mg of benzaldehyde,
viewing vertically against a white background (see Visual accurately weighed, and 500 mg of cyclohexylmethanol, ac-
Comparison under Spectrophotometry and Light-Scattering curately weighed, to a 25-mL volumetric flask, dissolve in
(851)). The Test solution has the color of water. and dilute with Test solution to volume, and mix. Transfer
Identification—Infrared Absorption (197F), on undried 0.5 mL of this solution to a 10-mL volumetric flask, add 1.0
specimen. mL of Ethylbenzene solution and 1.5 mL of Dicyclohexyl
solution, dilute with Test solution to volume, and mix.
Peroxide value (401): not more than 5.
Refractive index (831): between 1.538 and 1.541 at 20°. Standard solution 2 (where the Benzyl Alcohol under test
Acidity—Neutralize 50 mL of alcohol containing 1 mL of is intended for use in the manufacture of injectable dosage
forms)—Transfer about 250 mg of benzaldehyde, accu-
phenolphthalein TS with 0.10 N sodium hydroxide. Dis-
rately weighed, and about 500 mg of cyclohexylmethanol,
solve 10 mL of Benzyl Alcohol in 10 mL of the neutralized
alcohol, and titrate with 0.10 N sodium hydroxide to the first
and dilute with Test solution to volume, and mix. Transfer
appearance of a pink color that persists for not less than 30
0.5 mL of this solution to a 10-mL volumetric flask, add 1.0
seconds: not more than 1.0 mL is consumed.
mL of Ethylbenzene solution and 1.0 mL of Dicyclohexyl
Limit of nonvolatile residue—[NOTE—Ensure that the
solution, dilute with Test solution to volume, and mix.
Benzyl Alcohol to be examined complies with the test for
Peroxide value (401) before performing this test.] Evapo-
rate 10.0 g of Benzyl Alcohol on a water bath to dryness,
detector and a 0.32-mm x 30-m column coated with a 0.5-
and dry the residue at 105° for 1 hour. Cool in a desiccator,
um film of G16. Helium is used as the carrier gas flowing at
and weigh. The residue weighs not more than 5 mg: not
a rate of 1.2 mL per minute at 50°. The injection port and
more than 0.05% of nonvolatile residue is found.
detector temperatures are maintained at about 200° and
310°, respectively. The column temperature is programmed
Test solution—Use the Benzyl Alcohol specimen under
to increase linearly from 50° to 220° at a rate of 5° per min-
examination.
ute, and is maintained at 220° for 35 minutes. Chromato-
Ethylbenzene solution—Transfer 100 mg of ethylbenzene, graph the appropriate Standard solution, and record the
accurately weighed, to a 10-mL volumetric flask, dissolve in peak responses as directed for Procedure: the relative reten-
and dilute with Test solution to volume, and mix. Transfer tion times are about 0.28 for ethylbenzene, 0.59 for dicyclo-
1.0 mL of this solution to a 10-mL volumetric flask, dilute
with Test solution to volume, and mix.
Pharmacopeia! Forum
hexyl, 0.68 for benzaldehyde, 0.71 for cyclohexylmethanol, In the chromatogram of the Test solution, the sum of the
and 1.0 for benzyl alcohol; and the resolution, R, between areas of any peaks with retention times greater than that of
benzaldehyde and cyclohexylmethanol is not less than 3.0. benzyl alcohol is not greater than the area of the dicyclohex-
Procedure—Separately inject equal volumes (about 0.1 yl peak in the chromatogram of Standard solution 1 (0.3%)
uL) of the appropriate Standard solution and the Test solu- or in the chromatogram of Standard solution 2 (0.2%).
tion into the chromatograph, record the chromatograms, and Organic volatile impurities, Method V (467): meets the re-
measure the areas for the major peaks. [NOTE—Disregard quirements.
any peak having an area less than 0.01 times the area of Assay—To about 900 mg of Benzyl Alcohol, accurately
the ethylbenzene peak in the chromatogram of the appropri- weighed, add 15.0 mL of a freshly prepared mixture of pyr-
ate Standard solution. In the chromatogram of the Test solu- idine and acetic anhydride (7:1), and boil under reflux for 30
tion, verify that there are no peaks with the same retention minutes. Cool, add 25 mL of water, add 0.25 mL of a phe-
times as those of ethylbenzene or dicyclohexyl.] nolphthalein solution prepared by dissolving 100 mg of phe-
In the chromatogram of the Test solution, the area of any nolphthalein in 80 mL of alcohol and diluting with water to
peak corresponding to benzaldehyde is not greater than the 100 mL, and titrate with 1 N sodium hydroxide VS. Perform
difference between the area of the peak due to benzaldehyde a blank determination (see Titrimetry (541)). Calculate the
in the chromatogram of Standard solution 1 (0.15%) or in percentage of C7HgO taken by the formula:
the chromatogram of Standard solution 2 (0.05%) and the
IO.S\N(VB- Vy)IW,
area of the peak due to benzaldehyde in the chromatogram
of the Test solution. in which Vv and VB are the number of mL of 1 N sodium
In the chromatogram of the Test solution, the area of any hydroxide used for the Benzyl Alcohol and the blank, re-
peak corresponding to cyclohexylmethanol is not greater spectively; and W is the weight, in g, of Benzyl Alcohol ta-
than the difference between the area of the peak due to cy- ken.B1
clohexylmethanol in the chromatogram of Standard solu-

