Preformulation in Solid Dosage Form Development

  

Preformulation in

Solid Dosage Form

Development

DRUGS AND THE PHARMACEUTICAL SCIENCES

  A Series of Textbooks and Monographs

  

Executive Editor

James Swarbrick

  PharmaceuTech, Inc. Pinehurst, North Carolina

  

Advisory Board

  Harry G. Brittain Larry L. Augsburger

  Center for Pharmaceutical Physics University of Maryland Milford, New Jersey Baltimore, Maryland

  Robert Gurny Jennifer B. Dressman

  Universite de Geneve University of Frankfurt Institute of Geneve, Switzerland Pharmaceutical Technology

  Frankfurt, Germany

  Jeffrey A. Hughes

  University of Florida College

  Anthony J. Hickey

  of Pharmacy University of North Carolina Gainesville, Florida School of Pharmacy

  Vincent H. L. Lee

  Chapel Hill, North Carolina US FDA Center for Drug Evaluation and Research

  Ajaz Hussain

  Los Angeles, California Sandoz Princeton, New Jersey

  Kinam Park

  Purdue University

  Joseph W. Polli

  West Lafayette, Indiana GlaxoSmithKline Research Triangle Park North Carolina

  Jerome P. Skelly

  Alexandria, Virginia

  Stephen G. Schulman

  

University of Florida Elizabeth M. Topp

University of Kansas Gainesville, Florida Lawrence, Kansas

  Yuichi Sugiyama Peter York

  University of Tokyo, Tokyo, Japan University of Bradford School of Pharmacy

  GeoffreyT. Tucker

  Bradford, United Kingdom University of Sheffield Royal Hallamshire Hospital

  1. Pharmacokinetics, Milo Gibaldi and Donald Perrier

  

14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts,

Biomedical Assessments, Yie W. Chien

  

24. Anticancer and Interferon Agents: Synthesis and Properties, edited by

Raphael M. Ottenbrite and George B. Butler

  23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and Robert A. Nash

  22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme

  21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe and T. Colin Campbell

  20. Microencapsulation and Related Drug Processes, Patrick B. Deasy

  

19. The Clinical Research Process in the Pharmaceutical Industry, edited by

Gary M. Matoren

  18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry

  17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger

  

16. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality

Control, Second Edition, Revised and Expanded, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV

  15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo Gibaldi and Donald Perrier

  13. Orphan Drugs, edited by Fred E. Karch

  2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV

  12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky

  11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by James W. Munson

  

10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner and

Bernard Testa

  

9. Activated Charcoal: Antidotal and Other Medical Uses, David O. Cooney

  

8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz

  7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher T. Rhodes

  6. Sustained and Controlled Release Drug Delivery Systems, edited by Joseph R. Robinson

  5. New Drugs: Discovery and Development, edited by Alan A. Rubin

  4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa and Peter Jenner

  3. Microencapsulation, edited by J. R. Nixon

  25. Pharmaceutical Statistics: Practical and Clinical Applications,

  26. Drug Dynamics for Analytical, Clinical, and Biological Chemists, Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael J. Gudzinowicz

  27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos

  28. Solubility and Related Properties, Kenneth C. James

  

29. Controlled Drug Delivery: Fundamentals and Applications, Second Edition,

Revised and Expanded, edited by Joseph R. Robinson and Vincent H. Lee

  30. New Drug Approval Process: Clinical and Regulatory Management, edited by Richard A. Guarino

  31. Transdermal Controlled Systemic Medications, edited by Yie W. Chien

  32. Drug Delivery Devices: Fundamentals and Applications, edited by Praveen Tyle

  33. Pharmacokinetics: Regulatory • Industrial • Academic Perspectives, edited by Peter G. Welling and Francis L. S. Tse

  34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato

  

35. Transdermal Drug Delivery: Developmental Issues and Research Initiatives,

edited by Jonathan Hadgraft and Richard H. Guy

  36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, edited by James W. McGinity

  

37. Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-Sellassie

  38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch

  39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su, and Shyi-Feu Chang

  

