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1 Essential Pharmaceutics intheFlipped Classroom
to reect the American Association of Colleges of Pharmacy (AACP) Curriculum
Outcomes and Entrustable Professional Activities (COEPA) 2022 document.
In designing this “ipped class” course, the following learning objectives are
communicated to students through our syllabus:
1. Identify and explain the physicochemical and formulation properties of a drug
that inuence its absorption and stability.
(a) Identify and describe the factors that inuence the aqueous solubility and
partition coefcient of a drug. Explain the importance of appropriate aqueous solubility and partition coefcient in the formulation design and absorption of drugs.
(b) Understand and explain the ionization of weak acidic and weak basic drugs
and calculate the fraction of a drug in its ionized and unionized forms as a
function of pH.
(c) Describe how pKa and pH inuence the observed solubility and partitioning
of a drug.
(d) Identify, evaluate, and explain the factors that affect the chemical stability of
a drug under various environmental and packaging conditions.
(e) Identify and explain the factors that control the physical and microbiological
stability of a drug product under various environmental and packaging
conditions.
(f) Identify and explain the unique pharmaceutical challenges posed by con-
temporary biotechnology-based drug products (biopharmaceuticals).
2. Identify and explain the properties of a drug that inuence dosage form design
and its route of administration.
(a) Describe the various routes of administration available for drug delivery,
and discuss the advantages and disadvantages of each delivery system.
(b) Describe the characteristics of an ideal drug delivery system. Identify the
various types of liquid, solid, and semisolid dosage forms available.
(c) Discuss how the physicochemical properties of a drug inuence the design
of various dosage forms, including biotech drugs.
(d) Explain the various formulation approaches taken to improve the in-vitro
dissolution, solubility, stability, and absorption of drugs from different dosage forms.
(e) Identify physical-chemical and formulation properties that make a drug suit-
able for modied release/controlled release, and explain the various formulation approaches available for modifying drug release from dosage forms.
(f) Discuss the methods/techniques used for establishing the performance and
quality of dosage forms.
3. Identify and explain the dosage form features that inuence therapeutic
outcomes.
(a) Describe the role and functions of inactive/inert ingredients in different
types of dosage forms.
1.3 Achieving Learning Objectives
7
(b) Describe the various methods of compounding and/or manufacture of differ-
ent types of dosage forms.
(c) Explain the importance of packaging and storage conditions in expiration
dates and drug product quality and assurance.
(d) Select an appropriate packaging container based on the physicochemical
properties of the drug, which meets a patient’s need.
(e) Explain principles underlying the proper use of dosage forms, and their
inuence on bioavailability and therapeutic outcome.
(f) Determine the importance of selection of appropriate dosage form in drug
therapy.
(g) Explain the inuence of formulation, physiological, and anatomical factors
on drug absorption from dosage forms.
(h) Discuss how compliance and adherence can be improved by appropriate
dosage form selection.
(i) Select and recommend the best route of administration and dosage form for
a patient.
(j) Identify and prevent drug interactions and incompatibilities based on the
presence of active and inactive pharmaceutical ingredients.
(k) Identify, solve, and prevent drug therapy problems related to dosage form,
delivery system, and route of administration.
4. Make appropriate selection decisions for multisource drug products.
(a) Explain and understand the concepts of pharmaceutical equivalence, bio-
equivalence, and therapeutic equivalence. Understand the basis for thera-
peutic equivalence or nonequivalence.
(b) Use the Orange Book appropriately to select and recommend a drug.
(c) Select and recommend appropriate drug products according to scientic,
legal, and economic guidelines where appropriate.
5. Compound safe and effective extemporaneous pharmaceutical products.
(a) Apply relevant standards of practice (including ethical guidelines) to pre-
pare safe and effective dosage forms and perform in-process quality control.
(b) Search and apply the most accurate and standardized information on extem-
poraneous compounding.
(c) Evaluate the suitability of an extemporaneously compounded dosage form
for the administration of a drug for a patient.
(d) Identify physical and chemical incompatibilities among active and inactive
pharmaceutical ingredients of a formulation; recommend and follow
approaches to avoid incompatibilities and unwanted interactions.
