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AAPS Introductions in the Pharmaceutical Sciences
Ashlee D. Brunaugh
Daniel Moraga-Espinoza
Tania F. Bahamondez-Canas
Hugh D. C. Smyth
Robert O. Williams
Essential
Pharmaceutics
Second Edition
AAPS Introductions in the Pharmaceutical
Sciences
Volume 12
Founding Editor
Robin Zavod, Chicago College of Pharmacy, Midwestern University,
Downers Grove, IL, USA
Series Editor
Claudio Salomon, National University of Rosario, Rosario, Argentina
The AAPS Introductions in the Pharmaceutical Sciences book series is designed to
support pharmaceutical scientists at the point of knowledge transition. Springer and
the American Association of Pharmaceutical Scientists (AAPS) have partnered
again to produce a second series that juxtaposes the AAPS Advances in the
Pharmaceutical Sciences series. Whether shifting between positions, business
models, research project objectives, or at a crossroad in professional development,
scientists need to retool to meet the needs of the new scientific challenges ahead of
them. These educational pivot points require the learner to develop new vocabulary
in order to effectively communicate across disciplines, appreciate historical
evolution within the knowledge area with the aim of appreciating the current
limitations and potential for growth, learn new skills and evaluation metrics so that
project planning and subsequent evolution are evidence-based, as well as to simply
“dust the rust off” content learned in previous educational or employment settings,
or utilized during former scientific explorations. The Introductions book series will
meet these needs and serve as a quick and easy-to-digest resource for contemporary
science.
Ashlee D. Brunaugh • Daniel Moraga-Espinoza
Tania F. Bahamondez-Canas • Hugh D. C. Smyth
Robert O. Williams
Essential Pharmaceutics
Second Edition
Ashlee D. Brunaugh Daniel Moraga-Espinoza
College of Pharmacy University of Valparaíso
University of Michigan–Ann Arbor Valparaíso, Chile
Ann Arbor, MI, USA
Hugh D. C. Smyth
Tania F. Bahamondez-Canas College of Pharmacy
University of Valparaíso The University of Texas at Austin
Valparaíso, Chile Austin, TX, USA
Robert O. Williams
College of Pharmacy
The University of Texas at Austin
Austin, TX, USA
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
1
Essential Pharmaceutics in the Flipped Classroom������������������������������ 1
1.1 Overview of “Flipped Pharmaceutics” Course Format
and Structure ������������������������������������������������������������������������������������ 2
1.2 Building the Required Foundation for Student Success
in “Flipped Pharmaceutics”�������������������������������������������������������������� 3
1.3 Achieving Learning Objectives�������������������������������������������������������� 5
1.4 Specific “Flipped Class” Structure—How to Implement ���������������� 8
1.5 Flipped Pharmaceutics—A Pathway to Success������������������������������ 10
Further Readings���������������������������������������������������������������������������������������� 11
2 Overview of Biopharmaceutics and Regulatory Concepts
Relevant to Drug Product Design ���������������������������������������������������������� 13
2.1 Introduction�������������������������������������������������������������������������������������� 14
2.2 Utilization of Pharmacokinetic Data to Determine
Bioavailability and Bioequivalence�������������������������������������������������� 17
2.3 Biopharmaceutics Classification System������������������������������������������ 18
2.4 Overview of the Regulatory Pathways for Drug Product
Approval�������������������������������������������������������������������������������������������� 18
Further Reading ���������������������������������������������������������������������������������������� 21
3
Preformulation in Drug Product Design������������������������������������������������ 23
3.1 Introduction—Importance of Preformulation Studies
in Dosage Form Design�������������������������������������������������������������������� 25
3.2 Preformulation Studies—Factors Affecting Drug
Bioavailability ���������������������������������������������������������������������������������� 26
3.2.1 Solubility������������������������������������������������������������������������������ 26
3.2.2 Dissociation Constant/pKa���������������������������������������������������� 28
3.2.3 Dissolution���������������������������������������������������������������������������� 29
3.2.4 Partition Coefficient�������������������������������������������������������������� 29
3.2.5 Membrane Permeability�������������������������������������������������������� 31
3.2.6 Biopharmaceutics Classification System (BCS)������������������ 32
3.3 Preformulation Studies—Solid-State Characterization�������������������� 32
v
vi Contents
10
Topical and Transdermal Drug Delivery ���������������������������������������������� 151
10.1 Introduction������������������������������������������������������������������������������������ 153
10.2 Anatomy of the Skin—A Brief Review������������������������������������������ 153
10.3 Diffusion of Drug Through the Skin���������������������������������������������� 154
10.3.1 Application of Fick’s Law of Diffusion������������������������������ 154
10.3.2 Transport Through the Skin Layers������������������������������������ 155
10.3.3 In Vitro Analysis ���������������������������������������������������������������� 157
10.4 Mechanisms of Enhancing Drug Penetration Through Skin���������� 157