40. Modern Pharmaceutics: Second Edition, Revised and Expanded, edited by

Gilbert S. Banker and Christopher T. Rhodes

  41. Specialized Drug Delivery Systems: Manufacturing and Production Technology, edited by Praveen Tyle

  42. Topical Drug Delivery Formulations, edited by David W. Osborne and Anton H. Amann

  43. Drug Stability: Principles and Practices, Jens T. Carstensen

  44. Pharmaceutical Statistics: Practical and Clinical Applications, Second Edition, Revised and Expanded, Sanford Bolton

  45. Biodegradable Polymers as Drug Delivery Systems, edited by Mark Chasin and Robert Langer

  46. Preclinical Drug Disposition: A Laboratory Handbook, Francis L. S. Tse and James J. Jaffe

  47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong and Stanley K. Lam

  48. Pharmaceutical Bioequivalence, edited by Peter G. Welling,

  49. Pharmaceutical Dissolution Testing, Umesh V. Banakar

  50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded, Yie W. Chien

  

51. Managing the Clinical Drug Development Process, David M. Cocchetto and

Ronald V. Nardi

  

52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality

Control, Third Edition, edited by Sidney H. Willig and James R. Stoker

  53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan

  54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony J. Hickey

  55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by Adrian D. Nunn

  

56. New Drug Approval Process: Second Edition, Revised and Expanded,

edited by Richard A. Guarino

  

57. Pharmaceutical Process Validation: Second Edition, Revised and Expanded,

edited by Ira R. Berry and Robert A. Nash

  58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra

  59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A. Walters and Jonathan Hadgraft

  60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck

  61. Pharmaceutical Particulate Carriers: Therapeutic Applications, edited by Alain Rolland

  62. Drug Permeation Enhancement: Theory and Applications, edited by Dean S. Hsieh

  63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan

  

64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A. Halls

  65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie

  66. Colloidal Drug Delivery Systems, edited by Jo¨rg Kreuter

  

67. Pharmacokinetics: Regulatory • Industrial • Academic Perspectives, Second

Edition, edited by Peter G. Welling and Francis L. S. Tse

  68. Drug Stability: Principles and Practices, Second Edition, Revised and Expanded, Jens T. Carstensen

  69. Good Laboratory Practice Regulations: Second Edition, Revised and Expanded, edited by Sandy Weinberg

  70. Physical Characterization of Pharmaceutical Solids, edited by Harry G. Brittain

  

71. Pharmaceutical Powder Compaction Technology, edited by Go¨ran Alderborn

and Christer Nystro¨m

  

72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited by

Gilbert S. Banker and Christopher T. Rhodes

  73. Microencapsulation: Methods and Industrial Applications, edited by Simon Benita

  84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpe´

  

92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu, and

Roger Phan-Tan-Luu

  

91. Dermal Absorption and Toxicity Assessment, edited by Michael S. Roberts

and Kenneth A. Walters

  

90. Automation and Validation of Information in Pharmaceutical Processing,

edited by Joseph F. deSpautz

  89. Receptor-Based Drug Design, edited by Paul Leff

  

88. Development and Formulation of Veterinary Dosage Forms: Second Edition,

Revised and Expanded, edited by Gregory E. Hardee and J. Desmond

Baggot

  

87. Drug Products for Clinical Trials: An International Guide to Formulation •

Production • Quality Control, edited by Donald C. Monkhouse and Christopher T. Rhodes

  86. Pharmaceutical Project Management, edited by Tony Kennedy

  

85. Development of Biopharmaceutical Parenteral Dosage Forms, edited by

John A. Bontempo

  

83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts and

Richard H. Guy

  74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone

  82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded, edited by William R. Strohl

  81. Handbook of Pharmaceutical Granulation Technology, edited by Dilip M. Parikh

  

80. Pharmaceutical Statistics: Practical and Clinical Applications, Third Edition,

Sanford Bolton

  79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms:

Second Edition, Revised and Expanded, edited by James W. McGinity

  

78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality

Control, Fourth Edition, Revised and Expanded, Sidney H. Willig and

James R. Stoker

  

77. Microparticulate Systems for the Delivery of Proteins and Vaccines, edited

by Smadar Cohen and Howard Bernstein

  76. The Drug Development Process: Increasing Efficiency and Cost Effectiveness, edited by Peter G. Welling, Louis Lasagna, and Umesh V. Banakar

