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Foreword
curing many intransigent or hereditary disorders. Over the past several years, antibodies have emerged
as the top- selling pharmaceutical medications in the market. This is mostly attributed to their exceplogical developments such as antibodies- drug conjugates (ADC) have enhanced the therapeutic effects
of antibodies.
A new chapter on gene editing (Chapter 28) has also been added, which explains the genome editing
tools and their rapid technological advancements, focusing on basic laboratory research and clinical
facilitated by clustered regularly interspaced short palindromic repeats (CRISPR)- Cas9, transcription
growth in new diagnostic and therapeutic modalities based on gene editing.
A new chapter on immunotherapy (Chapter 29) is also included in this edition. This chapter
discusses basic immunology, cancer immunobiology, and passive and active immunotherapy strategies.
Immunotherapy boosts the immune system, aiding in cell destruction. It can be used alone or in combination with other treatments like cytokine therapies, oncolytic viruses, cancer vaccines, chimeric antigen
receptor T cell (CAR T) therapies, and combination immunotherapies. Advances in the understanding of
immune responsiveness and toxicity have resulted in innumerable approvals by the United States Food
and Drug Administration of products related to immune modulation.
In recent years, pharmaceutical sciences have enjoyed a profound increase in foundational and translational knowledge that has advanced drug discovery and development. This up- to- date book incorporates
this knowledge with contemporary research in basic and various sub- disciplines of the pharmaceutical
sciences to enable the holistic development of the next generation of students.
perspective of their practice to our next generations of students.
Keith M. Olsen, PharmD, FCCP, MCCM
Joseph D. Williams Endowed Dean
College of Pharmacy
Nebraska Medical Center
Omaha, NE
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Preface
This book is designed as a textbook for teaching basic principles of pharmaceutics, dosage form design, and
drug delivery to Doctor of Pharmacy (Pharm. D.) students in the United States and Bachelor of Pharmacy
(B. Pharm.) students in other countries. Although there are numerous books on the science of pharmaceutics and dosage form design, including Martin’s Physical Pharmacy and Pharmaceutical Sciences by
Sinko, Physicochemical Principles of Pharmacy by Florence and Attwood, Pharmaceutics: The Science
of Dosage Form Design by Aulton, Theory and Practice of Contemporary Pharmaceutics by Ghosh and
Jasti, and Pharmaceutical Sciences by Remington, these books cover different areas of the discipline in
varying depths and provide limited insight into contemporary practices and practical applications. Each
of these textbooks, by themselves, does not provide an integrated approach to the students. This leads the
students, as well as the teachers, to refer many textbooks to develop an overall understanding of the basic
physicochemical principles and their applications to the design and development of different pharmaceut-
The students need to know the basic physicochemical principles, the application of these principles
to the design of dosage forms, and the relevance of these principles to the biopharmaceutical aspects
of drugs. Another important aspect of teaching that is urgently needed in our Pharm. D. curricula is
to expose students to the latest developments in the application of biomaterials as well as protein and
nucleic acid- based pharmaceutical dosage forms and therapeutics, and various biotechnology- based
developments. Various books that are currently taught to students miss these latest developments in the
the successful training of future pharmacists because these therapeutic modalities and options are likely
that students can develop a better and overall understanding of the principles involved in dosage form
design and drug delivery. This book covers an in- depth discussion of what physiochemical parameters
can be used to design, develop, and evaluate biotechnological dosage forms for the delivery of proteins,
peptides, antibodies, oligonucleotides, siRNA, miRNA, and genes.
What’s new in the fourth edition of Pharmaceutical Dosage Forms and Drug Delivery? This edition has
chapters that provide contemporary practices. Updated chapters include “drug discovery,” “pharma math,”
“chemical kinetics,” “parenteral,” “protein and peptides therapeutics,” and “biotechnology- based drugs.”
The new chapters included are “antibodies therapeutics,” “genome editing,” and “immunotherapy.”
