British Phartnacopoeia

(Veterinary) 2014

The British Pharmacopoeia Commission has caused this British

Pharmacopoeia (Veterinary) 2014 to be prepared under regulation
317 (3) (b) of the Human Medicines Regulations 2012 and, in accordance
with regulation 317(4), the Ministers have arranged for it to be published.
It has been notified in draft to the European Commission in accordance
with Directive 98/34/EEC.

The monographs of the Seventh Edition of the European Pharmacopoeia

(2010), as amended by Supplements 7.1 to 7.8, published by the
Council of Europe are reproduced either in this edition of the British
Pharmacopoeia (Veterinary) or in the associated edition of the
British Pharmacopoeia.

see General Natices

Effective date: 1 January 2014

see Natices

London: The Stationery Office

In respect of Great Britain:

THE DEPARTMENT OF HEALTH

In respect of Northern Ireland:

THE DEPARTMENT OF HEALTH, SOCIAL SERVICES AND

PUBLlC SAFETY

© Crown Copyright 2013

Published by The Stationery Office on behalf of the Medicines and

Healthcare products Regulatory Agency (MHRA) except that:

European Pharmacopoeia monographs are reproduced with the permission

of the Council of Europe and are not Crown Copyright. These are
identified in the publication by a chaplet of stars.

This publication is a 'value added' producto If you wish to re-use the

Crown Copyright material from this publication, applications must be made
in writing, c1eady stating the material requested for re-use, and the purpose
for which it is required. Applications should be sent to: Dr S Atkinson,
MHRA, 5th Floor, 151 Buckingham Palace Road, London SW1W 9SZ.
First Published 2013

ISBN 978 011 3229 352

British Pharmacopoeia Commission Office:

MHRA
151 Buckingham Palace Road
London SW1W 9SZ
Telephone: +44 (0)20 3080 6561
E-mail: bpcom@mhra.gsi.gov.uk
Web site: http://www.pharmacopoeia.com

Laboratory:
British Pharmacopoeia Commission Laboratory
Queen's Road
Teddington
Middlesex TW11 OLY
Telephone: +44 (0)20 8943 8960
Fax: +44 (0)20 8943 8962
E-mail: bpcrs@mhra.gsi.gov.uk
Web site: http://www.pharmacopoeia.com
Contents

NOTICES
PREFACE

BRITISH PHARMACOPOEIA COMMISSION

EXPERT ADVISORY GROUPS, PANELS OF EXPERTS AND

WORIZING PARTIES
CODE OF PRACTICE

MEMBERSHIP
BP Commission, Expert Advisory Groups, Panels and Working Parties

STAFF
British Pharmacopoeia, BP Laboratory, Publisher

INTRODUCTION

Additions, Omissions, Technical Changes, Changes in Title

GENERAL NOTICES

MONOGRAPHS
Medicinal and Pharmaceutical Substances

Formulated Preparations: General Monographs

Formulated Preparations: Specific Monographs

Immunological Products

Surgical Materials

INFRARED REFERENCE SPECTRA

APPENDICES

SUPPLEMENTARY CHAPTERS
INDEX
 Notices

Monographs of the European Pharmacopoeia are distinguished by a chaplet

of stars against the title. The term European Pharmacopoeia, used without
qualification, means the Seventh Edition of the European Pharmacopoeia
comprising, unless otherwise stated, the main volume, published in 2010,
as amended by any subsequent supplements and revisions.

Patents In this Pharmacopoeia certain drugs and preparations have been inc1uded
notwithstanding the existence of actual or potential patent rights. In so far
as such substances are protected by Letters Patent their inc1usion in this
Pharmacopoeia neither conveys, nor implies, licence to manufacture.

Effective dates New and revised monographs of national origin enter into force on
1 January 2014. The monographs are brought into effect under
regulation 320(2) of the Human Medicines Regulations 2012.

Monographs of the European Pharmacopoeia have previously been

published by the European Directorate for the Quality of Medicines
& HealthCare in accordance with the Convention on the Elaboration of a
European Pharmacopoeia and have been brought into effect under
European Directives 2001l82/EC, 2001l83/EC and 2003/63/EC, as
amended, on medicines for human and veterinary use.

Vet-vi
Preface

The British Pharmacopoeia Commission has caused to be prepared

under regulation 317 (3) (b) of the Human Medicines Regulations 2012 a
compendium, namely this British Pharmacopoeia (Veterinary) 2014, and, in
accordance with regulation 317(4), the Ministers have arranged for it to be
published. It is a companion volume to the British Pharmacopoeia 2014.

The British Pharmacopoeia (Veterinary) 2014 contributes significantly to

the quality control of materials used in the practice of veterinary medicine.
It contains publicly available, legally enforceable standards that provide an
authoritative statement of the quality that a product, material or article is
expected to meet at any time during its period of use. The Pharmacopoeial
standards are designed to complement and assist the licensing and
inspection processes and are part of the overall system for safeguarding
animal and human health in the UIZ.

The British Pharmacopoeia Commission wishes to record its appreciation

of the services of all those who have contributed to the preparation of this
important work.

Vet-vii
 British Pharmacopoeia
Commission

The British Pharmacopoeia Commission is appointed, on behalf of the

Secretary of State for Health, by the Department of Health's Appointments
Team who are responsible for appointments to all of the Advisory Bodies
appointed under the Human Medicines Regulations 2012.
Under the terms of the Human Medicines Regulations 2012, the duties of
the British Pharmacopoeia Commission are as follows:

(a) the preparation and publication of any new edition of the British
Pharmacopoeia [regulations 317(1) and 317(4)];

(b) the preparation and publication of any compendium containing

information relating to substances and articles which are or may be
used in the practice of veterinary medicine or veterinary surgery
[regulations 317(3)(b) and 317(4)];

(c) the preparation and publication of a list of names to be used as the

headings to monographs in the British Pharmacopoeia [regulations
318(1) and 318(2)];

(d) the preparation of any amendments to the aboye publications

[regulation 317(S)(a)].

Members of the British Pharmacopoeia Commission are appointed for a

renewable term of 4 years and, under the requirements laid down by the
Office of the Commissioner for Public Appointments, can serve for a
maximum of 10 years.

In order to ensure that the British Pharmacopoeia Commission fulfils its

duties under the Human Medicines Regulations 2012, the members also
have the following duties:

(1) to frame clear and unequivocal technical advice in order to

discharge the Commission's responsibilities both for the British
Pharmacopoeia, the British Pharmacopoeia (Veterinary) and British
Approved Names and as the national pharmacopoeial authority with
respect to the European Pharmacopoeia;

(2) to develop clear policies for the preparation and publication of the
British Pharmacopoeia and its related publications;

(3) to serve on one or more Expert Advisory Groups or Panels of

Experts of the BP Commission, usual1y in the position of Chair or
Vice-Chair;

(4) to approve new and revised text for inclusion in new editions of the
British Pharmacopoeia and British Pharmacopoeia (Veterinary);

(5) to approve new and revised names for inclusion in new editions of
British Approved Names and its annual supplements.

Vet-viii
Expert Advisory Groups, Panels
of Experts and W orking Parties

Members of Expert Advisory Groups, Panels of Experts and Working

Parties are appointed by the British Pharmacopoeia Commission.