tion 1 (0.10%) or in the chromatogram of Standard
solution 2 (0.10%) and the area of the peak due to cyclohex-
ylmethanol in the chromatogram of the Test solution.
In the chromatogram of the Test solution, the sum of the
BRIEFING
areas of any peaks with retention times less than that of ben-
zyl alcohol, excluding the peaks due to benzaldehyde and Corn Starch, page 1244 of PF 21(5) [Sept.-Oct. 1995]. The
United States Pharmacopeia is the coordinating pharmacopeia for
cyclohexylmethanol, is not greater than four times the area the international harmonization of the compendial standards for the
Corn Starch monograph, as part of the process of international har-
of the ethylbenzene peak in the chromatogram of Standard monization of monographs and general analytical methods of the
European, Japanese, and United States pharmacopeias. The fol-
solution 1 (0.04%) or is not greater than two times the area lowing monograph, which represents the ADOPTION STAGE 6
document, is based on the corresponding monograph for Starch
of the ethylbenzene peak in the chromatogram of Standard that was prepared by the United States Pharmacopeia. The USP
draft was based in part on comments from the Japanese Pharmaco-
solution 2 (0.02%). poeia and the European Pharmacopoeia in response to the Provi-
sional Harmonized Text Stage 5A and 5B drafts prepared by USP.
The current NF monograph for Starch will be modified to exclude
Corn Starch. A new monograph will be presented for Corn Starch.
Pharmacopeial Forum
Differences between the International Harmonization Adoption A: Under a microscope, using not less than 20 x mag-
Stage 6 document for Corn Starch and the current NF Starch mono-
graph include the following: nification and using a mixture of glycerin and water (1:1) as
(1) Definition—Changed to include only Com Starch, as to con-
form to the individual monograph for Corn Starch. a mounting agent, it appears as either angular polyhedral
(2) Packaging and storage—-No change.
(3) Labeling—A requirement that the label indicate where it is granules of irregular sizes with diameters ranging from
intended for use in preparing Absorbable Dusting Powder is
added to ensure that microbial limits are met. about 2 urn to about 23 um or as rounded or spheroidal
(4) Botanical characteristics—This test has been modified and
moved to the Identification section. granules of irregular sizes with diameters ranging from
(5) Identification—A microscopic test is added that is similar to
the Botanical characteristics section. The other two tests are about 25 um to about 35 um. The central hilum consists
modified slightly for clarification.
(6) Microbial limits—The revised limit for the total combined of a distinct cavity or two- to five-rayed cleft, and there
molds and yeasts count in the test is based on comments re-
ceived. The addition of the requirements for Absorbable Dust- are no concentric striations. Between crossed nicol prisms,
ing Powder are based on specific microbial requirements for
Absorbable Dusting Powder. the starch granules show a distinct black cross intersecting at
(7) pH—The lower limit is expanded in order to conform with EP
standards. the hilum.
(8) Loss on drying—The revised test conditions reportedly corre-
spond to ISO 1666 and are preferred by users of starches be- B: Suspend 1 g of it in 50 mL of water, boil for 1 min-
cause of reduced testing time.
(9) Residue on ignition—The standard for this test is increased ute, and cool: a thin, cloudy mucilage is formed.
from 0.5% to 0.6% in order to conform with EP standards.
(10) Limit of iron—The test procedure is changed in order to con- C: To 10 mL of the mucilage obtained in Identification
form to EP standards.
(11) Limit of oxidizing substances—No change. test B, add 0.04 mL of iodine and potassium iodide TS: an
(12) Limit of sulfur dioxide—The change in the standard reflects
the corresponding limits proposed by the EC food laws. orange red to dark blue color is produced, which disappears
on heating.
(EMC: J. Lane) RTS—36496-1 Microbial limits (61)—The total aerobic microbial count
does not exceed 1000 per g, the total combined molds and
Add the following: yeasts count does not exceed 100 per g, and it meets the re-
quirements of the test for the absence of Escherichia coli.
•Corn Starch
Where it is intended for use in preparing Absorbable Dust-
ing Powder, it also meets the requirements of the tests for
» Corn Starch consists of the starch granules sepa- absence of Staphylococcus aureus and Pseudomonas aeru-
rated from the mature grain of corn [Zea mays ginosa.
Linne (Fam. Gramineae)]. pH (791)—Prepare a slurry by weighing 5.0 g of Corn