You have an updated, contemporary, new book that can serve as a textbook for Pharm. D. students and
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About the Authors
Ram I. Mahato is Parke- Davis Endowed Professor and Chairman of the Department of Pharmaceutical
Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE. He was a professor
at the University of Tennessee Health Science Center in Memphis, Research Assistant Professor at the
University of Utah in Salt Lake City, Senior Scientist at GeneMedicine, Inc., The Woodlands, TX, and
a postdoctoral fellow at the University of Southern California in Los Angeles, Washington University
in St. Louis, and Kyoto University, Japan. He received his PhD in Drug Delivery from the University
book chapters, holds 4 US patents, and has edited/ written 12 books and 14 journal issues (Total Google
Pharmaceutical Research
and an editorial board member of eight journals. He is a CRS and AAPS fellow, a permanent member of
ceutical sciences in the context of the latest advances in life and material sciences to solve challenging
drug delivery problems in therapeutics.
Ajit S. Narang is Vice President at Oric Pharmaceuticals in South San Francisco, CA. His primary
expertise is in oral drug delivery. He has over 18 years of pharmaceutical industry experience in
developing oral dosage forms and drug delivery platforms. Previously, he worked as a principal scientist
at Genentech, Inc. and Bristol- Myers Squibb, Co. (BMS) in New Brunswick, NJ, in the Drug Product
Science & Technology Department. In addition to BMS, he has worked for Ranbaxy Research Labs (currently a subsidiary of Daiichi Sankyo, Japan) and Morton Grove Pharmaceuticals (currently Wockhardt
USA). He holds an undergraduate Pharmacy degree from the University of Delhi, India, and graduate
degrees in Pharmaceutical Sciences from Banaras Hindu University, India and the University of Tennessee
Health Science Center (UTHSC) in Memphis, TN. He serves as the Excipient Focus Group chair- elect
for the American Association of Pharmaceutical Scientists (AAPS), Adjunct Faculty for the UTHSC, and
in dosage form development and drug delivery technologies that enable pharmaceutical development of
challenging molecules to resolve stability, pharmacokinetic, and pharmacodynamic issues. He has more
than 40 publications and three pending patent applications and has contributed to the development of
several marketed drug products.
Virender Kumar is an assistant professor of pharmaceutics in the College of Pharmacy and Pharmaceutical
Sciences at the University of Toledo Medical Center. He worked as a research assistant professor and a
postdoctoral at the University of Nebraska Medical Center (UNMC), Omaha. He also earned his PhD in
earned a master’s in Industrial Pharmacy from Saint Johns’ University, NY. He also earned M. Pharm and
B. Pharm from Guru Jambheshwar University, Hisar, Haryana, India. He has published 43 papers and six
book chapters, holds one US patent, and has edited/ written one book and two journal issues.
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Part I
Introductory Chapters
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1
Drug Discovery
LEARNING OBJECTIVES
On the completion of this chapter, the students should be able to
1. Differentiate between drug discovery and development processes.
2. Outline key elements of the contemporary process of drug discovery.
3. Identify different functional areas involved in drug discovery and their roles.
4. Differentiate drug discovery and development paradigms for small- and large- molecule drugs.
5.
and development.
1.1 Introduction
Throughout history, new drug discoveries have enabled human well- being and advancement, not only by
ensuring survival in the wake of infections and debilitating diseases but also by steadily advancing the
quality of life. For example, the discovery of penicillin by Alexander Fleming in 1928 saved countless lives
and paved the way for antibiotic medicines. More recent examples of life- saving medicines include the
discovery and commercialization of statins for the management of hypercholesterolemia and humanized
monoclonal antibodies (mAbs) targeting the immune checkpoints for the immunotherapy of cancer.