The duties of the members are as follows:

(a) to collaborate in the preparation and revision of Monographs,

Appendices and Supplementary Chapters for inclusion in the
British Pharmacopoeia and British Pharmacopoeia (Veterinary);

(b) to collaborate in the preparation and revision of Monographs,

Methods and General Chapters of the European Pharmacopoeia;

(c) to review reports from the British Pharmacopoeia Laboratory in

terms of technical content and, where possible, provide independent
experimental data to assist in decision making;

(d) to collaborate in the preparation and revision of the list of names to

be used as titles for monographs of the British Pharmacopoeia and
British Pharmacopoeia (Veterinary).

Members of Expert Advisory Groups, Panels of Experts and Working

Parties are usually appointed for a renewable term of 4 years.

Vet-ix
 Code of Practice

Members of the British Pharmacopoeia Commission and its supporting

Expert Advisory Groups, Panels of Experts and Working Parties are
required to comply with aCode of Practice on Declaration of Interests
in the Pharmaceutical Industry.

British Pharmacopoeia Cornrnission

Chairs and members of the British Pharmacopoeia Commission are

required to make a full declaration of interests on appointment and
annually thereafter. They must also inform the BP Secretariat promptly of
any changes to these interests during the year. These interests are published
in the Medicines Advisory Bodies Annual Reports which are available via
the MHRA website (http://www.mhra.gov.uk).

Relevant interests must be declared at meetings and are recorded in the

Minutes.

Expert Advisory Groups, Panels of Experts and Working Parties

Chairs and members are required to make a full declaration of interests on

appointment and to update the Secretariat if these interests change during
their term of office. A record is kept of those experts who have declared
specific interests, but these are not published.

Relevant interests must be declared at meetings and are recorded in the

Minutes.

Vet-x
 Membership of the British
Pharmacopoeia Commission

The list below includes those members who served during the period 2012
to 2013.

Chair Vacant, following the retirement of Professor David Woolfson on 30 June 2012.

Vice-Chair Mr V'Iain Fenton-May BPharm MIPharmM FRPharmS

Former Specialist Quality Controller to the Welsh Hospitals

Professor Donald Cairns BSe PhD MRPharmS CSei CChem FRSC

Head: School of Pharmacy and Lije Sciences, Robert Gordon University,
Aberdeen

Mr Barry Capon CBE MA DL (Lay representative)

Non-executive Director, Suffolk NHS Foundation Trust

Dr Graham D Cook BPharm PhD MRPharmS

Senior Director, Process Knowledge/Quality by Design, Pjizer

Mr Andrew Coulson BVetMed MSe MRCVS

Member of the Royal College of Veterinary Surgeons; former Superintending
Inspector, Science & Research Group, The Home Office

Professor Alastair Davidson BSe PhD FRPharmS

Visiting Professor of Pharmaceutical Sciences, University of Strathclyde

Dr Thomas D Duffyl BSe PhD FRPharmS CChem MRSC FCQI CQP

MRQA
Director, Lowden International (providing consultancy and training to
pharmaceutical organisations)

Mr Christopher Goddard BSe DIS CSei EurChem CChem FRSC

Quality Control Technical Manager, Recipharm Limited

Dr Keith Helliwell BPharm PhD

Senior Technical Adviser, William Ransom & Son PLC

Dr Rodney L Horder BPharm PhD MRPharmS

Former Divisional Vice President, Buropean Quality and Regulatory Strategy,
Abbott

Dr Gerard Lee BPharm PhD FRPharmS MRSC CChem

Former Group Manager of the British Pharmacopoeia and Laboratory Services
Section, MHRA; former Secretary & Scientific Director of the British
Pharmacopoeia Commission

Dr Brian R Matthews BPharm PhD FRPharmS FTOPRA MRI

Consultant on pharmaceutical and medical device regulatory affairs; former Senior
Director, BC Registration, Alcon Laboratories

Vet-xi
 Professor John Miller MSe PhD MRSC CChem
Visiting Professor, Strathclyde Institute of Pharmacy and Biomedical Sciences;
former Head of the EDQM Laboratory

Dr Ronald Torano BSe PhD MRSC CChem

Pharmacopoeial Intelligence and Advisóry Specialist; GlaxoSmithKline

Dr Lineoln Tsang BPharm LLB PhD FRSC FIBiol FRSA FRPharmS

Solicitor
Lije Sciences Lawyer; Partner, Arnold & Porter LLP

Mrs Josephine Turnbull LLB (Lay representative)

Chair of Tees, Esk and Wear Valley NHS Foundation Trust

Dr Paul Varley BSe PhD

Vice President of Biopharmaceutical Development, Medimmune Limited

Professor Elizabeth Williamson BPharm PhD MRPharmS

Professor of Pharmacy, University of Reading

Secretary and Scientific Dr Samantha Atkinson BSe MSe PhD MRSC; Visiting Fellow, Reading
Director University

1 Retired, 31 Deeember 2012.

Vet-xii
 Membership of Expert Advisory
Groups, Panels of Experts and
Working Parties

The Commission appointed the following Expert Advisory Groups, Panels

of Experts and Working Parties to advise it in carrying out its duties.
Membership has changed from time to time; the lists below include all who
have served during the period 2012 to 2013.

EXPERT ADVISORY GROUPS

ABS: Antibiotics R L Horder (Chair), G Cook (Vice-Chair), P Ellis, V Jaitely, P Jones,
A Livingstone, W Mann, J Miller, N Thomas, B White, 1 R Williams

HCM: Herbal and E Williamson (Chair)J LA Anderson (Vice-Chair), T Chapman, A Charvill,

Complementary K Helliwell, P Hylands, C Leon, A C Moffat, M Pires, M Rowan,
Medicines K Strohfeldt-Venables, J Sumal, C Wright, K Zhao
(Corresponding members SS Handa, A Krauss)

MC1: Medicinal A G Davidson (Chair), D Cairns (Vice-Chair), M Ahmed, J C Berridge,

Chemicals M Broughton, A J Caws, P Fleming, W J Lough, D Malpas, G Marco

MC2: Medicinal T D Duffy (ChairJ until 31 December 2012), G Cook (ChairJ ¡rom 1 January
Chemicals 2013), C T Goddard (Vice-Chair), M Cole, A Gibson, S Jones, M A Lee,
J Lim, J Miller, P Murray, J Qiu, M Turgoose
(Corresponding members M Brits, W Sherwin)

MC3: Medicinal V Fenton-May (Chair), E Williamson (Vice-Chair), S Arkle, C T Goddard,

Chemicals P Hampshire, W K L Pugh, B Rackstraw, R Torano, M Tubby,
1 R Williams

NOM: Nomenc1ature J K Aronson (Chair), L Tsang (Vice-Chair), M Ahmed, S Clarke, G Cook,

D Mehta, G P Moss, R Thorpe
(Corresponding members R G Balocco Mattavelli, E M Cortés Montejano,
A D McNaught, J S Robertson)
PCY: Pharmacy R L Horder (Chair), A D Woolfson (Vice-ChairJ until30 June 2012),
M Aulton, E Baker, N Broad, G Buckton, G Davison, G Ecc1eston,
D Elder, R Lowe, J MacDonald, B R Matthews, J F McGuire, S C Nichols
ULM: Unlicensed V Fenton-May (Chair), T D Duffy (Vice-ChairJ until 31 December 2012),
Medicines 1 Beaumont, S Branch, A Charvill, W Goddard, S Jones, M G Lee,
M A Oldcorne, N J Precious, J Rothwell, M Santillo, J Smith, P Weir