Starch, transferring to a suitable nonmetallic container,
and adding 25.0 mL of freshly boiled and cooled water. Agi-
ers.
tate continuously at a moderate rate for 1 minute. Stop the
Labeling—Where Corn Starch is intended for use in prepar- agitation and allow to stand for 15 minutes. Determine the
ing Absorbable Dusting Powder, it is so labeled and the la- pH to the nearest 0.1 unit: the pH, determined potentiome-
bel states that it must be subjected to further processing trically, is between 4.0 and 7.0.
during the preparation of Absorbable Dusting Powder.
Loss on drying (731)—Dry about 1 g, accurately weighed,
Identification— at 130° for 90 minutes: it loses not more than 15.0% of its
weight.
Pharmacopeial Forum
Residue on ignition (281): not more than 0.6%, determined Limit of sulfur dioxide—Not more than 50 ug per g.
on a 1.0-g test specimen. Ignition temperature 600° ± 50°. Reagents—
Limit of iron—Shake 1.5 g of Corn Starch with 15 mL of 2 Carbon dioxide—Use carbon dioxide, with a flow regula-
N hydrochloric acid, and filter. Transfer 10 mL of the filtrate tor that will maintain a flow of 100 + 10 mL per minute.
to a test tube, add 2 mL of citric acid solution (2 in 10), 0.1 Bromophenol blue indicator solution—Dissolve 100 mg
mL of thioglycolic acid, and mix. Add ION ammonium hy- of bromophenol blue in 100 mL of dilute alcohol (1 in 5),
droxide until the solution is distinctly alkaline to litmus, di- and filter if necessary.
lute with water to 20 mL, and mix {Test Solution). Prepare a Hydrogen peroxide solution—Dilute 30% hydrogen per-
Standard Iron Solution containing the equivalent of 10 ug of oxide with water to obtain a 3% solution. Just before use,
iron per mL as directed under Iron (241). Immediately be- add 3 drops of Bromophenol blue indicator solution, and
fore use, dilute an accurately measured volume of this solu- neutralize to a violet-blue endpoint with 0.01 N sodium hy-
tion quantitatively with water to obtain a Diluted Standard droxide. Do not exceed the endpoint.
Iron Solution containing the equivalent of 1 ug of iron per Apparatus—In this test, the sulfur dioxide is released
mL. Prepare the Standard Solution by transferring 10 mL of from the test specimen in a boiling acid medium and is re-
the Diluted Standard Iron Solution to a test tube and pro- moved by a stream of carbon dioxide. The separated gas is
ceeding in the same manner as directed for the preparation collected in a dilute hydrogen peroxide solution where the
of the Test Solution, beginning with "add 2 mL of citric acid sulfur dioxide is oxidized to sulfuric acid and titrated with
solution (2 in 10)." After 5 minutes, any pink color in the standard alkali. The apparatus consists essentially of a 500-
Test Solution is not more intense than that in the Standard mL three-neck, round-bottom, boiling flask, a separatory
Solution, corresponding to a limit of 10 ug of iron per g. funnel having a capacity of 100 mL or greater, a gas inlet
Limit of oxidizing substances—Transfer 4.0 g to a glass- tube of sufficient length to permit introduction of the carbon
stoppered, 125-mL conical flask, and add 50.0 mL of water. dioxide within 2.5 cm of the bottom of the boiling flask, a
Insert the stopper, and swirl for 5 minutes. Transfer to a reflux condenser having a jacket length of 200 mm, and a
glass-stoppered, 50-mL centrifuge tube, and centrifuge to delivery tube connecting the upper end of the reflux conden-
clarify. Transfer 30.0 mL of the clear supernatant liquid to ser to the bottom of a receiving test tube. Apply a thin film
a glass-stoppered, 125-mL conical flask. Add 1 mL of gla- of stopcock grease to the sealing surfaces of all of the joints
cial acetic acid and 0.5 g to 1.0 g of potassium iodide. Insert except the joint between the separatory funnel and the boil-
the stopper, swirl, and allow to stand for 25 to 30 minutes in ing flask, and clamp the joints to ensure tightness.
the dark. Add 1 mL of starch TS, and titrate with 0.002 N Procedure—Add 150 mL of water to the boiling flask.
sodium thiosulfate VS to the disappearance of the starch-io- Close the stopcock of the separatory funnel, and begin the
dine color. Perform a blank determination, and make any flow of carbon dioxide at a rate of 100 ± 5 mL per minute
necessary correction. Each mL of 0.002 N sodium thiosul- through the Apparatus. Start the condenser coolant flow.
fate is equivalent to 34 jig of oxidant, calculated as hydro- Add 10 mL of Hydrogen peroxide solution to a receiving
gen peroxide. Not more than 1.4 mL of 0.002 N sodium test tube. After 15 minutes, without interrupting the flow
thiosulfate is required (20 ug per g, calculated as H2O2). of carbon dioxide, remove the separatory funnel from the
Pharmacopeial Forum
boiling flask and transfer 25.0 g of test specimen into the

BRIEFING
boiling flask with the aid of 100 mL of water. Apply stop-
Potato Starch, page 1246 of PF 21(5) [Sept.-Oct. 1995]. The
cock grease to the outer joint of the separatory funnel, and European Pharmacopoeia is the coordinating pharmacopeia for the
international harmonization of the compendial standards for the
replace the separatory funnel in the boiling flask. Close the Potato Starch monograph, as part of the process of international
harmonization of monographs and general analytical methods of
stopcock of the separatory funnel, and add 80 mL of 2 N the European, Japanese, and United States pharmacopeias. The fol-
lowing monograph represents the ADOPTION STAGE 6 docu-
hydrochloric acid to the separatory funnel. Open the stop- ment. The EP draft was based in part on comments from the
Japanese Pharmacopoeia and the United States Pharmacopeia in
cock of the separatory funnel to permit the hydrochloric acid response to the Provisional Harmonized Text Stage 5A and 5B
drafts prepared by EP. The current NF monograph for Starch will
solution to flow into the boiling flask, guarding against the be modified to exclude Potato Starch. A new monograph will be
presented for Potato Starch.
escape of sulfur dioxide into the separatory funnel by clos- Differences between the International Harmonization Adoption
Stage 6 document for Potato Starch and the current NF Starch
ing the stopcock before the last few mL of hydrochloric acid monograph include the following:
(1) Definition—Changed to include only Potato Starch, as to con-
drain out. Position the Apparatus in a water bath, and boil form to the individual monograph for Potato Starch.
(2) Packaging and storage—No change.
the mixture for 1 hour. Remove the receiving test tube, and (3) Labeling—Deleted.
(4) Botanical characteristics—This test has been modified and
transfer its contents to a 200-mL wide-necked, conical flask. moved to the Identification section.
(5) Identification—A microscopic test is added that is similar to
Rinse the receiving test tube with a small portion of water, the Botanical characteristics section. The other two tests are
modified slightly for clarification.
add the rinsing to the 200-mL conical flask, and mix. Heat (6) Microbial limits—The revised limit for the total combined
molds and yeasts count in the test is based on comments re-
on a water bath for 15 minutes, and allow to cool. Add 0.1 ceived.
(7) pH—No change.
mL of Bromophenol blue indicator solution, and titrate the (8) Loss on drying—The revised test conditions reportedly corre-
spond to ISO 1666 and are preferred by users of starches be-
contents with 0.1 N sodium hydroxide VS until the color cause of reduced testing time.
(9) Residue on ignition—The standard for this test is increased
changes from yellow to violet-blue, with the color change from 0.5% to 0.6% in order to conform with EP standards.
(10) Limit of iron—The test procedure is changed in order to con-
lasting for at least 20 seconds. Perform a blank determina- form to EP standards.
(11) Limit of oxidizing substances—No change.
tion, and make any necessary correction (see Titrimetry (12) Limit of sulfur dioxide—The change in the standard reflects
the corresponding limits proposed by the EC food laws.
(541)). Calculate the content, in ug per g, of sulfur dioxide (13) Organic volatile impurities—No change.
in the test specimen taken by the formula:
1000(32.03) VNIW,
in which 32.03 is the milliequivalent weight of sulfur diox- Add the following:
ide, V is the volume, in mL, of titrant consumed, N is the
•Potato Starch
normality of the titrant, and W is the weight, in g, of test
specimen taken.
Organic volatile impurities, Method IV (467): meets the » Potato Starch is obtained from the tuber of So-
requirements.B1 latium tuberosum L.