10.4.1 Diffusion Coefficient���������������������������������������������������������� 158
10.4.2 Partition Coefficient������������������������������������������������������������ 159
10.4.3 Degree of Drug Saturation in the Formulation ������������������ 159
10.4.4 Electrical and Mechanical Methods of Increasing
Drug Transport�������������������������������������������������������������������� 159
10.5 Topical Semi-Solid Formulations �������������������������������������������������� 160
10.5.1 Ointment Bases ������������������������������������������������������������������ 160
10.5.2 Ointment Manufacture/Preparation������������������������������������ 162
10.5.3 Gels ������������������������������������������������������������������������������������ 162
10.6 Transdermal Patches ���������������������������������������������������������������������� 162
10.6.1 Patch Design, Formulation, and Manufacture�������������������� 164
10.6.2 Drug Release from Transdermal Patches���������������������������� 165
10.6.3 Patient Counseling—Transdermal Systems������������������������ 166
10.7 Additional Excipients Utilized in Topical and Transdermal
Dosage Forms �������������������������������������������������������������������������������� 167
Further Reading ���������������������������������������������������������������������������������������� 169
11 Oral Transmucosal Delivery ������������������������������������������������������������������ 171
11.1 Introduction������������������������������������������������������������������������������������ 172
11.2 Barriers for Oral Mucosal Drug Delivery �������������������������������������� 173
11.2.1 Oral Mucosal Membrane Barriers�������������������������������������� 173
11.2.2 Residence Time and Dilution���������������������������������������������� 174
11.2.3 Other Barriers and Considerations�������������������������������������� 174
11.3 Methods of Oral Transmucosal Administration������������������������������ 175
11.3.1 Tablets, Lozenges, and Troches������������������������������������������ 175
11.3.2 Films and Patches �������������������������������������������������������������� 175
11.3.3 Other Oral Transmucosal Dosage Forms���������������������������� 176
11.4 Excipients Used in Oral Transmucosal Formulations�������������������� 177
Further Reading ���������������������������������������������������������������������������������������� 179
12
Rectal and Vaginal Drug Delivery���������������������������������������������������������� 181
12.1 Introduction������������������������������������������������������������������������������������ 182
12.2 Rectal Route������������������������������������������������������������������������������������ 182
12.2.1 Rectum Anatomy���������������������������������������������������������������� 183
12.2.2 Rectal Dosage Forms���������������������������������������������������������� 184
12.3 Vaginal Route���������������������������������������������������������������������������������� 184
12.3.1 Vaginal Physiology ������������������������������������������������������������ 185
12.3.2 Vaginal Dosage Forms�������������������������������������������������������� 186
x Contents
15
Drug Product Design and Delivery of Biologics������������������������������������ 221
15.1 Introduction������������������������������������������������������������������������������������ 222
15.2 Production of Biologics������������������������������������������������������������������ 222
15.3 Formulation of Biologics���������������������������������������������������������������� 223
15.4 Devices for Administration of Biological Products
and Performance Testing���������������������������������������������������������������� 224
15.5 Characterization and Performance Testing of Biologics���������������� 228
15.6 Biosimilars�������������������������������������������������������������������������������������� 229
Futher Reading������������������������������������������������������������������������������������������ 230
Index�������������������������������������������������������������������������������������������������������������������� 231
About the Authors
xiii
xiv About the Authors
Hugh D. C. Smyth is the Alcon Centennial Professor, with tenure, in the Division
of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, University of
Texas at Austin. Dr. Smyth oversees multidisciplinary laboratory funded by NIH,
FDA, and industry that focuses on engineering new drug delivery systems with an
emphasis on drug delivery to the airways. He has over 350 published works. Dr.
Smyth is editor of four books and is an inventor on numerous patents or patent
applications. He has a Pharmacy and a Ph.D. degree from the University of Otago,
New Zealand. Dr. Smyth has worked as a practicing pharmacist and a scientist in
industry and has received training in several academic settings. He has been faculty
at the University of North Carolina at Chapel Hill and the University of New
Mexico. He was the American Association of Pharmaceutical Scientists (AAPS)
New Investigator award winner for Pharmaceutics and Pharmaceutical Technologies
in 2007. He also received the PhRMA Foundation New Investigator Award in phar-
maceutics in 2007. He gave the DDL Annual Lecture in 2022. He was the Editor-in-
Chief of Drug Development and Industrial Pharmacy from 2014 to 2022. Dr. Smyth
has started several companies resulting from technologies discovered in his labora-
tory which are now advancing these technologies for clinical use.