Vet-xiii
 PANELS OF EXPERTS
BIO: Biological and L Tsang (Chair), M A Dow (Vice-Chair), A F Bristow, D H Calam,
Biotechnological J Cook, L Findlay, A Onadipe, B Patel, A M Pickett, C Ponsar, 1 Rees,
Products D Sesardic, P Sheppard, W J Tarbit, J N A Tettey, A H Thomas,
R Thorpe, P Varley
BLP: Blood K Chidwick, A R Hubbard, S Jenkins, P Varley
Products
IGC: Inorganic and C T Goddard (Chair), A C Cartwright, P Henrys, D Malpas, C Mroz,
General Chemicals D Riches

MIC: Microbiology V Fenton-May (Chair), S Denyer, D P Hargreaves, B R Matthews,

P Newby

RAD: Radioactive J Ballinger, J Brain, D Graham, S R Hesslewood, G Inwards, P Maltby,

Materials A M Millar, R D Pickett, R Smith, S Waters

VET: Veterinary E Williamson (Chair), P Lees (Vice-Chair), A Cairns, A Coulson,

Medicines S Cockbill, D Evans, E Flahive, B Ward

VIP: Veterinary A M Brady, K Redhead, J Salt, P W Wells

Immunological
Products

WORKING PARTIES
CX: Excipients G Buckton (Chair), C Mroz (Vice-Chair), E Anno, R Cawthorne,
B R Matthews, M 1 Robertson, K Slevin

IP: Inhaled Products S C Nichols (Chair), y Adjibade, M Dagli Alberi, J Lim, J Qiu, 1 Vaughan
(Disbanded, 31
December 2012)

Vet-xiv
 Current British Pharmacopoeia
Staff

Secretariat M Vallender (Editor-in-ChiefJ

S Young (Head of Analytical Science)

M Barrett, H Corns, P Crowley, A Evans, J Francomb, A Gibb, P Holland,

R A Pask-Hughes, C Pitt, J Pound, F J Swanson, M Whaley

Administrative M Cumberbatch, B F Delahunty, W Jeffries, D Myburgh, J Paine,

N Salmon

ISO 9001
F527268

Vet-xv
 Current British Pharmacopoeia
Laboratory Staff

K Courtney (Laboratory Manager)

M Amblin, M Coxon, C Galdino, P Gallagher, E Iones, L Magee,

R Mannan, A Panchal, K Patel, N Patel, L Rae, E Sanderson, K Smith,
N Vadukal

/509001
F527613

Vet-xvi
Current Staff of the Publisher of
the British Pharmacopoeia

J Hook (Executive Director)

C Hackett (Project Manager)

K Cole and J Wilkinson (Client Services Managers)

P Allard, C Bailey, N Brownlow, M Grant, T Horsnell, A Jackson,

G Mannings, S Page, P Relfe, H Sinclair, 1 Webb

ISO 9001
F522428

Vet-xvii
Monographs

Medicinal and Pharmaceutical

Substances
2014
MEDICINAL ANO PHARMACEUTICAl
SUBSTANCES
Substances for Pharmaceutical *****
** * a direct gene product based on genetic modification,
Use *** *
(Ph Eur monograph 2034)
PhE~ ______________________________________________
DEFINITION
Substances for pharmaceutical use are any organic or
inorganic substances tbat are used as active substances or
excipients for the production of medicinal products for
human or veterinary use. They may be obtained from natural
sources or produced by extraction from raw materials,
fermentation or synthesis.
This general monograph do es not apply to herbal drugs,
herbal drugs for homoeopathic preparations, herbal drug
preparations, extracts, or motber tinctures for homoeopathic
preparations, which are the subject of separate general
monographs (Herbal drugs (1433), Herbal drugs for
homoeopathic preparations (2045), Herbal drug preparations
(1434), Extracts (0765), Mother tinctures for homoeopathic
preparations (2029)). It does not apply to raw materials for
homoeopathic preparations, except where tbere is an
individual monograph for tbe substance in tbe
non-homoeopatbic part of the Pharmacopoeia.
Where a substance for pharmaceutical use not described in
an individual monograph of the Pharmacopoeia is used in a
medicinal product prepared for tbe special needs of
individual patients, tbe need for compliance with tbe present
general monograph is decided in the light of a risk
assessment tbat takes account of the available quality of the
substance and its intended use.
Where medicinal products are manufactured using
substances for pharmaceutical use of human or animal origin,
the requirements of chapter 5.1.7. Viral safety apply.
Substances for pharmaceutical use may be used as such or as
starting materials for subsequent formulation to prepare
medicinal products. Depending on the formulation, certain
substances may be used either as active substances or as
excipients. Solid substances may be compacted, coated,
granulated, powdered to a certain fineness, or processed in
otber ways. A monograph is applicable to a substance
processed with an excipient only where such processing is
mentioned in the definition section of tbe monograph.
Substance for pharmaceutical use of special grade Unless
otberwise indicated or restricted in the individual
monographs, a substance for pharmaceutical use is intended
for human and veterinary use, and is of appropriate quality
for the manufacture of all dosage forms in which it can be
used.
Polymorphism Individual monographs do not usually specify
crystalline or amorphous forms, unless bioavailability is
affected. All forms of a substance for pharmaceutical use
comply witb tbe requirements of the monograph, unless
otberwise indicated.
PRODUCTION
Substances for pharmaceutical use are manufactured by
procedures that are designed to ensure a consistent quality
and comply witb tbe requirements of tbe individual
monograph or approved specification.
General Monographs Vet-37
The manufacture of active substances must take place under
conditions of good manufacturing practice.
The provisions of general chapter 5.10 apply to tbe control of
impurities in substances for pharmaceutical use.
Whetber or not it is specifically stated in the individual
monograph that the substance for pharmaceutical use:
-- is a recombinant protein or anotber substance obtained as
where applicable, tbe substance also complies with the
requirements of the general monograph Products of
recombinant DNA technology (0784);
is obtained from animals susceptible to transmissible
spongiform encephalopatbies otber than by experimental
challenge, where applicable, the substance also complies
with the requirements of the general monograph Products
with risk of transmitting agents of animal spongiform
encephalopathies (1483);
is a substance derived from a fermentation process,
whetber or not the micro-organisms involved are modified
by traditional procedures or recombinant DNA (rDNA)
technology, where applicable, tbe substance also complies
witb the requirements of the general monograph Products
of fermentation (1468).
If solvents are used during production, they are of suitable
quality. In addition, their toxicity and tbeir residuallevel are
taken into consideration (5.4). If water is used during
production, it is of suitable quality.
If substances are produced or processed to yield a certain
form or grade, that specific form or grade of the substance
complies witb tbe requirements of tbe monograph. Certain
functionality-related tests may be described to control
properties tbat may infiuence the suitability of tbe substance
and subsequently the properties of dosage forms prepared
from it.
Powdered substances may be processed to obtain a certain
degree of fineness (2.9.35).
Compacted substances are processed to increase the particle
size or to obtain particles of a specific form and/or to obtain
a substance witb a higher bulk density.
Coated active substances consist of particles of the active
substance coated witb one or more suitable excipients.
Granulated active substances are particles of a specified size
and/or form produced from the active substance by
granulation directly or with one or more suitable excipients.
If substances are processed with excipients, these excipients
comply witb tbe requirements of the relevant monograph or,
where no such monograph exists, tbe approved specification.
Where active substances have been processed witb excipients
to produce, for example, coated or granulated substances, the
processing is carried out under conditions of good
manufacturing practice and the processed substances are
regarded as intermediates in the manufacture of a medicinal
producto
CHARACTERS
The statements under tbe heading Characters
(e.g. statements about the solubility or a decomposition
point) are not to be interpreted in a strict sense and are not
requirements. They are given for information.
Where a substance may show polymorphism, this may be
stated under Characters in order to draw this to the attention
of tbe user who may have to take this characteristic into
consideration during formulation of a preparation.
Vet-38 General Monographs 2014