ers.
Pharmacopeial Forum
Limit of iron—Shake 1.5 g of Potato Starch with 15 mL of

Identification—
2 N hydrochloric acid, and filter. Transfer 10 mL of the fil-
A: Under a microscope, using a mixture of glycerin and
trate to a test tube, add 2 mL of citric acid solution (2 in 10),
water (1:1) as a mounting agent, it presents granules, either
0.1 mL of thioglycolic acid, and mix. Add ION ammonium
irregularly shaped, ovoid, or pear-shaped, usually 30 um to
hydroxide until the solution is distinctly alkaline to litmus,
100 um in size, but occasionally exceeding 100 um, or
dilute with water to 20 mL, and mix {Test Solution). Prepare
rounded, 10 um to 35 urn in size. There are occasional com-
a Standard Iron Solution containing the equivalent of 10 ug
pound granules having two or four components. The ovoid
of iron per mL as directed under Iron (241). Immediately
and pear-shaped granules have an eccentric hilum and the
before use, dilute an accurately measured volume of this so-
rounded granules acentric or slightly eccentric hilum. All
lution quantitatively with water to obtain a Diluted Standard
granules show clearly visible concentric striations. Between
Iron Solution containing the equivalent of 1 ug of iron per
crossed nicol prisms, the granules show a distinct black
mL. Prepare the Standard Solution by transferring 10 mL of
cross intersecting at the hilum.
the Diluted Standard Iron Solution to a test tube and pro-
B: Suspend 1 g of it in 50 mL of water, boil for 1 min-
ceeding in the same manner as directed for the preparation
ute, and cool: a thin, cloudy mucilage is formed.
of the Test Solution, beginning with "add 2 mL of citric acid
C: To 1 mL of the mucilage obtained in Identification
solution (2 in 10)." After 5 minutes, any pink color in the
test B, add 0.05 mL of iodine and potassium iodide TS: a
Test Solution is not more intense than that in the Standard
dark blue color is produced, which disappears on heating.
Solution, corresponding to a limit of 10 ug of iron per g.
Limit of oxidizing substances—Transfer 4.0 g to a glass-
does not exceed 1000 per g, the total combined molds and
stoppered, 125-mL conical flask, and add 50.0 mL of water.
yeasts count does not exceed 100 per g, and it meets the re-
Insert the stopper, and swirl for 5 minutes. Transfer to a
quirements of the test for the absence of Escherichia coli.
glass-stoppered, 50-mL centrifuge tube, and centrifuge to
pH (791)—Prepare a slurry by weighing 5.0 g of Potato
clarify. Transfer 30.0 mL of the clear supernatant liquid to
Starch, transferring to a suitable nonmetallic container,
a glass-stoppered, 125-mL conical flask. Add 1 mL of gla-
cial acetic acid and 0.5 g to 1.0 g of potassium iodide. Insert
tate continuously at a moderate rate for 1 minute. Stop the
the stopper, swirl, and allow to stand for 25 to 30 minutes in
agitation and allow to stand for 15 minutes. Determine the
the dark. Add 1 mL of starch TS, and titrate with 0.002 N
pH to the nearest 0.1 unit: the pH, determined potentiome-
sodium thiosulfate VS to the disappearance of the starch-io-
trically, is between 5.0 and 8.0.
dine color. Perform a blank determination, and make any
Loss on drying (731)—Dry about 1 g, accurately weighed, necessary correction. Each mL of 0.002 N sodium thiosul-
at 130° for 90 minutes: it loses not more than 20.0% of its fate is equivalent to 34 ug of oxidant, calculated as hydro-
weight.
gen peroxide. Not more than 1.4 mL of 0.002 N sodium
Residue on ignition (281)—not more than 0.6%, deter- thiosulfate is required (20 ug per g, calculated as H2O2).
mined on a 1.0-g test specimen. Ignition temperature 600° Limit of sulfur dioxide: not more than 50 ug per g.
+ 50°.
Pharmacopeial Forum
Reagents—
cock grease to the outer joint of the separatory funnel, and
Carbon dioxide—Use carbon dioxide, with a flow regula- replace the separatory funnel in the boiling flask. Close the
tor that will maintain a flow of 100 + 10 mL per minute. stopcock of the separatory funnel, and add 80 mL of 2 N
Bromophenol blue indicator solution—Dissolve 100 mg hydrochloric acid to the separatory funnel. Open the stop-
of bromophenol blue in 100 mL of dilute alcohol (1 in 5), cock of the separatory funnel to permit the hydrochloric acid
and filter if necessary. solution to flow into the boiling flask, guarding against the
Hydrogen peroxide solution—Dilute 30% hydrogen per- escape of sulfur dioxide into the separatory funnel by clos-
oxide with water to obtain a 3% solution. Just before use, ing the stopcock be/ore the last few mL of hydrochloric acid
add 3 drops of Bromophenol blue indicator solution, and drain out. Position the Apparatus in a water bath, and boil
neutralize to a violet-blue endpoint with 0.01 N sodium hy- the mixture for 1 hour. Remove the receiving test tube, and
droxide. Do not exceed the endpoint. transfer its contents to a 200-mL wide-necked, conical flask.
Apparatus—In this test, the sulfur dioxide is released Rinse the receiving test tube with a small portion of water,
from the test specimen in a boiling acid medium and is re- add the rinsing to the 200-mL conical flask, and mix. Heat
moved by a stream of carbon dioxide. The separated gas is on a water bath for 15 minutes, and allow to cool. Add 0.1
collected in a dilute hydrogen peroxide solution where the mL of Bromophenol blue indicator solution, and titrate the
sulfur dioxide is oxidized to sulfuric acid and titrated with contents with 0.1 N sodium hydroxide VS until the color
standard alkali. The apparatus consists essentially of a 500- changes from yellow to violet-blue, with the color change
mL three-neck, round-bottom boiling flask, a separatory lasting for at least 20 seconds. Perform a blank determina-
funnel having a capacity of 100 mL or greater, a gas inlet tion, and make any necessary correction (see Titrimetry
tube of sufficient length to permit introduction of the carbon (541)). Calculate the content, in ug per g, of sulfur dioxide
dioxide within 2.5 cm of the bottom of the boiling flask, a in the test specimen taken by the formula:
reflux condenser having a jacket length of 200 mm, and a
delivery tube connecting the upper end of the reflux conden-
ser to the bottom of a receiving test tube. Apply a thin film in which 32.03 is the milliequivalent weight of sulfur diox-
of stopcock grease to the sealing surfaces of all of the joints ide, V is the volume, in mL, of titrant consumed, N is the
except the joint between the separatory funnel and the boil- normality of the titrant, and W is the weight, in g, of test
ing flask, and clamp the joints to ensure tightness. specimen taken.
Procedure—Add 150 mL of water to the boiling flask. Organic volatile impurities, Method IV (467): meets the
Close the stopcock of the separatory funnel, and begin the requirements.B1
flow of carbon dioxide at a rate of 100 + 5 mL per minute
through the Apparatus. Start the condenser coolant flow.
Add 10 mL of Hydrogen peroxide solution to a receiving
test tube. After 15 minutes, without interrupting the flow
of carbon dioxide, remove the separatory funnel from the
boiling flask, and transfer 25.0 g of test specimen into the
boiling flask with the aid of 100 mL of water. Apply stop-
Pharmacopeial Forum
Identification—
BRIEFING
A: Under a microscope, using a mixture of glycerin and
Wheat Starch, page 1248 of PF 21(5) [Sept.-Oct. 1995]. The water (1:1) as a mounting agent, it presents large and small
European Pharmacopoeia is the coordinating pharmacopeia for the
international harmonization of the compendial standards for the granules, and very rarely, intermediate sizes. The large gran-
Wheat Starch monograph, as part of the process of international
