i

MARTIN’S PHYSICAL PHARMACY

AND PHARMACEUTICAL SCIENCES
Physical Chemical and Biopharmaceutical Principles
in the Pharmaceutical Sciences
SIXTH EDITION

Editor
PATRICK J. SINKO, PhD, RPh
Professor II (Distinguished)
Parke-Davis Chair Professor in Pharmaceutics and Drug Delivery
Ernest Mario School of Pharmacy
Rutgers, The State University of New Jersey
Piscataway, New Jersey

Assistant Editor
YASHVEER SINGH, PhD
Assistant Research Professor
Department of Pharmaceutics
Ernest Mario School of Pharmacy
Rutgers, The State University of New Jersey
Piscataway, New Jersey
Editor: David B. Troy
Product Manager: Meredith L. Brittain
Vendor Manager: Kevin Johnson
Designer: Holly McLaughlin
Compositor: Aptara® , Inc.

Sixth Edition

Copyright 
c 2011, 2006 Lippincott Williams & Wilkins, a Wolters Kluwer business.
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987654321

Library of Congress Cataloging-in-Publication Data

Martin’s physical pharmacy and pharmaceutical sciences : physical

chemical and biopharmaceutical principles in the pharmaceutical
sciences.—6th ed. / editor, Patrick J. Sinko ; assistant editor,
Yashveer Singh.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-7817-9766-5
1. Pharmaceutical chemistry. 2. Chemistry, Physical and theoretical.
I. Martin, Alfred N. II. Sinko, Patrick J. III. Singh, Yashveer.
IV. Title: Physical pharmacy and pharmaceutical sciences.
[DNLM: 1. Chemistry, Pharmaceutical. 2. Chemistry, Physical. QV 744
M386 2011]
RS403.M34 2011
615 .19—dc22 2009046514

DISCLAIMER

Care has been taken to confirm the accuracy of the information present and to describe generally
accepted practices. However, the authors, editors, and publisher are not responsible for errors or
omissions or for any consequences from application of the information in this book and make no
warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents
of the publication. Application of this information in a particular situation remains the professional
responsibility of the practitioner; the clinical treatments described and recommended may not be
considered absolute and universal recommendations.
The authors, editors, and publisher have exerted every effort to ensure that drug selection and
dosage set forth in this text are in accordance with the current recommendations and practice at the
time of publication. However, in view of ongoing research, changes in government regulations, and the
constant flow of information relating to drug therapy and drug reactions, the reader is urged to check
the package insert for each drug for any change in indications and dosage and for added warnings
and precautions. This is particularly important when the recommended agent is a new or infrequently
employed drug.
Some drugs and medical devices presented in this publication have Food and Drug Administration
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 Dedicated to my parents Patricia and Patrick Sinko,
my wife Renee, and my children Pat, Katie (and Maggie)
 DEDICATION
ALFRED N. MARTIN (1919–2003)
This fiftieth anniversary edition of Martin’s Physical Phar- focus, and philosophy of pharmaceutical education during the
macy and Pharmaceutical Sciences is dedicated to the mem- 1960s and the 1970s and paved the way for the specialty dis-
ory of Professor Alfred N. Martin, whose vision, creativity, ciplines of biopharmaceutics and pharmacokinetics which,
dedication, and untiring effort and attention to detail led to along with physical pharmacy, were necessary underpinnings
the publication of the first edition in 1960. Because of his of a scientifically based clinical emphasis in the teaching of
national reputation as a leader and pioneer in the then emerg- pharmacy students, which is now pervasive throughout phar-
ing specialty of physical pharmacy, I made the decision to maceutical education.
join Professor Martin’s group of graduate students at Pur- From the time of the initial publication of Physical Phar-
due University in 1960 and had the opportunity to witness macy to the present, this pivotal and classic book has been
the excitement and the many accolades of colleagues from widely used both as a teaching textbook and as an indis-
far and near that accompanied the publication of the first pensible reference for academic and industrial researchers in
edition of Physical Pharmacy. The completion of that work the pharmaceutical sciences throughout the world. This sixth
represented the culmination of countless hours of painstak- edition of Martin’s Physical Pharmacy and Pharmaceutical
ing study, research, documentation, and revision on the part Sciences serves as a most fitting tribute to the extraordinary,
of Dr. Martin, many of his graduate students, and his wife, heroic, and inspired vision and dedication of Professor Mar-
Mary, who typed the original manuscript. It also represented tin. That this book continues to be a valuable and widely
the fruition of Professor Martin’s dream of a textbook that used textbook in schools and colleges of pharmacy through-
would revolutionize pharmaceutical education and research. out the world, and a valuable reference to pharmaceutical
Physical Pharmacy was for Professor Martin truly a labor of scientists and researchers, is a most appropriate recognition
love, and it remained so throughout his lifetime, as he worked of the life’s work of Alfred Martin. All who have contributed
unceasingly and with steadfast dedication on the subsequent to the thorough revision that has resulted in the publication
revisions of the book. of the current edition have retained the original format and
The publication of the first edition of Physical Pharmacy fundamental organization of basic principles and topics that
generated broad excitement throughout the national and inter- were the hallmarks of Professor Martin’s classic first edition
national academic and industrial research communities in of this seminal book.
pharmacy and the pharmaceutical sciences. It was the world’s Professor Martin always demanded the best of himself, his
first textbook in the emerging discipline of physical pharmacy students, and his colleagues. The fact that the subsequent and
and has remained the “gold standard” textbook on the appli- current editions of Martin’s Physical Pharmacy and Phar-
cation of physical chemical principles in pharmacy and the maceutical Sciences have remained faithful to his vision of
pharmaceutical sciences. Physical Pharmacy, upon its publi- scientific excellence as applied to understanding and apply-
cation in 1960, provided great clarity and definition to a dis- ing the principles underlying the pharmaceutical sciences is
cipline that had been widely discussed throughout the 1950s indeed a most appropriate tribute to Professor Martin’s mem-
but not fully understood or adopted. Alfred Martin’s Physi- ory. It is in that spirit that this fiftieth anniversary edition is
cal Pharmacy had a profound effect in shaping the direction formally dedicated to the memory of that visionary and cre-
of research and education throughout the world of pharma- ative pioneer in the discipline of physical pharmacy, Alfred
ceutical education and research in the pharmaceutical indus- N. Martin.
try and academia. The publication of this book transformed
pharmacy and pharmaceutical research from an essentially
empirical mix of art and descriptive science to a quantita- John L. Colaizzi, PhD
tive application of fundamental physical and chemical scien- Rutgers, The State University of New Jersey
tific principles to pharmaceutical systems and dosage forms. Piscataway, New Jersey
Physical Pharmacy literally changed the direction, scope, November 2009