Robert O. Williams Bill Williams is the Johnson & Johnson Centennial Chair
and Professor of Pharmaceutics and the Division Head of Molecular Pharmaceutics
and Drug Delivery at the College of Pharmacy, University of Texas at Austin. He
earned a B.S. in Biology from Texas A&M University, a B.S. in Pharmacy from the
About the Authors xv
of class and assess the students’ knowledge of the key concepts covered by these
preclass readings. Grades obtained by students in these assessments count
toward their final grade, which provides an incentive to complete the prereading
assignment prior to the class.
3. Cumulative exam assessments: Instead of having two or three high-stake major
exams during the semester, we have recently implemented an innovative assess-
ment tool. In our class, the Cumulative Exam is made up of a series of 11 indi-
vidual tests covering each module (e.g., each technical chapter in this book) and
made up of questions covering only the prior week’s case studies. The Cumulative
Exam is administered by electronic exam software and is given at the beginning
of each class period. These 11 Cumulative Exams represent 100% of the stu-
dent’s grade for their major exam, which the student has accumulated along the
way (Explanation: Each one of the 11 Cumulative Exams represents 9.09% of
the total Cumulative Exam, so 11 × 9.09% = 100%). We also implemented an
alternative assessment strategy in which students can individually choose to take
an Optional Final Exam for any reason at the end of the semester, which replaces
their Cumulative Exam grade. The Optional Final Exam is cumulative and made
up of questions that cover all materials from the entire semester, including pre-
readings, mini-lectures, and case studies.
4. In-class team based learning: Class time is then focused on the strategic applica-
tion of the pre-class reading assignments through practical, hands-on activities.
All teams are required to complete two research-based drug product design
assignments (referred to as “case studies”). Fifty-five minutes are allotted for
each assignment, and a 55-min countdown clock helps keep the teams aware of
the time remaining. To successfully complete the assignment, groups are required
to utilize a variety of online information resources in order to answer a series of
analytical questions. During the time allotted for each case study, faculty, gradu-
ate student teaching assistants, and experienced PharmD student assistants (these
are PharmD students who already passed the course and are funded through an
Academic Assistant position) continuously interact and engage the teams to
facilitate learning (our student:instructor ratio is typically no more than 15:1). At
various points during the case study, the countdown clock is stopped and faculty
deliver two or three mini-lectures consisting of 2–3 slides each on different tech-
nical/scientific aspects of the case study, thus linking the student’s prereading
class assignments (facts) to the case study (applying facts to concepts).
Implementation of our model required input and coordination with faculty across
the PharmD curriculum at the University of Texas at Austin. Incoming students to
our flipped pharmaceutics course are in the second semester of their first year of the
4 1 Essential Pharmaceutics in the Flipped Classroom
Fig. 1.1 The flipped pharmaceutics course is strategically placed in the PharmD curriculum to
ensure students have the necessary foundational knowledge and critical thinking skills to achieve
success in class. The source for foundation facts, information literacy skills, and communication
skills is color coded according to the prerequisite courses offered in the immediately preceding
Fall semester of the PharmD first year
PharmD program. By this point in the curriculum, students have completed a num-
ber of foundational courses that are crucial in laying the groundwork for the topics
covered in the flipped pharmaceutics course (Fig. 1.1). We mapped each of these
prerequisite courses to confirm that students would have the necessary background
before beginning our flipped class. We also note that the placement of our course in
the curriculum is such that the students have not yet completed their second semes-
ter of Physiology/Pathophysiology and Pharmaceutical Biochemistry, which take
1.2 Building the Required Foundation for Student Success in “Flipped Pharmaceutics” 5
place concurrently with this pharmaceutics course in the spring semester of year
one of the PharmD program. We, thus, strategically structure our flipped course
content such that the students are assured to have covered a specific topic before it
is used in class (e.g., we ensure that anatomy of the eye is covered outside our
course prior to the introduction of ophthalmic drug products).
As the flipped pharmaceutics course has evolved over the past 10 years, we have
come to understand that student acquisition of the necessary information literacy
skills prior to beginning our course is a key component to ensuring student success.
