Formulation, Processing, and Performance

DRUGS AND THE PHARMACEUTICAL SCIENCES Executive Editor

James Swarbrick

PharmaceuTech, Inc. Pinehurst, North Carolina

Advisory Board

Larry L. Augsburger Harry G. Brittain University of Maryland

Center for Pharmaceutical Physics Baltimore, Maryland

Milford, New Jersey Jennifer B. Dressman

Anthony J. Hickey Johann Wolfgang Goethe University

University of North Carolina School of Frankfurt, Germany

Pharmacy Chapel Hill, North Carolina

Jeffrey A. Hughes University of Florida College of

Ajaz Hussain

U.S. Food and Drug Administration Gainesville, Florida

Pharmacy

Frederick, Maryland Trevor M. Jones

Hans E. Junginger The Association of the

Leiden/Amsterdam Center British Pharmaceutical Industry

for Drug Research London, United Kingdom

Leiden, The Netherlands Vincent H. L. Lee

Stephen G. Schulman University of Southern California

University of Florida Los Angeles, California

Gainesville, Florida Jerome P. Skelly

Elizabeth M. Topp Alexandria, Virginia

University of Kansas School of Pharmacy

Geoffrey T. Tucker Lawrence, Kansas University of Sheffield

Royal Hallamshire Hospital Peter York Sheffield, United Kingdom

University of Bradford School of Pharmacy Bradford, United Kingdom

DRUGS AND THE PHARMACEUTICAL SCIENCES

A Series of Textbooks and Monographs

1. Pharmacokinetics, Milo Gibaldi and Donald Perrier 2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total

Quality Control, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV

3. Microencapsulation, edited by J. R. Nixon 4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa

and Peter Jenner 5. New Drugs: Discovery and Development, edited by Alan A. Rubin 6. Sustained and Controlled Release Drug Delivery Systems,

edited by Joseph R. Robinson 7. Modern Pharmaceutics, edited by Gilbert S. Banker

and Christopher T. Rhodes 8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz 9. Activated Charcoal: Antidotal and Other Medical Uses, David O. Cooney

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

and Bernard Testa 11. Pharmaceutical Analysis: Modern Methods (in two parts),

edited by James W. Munson 12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky 13. Orphan Drugs, edited by Fred E. Karch 14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts,

Biomedical Assessments, Yie W. Chien 15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo Gibaldi

and Donald Perrier 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

17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger 18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry 19. The Clinical Research Process in the Pharmaceutical Industry,

edited by Gary M. Matoren 20. Microencapsulation and Related Drug Processes, Patrick B. Deasy 21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe

and T. Colin Campbell 22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme 23. Pharmaceutical Process Validation, edited by Bernard T. Loftus

and Robert A. Nash

24. Anticancer and Interferon Agents: Synthesis and Properties, edited by Raphael M. Ottenbrite and George B. Butler

25. Pharmaceutical Statistics: Practical and Clinical Applications, Sanford Bolton

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, Francis L. S. Tse, and Shrikant V. Dinghe

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 Jörg 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 Göran Alderborn and Christer Nyström

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

74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone 75. Clinical Research in Pharmaceutical Development, edited by Barry Bleidt

and Michael Montagne 76. The Drug Development Process: Increasing Efficiency and Cost

Effectiveness, edited by Peter G. Welling, Louis Lasagna, and Umesh V. Banakar

77. Microparticulate Systems for the Delivery of Proteins and Vaccines, edited by Smadar Cohen and Howard Bernstein

78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Fourth Edition, Revised and Expanded, Sidney H. Willig and James R. Stoker

79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms:

Second Edition, Revised and Expanded, edited by James W. McGinity 80. Pharmaceutical Statistics: Practical and Clinical Applications,

Third Edition, Sanford Bolton 81. Handbook of Pharmaceutical Granulation Technology, edited by

Dilip M. Parikh 82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded,

edited by William R. Strohl 83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts

and Richard H. Guy 84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpé 85. Development of Biopharmaceutical Parenteral Dosage Forms,

edited by John A. Bontempo 86. Pharmaceutical Project Management, edited by Tony Kennedy 87. Drug Products for Clinical Trials: An International Guide to Formulation •

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

88. Development and Formulation of Veterinary Dosage Forms: Second

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

89. Receptor-Based Drug Design, edited by Paul Leff 90. Automation and Validation of Information in Pharmaceutical Processing,

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

and Kenneth A. Walters

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

and Roger Phan-Tan-Luu 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 Lennernäs 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

115. Drug Targeting Technology: Physical • Chemical • Biological Methods, edited by Hans Schreier

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 Rüttinger

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

Injectable Dispersed Systems

Formulation, Processing, and Performance

Diane J. Burgess

University of Connecticut Storrs-Mansfield, Connecticut, U.S.A.

Boca Raton London New York Singapore

Published in 2005 by Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742

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International Standard Book Number-10: 0-8493-3699-6 (Hardcover) International Standard Book Number-13: 978-0-8493-3699-7 (Hardcover)

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This book is dedicated to my parents Violet Isabel Burgess and George Gartly Burgess.