(e) Calculate and measure the correct quantity of active and inactive pharma-
ceutical ingredients.
(f) Use correct laboratory measuring procedures to obtain the desired quantity
of all formulation ingredients.
(g) Use good extemporaneous compounding practices in the preparation of a
patient-specic drug product.
8
1 Essential Pharmaceutics intheFlipped Classroom
(h) Design and maintain an adequate operational facility for compounding
pharmaceutical products.
6. Preparing safe and effective sterile dosage forms and enteral nutrition products.
(a) Apply relevant standards of practice (including ethical guidelines) to pre-
pare safe and effective sterile dosage forms and perform in-process quality
control.
(b) Calculate and measure the correct quantity of ingredients for preparing a
sterile product.
(c) Use proper aseptic techniques to prepare sterile products.
(d) Identify physical and chemical incompatibilities among active and inactive
components of sterile formulations; recommend and follow approaches to
avoid unwanted interactions and incompatibilities.
(e) Use sterilization methods that are appropriate for the drug and product.
(f) Calculate the rate of drug administration based on the prescription order and
the type of infusion pump used.
(g) Determine a patient’s uid, electrolyte, and nutritional needs, and calculate
the composition of parenteral or enteral nutrition sources to meet their needs.
(h) Apply appropriate quality control procedures for sterile products.
(i) Evaluate the impact of physical and chemical stability on a sterile product.
(j) Design and maintain an adequate operational facility for compounding ster-
ile pharmaceutical products.
7. Maintain professional competence by identifying and analyzing emerging issues
in pharmaceutical dosage forms and compounding.
This is accomplished in the ipped classroom course by assigning real-life problems that the students must strategically evaluate and solve using the pharmaceuticsrelated knowledge acquired through their independent reading or team research
conducted during class. Students must master the “Pharmaceutics” portal and gain
the skills to effectively use and cite the literature to support their answers.
1.4 Specic “Flipped Class” Structure—How toImplement
In the rst class of ipped pharmaceutics, we introduce discipline-specic information resources during an interactive tutorial session. Students participate in an
instructor-guided case study, in which they are provided hands-on training and
opportunities to practice accessing and retrieving specialized scientic information
from a variety of online resources (e.g., United States Pharmacopeia/National
Formulary Online), drug substance databases (e.g., TOXNET, Reaxys), package
inserts (e.g., DailyMed), and patents (e.g., US Patent and Trademark Ofce, US
Food and Drug Administration Orange Book, US Food and Drug Administration
Purple Book, Google Patents). At this point, students are introduced to the
Pharmaceutics Web Portal, which consolidates these various drug product resources
1.4 Specic “Flipped Class” Structure—How toImplement
9
Fig. 1.2 Cycle of a typical ipped pharmaceutics class
into a student-friendly course guide. Figure1.2 provides a graphic overview of how
the typical ipped pharmaceutics class is conducted after this initial introductory
session.
One week prior to the class meeting time, students are given a pre-reading assignment consisting primarily of reading and understanding a specic 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 instructors who wish to implement their own ipped-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 studies 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 intheFlipped 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 covering 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 following 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 difculty. 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 strategies. As the semester progresses, this format is dropped to allow students to determine their own keywords.
1.5 Flipped Pharmaceutics—A Pathway toSuccess
The rst PharmD cohort to participate in our ipped-classroom model graduated in
2017. North American Pharmacist Licensure Examination (NAPLEX) rst-time
attempt pass rate for UTCOP that year was 95%, compared to a national average of
88%. We have worked to improve our course each year it is taught, and this is
reected in the 2022 rst-attempt NAPLEX pass rate for UTCOP, which was 87%,
compared to a national average of 80%.
In addition to providing a solid foundation for prospective clinical pharmacists,
we have also had great success in utilizing our course to teach rst-year PhD students in the University of Texas at Austin’s Molecular Pharmaceutics and Drug
Delivery program. Our students have reported that the integration of information
literacy skill building in the course has improved their condence and performance
in effectively and efciently solving patient-health-related and pharmaceuticsrelated problems.