IDENTIFICAnON The requirements aboye do not apply to biological and

Where under Identification an individual monograph biotechnological products, oligonuc1eotides,
contains subdivisions entitled 'First identification' and radiopharmaceuticals, products of fermentation and semi-
'Second identification', the test or tests that constitute the synthetic products derived therefrom, to crude products of
'First identification' may be used in all circumstances. animal or plant origin or herbal products.
The test or tests that constitute the 'Second identification' For active ~ubstances in a new application for a medicinal
may be used in pharmacies provided it can be demonstrated product for human use, the requirements of the guideline on
that the substance or preparation is fully traceable to a batch the limits of genotoxic impurities and the corresponding
certified to comply with all the other requirements of the questions and answers documents published on the website
monograph. of the European Medicines Agency (or similar evaluation
Certain monographs give two or more sets of tests for the principies for non-European Union member states) must be
purpose of the first identification, which are equivalent and followed.
may be used independently. One or more of these sets Residual solvents
usually contain a cross-reference to a test prescribed in the Are limited according to the principies defined in chapter
Tests section of the monograph. It may be used to simplify 5.4, using general method 2.4.24 or another suitable method.
the work of the analyst carrying out the identification and the Where a quantitative determination of a residual solvent is
prescribed tests. For example, one identification set cross- carried out and a test for loss on drying is not carried out,
refers to a test for enantiomeric purity while the other set the content of residual solvent is taken into account for
gives a test for specific optical rotation: the intended purpose calculation of the assay content of the substance, the specific
of the two is the same, that is, verification that the correct optical rotation and the specific absorbance.
enantiomer is presento
Microbiologica! quaüty
TESTS Individual monographs give acceptance criteria for
Polymorphism (5.9) microbiological quality wherever such control is necessary.
If the nature of a crystalline or amorphous form imposes Table 5.1.4.-2. - Aeeeptanee eriteria for mierobiologieal quality of
restrictions on its use in preparations, the nature of the non-sterile substanees for pharmaeeutieal use in chapter 5.1.4.
specific crystalline or amorphous form is identified, its M icrobiological quality of non-sterile pharmaceutieal preparations
morphology is adequately controlled and its identity is stated and substances for pharmaeeutical use gives recommendations
on the labe!' on microbiological quality that are of general relevance for
Related substances substances subject to microbial contamination. Depending on
Unless otherwise prescribed or justified and authorised, the nature of the substance and its intended use, different
organic impurities in active substances are to be reported, acceptance criteria may be justified.
identified wherever possible, and qualified as indicated in Steriüty (2.6.1)
Table 2034.-1 or in Table 2034.-2 for peptides obtained by If intended for use in the manufacture of sterile dosage forms
chemical synthesis. without a further appropriate sterilisation procedure, or if
offered as sterile grade, the substance for pharmaceutical use
Table 2034.-1. - Reporting, identification and qualification of complies with the test for sterility.
organic impurities in active substances Bacteria! endotoxins (2.6.14)
Use Maximum Report- Identification Qualification If offered as bacterial endotoxin-free grade, the substance for
daily ing threshold lhreshold pharmaceutical use complies with the test for bacterial
dose lhreshold endotoxins. The limit and test method (if not gelation
Human ,;; 2 gjday > 0.05 per > 0.10 per > 0.15 per method A) are stated in the individual monograph. The limit
use or cent cent or a cenl or a
human and daily intake daily inlake is calculated in accordance with Test for bacterial endotoxins:
velerinary of> 1.0 mg of> 1.0 mg guidelines in chapter 2.6.14. Bacterial endotoxins, unless a
use (whichever is (whichever is
lhe lower) the lower)
lower limit is justified from results from production batches
Human > 2 gjday > 0.03 per > 0.05 per cenl > 0.05 per cenl
or is required by the competent authority. Where a test for
use or cent bacterial endotoxins is prescribed, a test for pyrogens is not
human and required.
veterinary
use Pyrogens (2.6.8)
Veterinary Nol > 0.10 per > 0.20 per cenl > 0.50 per cent If the test for pyrogens is justified rather than the test for
use only applicable cenl
bacterial endotoxins and if a pyrogen-free grade is offered,
the substance for pharmaceutical use complies with the test
for pyrogens. The limit and test method are stated in the
Table 2034.-2. - Reporting, identification and qualification of individual monograph or approved by the competent
organic impurities in peptides obtained by chemical synthesis authority. Based on appropriate test validation for bacterial
Reporting Identification Qualification endotoxins and pyrogens, the test for bacterial endotoxins
lhreshold threshold lhreshold may replace the test for pyrogens.
> 0.1 per cent > 0.5 per cenl > 1.0 per cent Additional properties
Control of additional properties (e.g. physical characteristics,
functionality-related characteristics) may be necessary for
Specific thresholds may be applied for impurities known to individual manufacturing processes or formulations. Grades
be unusually potent or to produce toxic or unexpected (such as sterile, endotoxin-free, pyrogen-free) may be
pharmacological effects. produced with a view to manufacture of preparations for
If the individual monograph does not provide suitable control parenteral administration or other dosage forms and
for a new impurity, a suitable test for control must be
developed and inc1uded in the specification for the substance.
2014
appropriate requirements may be specified in an individual
monograph.
ASSAY
Unless justified and authorised, contents of substances for
pharmaceutical use are determined. Suitable methods are
used.
LABELLING
In general, labelling is subject to supranational and national
regulation and to intemational agreements. The statements
under the heading Labelling therefore are not comprehensive
and, moreover, for the purposes of the Pharmacopoeia only
those statements that are necessary to demonstrate
compliance or non-compliance with the monograph are
mandatory. Any other labelling statements are induded as
recommendations. When the term 'label' is used in the
Pharmacopoeia, the labelling statements may appear on the
container, the package, a leaflet accompanying the package or
a certificate of analysis accompanying the artide, as decided
by the competent authority.
Where appropriate, the label sta tes that the substance is:
-- intended for a specific use;
-- of a distinct crystalline form;
-- of a specific degree of fineness;
-- compacted;
-- coated;
-- granulated;
-- sterile;
-- free from bacterial endotoxins;
-- free from pyrogens;
-- containing gliding agents.
Where applicable, the labe! states:
-- the degree of hydration;
-- the name and concentration of any excipient.
___________________________________________
Acepromazine Maleate
HXCOOH
H COOH
442.5 3598-37-6
Action and use
Dopamine receptor antagonist; neuroleptic.
Preparations
Acepromazine Injection
Acepromazine Tablets
DEFINITION
Acepromazine Maleate is 2-acetyl-
10-(3-dimethylaminopropyl) phenothiazine hydrogen
maleate. It contains not les s than 98.5% and not more than
101.0% of C19H22N20S,C4H404, ca1culated with reference
to the dried substance.
CHARACTERISTICS
A yellow, crystalline powder.
Soluble in water; freely soluble in chloroform; soluble in
ethanol (96%); slightly soluble in ether.
Alfadolone Acetate Vet-39
IDENTIFICATION
A. Dissolve 20 mg in 2 mL of water, add 3 mL of 2M sodium
hydroxide, extract with 5 mL of cyclohexane and evaporate to
dryness under reduced pressure. The infrared absorption
spectrum of the residue, Appendix II A, is concordant with
the .reference spectrum of acepromazine (RSV 01).
B. Complies with the test for identification of phenothiazines,
Appendix III A, applying to the plate 1 JlL of each solution
and using acepromazine malea te BPCRS for the preparation of
solution (2).
C. Dissolve 0.2 g in a mixture of 3 mL of water and 2 mL of
5M sodium hydroxide and shake with three 3-mL quantities of
ether. Add to the aqueous solution 2 mL of bromine solution,
warm in a water bath for 10 minutes, heat to boiling, cool
and add 0.25 mL to a solution of 10 mg of resorcinol in 3 mL
of sulfuric acid. A bluish black colour develops on heating for
15 minutes in a water bath.
TESTS
Acidity
pH of a 1.0% w/v solution, 4.0 to 4.5, Appendix V L.
Melting point
136° to 139°, Appendix V A.
Related substances
Complies with the test for related substances in phenothiazines,
Appendix III A, but using a mixture of 75 volumes of
n-hexane, 17 volumes of butan-2-one and 8 volumes of
diethylamine as the mobile phase.
Loss on drying
When dried to constant weight at 105°, loses not more than
1.0% of its weight. Use 1 g.
Sulfated ash
Not more than 0.2%, Appendix IX A.
~Ew
ASSAY
Dissolve 0.4 g in 50 mL of acetic anhydride and carry out
Method 1 for non-aqueous titration, Appendix VIII A, using
crystal violet solution as indicator. Each mL of 0.1 M perchloric
acid VS is equivalent to 44.25 mg of C19H22N20S,C4H404'
Alfadolone Acetate
OAc
H "
HO H
390.5 23930-37-2
Action and use
Intravenous general anaesthetic.
DEFINITION
Alfadolone Acetate is 3a-hydroxy-11 ,20-dioxo-5a-pregnan-
21-yl acetate. It contains not less than 96.0% and not more
than 103.0% of C23H340S' ca1culated with reference to the
dried substance.
CHARACTERISTICS
A white to creamy white powder.