iv
 PREFACE
Ever since the First Edition of Martin’s Physical Pharmacy moved to the Web (see the “Additional Resources” section
was published in 1960, Dr. Alfred Martin’s vision was to pro- later in this preface).
vide a text that introduced pharmacy students to the applica-
tion of physical chemical principles to the pharmaceutical sci-
ences. This remains a primary objective of the Sixth Edition. SIGNIFICANT CHANGES FROM THE FIFTH EDITION
Martin’s Physical Pharmacy has been used by generations of
pharmacy and pharmaceutical science graduate students for Important changes include new chapters on Pharmaceutical
50 years and, while some topics change from time to time, Biotechnology and Oral Solid Dosage Forms. Three chap-
the basic principles remain constant, and it is my hope that ters were rewritten de novo on the basis of the valuable
each edition reflects the pharmaceutical sciences at that point feedback received since the publication of the Fifth Edi-
in time. tion. These include Chapter 1 (“Introduction”), which is
now called Interpretive Tools; Chapter 20 (“Biomaterials”),
which is now called Pharmaceutical Polymers; and Chap-
ORGANIZATION ter 23 (“Drug Delivery Systems”), which is now called
Drug Delivery and Targeting.
As with prior editions, this edition represents an updating of
most chapters, a significant expansion of others, and the addi-
tion of new chapters in order to reflect the applications of the ADDITIONAL RESOURCES
physical chemical principles that are important to the Phar-
maceutical Sciences today. As was true when Dr. Martin was Martin’s Physical Pharmacy and Pharmaceutical Sciences,
at the helm, this edition is a work in progress that reflects Sixth Edition, includes additional resources for both instruc-
the many suggestions made by students and colleagues in tors and students that are available on the book’s companion
academia and industry. There are 23 chapters in the Sixth Web site at thepoint.lww.com/Sinko6e.
Edition, as compared with 22 in the Fifth Edition. All chap-
ters have been reformatted and updated in order to make
the material more accessible to students. Efforts were made
Instructors
to shorten chapters in order to focus on the most important Approved adopting instructors will be given access to the
subjects taught in Pharmacy education today. Care has been following additional resources:
taken to present the information in “layers” from the basic
■ Practice problems and answers to ascertain student under-
to more in-depth discussions of topics. This approach allows
standing.
the instructor to customize their course needs and focus their
course and the students’ attention on the appropriate topics
and subtopics. Students
With the publication of the Sixth Edition, a Web-based
Students who have purchased Martin’s Physical Pharmacy
resource is also available for students and faculty members
and Pharmaceutical Sciences, Sixth Edition, have access to
(see the “Additional Resources” section later in this preface).
the following additional resources:
■ A separate set of practice problems and answers to rein-
FEATURES force concepts learned in the text.
In addition, purchasers of the text can access the searchable
Each chapter begins with a listing of Chapter Objectives that
Full Text Online by going to the Martin’s Physical Phar-
introduce information to be learned in the chapter. Key Con-
macy and Pharmaceutical Sciences, Sixth Edition, Web site
cept Boxes highlight important concepts, and each Chapter
at thePoint.lww.com/Sinko6e. See the inside front cover of
Summary reinforces chapter content. In addition, illustra-
this text for more details, including the passcode you will
tive Examples have been retained, updated, and expanded.
need to gain access to the Web site.
Recommended Readings point out instructive additional
sources for possible reference. Practice Problems have been
Patrick Sinko
Piscataway, New Jersey