  75. Clinical Research in Pharmaceutical Development, edited by Barry Bleidt and Michael Montagne

  

93. Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes III

  94. Pharmaceutical Excipients: Characterization by IR, Raman, and NMR Spectroscopy, David E. Bugay and W. Paul Findlay

95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain

  

96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products,

edited by Louis Rey and Joan C.May

  

97. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,

Third Edition, Revised and Expanded, edited by Robert L. Bronaugh and Howard I. Maibach

  

98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and

Development, edited by Edith Mathiowitz, Donald E. Chickering III, and

Claus-Michael Lehr

  99. Protein Formulation and Delivery, edited by Eugene J. McNally 100. New Drug Approval Process: Third Edition, The Global Challenge, edited by Richard A. Guarino 101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid

  102. Transport Processes in Pharmaceutical Systems, edited by Gordon L. Amidon, Ping I. Lee, and Elizabeth M. Topp 103. Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois A. Kotkoskie 104. The Clinical Audit in Pharmaceutical Development, edited by Michael R. Hamrell

105. Pharmaceutical Emulsions and Suspensions, edited by Francoise Nielloud

and Gilberte Marti-Mestres 106. Oral Drug Absorption: Prediction and Assessment, edited by Jennifer B. Dressman and Hans Lennerna¨s 107. Drug Stability: Principles and Practices, Third Edition, Revised and Expanded, edited by Jens T. Carstensen and C. T. Rhodes 108. Containment in the Pharmaceutical Industry, edited by James P. Wood

109. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality

  

Control from Manufacturer to Consumer, Fifth Edition, Revised and

Expanded, Sidney H. Willig 110. Advanced Pharmaceutical Solids, Jens T. Carstensen 111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation,

  Second Edition, Revised and Expanded, Kevin L. Williams 112. Pharmaceutical Process Engineering, Anthony J. Hickey and David Ganderton 113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer and Rachel F. Tyndale 114. Handbook of Drug Screening, edited by Ramakrishna Seethala and Prabhavathi B. Fernandes

  116. Drug–Drug Interactions, edited by A. David Rodrigues 117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian and Anthony J. Streeter 118. Pharmaceutical Process Scale-Up, edited by Michael Levin

  119. Dermatological and Transdermal Formulations, edited by Kenneth A. Walters 120. Clinical Drug Trials and Tribulations: Second Edition, Revised and Expanded, edited by Allen Cato, Lynda Sutton, and Allen Cato III 121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher T. Rhodes 122. Surfactants and Polymers in Drug Delivery, Martin Malmsten

123. Transdermal Drug Delivery: Second Edition, Revised and Expanded, edited

by Richard H. Guy and Jonathan Hadgraft 124. Good Laboratory Practice Regulations: Second Edition, Revised and Expanded, edited by Sandy Weinberg

125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package

Integrity Testing: Third Edition, Revised and Expanded, Michael J. Akers, Daniel S. Larrimore, and Dana Morton Guazzo

  

126. Modified-Release Drug Delivery Technology, edited by Michael J. Rathbone,

Jonathan Hadgraft, and Michael S. Roberts 127. Simulation for Designing Clinical Trials: A Pharmacokinetic-Pharmacodynamic Modeling Perspective, edited by Hui C. Kimko and Stephen B. Duffull

128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharmaceutics,

edited by Reinhard H. H. Neubert and Hans-Hermann R € uttinger

129. Pharmaceutical Process Validation: An International Third Edition, Revised

and Expanded, edited by Robert A. Nash and Alfred H. Wachter 130. Ophthalmic Drug Delivery Systems: Second Edition, Revised and Expanded, edited by Ashim K. Mitra

131. Pharmaceutical Gene Delivery Systems, edited by Alain Rolland and Sean

M. Sullivan 132. Biomarkers in Clinical Drug Development, edited by John C. Bloom and Robert A. Dean

133. Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellassie and

Charles Martin 134. Pharmaceutical Inhalation Aerosol Technology: Second Edition, Revised and Expanded, edited by Anthony J. Hickey

135. Pharmaceutical Statistics: Practical and Clinical Applications, Fourth Edition,

Sanford Bolton and Charles Bon

136. Compliance Handbook for Pharmaceuticals, Medical Devices, and Biologics,

edited by Carmen Medina

  

137. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products:

Second Edition, Revised and Expanded, edited by Louis Rey and Joan C. May

138. Supercritical Fluid Technology for Drug Product Development, edited by

Peter York, Uday B. Kompella, and Boris Y. Shekunov 139. New Drug Approval Process: Fourth Edition, Accelerating Global Registrations, edited by Richard A. Guarino 140. Microbial Contamination Control in Parenteral Manufacturing, edited by Kevin L. Williams

141. New Drug Development: Regulatory Paradigms for Clinical Pharmacology

and Biopharmaceutics, edited by Chandrahas G. Sahajwalla 142. Microbial Contamination Control in the Pharmaceutical Industry, edited by Luis Jimenez 143. Generic Drug Product Development: Solid Oral Dosage Forms, edited by Leon Shargel and Izzy Kanfer 144. Introduction to the Pharmaceutical Regulatory Process, edited by Ira R. Berry 145. Drug Delivery to the Oral Cavity: Molecules to Market, edited by Tapash K. Ghosh and William R. Pfister 146. Good Design Practices for GMP Pharmaceutical Facilities, edited by Andrew Signore and Terry Jacobs 147. Drug Products for Clinical Trials, Second Edition, edited by Donald Monkhouse, Charles Carney, and Jim Clark 148. Polymeric Drug Delivery Systems, edited by Glen S. Kwon

  149. Injectable Dispersed Systems: Formulation, Processing, and Performance, edited by Diane J. Burgess

150. Laboratory Auditing for Quality and Regulatory Compliance, Donald Singer,

Raluca-Ioana Stefan, and Jacobus van Staden 151. Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation, edited by Stanley Nusim

152. Preclinical Drug Development, edited by Mark C. Rogge and David R. Taft

153. Pharmaceutical Stress Testing: Predicting Drug Degradation, edited by Steven W. Baertschi 154. Handbook of Pharmaceutical Granulation Technology: Second Edition, edited by Dilip M. Parikh

155. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,

Fourth Edition, edited by Robert L. Bronaugh and Howard I. Maibach

156. Pharmacogenomics: Second Edition, edited by Werner Kalow, Urs A. Meyer and Rachel F. Tyndale

157. Pharmaceutical Process Scale-Up, Second Edition, edited by Michael Levin

  159. Nanoparticle Technology for Drug Delivery, edited by Ram B. Gupta and Uday B. Kompella 160. Spectroscopy of Pharmaceutical Solids, edited by Harry G. Brittain 161. Dose Optimization in Drug Development, edited by Rajesh Krishna 162. Herbal Supplements-Drug Interactions: Scientific and Regulatory Perspectives, edited by Y. W. Francis Lam, Shiew-Mei Huang, and Stephen D. Hall 163. Pharmaceutical Photostability and Stabilization Technology, edited by Joseph T.Piechocki and Karl Thoma 164. Environmental Monitoring for Cleanrooms and Controlled Environments, edited by Anne Marie Dixon

165. Pharmaceutical Product Development: In Vitro-In Vivo Correlation, edited by

Dakshina Murthy Chilukuri, Gangadhar Sunkara, and David Young

166. Nanoparticulate Drug Delivery Systems, edited by Deepak Thassu, Michel Deleers, and Yashwant Pathak 167. Endotoxins: Pyrogens, LAL Testing and Depyrogenation, Third Edition, edited by Kevin L. Williams 168. Good Laboratory Practice Regulations, Fourth Edition, edited by Anne Sandy Weinberg

169. Good Manufacturing Practices for Pharmaceuticals, Sixth Edition, edited by

Joseph D. Nally 170. Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-soluble Drugs, edited by David J. Hauss 171. Handbook of Bioequivalence Testing, Sarfaraz K. Niazi

  

172. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes,

edited by Robert O. Williams III, David R. Taft, and Jason T. McConville 173. Clean-in-Place for Biopharmaceutical Processes, edited by Dale A. Seiberling

174. Filtration and Purification in the Biopharmaceutical Industry, Second Edition,

edited by Maik W. Jornitz and Theodore H. Meltzer 175. Protein Formulation and Delivery, Second Edition, edited by Eugene J. McNally and Jayne E. Hastedt

176. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, edited by

James McGinity and Linda A. Felton

177. Dermal Absorption and Toxicity Assessment, Second Edition, edited by

Michael S. Roberts and Kenneth A. Walters

178. Preformulation in Solid Dosage Form Development, edited by Moji

Christianah Adeyeye and Harry G. Brittain

  

Edited by

Moji Christianah Adeyeye

  

Duquesne University

Pittsburgh, Pennsylvania, USA

Harry G. Brittain

  

Center for Pharmaceutical Physics

Milford, New Jersey, USA

Preformulation in

Solid Dosage Form

  

Development Informa Healthcare USA, Inc.

  52 Vanderbilt Avenue New York, NY 10017 ª 2008 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8247-5809-9 (Hardcover) International Standard Book Number-13: 978-0-8247-5809-7 (Hardcover)

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Library of Congress Cataloging-in-Publication Data

Preformulation in solid dosage form development / edited by Moji Christianah Adeyeye,

Harry G. Brittain. p. ; cm. – (Drugs and the pharmaceutical sciences ; 178) Includes bibliographical references and index.

  ISBN-13: 978-0-8247-5809-7 (hb : alk. paper)

  ISBN-10: 0-8247-5809-9 (hb : alk. paper) 1. Solid dosage forms. 2. Drug development. 3. Pharmaceutical chemistry.

I. Adeyeye, Moji C. II. Brittain, H. G. III. Series.

  [DNLM: 1. Chemistry, Pharmaceutical. 2. Dosage Forms. 3. Pharmaceutical Preparations–chemical synthesis. W1 DR893B v.178 2008 / QV 744 P923 2008] RS201.S57P74 2008 615 .19–dc22

  2007033181 For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Ave., 16th floor, New York, NY 10017. Visit the Informa web site at www.informa.com

  

Prefaces

  I The conception of writing a book on preformulation began many years ago

  after noticing the dearth of information on characterization of chemical entities and excipients in pharmaceutical drug development while developing lecture notes for the Formulation and Development course that I teach in my school. As a teacher in the “ivory tower,” I found this intriguing, knowing that future industry scientists passing through institutions of higher learning need exposure to the basic information as well as current and relevant advances in conducting preformulation research in the industry. During the 1996 American Association of Pharmaceutical Scientists meeting, I brought this up at the preformulation focus group meeting where several colleagues volunteered to contribute chapters toward the making of the book.

  The intent of this book is to equip both academia and the pharmaceutical industry with adequate basic and applied principles important to the characterization of drugs, excipients, and products during the preformulation stage in development. The issues of predictability, identification, and product development of drug substances during the preformulation phase and into Phase I clinical trials have been addressed. The relevance of these to setting acceptance criteria (indicative of building quality into the product instead of adding quality) for regulatory purposes has been emphasized. Each chapter has been written with the industry scientist/practitioner and the regulatory authorities in mind so that the book can serve as a handbook and reference text for answering questions or problem solving.

  During the evolution of the writing process, several colleagues encouraged me and contributed toward the rationale for writing the book, and these include George Wong and Ivan Santos. I am very grateful for my co-editor, Harry G. Brittain, for his ebullience and encouragement during the making of the book.

  Moji Christianah Adeyeye iv Prefaces

  II If you ask 20 workers in the pharmaceutical field what is meant by the

  science of “preformulation,” I have no doubt that you will receive 20 different answers. To the early-stage scientist, it represents the process of characterizing a new drug substance, to learn about its properties and tendencies. Working through a pre-planned program of investigational work, scientists obtain a wide range of information. Clearly they cannot learn everything, and in fact, the time and money constraints of modern drug development often dictate that the minimal amount of work is done that will satisfy a regulatory agency. Industrial preformulation groups march through two or three compounds per month, gather the type of data they think will be of use later on, and write a report that they hope will be read by everyone who comes after them in the process.

  To the latter-stage scientist, preformulation represents the stage where someone else has profiled a drug candidate to such a degree that he or she has all the information needed to complete the development process. Unfortunately, since this worker has usually had relatively little input into the design of the preformulation studies, it is not a given that the preformulation report will contain all that is really needed. There ordinarily follows a scrambling for new information, or (worse yet) an era of trouble shooting and formulation fixing. Everyone in late-stage development under- stands that the process is inevitable, but no one has to like it.