 Vet-40 Alfaxalone
Practically insoluble in water; freely soluble in chloroform;
soluble in ethanol (96%); practically insoluble in petroleum
spirit (boiling range, 60° to 80°).
IDENTIFICATION
A. The infrared absorption spectrum, Appendix II A, is
concordant with the reference spectrum of alfadolone acetate
(RSV02).
B. The light absorption, Appendix II B, in the range 230 to
350 nm of a 0.4% w/v solution in ethanol (96%) exhibits a
maximum only at 290 nm. The absorbance at 290 nm is
about 0.7.
C. Complies with the test for identification of steroids,
Appendix III A, using impregnating solvent 11 and mobile phase
D.
TESTS
Light absorption
Absorbance of a 0.20% w/v solution in ethanol (96%) at
235 nm, not more than 0.60, calculated with reference to the
dried substance, Appendix II B.
Related substances
Carry out the method for thin-layer chromatography,
Appendix III A, using silica gel G as the coating substance
and a mixture of equal volumes of ethyl acetate and toluene as
the mobile phase. Apply separately to the plate 10 ¡lL of each
of three solutions of the substance being examined in a
mixture of equal volumes of chloroform and methanol
containing (1) 5.0% w/v, (2) 0.15% w/vand (3) 0.050% w/v.
After removal of the plate, dry it in a current of air until the
solvent has evaporated, spray with a saturated solution of
cerium (IV) sulfate in sulfuric acid (50%) and heat at 110° for
1 hour. Any secondary spot in the chromatogram obtained
with solution (1) is not more intense than the spot in the
chromatogram obtained with solution (2) (3%) and not more
than one such spot is more intense than the spot in the
chromatogram obtained with solution (3) (1 %).
Loss on drying
When dried to constant weight at 105°, loses not more than
l.0% of its weight. Use 1 g.
Sulfated ash
Not more than 0.1 %, Appendix IX A.
ASSAY
Carry out the tetrazolium assay of steroids, Appendix VIII J,
allowing the reaction to proceed at 35° for 2 hours. Calculate
the content of C23H340S from the absorbance obtained by
repeating the operation using alfadolone acetate BPCRS in
place of the substance being examined.
Alfaxalone
H~
HO
H
332.5 23930-19-0
Action and use
Intravenous general anaesthetic.
2014
DEFINITION
Alfaxalone is 3a-hydroxy-5a-pregnane-11, 20-dione.
It contains not less than 95.0% and not more than 103.0%
of C21H3203, calculated with reference to the dried
substance.
CHARACTERISTICS
A white to creamy white powder.
Practically insoluble in water; freely soluble in chloroform;
soluble in ethanol (96%); practically insoluble in petroleum
spirit (boiling range, 60° to 80°).
IDENTIFICATION
A. The infrared absorption spectrum, Appendix II A, is
concordant with the reference spectrum of alfaxalone (RSV 03).
B. Complies with the test for identification of steroids,
Appendix III A, using impregnating solvent 11 and mobile phase
D.
C. In the Assay, the chromatogram obtained with solution
(2) shows a peak having the same retention time as the peak
due to alfaxalone BPCRS in the chromatogram obtained with
solution (1).
TESTS
Light absorption
Absorbance of a 0.20% w/v solution in ethanol (96%) at
235 nm, not more than 0.20, calculated with reference to the
dried substance, Appendix II B.
Related substances
Carry out the method for thin-layer chromatography,
Appendix III A, using silica gel G as the coating substance
and a mixture of equal volumes of ethyl acetate and toluene as
the mobile phase. Apply separately to the plate 10 ¡lL of each
of three solutions of the substance being examined in a
mixture of equal volumes of chloroform and methanol
containing (1) 5.0% w/v, (2) 0.15% w/vand (3) 0.050% w/v.
After removal of the plate, dry it in a current of air until the
solvent has evaporated, spray with a saturated solution of
cerium (IV) sulfate in sulfuric acid (50%) and heat at 110° for
1 hour. Any secondary spot in the chromatogram obtained
with solution (1) is not more intense than the spot in the
chromatogram obtained with solution (2) (3%) and not more
than one such spot is more intense than the spot in the
chromatogram obtained with solution (3) (1 %).
Loss on drying
When dried to constant weight at 105°, loses not more than
1.0% of its weight. Use 1 g.
Sulfated ash
Not more than 0.1 %, Appendix IX A.
ASSAY
Carry out the method for liquid chromatography,
Appendix III D, using the following solutions. For solution
(1) dilute 25 mL of a solution in propan-2-01 R1 containing
0.2% w/v of alfaxalone BPCRS, 0.01 % w/v of alfadolone
acetate BPCRS and 0.03% w/v of betamethasone BPCRS
(internal standard) to 100 mL with carbon dioxide-free water.
For solution (2) dilute 25 mL of a solution in propan-2-01 R1
containing 0.2% w/v of the substance being examined to
100 mL with carbon dioxide-free water. For solution (3) dilute
25 mL of a solution in propan-2-01 Rl containing 0.2% w/v of
the substance being examined and 0.03% w/v ofthe internal
standard to 100 mL with carbon dioxide-free water.
The chromatographic procedure may be carried out using
(a) a stainless steel column (10 cm x 5 mm) packed with
octadecylsilyl silica gel for chromatography (5 ¡lm) (Spherisorb
ODS 1 is suitable) and maintained at 60°, (b) as the mobile
2014
phase with a ftow rate of 1 mL per minute a mixture of
propan-2-ol Rl and carbon dioxide-free water adjusted so that
the resolution factor between the peaks due to alfadolone
acetate (retention time about 5 minutes) and alfaxalone
(retention time about 6 minutes) is more than 1.0 (a mixture
of 25 volumes of propan-2-ol Rl and 75 volumes of carbon
dioxide-free water is usually suitable) and (c) a detection
wavelength of 205 nm.
Calculate the content of C21H3203 in the substance being
examined using the declared content of C21H3203 in
alfaxalone BPCRS; peak areas or peak heights may be used
irrespective of the symmetry factor.
Amitraz
Action and use
Topical parasiticide; acaricide.
Prepararlon
Amitraz Dip Concentrate (Liquid)
DEFINITION
Amitraz is N-methylbis (2,4-xylyliminomethyl) amine.
It contains not less than 97.0% and not more than 101.0%
of C19H23N3, calculated with reference to the anhydrous
substance.
CHARACTERISTICS
A white to buff powder.
Practically insoluble in water; decomposes slowly in ethanol
(96%); freely soluble in acetone.
IDENTIFICATION
The infrared absorption spectrum, Appendix II A, is concordant
with the reference spectrum of amitraz (RSV 04).
TESTS
Re1ated substances
Carry out the method for gas chromatography,
Appendix III B, using the following solutions.
0.010% w/v of 2)4-dimethylaniline, 0.20% w/v of
form-2')4'-xylidide BPCRS and 0.20% w/v of N)N'-bis(2) 4-
xylyl)formamidine BPCRS in methyl acetate (solution A)
Disperse 30 mg of N-methyl-N'-(2)4-xylyl)formamidine
hydrochloride BPCRS in 5 mL of methyl acetate, add about
32 mg of triethylamine, mix with the aid of ultrasound for
2 minutes, filter, wash the filter with a small amount of
methyl acetate and add sufficient methyl acetate to the
combined filtrate and washings to produce 25 mL (solution
B) (about 0.1 % w/v of N-methyl-N'-(2)4-xylyl)formamidine).
(1) 5.0% w/v solution of the substance being examined in
methyl acetate.
(2) A mixture of equal volumes of solution A and solution B.
CHROMATOGRAPHIC CONDITIONS
(a) Use a fused silica capillary column (10 m x 0.53 mm)
bonded with a film (5 ¡.tm) of poly (methyl(95)phenyl(5)]
siloxane (Chrompack CP-SIL 8 CB is suitable).
Amitraz Vet-41
(b) Use helium as the carrier gas at 12 mL per minute.
(c) Use gradient conditions at an initial temperature of l25°,
maintained at 125° for 5 minutes, increasing linearly to 270°
at arate of 5° per minute and maintained at 270° for
15 minutes
(d) Use an inlet temperature of 230°.
(e) Use a ftame ionisation detector at a temperature of 300°.
(f) Inject 1 ~lL of each of solutions (1) and (2).
In the chromatogram obtained with solution (2) the peaks
following the solvent peak, in order of emergence, are due to
2,4-dimethylaniline, form-2',4'-xylidide, N-methyl-
N'-(2,4-xylyl)forrnamidine and N,N'-bis(2,4-
xylyl)formamidine.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak corresponding to 2,4-dimethylaniline,
form-2' ,4'-xylidide, N-methyl-N'-(2,4-xylyl)formamidine and
N,N'-bis(2,4-xylyl)forrnamidine is not greater than the area
of the corresponding peak in the chromatogram obtained
with solution (2) (0.1 %, 2%, 1% and 2% respectively);
the area of any other secondary peak is not greater than the
area of the peak due to 2,4-dimethylaniline in the
chromatogram obtained with solution (2) (0.1 %).
Water
Not more than 0.1 % w/w, Appendix IX C, Method lA.
Use 5 g and a mixture of equal volumes of chloroform and
2-chloroethanol in place of anhydrous methanol.
Sulfated ash
Not more than 0.2%, Appendix IX A.
ASSAY
Carry out the method for gas chromatography,
Appendix III B, using the following solutions.
Prepare a 2% v/v solution of squalane (internal standard) in
methyl aceta te (solution C).
(1) 0.15 g ofthe substance being examined in sufficient
methyl acetate to produce 30 mL.
(2) 0.15 g of the substance being examined in 10 mL of
solution C and add sufficient methyl acetate to produce
30 mL.
(3) 1.50% w/v solution of amitraz BPCRS in solution C and
dilute 1 volume of this solution to 3 volumes with methyl
acetate.
CHROMATOGRAPHIC CONDITIONS
(a) Use a fused silica capillary column (15 m x 0.53 mm)
coated with a 1.5 ~lm film of methyl silicone gum
(Chrompack CP-Sil 5 CB is suitable).
(b) Use helium as the carrier gas at 12 mL per minute.
(c) Use isothermal conditions maintained at 220°.
(d) Use an inlet temperature of 230°.
(e) Use a ftame ionisation detector at a temperature of 300°.
(f) Inject 1 ¡.tL of each solution.
SYSTEM SUITABILITY
The assay is not valid unless, in the chromatogram obtained
with solution (3), the resolution factor between the peaks
corresponding to squalane and amitraz is at least 3.0.
LIMITS
Calculate the content of CI9H23N3 from the chromatograms
obtained using the declared content of Cl9H23N3 in
amitraz BPCRS.
Vet-42 Amprolium Hydrochloride 2014