harmonization of monographs and general analytical methods of ules, usually 10 urn to 60 urn in diameter, are discoid or,
the European, Japanese, and United States pharmacopeias. The fol-
lowing monograph represents the ADOPTION STAGE 6 docu- more rarely, reniform when seen face-on. The central hilum
ment. The EP draft was based in part on comments from the
Japanese Pharmacopoeia and the United States Pharmacopeia in and striations are invisible or barely visible and the granules
response to the Provisional Harmonized Text Stage 5A and 5B
drafts prepared by EP. The current NF monograph for Starch will sometimes show cracks on the edges. Seen in profile, the
be modified to exclude Wheat Starch. A new, monograph will be
presented for Wheat Starch.
granules are elliptical and fusiform and the hilum appears
Differences between the International Harmonization Adoption
Stage 6 document for Wheat Starch and the current NF Starch as a slit along the main axis. The small granules, rounded
monograph include the following:
(1) Definition—Changed to include only Wheat Starch, as to con- or polyhedral, are 2 um to 10 urn in diameter. Between
form to the individual monograph for Wheat Starch.
(2) Packaging and storage—No change. crossed nicol prisms, the granules show a distinct black
(3) Labeling—Deleted.
(4) Botanical characteristics—This test has been modified and cross intersecting at the hilum.
moved to the Identification section.
(5) Identification—A microscopic test is added that is similar to B: Suspend 1 g of it in 50 mL of water, boil for 1 min-
the Botanical characteristics section. The other two tests are
modified slightly for clarification. ute, and cool: a thin, cloudy mucilage is formed.
(6) Microbial limits—The revised limit for the total combined
molds and yeasts count in the test is based on comments re- C: To 1 mL of the mucilage obtained in Identification
ceived.
(7) pH—No change. test B, add 0.05 mL of iodine and potassium iodide TS: a
(8) Loss on drying—The revised test conditions reportedly corre-
spond to ISO 1666 and are preferred by users of starches be- dark blue color is produced, which disappears on heating.
cause of reduced testing time.
(9) Residue on ignition—The standard for this test is increased Microbial limits (61)—The total aerobic microbial count
from 0.5% to 0.6% in order to conform with EP standards.
(10) Total Protein—This test is added to conform with EP. does not exceed 1000 per g, the total combined molds and
(11) Limit of iron—The test procedure is changed in order to con-
form to EP standards.
(12) Limit of oxidizing substances—No change. yeasts count does not exceed 100 per g, and it meets the re-
(13) Limit of sulfur dioxide—The change in the standard reflects
the corresponding limits proposed by the EC food laws. quirements of the test for the absence of Escherichia coli.
pH (791)—Prepare a slurry by weighing 5.0 g of Wheat
(EMC: J. Lane) RTS—36496-04 Starch, transferring to a suitable nonmetallic container,
Add the following: tate continuously at a moderate rate for 1 minute. Stop the
•Wheat Starch agitation, and allow to stand for 15 minutes. Determine the
pH to the nearest 0.1 unit: the pH, determined potentiome-
trically, is between 4.5 and 7.0.
» Wheat Starch is obtained from the caryopsis of Loss on drying (731)—Dry about 1 g, accurately weighed,
Triticum aestivum L. (T. vulgare VilL). at 130° for 90 minutes: it loses not more than 15.0% of its
weight.
ers. Residue on ignition (281): not more than 0.6%, determined
on a 1.0-g test specimen. Ignition temperature 600° ± 50°.
Pharmacopeial Forum
Total protein: not more than 0.3% of total protein (corre- Limit of iron—Shake 1.5 g of Wheat Starch with 15 mL of
sponding to 0.048% N2, conversion factor: 6.25). 2 N hydrochloric acid, and filter. Transfer 10 mL of the fil-
Procedure—Accurately weigh 6.0 g of test substance con- trate to a test tube, add 2 mL of citric acid solution (2 in 10),
taining about 2 mg of nitrogen, transfer to a combustion 0.1 mL of thioglycolic acid, and mix. Add ION ammonium
flask, and add 4 g of a powdered mixture of 100 g of potas- hydroxide until the solution is distinctly alkaline to litmus,
sium sulfate, 5 g of cupric sulfate, and 2.5 g of selenium, and dilute with water to 20 mL, and mix (Test Solution). Prepare
three glass beads. Wash any adhering particles from the a Standard Iron Solution containing the equivalent of 10 ug
neck into the flask with 5 mL of sulfuric acid, allowing it of iron per mL as directed under Iron (241). Immediately
to run down the sides of the flask, and mix the contents before use, dilute an accurately measured volume of this so-
by rotation. Close the mouth of the flask loosely, for exam- lution quantitatively with water to obtain a Diluted Standard
ple by means of a glass bulb with a short stem, to avoid ex- Iron Solution containing the equivalent of 1 ug of iron per
cessive loss of sulfuric acid. Heat gradually at first, then mL. Prepare the Standard Solution by transferring 10 mL of
increase the temperature until there is vigorous boiling with the Diluted Standard Iron Solution to a test tube and pro-
condensation of sulfuric acid in the neck of the flask; pre- ceeding in the same manner as directed for the preparation
cautions should be taken to prevent the upper part of the of the Test Solution, beginning with "add 2 mL of citric acid
flask from becoming overheated. Continue the heating for solution (2 in 10)." After 5 minutes, any pink color in the
30 minutes, unless otherwise prescribed. Cool, dissolve Test Solution is not more intense than that in the Standard
the solid material by cautiously adding to the mixture 25 Solution, corresponding to a limit of 10 fig of iron per g.
mL of water, cool again, and place in a steam distillation Limit of oxidizing substances—Transfer 4.0 g to a glass-
apparatus. Add 30 mL of sodium hydroxide solution (42 stoppered, 125-mL conical flask, and add 50.0 mL of water.
in 100), and distil immediately by passing steam through Insert the stopper, and swirl for 5 minutes. Transfer to a
the mixture. Collect about 40 mL of distillate in 20.0 mL glass-stoppered, 50-mL centrifuge tube, and centrifuge to
of 0.01 N hydrochloric acid and enough water to cover clarify. Transfer 30.0 mL of the clear supernatant liquid to
the tip of the condenser. Towards the end of the distillation, a glass-stoppered, 125-mL conical flask. Add 1 mL of gla-
lower the receiver so that the tip of the condenser is above cial acetic acid and 0.5 g to 1.0 g of potassium iodide. Insert
the surface of the acid. Take precautions to prevent any the stopper, swirl, and allow to stand for 25 to 30 minutes in
water on the outer surface of the condenser from reaching the dark. Add 1 mL of starch TS, and titrate with 0.002 N
the contents of the receiver. Titrate the distillate with 0.01 sodium thiosulfate VS to the disappearance of the starch-io-
N sodium hydroxide, using Methyl Purple TS as indicator dine color. Perform a blank determination, and make any
(n2 mL of 0.01 N sodium hydroxide). necessary correction. Each mL of 0.002 N sodium thiosul-
Repeat the test using about 50 mg of glucose in place of fate is equivalent to 34 ug of oxidant, calculated as hydro-
the substance to be examined (n2 mL of 0.01 N sodium hy- gen peroxide. Not more than 1.4 mL of 0.002 N sodium
droxide). thiosulfate is required (20 ug per g, calculated as H2O2).
Content of nitrogen = (0.01401 (n2 - n,)) / m, Limit of sulfur dioxide—Not more than 50 ug per g.
where m is the amount of test substance weighed, in grams.
Pharmacopeial Forum
Reagents— of carbon dioxide, remove the separatory funnel from the