  In the present volume, Professor Adeyeye and I have tried to outline a program of preformulation that fits better with the modern school of drug development. All of the traditional investigations are contained, but we have tried to look forward through the development process so that appropriate preformulation activities are included in the early work. We equally believe that computational prediction can play an important role in the characterization of drug compounds, and have used the term “preliminary preformulation” to cover such work. It is our hope that we have covered all the topics of importance to preformulation work, and that we have set out a program that can be successfully applied to the majority of drug candidates.

  Harry G. Brittain Contents

  Prefaces iii Contributors vii

  PART 1: INTRODUCTION

  1.1 Introduction and Overview to the Preformulation Development of Solid Dosage Forms

  1 Harry G. Brittain

  PART 2: PRELIMINARY PREFORMULATION

  2.1 Accelerating the Course of Preliminary Preformulation Through Prediction of Molecular Physical Properties and Integrated Analytical Data Management

  17 Robert S. DeWitte, Michel Hachey, and Harry G. Brittain

  2.2 Prediction of Crystallographic Characteristics 41 Stephen Spanton

  2.3 Salt Selection for Pharmaceutical Compounds 63 Sherif I. Badawy, Miriam K. Franchini, and Munir A. Hussain

  2.4 Intelligent Preformulation Design and Predictions Using Artificial Neural Networks

  81 Nkere K. Ebube

  PART 3: PROFILING THE DRUG SUBSTANCE

  3.1 Developing a Profile of the Active Pharmaceutical Ingredient 115 Harry G. Brittain

  3.2 Particle Morphology and Characterization in Preformulation 145 Alan F. Rawle

  3.3 Preparation and Identification of Polymorphs and Solvatomorphs

  185 vi Contents

  3.4 X-Ray Diffraction Methods for the Characterization of Solid Pharmaceutical Materials 229 J. R. Blache´re and Harry G. Brittain

  3.5 Spectroscopic Methods for the Characterization of Drug Substances 253 Harry G. Brittain

  3.6 Thermal Analysis and Calorimetric Methods for the Characterization of New Crystal Forms 279 Denette K. Murphy and Shelley Rabel

  3.7 Solubility Methods for the Characterization of New Crystal 323

  Forms Harry G. Brittain

  PART 4: DEVELOPMENT OF THE IDEAL FORMULATION

  4.1 Overview of the Solid Dosage Form Preformulation Program 347 Harry G. Brittain

  4.2 Drug–Excipient Interaction Occurrences During Solid Dosage Form Development 357 Moji Christianah Adeyeye

  4.3 Methodology for the Evaluation of Chemical and Physical Interactions Between Drug Substances and Excipients 437 Harry G. Brittain

  4.4 Dissolution Testing 477 George Wong and Charles C. Collins

  PART 5: BEYOND PERFORMULATION

  5.1 Structure, Content, and Format of the Preformulation Report 557 Ram N. Gidwani

  5.2 Significance of Drug Substance Physicochemical Properties in 571

  Regulatory Quality by Design Sau Lawrence Lee, Andre S. Raw, and Lawrence Yu

  Index 585

  

Contributors

  Moji Christianah Adeyeye School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania, U.S.A. Sherif I. Badawy Bristol-Myers Squibb Pharmaceutical Research Institute, New Brunswick, New Jersey, U.S.A.

  Department of Materials Science and Engineering, J. R. Blache´re University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

  Center for Pharmaceutical Physics, Milford, Harry G. Brittain New Jersey, U.S.A.

  College of Pharmacy, East Tennessee State University, Charles C. Collins Johnson City, Tennessee, U.S.A.

  Advanced Chemistry Development, Inc., Toronto, Robert S. DeWitte Ontario, Canada Nkere K. Ebube Biovail Technologies, Chantilly, Virginia, U.S.A.

  Miriam K. Franchini Sanofi-Aventis, Bridgewater, New Jersey, U.S.A. Ram N. Gidwani Pharmaceutical Consultant, Milford, New Jersey, U.S.A.