STORAGE B. The light absorption, Appendix II B, in the range 230 to

Amitraz should be kept in a well-c1osed container, which may 350 nm of a 0.002% w/v solution in O.IM hydrochloric acid
contain paraformaldehyde, packed in separate sachets as a exhibits two maxima, at 246 nm and 262 nm. The
stabiliser. absorbances at the maxima are about 0.84 and about 0.80,
respectively.
IMPURITIES
C. To 1 mg .add 5 mL of naphthalenediol reagent solution;
a deep violet colour is produced.
~NH2
D. Yields the reactions characteristic of chlorides,
Me ~ Me Appendix VI.
TESTS
A. 2,4-dimethylaniline (2,4-xylidine), Picoline
Dissolve 1.5 g in 30 mL of water in a distillation flask, add
20 mL of a saturated solution of potassium carbonate
~NHCHO
sesquihydrate, connect the flask to a coarse-fritted aerator

Me ~ Me extending to the bottom of a 100-mL graduated cylinder

containing 50 mL of 0.05M hydrochloric acid, and pass air,
which has previously been passed through sulfuric acid and
B. form-2',4'-xylidide, glass wool, through the system for 60 minutes. To 5 mL of
the hydrochloric acid solution add sufficient
~N~NHMe 0.05M hydrochloric acid to produce 200 mL. The absorbance of
the resulting solution at 262 nm is not greater than 0.52,
Me ~ Me Appendix II B.
Loss on drying
C. N-methyl-N' -(2,4-xylyl)formamidine, When dried to constant weight at 100° at a pressure not
exceeding 0.7 kPa, loses not more than l.0% of its weight.
Use 1 g.
Sulfated ash
Not more than 0.1 %, Appendix IX A.
ASSAY
Carry out Method 1 for non-aqueous titration,
Appendix VIII A, using 0.3 g and 1-naphtholbenzein solution
D. N,N'-bis(2,4-xylyl)formamidine.
as indicator. Each mL of O.IM perchloric acid VS is equivalent
to 15.77 mg OfC14H19CIN4,HCI.

Amprolium Hydrochloride
Apramycin Sulfate
Apramycin Sulphate

CI-,HCI

315.3 137-88-2

Action and use

Antiprotozoal; prevention and treatment of coccidiosis
(veterinary) .