In-class activities require extensive utilization of primary literature, patents, data-
bases, etc. This information is analyzed by students in teams, already armed with the
knowledge obtained from concepts provided in this book. Extensive work conducted
by PharmD/MSc student Natalia Malesa as part of her master’s thesis revealed that
integration of information literacy training in coursework prior to the start of flipped
pharmaceutics increased student performance of the course, as student perception of
their own information literacy abilities. In response to these findings, faculty have
incorporated an introduction to these information literacy skills in the “Introduction
to Pharmacy Practice” course that students complete in the first Fall semester of
their first year. Through this course, students gain experience using bibliographic
databases for biomedical research, including Google Scholar, PubMed/MEDLINE,
ScienceDirect, and Web of Science. With assistance from a pharmacy subject spe-
cialist librarian, students learn optimal search strategies for these databases, such as
the utilization of Medical Subject Headings (MeSH). Students are also instructed in
how to locate tertiary resources and how to appropriately cite references. In our
flipped pharmaceutics course, we continue to build these information literacy skills
by introducing search strategies that are more specific to drug products, including
the use of patents, the US Pharmacopeia/National Formulary Online, drug substance
databases (e.g., TOXNET, Reaxys), medication package inserts, and FDA resources
including the Orange Book and the Inactive Ingredients Database. With assistance
from The University of Texas at Austin library system, we have designed a course
web portal that contains links to each of these resources, in addition to guides on
how to use each database, how to read US patents, and how to appropriately cite
references, and it is located here: https://guides.lib.utexas.edu/pharmacy/pharma-
ceutics. Students utilize these resources in class and beyond, with many students
reporting years later to us how helpful the web portal is throughout the PharmD
curriculum. Overall, the information literacy skills that are developed in flipped
pharmaceutics become invaluable to our students as they progress through the cur-
riculum and begin work in clinical and industry settings.
Learning objectives for the flipped pharmaceutics course at UTCoP were initially
designed and are regularly updated to reflect PharmD accreditation standards in the
United States. For example, learning objectives in our course were recently updated
6 1 Essential Pharmaceutics in the Flipped Classroom
into a student-friendly course guide. Figure 1.2 provides a graphic overview of how
the typical flipped pharmaceutics class is conducted after this initial introductory
session.
One week prior to the class meeting time, students are given a pre-reading assign-
ment consisting primarily of reading and understanding a specific chapter from this
book. Most individual chapters serve as a separate module. Students gain additional
experience in accessing drug information and related resources by occasionally
accessing and reading research articles and review papers relevant to the topic of the
upcoming case study. A list of relevant papers is included at the end of each chapter
of this book to provide examples of possible “prereading assignments” for instruc-
tors who wish to implement their own flipped-classroom model. Additionally, a list
of learning objectives is provided to guide at-home study, which are incorporated
into each chapter of this text.
For example, at the start of the class, students are given two assessments, the
Cumulative Exam (explained above) and the Readiness Assessment quiz. These
assessments ensure that students are motivated to review their last week’s case stud-
ies and to complete the prereading assignments. Based on the results of the Readiness
Assessment quiz, the instructors can determine which concepts require further
10 1 Essential Pharmaceutics in the Flipped Classroom
review and explanation before starting the case studies. Following these tests, a
mini-lecture is typically given to students to provide context to the products featured
in the case studies.
The teams then begin work on the product case study, which was provided in the
form of a structured worksheet, typically with six to seven multipart questions cov-
ering various aspects of the drug product design and key pharmaceutical concepts.
Each case study is focused on a marketed drug product that students will likely
encounter in their professional careers. These case studies are designed in the fol-
lowing general topics based on real-world examples:
• Question 1—Understanding the problem that existed and needed to be solved for
this particular drug substance or disease state using pharmaceutics approaches.
• Questions 2 and 3—Gathering data on physicochemical properties and charac-
teristics of the drug and excipients.
• Questions 4 and 5—Synthesize foundational knowledge and new information to
understand formulation and drug delivery system properties.
• Questions 6 and 7—Applying new pharmaceutics understanding to answer clini-
cal pharmacy questions related to pharmaceutics principles.
During the course of the case study, instructors meet individually with teams to
provide guidance through areas of difficulty. Structured and ad hoc breaks are taken
to review concepts with the entire class. During these breaks, teams are regularly
called upon to provide answers to questions regarding their drug product design
assignments. Finally, drug product design assignment questions are formatted to
emphasize keywords that can be helpful for students when optimizing search strate-
gies. As the semester progresses, this format is dropped to allow students to deter-
mine their own keywords.