Further Readings
11
Application of the ipped classroom model to the subject of pharmaceutics has
been demonstrated to promote the development of the necessary skills to achieve
student success in the classroom and beyond. We hope that through this foundational textbook, similar success can be obtained in pharmaceutical programs around
the world.
Further Readings
Suggested readings include the following texts:
Herreid CF, Schiller NA.Case studies and the ipped classroom. J Coll Sci Teach. 2013;42(5):62–6.
Kang HY, Kim HR. Impact of blended learning on learning outcomes in the public healthcare
education course: a review of ipped classroom with team-based learning. BMC Med Educ.
2021;21(1):1–8.
Rotellar C, Cain J. Research, perspectives, and recommendations on implementing the ipped
classroom. Am J Pharm Educ. 2016;80(2):34.
Schwartzstein RM, Roberts DH.Saying goodbye to lectures in medical school—paradigm shift or
passing fad? N Engl J Med. 2017;377(7):605–7.
Chapter 2
Overview ofBiopharmaceutics
andRegulatory Concepts Relevant toDrug
Product Design
Abstract This chapter is new to this edition. Basic pharmacokinetic and biophar-
maceutics concepts that are central to drug delivery and drug product design are
reviewed, as are the regulatory pathways for generic and novel drug product
approval in the United States.
Keywords Bioavailability · Biopharmaceutics · Pharmacokinetics ·
Bioequivalence · Absorption
Learning Objectives
1. Explain the approval process for a drug by the Food and Drug Administration.
2. Describe the pharmacokinetic parameters that are derived from a plot of drug
concentration in the blood versus time.
3. Compare a drug to a drug product.
4. Explain the four pharmacokinetic parameters of ADME.
5. Compare a generic drug and a new molecular entity.
6. Compare an abbreviated new drug application and a new drug application.
7. Explain what the Orange Book is used for.
8. Explain the approved product label.
Key Concepts
Students should know and be able to describe each of the following concepts as they
review this chapter:
1. Abbreviated new drug application
2. Absolute bioavailability
3. Absorption
4. Absorption rate
5. Area-under-the-curve (AUC)
6. Bioavailability
13© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
A. D. Brunaugh et al., Essential Pharmaceutics, AAPS Introductions in the
Pharmaceutical Sciences 12, https://doi.org/10.1007/978-3-031-52520-9_2
14
2 Overview of Biopharmaceutics and Regulatory Concepts Relevant to Drug Product…
7. Bioequivalence
8. Biological products
9. Biologic license application
10. Biopharmaceutics
11. Central compartment
12. Distribution
13. Dosage form
14. Drug
15. Drug product
16. FDA-approved label
17. Generic drug
18. Investigational new drug application
19. Maximum plasma concentration (C
max
)
20. New drug application
21. New molecular entity
22. One-compartment model
23. Orange Book
24. Peripheral compartment
25. Pharmacokinetics
26. Relative bioavailability
27. Time to maximum concentration (T
max
)
28. Two-compartment model
2.1 Introduction
Biopharmaceutics and pharmacokinetics are important areas of research related to
the design of drug products. As such, a brief review of these concepts is presented
herein to provide context for this course. Biopharmaceutics, as dened by the Food
and Drug Administration (FDA), is a broad-based scientic discipline that studies
the effect and interplay of the physicochemical properties of a drug, its dosage form,
and the intended route of administration on the rate and extent of the drug’s absorption. In practical terms, it refers to the study of the physicochemical properties of
drugs and their dosage forms and delivery route of administration as it relates to the
onset, duration, and intensity of drug action. Pharmacokinetics is dened as the
study of the movement of drugs in the body over time. It is colloquially referred to
as “what the body does to the drug.” The four main parameters generally considered
in pharmacokinetics are absorption, distribution, metabolism, and excretion
(ADME). In terms of pharmacokinetic analysis, absorption refers to the movement
of the drug from the site of administration into the systemic circulation. Distribution
refers to the movement of the drug between the intravascular (blood/plasma) and
extravascular (intracellular and extracellular) compartments of the body. Over time,
2.1 Introduction
Fig. 2.1 Illustration of the concepts of absorption, distribution, and metabolism based on the
nonsteroidal anti-inammatory drug ibuprofen
15
drugs within the circulation are metabolized and excreted from the body by the liver
and kidneys.
