Pharmaceutical Dosage Forms and Drug Delivery, Third Edition: Revised and Expanded

729 Pages·2018·4.35 MB·English

by  Ram I. Mahato

Pharmaceutical Dosage
Forms and Drug Delivery

Pharmaceutical Dosage
Forms and Drug Delivery
Third Edition: Revised and Expanded
by
Ram I. Mahato, PhD
Department of Pharmaceutical Sciences,
University of  Nebraska Medical Center
Omaha, NE
Ajit S. Narang, PhD
Small Molecule Pharmaceutical Sciences, Genentech, Inc.
One DNA Drive, South San Francisco, CA
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2018 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Printed on acid-free paper
International Standard Book Number-13: 978-1-4822-5362-7 (Hardback)
This book contains information obtained from authentic and highly regarded sources. Reasonable
efforts have been made to publish reliable data and information, but the author and publisher cannot
assume responsibility for the validity of all materials or the consequences of their use. The authors and
publishers have attempted to trace the copyright holders of all material reproduced in this publication
and apologize to copyright holders if permission to publish in this form has not been obtained. If any
copyright material has not been acknowledged please write and let us know so we may rectify in any
future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced,
transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or
hereafter invented, including photocopying, microfilming, and recording, or in any information
storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.
copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC),
222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that
provides licenses and registration for a variety of users. For organizations that have been granted a
photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are
used only for identification and explanation without intent to infringe.
Library of Congress Cataloging‑in‑Publication Data
Names: Mahato, Ram I., author. | Narang, Ajit S., author.
Title: Pharmaceutical dosage forms and drug delivery : third edition, revised
and expanded / Ram I. Mahato and Ajit S. Narang.
Description: Third edition. | Boca Raton : CRC Press, [2017] | Includes
bibliographical references and index.
Identifiers: LCCN 2017017702| ISBN 9781482253627 (hardback : alk. paper) |
ISBN 9781315156941 (ebook)
Subjects: LCSH: Drugs--Dosage forms. | Drug delivery systems.
Classification: LCC RS200 .M34 2017 | DDC 615.1/9--dc23
LC record available at https://lccn.loc.gov/2017017702
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
I dedicate this book to my wife Subhashini, my children Kalika
and Vivek for their love and support; my late mother Sarswati for
believing in me; and to my students and mentors who have always
helped me in my quest for learning and in achieving higher goals.
CRC Press
Taylor & Francis Group Ram I. Mahato
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
To Tirath Singh and Gurdip Kaur, my parents, who
© 2018 by Taylor & Francis Group, LLC
taught me simplicity, sincerity, and hard work.
CRC Press is an imprint of Taylor & Francis Group, an Informa business
Ajit S. Narang
No claim to original U.S. Government works
Printed on acid-free paper
International Standard Book Number-13: 978-1-4822-5362-7 (Hardback)
This book contains information obtained from authentic and highly regarded sources. Reasonable
efforts have been made to publish reliable data and information, but the author and publisher cannot
assume responsibility for the validity of all materials or the consequences of their use. The authors and
publishers have attempted to trace the copyright holders of all material reproduced in this publication
and apologize to copyright holders if permission to publish in this form has not been obtained. If any
copyright material has not been acknowledged please write and let us know so we may rectify in any
future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced,
transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or
hereafter invented, including photocopying, microfilming, and recording, or in any information
storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.
copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC),
222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that
provides licenses and registration for a variety of users. For organizations that have been granted a
photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are
used only for identification and explanation without intent to infringe.
Library of Congress Cataloging‑in‑Publication Data
Names: Mahato, Ram I., author. | Narang, Ajit S., author.
Title: Pharmaceutical dosage forms and drug delivery : third edition, revised
and expanded / Ram I. Mahato and Ajit S. Narang.
Description: Third edition. | Boca Raton : CRC Press, [2017] | Includes
bibliographical references and index.
Identifiers: LCCN 2017017702| ISBN 9781482253627 (hardback : alk. paper) |
ISBN 9781315156941 (ebook)
Subjects: LCSH: Drugs--Dosage forms. | Drug delivery systems.
Classification: LCC RS200 .M34 2017 | DDC 615.1/9--dc23
LC record available at https://lccn.loc.gov/2017017702
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com