Carbon dioxide—Use carbon dioxide, with a flow regula- boiling flask, and transfer 25.0 g of test specimen into the
tor that will maintain a flow of 100 + 10 mL per minute. boiling flask with the aid of 100 mL of water. Apply stop-
Bromophenol blue indicator solution—Dissolve 100 mg cock grease to the outer joint of the separatory funnel, and
of bromophenol blue in 100 mL of dilute alcohol (1 in 5), replace the separatory funnel in the boiling flask. Close the
and filter if necessary. stopcock of the separatory funnel, and add 80 mL of 2 N
Hydrogen peroxide solution—Dilute 30% hydrogen per- hydrochloric acid to the separatory funnel. Open the stop-
oxide with water to obtain a 3% solution. Just before use, cock of the separatory funnel to permit the hydrochloric acid
add 3 drops of Bromophenol blue indicator solution, and solution to flow into the boiling flask, guarding against the
neutralize to a violet-blue endpoint with 0.01 N sodium hy- escape of sulfur dioxide into the separatory funnel by clos-
droxide. Do not exceed the endpoint. ing the stopcock before the last few mL of hydrochloric acid
Apparatus—In this test, the sulfur dioxide is released drain out. Position the Apparatus in a water bath, and boil
from the test specimen in a boiling acid medium and is re- the mixture for 1 hour. Remove the receiving test tube, and
moved by a stream of carbon dioxide. The separated gas is transfer its contents to a 200-mL wide-necked, conical flask.
collected in a dilute hydrogen peroxide solution where the Rinse the receiving test tube with a small portion of water,
sulfur dioxide is oxidized to sulfuric acid and titrated with add the rinsing to the 200-mL conical flask, and mix. Heat
standard alkali. The apparatus consists essentially of a 500- on a water bath for 15 minutes and allow to cool. Add 0.1
mL three-neck, round-bottom, boiling flask, a separatory mL of Bromophenol blue indicator solution, and titrate the
funnel having a capacity of 100 mL or greater, a gas inlet contents with 0.1 N sodium hydroxide VS until the color
tube of sufficient length to permit introduction of the carbon changes from yellow to violet-blue, with the color change
dioxide within 2.5 cm of the bottom of the boiling flask, a lasting for at least 20 seconds. Perform a blank determina-
reflux condenser having a jacket length of 200 mm, and a tion, and make any necessary correction (see Titrimetry
delivery tube connecting the upper end of the reflux conden- (541)). Calculate the content, in ug per g, of sulfur dioxide
ser to the bottom of a receiving test tube. Apply a thin film in the test specimen taken by the formula:
of stopcock grease to the sealing surfaces of all of the joints
1000(32.03) VNIW,
except the joint between the separatory funnel and the boil-
ing flask, and clamp the joints to ensure tightness. in which 32.03 is the milliequivalent weight of sulfur diox-
ide, V is the volume, in mL, of titrant consumed, iV" is the
Procedure—Add 150 mL of water to the boiling flask.
normality of the titrant, and W is the weight, in g, of test
Close the stopcock of the separatory funnel, and begin the
specimen taken.
flow of carbon dioxide at a rate of 100 ± 5 mL per minute
through the Apparatus. Start the condenser coolant flow. Organic volatile impurities, Method IV (467): meets the
Add 10 mL of Hydrogen peroxide solution to a receiving requirements. B1
test tube. After 15 minutes, without interrupting the flow
Pharmacopeial Forum
presented in this chapter is generally applicable to most