Bioavailability, as described by the FDA for a given formulation, means to provide an estimate of the relative fraction of the orally administered dose that is
absorbed into systemic circulation and can be measured by comparing a systemic
exposure prole to that of a suitable reference product. In practice, it is described as
the rate and extent to which the active drug or moiety is absorbed from a drug product and becomes available at the site of action. Bioavailability encompasses pharmacokinetic concepts of absorption, distribution, and metabolism, as this will
impact drug availability at the site of action (see Fig.2.1). Metabolism can precede
distribution and reduce bioavailability, such as the case with rst-pass metabolism
of certain drugs in the liver when administered via the oral route. Protein binding
can also impact availability of the drug at its target site of action. Many drugs reversibly bind to albumin and alpha-1-acid glycoprotein in the plasma. The propensity
toward this binding is inuenced by the lipophilicity and acid-base properties of the
drug, and levels of plasma proteins can vary among patients and in certain disease
states. If bound to plasma protein, passive diffusion of the drug through cell membranes will be reduced due to the higher molecular mass of the drug-protein complex. For this reason, often only the “fraction unbound” of the drug is considered to
be pharmacologically active and determining plasma protein binding afnity is an
important step in drug development. Albumin-drug binding has also been used to
enhance drug biodistribution, bioavailability, and circulation time, as albumin interacts with many receptors that can be utilized to manipulate drug distribution. An
example of a commercial product utilizing this strategy is Abraxane® (paclitaxel), in
which the drug is manufactured in an albumin-bound form.
16
2 Overview of Biopharmaceutics and Regulatory Concepts Relevant to Drug Product…
Though drugs can distribute and pharmacologically act in many different areas
of the body (e.g., tissues, cells, organelles), there is often limited access to the site
of therapeutic action for sampling to quantify drug levels. Instead, the primary
physiological uids that are used to quantify drug concentrations are blood (or
plasma or serum) and urine. Drug concentrations from these uids are then plotted
as a function of time, and mathematical models are used to predict drug absorption,
distribution, metabolism, and excretion. In these models, the human body is
described as a series of compartments that are designated based on blood ow. The
central compartment refers to the blood and other highly perfused organs, such as
the liver, kidneys, and lungs. Distribution of the drug to these tissues is considered
to be instantaneous, based upon the high level of blood ow. The peripheral com-
partment refers to tissues in which the drug distributes more slowly, such as the
skin, fat, and muscles. The rate of transfer between the central and peripheral compartments and elimination from the central compartment can then be mathematically modeled using differential equations. Drugs that instantly distribute to all
tissues can be described using a one-compartment model, while drugs that do not
instantly distribute and instead exhibit a different rate of diffusion to peripheral
compartment tissues can be described using a two-compartment model. Drug
absorption is also incorporated in pharmacokinetic models. Drugs that are administered intravascularly (i.e., intravenously) will not exhibit an absorption phase, as all
of the injected drug is instantaneously available in the systemic circulation. Drugs
that are administered extravascularly (e.g., orally, intramuscularly) will exhibit an
absorption phase preceding a peak, the rate of which will depend upon the mechanism of release from the dosage form and physiological factors (e.g., gastrointestinal transit time in the case of oral drug delivery) (see Fig.2.2).
Important parameters obtained from the drug plasma concentration versus time
curve include the maximum plasma concentration (Cmax), time to maximum con-
centration (Tmax), and area-under-the-curve (AUC). C
refers to the highest drug
max
concentration obtained in the prole (see Fig. 2.3) and represents the maximum
systemic exposure to the drug. T
refers to the time at which the maximum plasma
max
concentration occurs. The AUC is obtained by integrating the drug plasma concentration with respect to time and is used as a measure of the total systemic exposure
Fig. 2.2 Graphical representation of concentration of drug in the plasma versus time, where the
drug is administered either intravascularly (e.g., one-compartment (a) or two-compartment (b)
model) or extravascularly (e.g., one-compartment (c) or two-compartment model (d))