  Michel Hachey Advanced Chemistry Development, Inc., Toronto, Ontario, Canada Munir A. Hussain Bristol-Myers Squibb Pharmaceutical Research Institute, New Brunswick, New Jersey, U.S.A.

  Sau Lawrence Lee Office of Generic Drugs, United States Food and Drug Administration, Rockville, Maryland, U.S.A.

  Bristol-Myers Squibb Company, New Brunswick, Denette K. Murphy New Jersey, U.S.A.

  ALZA Corporation, Mountain View, California, U.S.A. Shelley Rabel

  Office of Generic Drugs, United States Food and Drug Andre S. Raw Administration, Rockville, Maryland, U.S.A. viii Contributors

  GPRD Structural Chemistry, Abbott Laboratories, Stephen Spanton Abbott Park, Illinois, U.S.A.

  Global R&D Operations, Johnson & Johnson, Skillman, George Wong New Jersey, U.S.A.

  Office of Generic Drugs, United States Food and Drug Lawrence Yu Administration, Rockville, Maryland, U.S.A. Part 1: Introduction

1.1 Introduction and Overview to the

  

Preformulation Development of Solid

Dosage Forms

Harry G. Brittain

Center for Pharmaceutical Physics, Milford, New Jersey, U.S.A.

  

Once an organic compound has been discovered and shown by one scientific

group to have some type of desirable pharmacological activity, it will remain

a mere curiosity unless a completely different group of scientists incorporate

the compound in a formulation that facilitates its activity. This latter group

of investigators constitutes the development effort, and it is their work that

turns an interesting compound into an actual drug substance.

  Out of the many types of formulations that could be contemplated for

a drug substance, the solid oral dose form (i.e., tablets and capsules) con-

tinues to be the most important. For this reason, the remainder of the

coverage in this volume will center on the development of solid dosage

forms, although many of the principles involved will be seen to be applicable

to other dosage forms such as liquids, suspensions, emulsions, semisolids,

suppositories, and aerosols, to name a few.

  Historically, the preformulation stage of drug development has been

considered to consist mostly of drug substance profiling, and indeed most of

the leading reviews have followed this view (1–6). However, there is far more

to the development of drug products than characterization of the active

pharmaceutical ingredient, and in its fullest incarnation, preformulation

would also extend to studies of drug–excipient compatibilities. At this point,

one could simply employ the Edisonian approach of trying all combinations

of drugs and excipients to see what would constitute an appropriate for-

2 Brittain

  

screening. Clearly, it makes more sense to develop profiles of the physical

and chemical properties of drug substances and excipients, and to then use

this information in order to develop more robust formulations.

  For example, while the degree of acidity or basicity of a substance

dissolved in an aqueous medium can be adequately defined in terms of pH,

comparable expressions for the acidity or basicity of the surface of a solid

are more complicated. Such evaluations would be of importance to a pre-

formulation study, as it is known that acidic or basic surfaces of solids can

function as catalytic agents. The a priori knowledge regarding the degree of

acidity of a surface, or the stoichiometry of binding sites, would be of great

use to formulators, and its acquisition would serve to streamline pre-

formulation studies, especially if the body of information was available for

the drug substance as well as the excipients intended for its formulation. In

the absence of such knowledge, formulators can only assume the existence of

certain characteristics of the materials they are working with, and then base

their compounding on assumptions rather than hard facts.

  The depth of the problem is extremely important, since in a dosage form,

under suitable conditions, a drug substance may undergo a variety of inter-

actions or transformations through one or more chemical or physical reac-

tions. The understanding of these solid–solid interactions is highly critical to a

successful outcome for the development process, as they can lead to the for-

mation of new impurities, incomplete mass balance, destruction of the dosage

form, and changes in physicochemical properties (stability, solubility, dis-

solution profile, degree of crystallinity, and hygroscopicity). Any or all of

these could have a most unfortunate outcome that ultimately results in an

inability to obtain successful registration of the drug substance. Hence, the

elucidation of possible chemical and/or physical reactions is an absolute

requirement to establish the stability of a given dosage form, and an under-

standing of the plausible range of solid–solid reactions available to a drug

substance should be established once a full preformulation study is completed.