GENERAL CHAPTERS
compressed tablets. Measurement of tablet friability supple-
ments other physical strength measurements, such as tablet
General Information breaking force.

Use a drum* with an internal diameter between 283 and
291 mm and a depth between 36 and 40 mm, of transparent
synthetic polymer with polished internal surfaces, and sub-
BRIEFING ject to minimum static build-up (see Figure for a typical ap-
paratus). One side of the drum is removable. The tablets are
(1216) Tablet Friability, USP 25 page 2255 and page 7466 of
PF25(1) [Jan.-Feb. 1999]. The United States Pharmacopeia is the tumbled at each turn of the drum by a curved projection with
test methods as provided in this general information chapter. The an inside radius between 75.5 and 85.5 mm that extends
presented text, which represents the OFFICIAL INQUIRY
STAGE 4 draft in the harmonization process, is based on com- from the middle of the drum to the outer wall. The outer dia-
ments received in response to the previously published Proposal
Stage 3 draft. The Expert Committee on Pharmaceutical Dosage meter of the central ring is between 24.5 and 25.5 mm. The
Forms invites comments regarding these In-Process Revision pro-
posals. Comments should be submitted by September 13,2002. drum is attached to the horizontal axis of a device that ro-
This draft differs from the Proposal Stage 3 draft as follows:
(1) Paragraph 1—The term "tablet crushing strength" is changed tates at 25 ± 1 rpm. Thus, at each turn the tablets roll or
to "tablet breaking force," a more commonly used terminol-
ogy. slide and fall onto the drum wall or onto each other.
(2) Paragraph 2—The drum description "not subject to static
build-up" is revised to "subject to minimum static build-
up" to acknowledge that inclination to static build-up is an 287.0±4.0 mm
inside diameter
intrinsic property of plastic materials. A statement providing
the limits for the apparatus central ring outer diameter is also
added.
(3) Paragraph 3—The sample weight for tablets with a unit mass
equal to or less than 650 mg is revised from "corresponding
to 6.5 g" to "corresponding as near as possible to 6.5 g" to
reflect experimental weighing variability.
(4) Paragraph 4—The directions for interpretation of test results
are clarified with a revision of "If the results are doubtful" to
"If the results are difficult to interpret." The drum base angle
is clarified with a revision of "an angle of about 10° with the
bench top" to "an angle of about 10° with the horizontal."
(5) Paragraph 5—For clarification, the use of the drum with dual 10.0±0.1 mm
iameter
scooping supports is revised from "is also available" to "is
also permitted."
(6) Tablet Friability Apparatus—The dimensions for external
drum diameter and central axle diameter provided in the Stage
3 draft figure are deleted based on comments indicating that
302.5 ±4.0 mm
diameter
-I
these dimensions are irrelevant to the test results.
Tablet Friability Apparatus