Prominent examples among the quality- of- life improving therapeutics are the drugs for the management
of pain, hypertension, gastrointestinal disorders, and countless others. New drug discovery remains a
continuing priority and exhibits relentless efforts of governments, private corporations, and academia
alike. This chapter will outline contemporary practices in new drug discovery and development, with
an emphasis on the interdisciplinary process, stage- gate paradigm, and the key features that ensure the
1.1.1 Elements of Drug Discovery
Early discovery starts with identifying disease areas and molecular targets that may be useful in the
clinical setting to modulate a particular disease condition. Several drug candidates that may be able to
produce the desired outcome at the chosen drug targets are produced. The activity of these candidates
is assessed in in vitro
relationships (SARs) are developed to help narrow down the drug candidates to the ones with the greatest
Early discovery is involved not only in the generation of drug candidates but also in the assessment of
their activity and toxicity in cell culture- based, in vitro, and in vivo systems (animal species). These often
require the development of disease models on which compounds can be tested. Assessment of the relative
activity and potential of different compounds must be made under a multitude of criteria, thus requiring
DOI: 10.1201/9781003389378-2
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Pharmaceutical Dosage Forms and Drug Delivery
an effort to optimize the relative performance of a compound in several attributes that are important for
success in the overall discovery and development process.
The typical drug discovery and development process (Figure 1.1) involves a series of iterative work
efforts and continue to develop concurrently with the discovery of drug candidate screening. Target
screening and validation involve the following steps:
• Understanding disease pathophysiology and underlying cellular or subcellular mechanisms.
• Target engagement– effect studies in cell culture or in vitro systems, with a view to develop a high-
throughput assay that can be used to screen new drug candidates.
• Efcacy, toxicity, and preliminary pharmacokinetic studies in animals relevant to disease pathophysiology and candidate drugs. These studies may involve the use of transgenic animals that
exhibit the disease or modulation of particular biochemical processes and the use of antisense
oligonucleotides or RNA- silencing approaches to modulate subcellular genetic pathways.
The discovery of new drug candidates relies on target screening and validation efforts to identify the
right target and provide a high- throughput screening assay to shortlist compounds from vast institutional
libraries and synthetic capabilities. Drug discovery efforts focus on the following:
• Target engagement and evaluation
can be measured in terms of percentage. The ability of a quantitated extent of interaction to produce
• Molecule search
in silico molecular modeling studies that try to assess the molecular mechanism and location of
molecules that can be tested based on these assessments.
•
lead optimization efforts focus on developability assessment
FIGURE 1.1 Key activities involved in drug discovery and development research.
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Drug Discovery
5
enable the progression of a molecule through later stages of drug development. These assessments
assessment of the observed or predictable liabilities of adverse effects.
The drug development
enable clinical trials through various phases of drug development to generate the needed data package
for regulatory approval and commercialization. The details of the drug development studies will be the
subject of Chapter 2.
1.1.1.1 Sources of Drugs
bination of (1) molecular physiology and pathophysiology, that is, research on the molecular mechanisms
tualization and synthesis/ procurement of potential new molecules that may also involve random selection
and broad biological screening.
The sources of new drugs are varied (Figure 1.2). New molecular entities (NMEs) can be of synthetic
1.1.1.1.1 Plant Sources
Natural compounds extracted from plants have often provided novel structures for therapeutic applications.
For example, vincristine is derived from the periwinkle plant Vinca rosea, etoposide is from the mandrake
plant Podophyllum peltatum Taxus brevifolia, doxorubicin is a fermenta-
tion product of the bacteria Streptomyces, - asparaginase is from Escherichia coli or Erwinia carotovora,
rhizoxin is from the fungus Rhizopus chinensis, cytarabine is from the marine sponge Cryptotethya crypta,
and bryostatin is from the sea moss Bugula neritina. Another example is paclitaxel (Taxol®), prepared
widely used drugs in the management of congestive heart failure, weakened heart, and irregular heartbeat
(arrhythmia). The common garden plant, the foxglove or Digitalis purpurea, is the source of digoxin.
1.1.1.1.2 Organic Synthesis
Chemical synthesis could involve (a) synthesis of analogs of natural compounds in an effort to improve
(c) synthesis of a new, unique chemical structure.
FIGURE 1.2 Different sources of drug molecules.
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