  After careful evaluation of the current trends and practices in pre-

formulation, and considering where the field ought to be headed, it seemed

appropriate to define four areas of activity. These areas roughly follow the

chronological sequence of drug development and can be envisioned as

beginning with a preliminary preformulation stage, continuing with a pro-

gram of drug substance profiling and development of the ideal formulation,

and concluding with technology transfer steps.

  Preliminary preformulation can be thought of as the stage where one

may only know the identity and structure of the organic molecule that is

proposed to be a drug candidate. Information that can be deduced at this

stage is seen to be intrinsic to the drug candidate and is independent of the

perturbing influence of physical phases. However, the information can be

very valuable as a background that permits one to better understand the Preformulation Development of Solid Dosage Forms

  3 Now that the sophistication of computational programs is reaching

the point that one may calculate many of these quantities to an acceptable

degree of accuracy, one may use the structural formula of a compound to

calculate its ionization constant (S), the pH dependence of its partition

coefficient, and its aqueous solubility tendencies. Very often, this informa-

tion alone can be used to determine whether the free acid or free base form

of the compound will have sufficient properties or whether a salt form of the

substance might be more appropriate.

  As an example, consider ibuprofen (2-(4-isobutylphenyl)propanoic

acid) as a potential drug substance. The structure of the molecule is fairly

simple (given below), and one would anticipate the important physical

chemistry to be dominated by the chemistry of the carboxylate group. Using

the PhysChem program [sourced from Advanced Chemistry Development

(ACD)], the pK a value of the carboxylate group can be calculated to be

4.41 – 0.01. Although this pK a value is not exactly equal to the reported

ionization constant that was determined to be in the range of 4.5 to 4.6 by

potentiometric titration in mixed organic/aqueous solvent systems (7), the

number is sufficiently close to reality so that it may be used to deduce other

important properties of the molecule.

  CH ₃ O CH ₃ OH H C ₃ The next step in the computational process would be to calculate the

partition coefficient and the pH dependence of the distribution coefficient.

  

For ibuprofen, the ACD program calculates the octanol/water partition

coefficient to be log P ¼ 3.72 – 0.23, indicating that the compound is

expected to be substantially hydrophobic in its neutral form. As might be

anticipated, the carboxylate group of ibuprofen yields a strong pH depen-

dence in the distribution coefficient, as shown in Figure 1. The calculation

indicates that while ibuprofen is predicted to be hydrophobic at low pH, it is

also predicted to be hydrophilic at high pH once the carboxylate group

becomes ionized.

  It is a fundamental precept of solubility theory that hydrophilic

compounds should exhibit good solubility in aqueous media. As shown in

Figure 2, the calculated pH dependence of solubility is consistent with

this prediction, with the compound being predicted to be highly soluble

above pH 7.

  By performing these simple calculations, one would reach the con-

4 Brittain

  4

  3

2 Calculated log D

  1

  2

  4

  6

  8

  10

  12

  14

pH

Figure 1 pH dependence of the distribution coefficient of ibuprofen, calculated

using the PhysChem program from Advanced Chemistry Development.

maximize its aqueous solubility. If this decision was made, then the next step

would entail prediction of an appropriate salt form. Fortunately, the ioni-

zation constants for potential salt formers can be calculated with relative

₊

ease. It is relatively easy to show that for the reaction of ibuprofen free acid

(H-ibu) with a basic substance (B) to yield the salt (HB )(ibu ),

  þ H-ibu þ B Ð HB þ ibu ð1Þ the value for the salt formation constant (K s ),

  þ ½ibu Š½HB Š K

  ¼ ð2Þ s

  ½H-ibuŠ½BŠ is given by (8) Preformulation Development of Solid Dosage Forms

  5 300 225 bility (mg/mL) u

  150 lated sol u Calc

  75

  2

  4

  6

  8

  10

  12

  14

pH

  

Figure 2 pH dependence of the aqueous solubility of ibuprofen, calculated using the

PhysChem program from Advanced Chemistry Development.

  In Equation 3, K is the ionization constant expression for the free _a

acid, K is the ionization constant expression for the free base, and K is the

_{b w}

autoionization constant of water. When converted to the Sørensen scale, Eq.

  3 becomes pK ¼ pK þ pK pK ð4Þ s a b w