DEFINITION
Amprolium Hydrochloride is 1-(4-amino-2-propylpyrimidin-
5-ylmethyl)-2-methylpyridinium chloride hydrochloride. 41194-16-5
lt contains not les s than 97.5% and not more than 10l.0%
of C14H19CIN4,HCI, ca1culated with reference to the dried Action and use
substance. Aminoglycoside antibacterial.
CHARACTERISTICS Preparations
A white or almost white powder; odourless or almost Apramycin Veterinary Oral Powder
odourless. Apramycin Premix
Freely soluble in water; slightly soluble in ethanol (96%); very
DEFINITION
slightly soluble in ether; practically insoluble in chloroforrn.
Apramycin Sulfate is the sulfate of
IDENTIFICATION 4-0- [(2R,3R,4aS,6R, 7S,8R,8aR)- 3-amino-6-(4-amino-
A. The infrared absorption spectrum, Appendix II A, is 4-deoxY-O:-D-glucopyranosyloxy)-8-hydroxy-7 -
concordant with the reference spectrum of amprolium methylaminoperhydropyrano[3,2-b]pyran-2-yl]-
hydrochloride (RSV 07). 2-deoxystreptamine. It is produced by the growth of certain
2014
strains of Streptomyces tenebrarius or obtained by any other
means. The potency is not less than 450 Units per mg,
calculated with reference to the anhydrous substance.
CHARACTERISTICS
A light brown powder or granular material; hygroscopic.
Freely soluble in water; practically insoluble in acetone, in
ethanol (96%), in ether and in methanol.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography,
Appendix III A, using the following solutions in water.
(1) 0.1 % w/v of the substance being examined.
(2) 0.07% w/v of apramycin BPCRS.
(3) 0.07% w/v of each of apramycin BPCRS and
tobramycin BPCRS.
CHROMATOGRAPHIC CONDITIONS
(a) Use a silica gel F 254 precoated plate (Merck silica gel 60
F 254 plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 5 pL of each solution.
(d) Develop the plate to 10 cm.
(e) After removal of the plate, allow it to dry in a current of
warm air, spray with a mixture of equal volumes of a
46% w/v solution of sulfuric acid and a 0.2% w/v solution of
naphthalene-l,3-diol in ethanol (96%) and heat at 150 0 for
5 to 10 minutes.
MOB/LE PHASE
20 volumes of ehloroform, 40 volumes of 13.5M ammonia and
60 volumes of methanol, equilibrated for 1 hour before use.
SYSTEM SUITABILITY
The test is not valid unless the chromatogram obtained with
solution (3) shows two clearly separated principal spots.
CONFIRMATION
The principal spot in the chromatogram obtained with
solution (1) corresponds in colour and position to that in the
chromatogram obtained with solution (2).
B. In the test for Related substances, the retention time of
the principal peak in the chromatogram obtained with
solution (1) corresponds to that of the principal peak in the
chromatogram obtained with solution (2).
C. Yields reaction A characteristic of sulfates, Appendix VI.
TESTS
Sulfate
26.0 to 33.0% of S04' calculated with reference to the
anhydrous substance, when determined by the following
method. Dissolve 0.25 g in 100 mL of water, adjust to pH 11
with 13.5M ammonia and add 10 mL of O.IM barium ehlonde
VS. Titrate with O.IM disodium edetate VS using 0.5 mg of
phthalein purple as indicator; add 50 mL of ethanol (96%)
when the colour of the solution begins to change and
continue the titration until the violet-blue colour disappears.
Each mL of 0.1 M barium chloride VS is equivalent to
9.606 mg of S04.
Caerulomycin and dipyridyl derivatives
Dissolve 0.5 g in water in a 100 mL graduated fiask, add
10 mL of methanol and dilute to 100 mL with water. Place
5 mL in a 25 mL graduated fiask and add 5 mL of an
acetate buffer prepared by dissolving 8.3 g of anhydrous
sodium acetate in 25 mL of water, adding 12 mL of glacial
acetic acid and diluting to 100 mL with water. Mix, add 1 mL
of a 10% w/v solution of hydroxylamine hydroehloride in water
and mix again. Add 5 mL of a 1% w/v solution of ammonium
Apramycin Sulfate Vet-43
iron(Il) sulfate and dilute to 25 mL with water. Measure the
absorbanee of the resulting solution at 520 nm,
Appendix II B, using in the reference cell a solution obtained
by carrying out the same procedure without the substance
being examined. The absorbance is not greater than that
obtained by repeating the test using 5 mg of 2,2'-dipyridyl
dissolved in 10 mL of methanol and diluted to 100 mL with
water and beginning at the words 'Place 5 mL in a 25 mL
graduated fiask ... ' (1 %).
Related substances
Carry out the method for liquid chromatography,
Appendix III D, using the following solutions in water.
(1) 0.50% w/v of the substance being examined.
(2) 0.35% w/v of apramycin BPCRS.
(3) Dilute 1 volume of solution (1) to 20 volumes.
(4) Dilute 1 volume of solution (3) to 50 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a column (25 cm x 4 mm) packed with fast cation-
exchange polymeric beads (13 pm) with sulfonic acid
functional groups (Dionex Fast Cation-l R is suitable) and a
stainless steel post-column reaction coil (380 cm x 0.4 mm)
with internal baffles. Use in the reaction coil ninhydrin reagent
1 at a fiow rate approximately the same as that for the mobile
phase.
(b) Use gradient elution and the mobile phase described
below.
(c) Use a fiow rate of 0.8 mL per minute.
(d) Use a column temperature of 130°. Maintain the
post-column reaction coil at the same temperature.
(e) Use a detection wavelength of 568 nm.
(1) Inject 20 pL of each solution.
MOBILE PHASE
Mobile phase A A solution containing 1.961 % w/v of sodium
citrate, 0.08% v/v of liquefied phenol and 0.5% v/v of
thiodiglyeol, adjusted to pH 4.25 using hydrochloric aeid.
Mobile phase B A solution containing 4.09% w/v of sodium
chloride and 3.922% w/v of sodium citrate with 0.08% v/v of
liquefied phenol, adjusted to pH 7.4 with hydrochlorie aeid.
Equilibrate the column using a mixture containing 75% of
mobile phase A and 25% of mobile phase B. After each
injection elute for 3 minutes using the same mixture and
then carry out a linear gradient elution for 6 minutes to
100% of mobile phase B. Elute for a further 21 minutes
using 100% of mobile phase B, then step-wise re-equilibrate
to a mixture of 75% of mobile phase A and 25% of mobile
phase B and elute for at least 10 minutes.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained
with solution (2), the resolution factor between the peaks due
to compound A and 3-hydroxyapramycin, identified using
the reference chromatogram supplied with apramycin BPCRS,
is at least 0.8.
LIMITS
Multiply the areas of all the secondary peaks by 0.5. [NOTE:
This is to ensure that the impurities are calculated relative to
Apramycin Sulfate (which contains about 50% w/w of
apramycin).]
In the chromatogram obtained with solution (1):
the areas of any peaks corresponding to 3-hydroxyapramycin,
lividamine/2-deoxystreptamine (combined), compound A and
compound B (identified using the reference chromatogram
Vet-44 Azaperone 2014

supplied with apramycin BPCRS) are not greater than 1.4,
1.0, 0.4 and 0.4 times respectively the area of the principal
peak in the chromatogram obtained with solution (3) (7%,
5%, 2% and 2% respectively);
the area of any other secondary peak is not greater than
0.4 times the area of the principal peak in the chromatogram
obtained with solution (3) (2%);
the sum of the areas of aH the secondary peaks is not greater
than 3 times the area of the principal peak in the
chromatogram obtained with solution (3) (15%).
Disregard any peak with an area les s than the area of the
peak in the chromatogram obtained with solution (4) (0.1%).
LABELLING
The label states (1) that the material is suitable for parenteral
use; (2) where applicable, that it is sterile.
Apramycin Sulfate intended for use in the manufacture of a
parenteral dosage form without a further appropriate sterilisation
procedure c011Jplies with the following additional requirement.
Sterility
Complies with the test for sterility, Appendix XVI A.
IMPURITIES
-;:?' N