(PDF: L. Paul) RTS—22182-1
For tablets with a unit mass equal to or less than 650 mg,
take a sample of whole tablets corresponding as near as pos-
Change to read:
sible to 6.5 g. For tablets with a unit mass of more than 650
•(1216) TABLET FRIABILITY mg, take a sample of 10 whole tablets. The tablets should be
This chapter provides guidelines for the friability determi- * The apparatus meeting these specifications is available
from laboratory supply houses such as VanKel Technology
nation of compressed, uncoated tablets. The test procedure Group, 13000 Weston Parkway, Cary, NC 27513, or from
Erweka Instruments, Inc., 56 Quirk Road, Milford, CT
06460.
Pharmacopeial Forum
carefully dedusted prior to testing. Accurately weigh the

tablet sample, and place the tablets in the drum. Rotate the REFERENCE TABLES
drum 100 times, and remove the tablets. Remove any loose
dust from the tablets as before, and accurately weigh.
Generally, the test is run once. If obviously cracked,
cleaved, or broken tablets are present in the tablet sample
after tumbling, the sample fails the test. If the results are dif- BRIEFING
ficult to interpret or if the weight loss is greater than the tar- Description and Relative Solubility for Harmonization arti-
cles. This new section will accumulate sites of Description and So-
geted value, the test should be repeated twice and the mean lubility items as needed.
of the three tests determined. A maximum weight loss of not
(EMC: J. Lane) RTS—36456-1; 36456-2; 36496-1; 36496-3;
more than 1% of the weight of the tablets being tested is 36496-4
considered acceptable for most products. In the case of

new formulations, an initial weight loss of 0.8% would be
Add the following:
permitted until sufficient packaging data are obtained to ex-
•Citric Acid, Anhydrous: Colorless, translucent crystals,
tend the limit to a targeted value of 1%.
or white, granular to fine, crystalline powder. Efflorescent in
If tablet size or shape causes irregular tumbling, adjust the
dry air. Melts at about 153°, with decomposition. Very so-
drum base so that the base forms an angle of about 10° with
luble in water; freely soluble in alcohol; very slightly solu-
the horizontal and the tablets no longer bind together when
ble in ether. NF category: Acidifying agent; buffering
lying next to each other, which prevents them from falling
agent. B1
freely.
Add the following:
Effervescent tablets and chewable tablets may have differ-
"Citric Acid, Monohydrate: Colorless, translucent crys-
ent specifications as far as friability is concerned, and these
tals, or white, granular to fine, crystalline powder. Very so-
tablets normally require special packaging. In the case of
luble in water; freely soluble in alcohol; very slightly
hygroscopic tablets, a humidity-controlled environment (re-
soluble in ether. NF category: Acidifying agent; buffering
lative humidity less than 40%) is required for testing.
agent. B1
A drum with dual scooping supports for the running of
Add the following:
two samples at one time is also permitted.B1
"Corn Starch: Irregular, angular, white masses or fine
powder. Is odorless, and has a slight, characteristic taste. In-
soluble in cold water and in alcohol. NF category: Tablet
and/or capsule diluent; tablet disintegrant.B1
Add the following:
"Potato Starch: Irregular, angular, w

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,.

]fhe Journal of Standards Development and Official Compendia Revision

• Announcement of the Pharmacopeia!

• First Interim Revision Announcement

Hydrochlorothiazide (USP 26) 60

THE JOURNAL OF STANDARDS DEVELOPMENT AND OFFICIAL COMPENDIA REVISION

PF includes the following:

Public Review and Comment Process

USP Expert Committee approves item

USP Scientific Staff Liaison and the

Item published in PF for public review

Public comment received

USP Scientific Staff Liaison compiles and

Further revision needed No further revision needed

/ Revision proposal becomes official;

Proposed and Adopted Revisions

Section Content How Readers Can Respond

Policies and Announcements

Stimuli to the Revision Process

Reference Standards Catalog

Chromatographic Reagents Used in USP-NF and Pharmacopeial Forum

EXPERT COMMITTEE DESIGNATIONS'

The names of the Committees and their abbreviations are as follows:

* HDQ Indicates USP Headquarters items.

STAFF E-MAIL PHONE ASSIGMENT

New monograph development

STAFF DIRECTORY {Continued)

STAFF E-MAIL PHONE ASSIGMENT

Claudia C. Okeke, Scientist cco@usp.org (301) 816-8243 Compounding Pharmacy (CRX);

UPDATE ON THE ANNUAL EDITION OF USP-NF. CHROMATOGRAPHIC REAGENTS NOW AVAILABLE.

Calendar of Pharmacopeial Education Courses-2002

For further information, contact Barbara B. Hubert, Director

Publication Publication Date Official Date

Publication Due Date

FIRST INTERIM REVISION ANNOUNCEMENT 25

FIRST INTERIM REVISION

By authority of the United States Pharmacopeial Convention, Inc.

Mary Anne Koda-Kimble, Chair Roger L. Williams, Executive Vice President

John W. Gasper, Director, Executive Secretariat

Official February 1, 2002. Released January 2, 2002.

New USP Reference Standards

solution with 1 volume of methanol. Make adjustments if

Praziquantel [erratum] (2nd Supp) 84

when the article is recognized in the USP. The standards apply

'Products Not Marketed in the United States—Interest in

Nutritional and Other Dietary Supplements—The designation BRIEFING

Packaging and storage—Preserve in tight containers.

USP Reference standards (11)—USP Alendronate Sodium

(PA5: J. Esker) RTS—35823-1 chromatogram of the Assay preparation corresponds to that

Erratum: obtained in the Assay.

Medium: water; 900 mL.

Determine the amount of C4Hi2NNaO7P2 • 3H2O dis-

seconds. Centrifuge the mixture for 10 minutes. Use a

0.1% 9-Fluorenylmethyl chloroformate solution— screw-cap centrifuge tube".

to obtain 4 liters of solution, and mix.

Amoxicillin Tablets, USP 25 page 135. It is proposed to

(BPC: M. Marques) RTS—35022-1

Time: 90 minutes. (PA7: W. Wright) RTS—35542-3; 35557-1