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 CONTRIBUTORS
GREGORY E. AMIDON, PhD TERUNA J. SIAHAAN, PhD
Research Professor Professor
Department of Pharmaceutical Sciences Department of Pharmaceutical Chemistry
College of Pharmacy University of Kansas
University of Michigan Lawrence, Kansas
Ann Arbor, Michigan
YASHVEER SINGH, PhD
CHARLES RUSSELL MIDDAUGH, PhD Assistant Research Professor
Distinguished Professor Department of Pharmaceutics
Department of Pharmaceutical Chemistry Ernest Mario School of Pharmacy
University of Kansas Rutgers, The State University of New Jersey
Lawrence, Kansas Piscataway, New Jersey

HOSSEIN OMIDIAN, PhD PATRICK J. SINKO, PhD, RPh

Assistant Professor Professor II (Distinguished)
Department of Pharmaceutical Sciences Parke-Davis Chair Professor in Pharmaceutics and Drug Delivery
College of Pharmacy Ernest Mario School of Pharmacy
Nova Southeastern University Rutgers, The State University of New Jersey
Ft. Lauderdale, Florida Piscataway, New Jersey

KINAM PARK, PhD HAIAN ZHENG, PhD

Showalter Distinguished Professor Assistant Professor
Department of Biomedical Engineering Department of Pharmaceutical Sciences
Professor of Pharmaceutics Albany College of Pharmacy and Health Sciences
Departments of Biomedical Engineering and Pharmaceutics Albany, New York
Purdue University
West Lafayette, Indiana

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 ACKNOWLEDGMENTS
The Sixth Edition reflects the hard work and dedication of I would like to acknowledge Dr. Mayur Lodaya for his con-
many people. In particular, I acknowledge Drs. Gregory Ami- tributions to the continuous processing section of Chapter 22
don (Ch 22), Russell Middaugh (Ch 21), Hamid Omidian on Oral Dosage forms.
(Chs 20 and 23), Kinam Park (Ch 20), Teruna Siahaan (Ch Numerous graduate students contributed in many ways
21), and Yashveer Singh (Ch 23) for their hard work in spear- to this edition, and I am always appreciative of their in-
heading the efforts to write new chapters or rewrite existing sights, criticisms, and suggestions. Thanks also to Mrs. Amy
chapters de novo. In addition, Dr. Singh went beyond the Grabowski for her invaluable assistance with coordination
call of duty and took on the responsibilities of Assistant efforts and support interactions with all contributors.
Editor during the proofing stages of the production of the To all of the people at LWW who kept the project mov-
manuscripts. Through his efforts, I hope that we have caught ing forward with the highest level of professionalism, skill,
many of the minor errors from the fourth and fifth editions. I and patience. In particular, to David Troy for supporting our
also thank HaiAn Zheng, who edited the online practice prob- vision for this project and Meredith Brittain for her excep-
lems for this edition, and Miss Xun Gong, who assisted him. tional eye for detail and her persistent efforts to keep us on
The figures and experimental data shown in Chapter 6 track.
were produced by Chris Olsen, Yuhong Zeng, Weiqiang And to my wonderful wife, Renee, who deserves enor-
Cheng, Mangala Roshan Liyanage, Jaya Bhattacharyya, mous credit for juggling her hectic professional life as a
Jared Trefethen, Vidyashankara Iyer, Aaron Markham, Julian pharmacist and her expert skill as the family organizer while
Kissmann and Sangeeta Joshi of the Department of Pharma- maintaining a sense of calmness in what is an otherwise
ceutical Chemistry at the University of Kansas. The section chaotic life.
on drying of biopharmaceuticals is based on a series of lec-
tures and overheads presented by Dr. Pikal of the University Patrick Sinko
of Connecticut in April of 2009 at the University of Kansas. Piscataway, New Jersey

vii
 CONTENTS
1 INTERPRETIVE TOOLS 1 13 DRUG RELEASE AND DISSOLUTION 300

2 STATES OF MATTER 17 14 CHEMICAL KINETICS AND STABILITY 318

3 THERMODYNAMICS 54 15 INTERFACIAL PHENOMENA 355

4 DETERMINATION OF THE PHYSICAL PROPERTIES 16 COLLOIDAL DISPERSIONS 386

OF MOLECULES 77
17 COARSE DISPERSIONS 410
5 NONELECTROLYTES 109
18 MICROMERITICS 442
6 ELECTROLYTE SOLUTIONS 129
19 RHEOLOGY 469
7 IONIC EQUILIBRIA 146
20 PHARMACEUTICAL POLYMERS 492
8 BUFFERED AND ISOTONIC SOLUTIONS 163
21 PHARMACEUTICAL BIOTECHNOLOGY 516
9 SOLUBILITY AND DISTRIBUTION PHENOMENA 182
22 ORAL SOLID DOSAGE FORMS 563
10 COMPLEXATION AND PROTEIN BINDING 197
23 DRUG DELIVERY AND TARGETING 594
11 DIFFUSION 223
Index 647
12 BIOPHARMACEUTICS 258

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