Sulfated ash ~I OMe

Not more than 1.0%, Appendix IX A, Method II. Use 1 g.
N~
Water
Not more than 14.0% w/w, Appendix IX C. Use 0.2 g and
20 mL of a mixture containing 1 volume of methanol and H N
I

2 volumes of formamide as the solvento The solvent mixture OH

must be prepared at least 12 hours before use and should be
stored in an airtight container. A. caerulomycin,
ASSAY
Carry out the microbiological assay of antibiotics, HO

HO~O\
Appendix XIV A, Method B. The precision of the assay is
such that the fiduciallimits of error are not less than 95% OH
and not more than 105% ofthe estimated potency. ~~NH2
Apramycin Sulfate intended for use in the manufacture of a
parenteral dosage form is decolourised and complies with the above NH 2 O NH
2
requirements with the following modifications.
Preparation B. lividamine,
Apramycin Injection
DEFINITION
The potency is not les s than 576 Units per mg, ca1culated
with reference to the anhydrous substance.
Related substances
Carry out the method as described aboye.
LIMITS
C. 2-deoxystreptamine
Multiply the areas of aH the secondary peaks by 0.5. [NOTE: D. 3-hydroxyapramycin; R = OH,
This is to ensure that the impurities are ca1culated relative to
E. 'compound A',
Apramycin Sulfate (which contains about 50% w/w of
apramycin).] F. 'compound B'.
In the chromatogram obtained with solution (1):
the areas of any peaks corresponding to 3-hydroxyapramycin,
lividamine/2-deoxystreptamine (combined) and compound A
(identified using the reference chromatogram supplied with Azaperone
apramycin BPCRS) are not greater than the area of the
principal peak in the chromatogram obtained with solution (Azaperone for Veterinary Use,
(3) (5% of each); Ph Eur monograph 1708)
the area of any peak corresponding to compound B is not
greater than 0.4 times the area of the principal peak in the
chromatogram obtained with solution (3) (2%);
the area of any other secondary peak is not greater than
0.4 times the area of the principal peak in the chromatogram
obtained with solution (3) (2%);
the sum of the areas of aH the secondary peaks is not greater
than 2.4 times the area of the principal peak in the
chromatogram obtained with solution (3) (12%). 1649-18-9
Disregard any peak with an area les s than the area of the
Action and use
peak in the chromatogram obtained with solution (4) (0.1 %).
Dopamine receptor antagonist; neuroleptic (veterinary).
STORAGE Preparation
If the substance is sterile, the container should be sterile, Azaperone Injection
tamper-evident and sealed so as to exc1ude micro-organisms.
2014 Azaperone Vet-45

~E~ ____________________________________________ System suitability Reference solution (a):

-- resolution: minimum 8.0 between the peaks due to
DEFINITION
azaperone and benperidol.
1-(4-Fluorophenyl)-4- [4-(pyridin-2-yl)piperazin-1-yl)butan-
l-one. Limits:
-- impurity A: not more than the area of the principal peak
Content in the chromatogram obtained with reference solution (b)
99.0 per cent to 10l.0 per cent (dried substance). (0.25 per cent);
CHARACTERS -- unspecified impurities: for each impurity, not more than
Appearance 0.8 times the area of the principal peak in the
White or almost white powder. chromatogram obtained with reference solution (b)
Solubility
(0.20 per cent);
-- sum of impurities B and C: not more than 3 times the area
Practically insoluble in water, freely soluble in acetone and in
methylene chloride, soluble in ethanol (96 per cent). of the principal peak in the chromatogram obtained with
reference solution (b) (0.75 per cent);
It shows polymorphism (5.9). -- total: not more than 4 times the area of the principal peak
IDENTIFICATION in the chromatogram obtained with reference solution (b)
Infrared absorption spectrophotometry (2.2.24). (l.O per cent);
Preparation Discs. -- disregard limit: 0.2 times the area of the principal peak in
the chromatogram obtained with reference solution (b)
Comparison azaperone CRS.
(0.05 per cent).
If the spectra obtained show differences, dissolve the
Loss on drying (2.2.32)
substance to be examined and the reference substance
separately in acetone R, evaporate to dryness and record new Maximum 0.5 per cent, determined on 1.000 g by drying
in vacuo at 60 oC for 4 h.
spectra using the residues.
Sulfated ash (2.4.14)
TESTS
Maximum 0.1 per cent, determined on l.0 g.
Appearance of solution
The solution is clear (2.2.1) and not more intensely coloured ASSAY
than reference solution Y6 (2.2.2, Method 11). Dissolve 0.130 g in 70 mL of a mixture of 1 volume of
Dissolve 1.0 g in 25 mL of a 14 gIL solution of tartaric anhydrous acetic acid R and 7 volumes of methyl ethyl ketone R.
acid R. Titrate with 0.1 M perchloric acid, using 0.2 mL of
naphtholbenzein solution R as indicator.
Related substances
Liquid chromatography (2.2.29). 1 mL of 0.1 M perchloric acid is equivalent to 16.37 mg of
C19H22FN30.
Test solution Dissolve 0.100 g of the substance to be
examined in methanol R and dilute to 10.0 mL with the same STORAGE
solvent. Protected from light.
Reference solution (a) Dissolve 5.0 mg of azaperone CRS and IMPURITIES
6.0 mg of benperidol CRS in methanol R and dilute to Specified impurities A, B, C.
200.0 mL with the same solvent.
Reference solution (b) Dilute 1.0 mL of the test solution to
100.0 mL with methanol R. Dilute 5.0 mL of the solution to
20.0 mL with methanol R.
Column:
-- size: 1 = 0.10 m, 0 = 4.6 mm;
-- stationary phase: base-deactivated octadecylsz7yl silica gel for ('¡
chromatography R (3 ¡..un);
-- temperature: 25 oc. ~R
F o
Mobile phase:
-- mobile phase A: dissolve 1.4 g of anhydrous sodium sulfate R
A. 1-(2-fiuorophenyl)-4-[4-(pyridin-2-yl)piperazin-1-yl)butan-
in 900 mL of water R, add 16.0 mL of 0.01 M sulfuric
l-one,
acid and dilute to 1000 mL with water R;
-- mobz7e phase B: methanol R,.
Time Mobile phase A Mobile phase B RiIl
~R
(min) (per cent V!fI) (per cent V!fI)
0-15 95.....; 20 5.....; 80
O
15 - 20 20 80

B. 4-[ 4-(pyridin-2-yl)piperazin-1-yl)-1-[4-[4-(pyridin-
2-yl)piperazin-1-yl)phenyl)butan-1-one,
Flow rate l.5 mUmin.
Detection Spectrophotometer at 230 nm.
1njection 1O J-lL.
Relative retention With reference to azaperone
(retention time = about 9 min): impurity A = about 0.9;
impurity B = about l.l; impurity C = about l.l5.