Contents
Foreword xxxi
Preface xxxiii
Acknowledgments xxxv
About the authors xxxvii
Part I
Introductory chapters 1
1 Drug discovery 3
1.1 Introduction 3
1.1.1 Elements of drug discovery 4
1.1.2 Sources of drugs 6
1.1.2.1 Plant sources 6
1.1.2.2 Organic synthesis 7
1.1.2.3 Use of animals 7
1.1.2.4 Genetic engineering 7
1.1.2.5 Gene therapy 8
1.2 Collaborating disciplines 8
1.2.1 Biology 9
1.2.2 Chemistry 10
1.2.3 Pharmaceutics 11
1.2.4 Animal toxicology 11
1.2.5 Clinical pharmacology 12
1.2.6 Analytical and bioanalytical sciences 12
1.2.7 Regulatory sciences 13
1.3 Small- versus large-molecule paradigms 14
1.3.1 Preclinical discovery and toxicology assessment 17
1.3.2 Pharmaceutical development 18
1.3.3 Clinical development 18
vii
viii Contents
1.4 Contemporary drug discovery case studies 18
1.4.1 Statins 18
1.4.2 Immuno-oncology 19
1.5 Summary and outlook to the future 21
Review questions 21
References 22
Further reading 23
2 Drug development 25
2.1 Introduction 25
2.2 Stage-gate process of new drug discovery and development 29
2.2.1 Preclinical development 30
2.2.1.1 Physicochemical characterization 30
2.2.1.2 Efficacy studies 30
2.2.1.3 Toxicology studies 31
2.2.2 Clinical development 31
2.2.2.1 Phase I clinical trials 33
2.2.2.2 Phase II clinical trials 33
2.2.2.3 Phase III clinical trials 34
2.2.2.4 Evolving clinical development paradigms 34
2.3 Pharmaceutical development 35
2.3.1 Preformulation and formulation studies 36
2.3.2 Stage-appropriate drug product design 36
2.3.3 Stability 36
2.3.4 Bioavailability 37
2.3.5 Manufacturability 38
2.4 Regulatory approval 38
2.4.1 Investigational new drug application 39
2.4.2 New drug application 40
2.4.2.1 Basis of approval 40
2.4.2.2 Role of advisory committees 40
2.4.3 Biologics license application 41
2.4.4 Abbreviated new drug application 41
2.4.5 Biosimilars 42
2.4.6 Approval and postmarketing surveillance 42
2.4.7 Accelerated development/review 42
2.5 Postcommercialization activities 43
2.5.1 Manufacturing support 43
2.5.2 Intellectual property 43
2.5.3 Life cycle management 44
Contents ix
Review questions 45
Further reading 47
3 Pharmaceutical considerations 49
3.1 Introduction 49
3.2 Advantages of pharmaceutical dosage forms 50
3.3 Influential factors in dosage form design 51
3.3.1 Molecular size and volume 51
3.3.2 Drug solubility and pH 53
3.3.3 Lipophilicity and partition coefficient 55
3.3.4 Polymorphism 58
3.3.5 Stability 59
3.3.6 pK /Dissociation constants 60
a
3.3.7 Degree of ionization and pH-partition theory 63
3.3.7.1 Limitations of pH-partition theory 64
Review questions 65
Further reading 66
4 Biopharmaceutical considerations 69
4.1 Introduction 69
4.2 Diffusion 70
4.2.1 Drug transport across a polymeric barrier 70
4.2.1.1 Molecular diffusion 70
4.2.1.2 Pore diffusion 71
4.2.1.3 Matrix erosion 71
4.2.2 Principles of diffusion 72
4.2.2.1 Fick’s first law 72
4.2.2.2 Fick’s second law 73
4.2.3 Diffusion rate 73
4.2.3.1 Diffusion cell 74
4.2.3.2 Spherical membrane-controlled
drug delivery system 75
4.2.3.3 Pore diffusion 76
4.2.3.4 Determining permeability coefficient 76
4.2.3.5 Lag time in non-steady state diffusion 77
4.2.3.6 Matrix (monolithic)-type
non-degradable system 77
4.2.3.7 Calculation examples 78