Preface

With the increasing number of biopharmaceutical products, the emerging market for gene therapeutics, and the high proportion of small molecule new drug candidates that have very poor solubility, the need for parenteral dispersed system pharmaceuticals is growing rapidly. This book serves as a current in-depth text for the design and manufacturing of parenteral dispersed systems. The fundamental physicochem- ical and biopharmaceutical principles governing dispersed systems are covered together with design, processing, product performance, characterization, quality assurance, and regula- tory concerns. A unique and critically important element of this work is the inclusion of practical case studies together with didactic discussions. This approach allows the illustra- tion of the application of dispersed systems technology to current formulation and processing problems and, therefore, this will be a useful reference text for industrial research and development scientists and will help them in making choices of appropriate dosage forms and consequent formula- tion strategies for these dosage forms. Quality control and With the increasing number of biopharmaceutical products, the emerging market for gene therapeutics, and the high proportion of small molecule new drug candidates that have very poor solubility, the need for parenteral dispersed system pharmaceuticals is growing rapidly. This book serves as a current in-depth text for the design and manufacturing of parenteral dispersed systems. The fundamental physicochem- ical and biopharmaceutical principles governing dispersed systems are covered together with design, processing, product performance, characterization, quality assurance, and regula- tory concerns. A unique and critically important element of this work is the inclusion of practical case studies together with didactic discussions. This approach allows the illustra- tion of the application of dispersed systems technology to current formulation and processing problems and, therefore, this will be a useful reference text for industrial research and development scientists and will help them in making choices of appropriate dosage forms and consequent formula- tion strategies for these dosage forms. Quality control and

assurance as well as regulatory aspects that are essential to parenteral dispersed system product development are dis- cussed in detail. This book also tackles current issues of in vitro testing of controlled release parenterals as well as the development of in vitro and in vivo relationships for these dosage forms.

This work is equally relevant to industrial and academic pharmaceutical scientists. The text is written in a way that the different chapters and case studies can be read indepen- dently, although the reader is often referred to other sections of the book for more in-depth information on specific topics. The case studies provide the reader with real problems that have been faced and solved by pharmaceutical scientists and serve as excellent examples for industrial scientists as well as for academics. This text will not only serve as a prac- tical guide for pharmaceutical scientists involved in the research and development of parenteral dosage forms, but will also be a resource for scientists new to this field. The fun- damental aspects together with the practical case studies make this an excellent textbook for graduate education.

The book is laid out as follows: Section (I) Basic Princi- ples; Section (II) Dosage Forms; Section (III) Case Studies; and Section (IV) Quality Assurance and Regulation. The basic principles section includes physicochemical and biopharma- ceutical principles, characterization and analysis and in vitro and in vivo release testing and correlation of in vitro and in vivo release data. The dosage forms covered in Section II are suspensions, emulsions, liposomes, and microspheres. These chapters detail design and manufacturing and a ratio- nale for selection as well as any specific considerations for the individual parenteral dosage forms. Some formulation and processing aspects are common to all dosage forms and these are discussed in the basic principles chapters or the reader is referred to the appropriate chapter or case study. The dosage form chapters are followed by a case study section where nine case studies are presented that address: biopharmaceutical aspects of controlled release parenteral dosage forms; liposome formulation, design and product development; emul- sion formulation, scale up and sterilization; microspheres

Preface vii

formulation and processing as well as microsphere in vitro and in vivo release studies; and development and scale up of a nanocrystalline suspension. The final section of the book covers quality assurance and regulatory aspects as well as an FDA perspective.

Diane J. Burgess

Contents

Preface . . . . v Acknowledgments . . . . xvii Contributors . . . . xix

SECTION I: Basic Principles

1. Physical Stability of Dispersed Systems . . . . . . 1 Diane J. Burgess

1. Introduction and Theory . . . . 1

2. Colloid and Interfacial Chemistry . . . . 2

3. Thermodynamics of Dispersed Systems . . . . 10

References . . . . 34

2. Biopharmaceutical Principles of Injectable Dispersed Systems . . . . . . . . . . . . . . . . . . . . . . . 39

C. Oussoren, H. Talsma, J. Zuidema, and F. Kadir

1. Introduction . . . . 39

2. Drug Absorption from Conventional Formulations . . . . 42

3. Drug Absorption from Drug Carrier Systems . . . . 49

ix ix

4. Factors Influencing Drug Absorption . . . . 55

5. Carrier Kinetics and Targeting . . . . 60

6. Tissue Protective Effect of Dispersed Systems . . . . 63

7. Summary . . . . 65 References . . . . 66

3. Characterization and Analysis of Dispersed Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Jim Jiao and Diane J. Burgess

1. Introduction . . . . 77

2. Particle Size Measurement . . . . 79

3. Zeta Potential . . . . 97

4. Rheology . . . . 107

5. Conclusions . . . . 116 References . . . . 116

4. In Vitro =In Vivo Release from Injectable Dispersed Systems . . . . . . . . . . . . . . . . . . . . . . . 125 Brian C. Clark, Paul A. Dickinson, and Ian T. Pyrah

1. In Vitro Release . . . . 125

2. Data Manipulation . . . . 139

3. In Vivo Release . . . . 142

4. Bioanalysis . . . . 149

5. Injectability . . . . 150

6. Conclusions . . . . 151 References . . . . 153

5. In Vitro =In Vivo Correlation for Modified Release Injectable Drug Delivery Systems . . . . . . . . . . 159 David Young, Colm Farrell, and Theresa Shepard

1. Introduction . . . . 159

2. A General Approach to Developing a Level A IVIVC . . . . 161

3. Issues Related to Developing an IVIVC

for Modified Release Parental Drug Delivery Systems . . . . 166

4. Conclusion . . . . 174 References . . . . 175

Contents xi

SECTION II: Dosage Forms

6. Coarse Suspensions: Design and Manufacturing . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Steven L. Nail and Mary P. Stickelmeyer

1. Introduction . . . . 177

2. Preparation and Characterization of the Drug . . . . 180

3. Biopharmaceutical Considerations . . . . 184

4. Physical Stability of Coarse Suspensions . . . . 191

5. Formulation of Parenteral Suspensions . . . . 197

6. Manufacture of Parenteral Coarse Suspensions . . . . 203

7. Evaluation of Product Quality . . . . 208

8. Conclusion . . . . 209 References . . . . 210

7. Emulsions: Design and Manufacturing . . . . . . 213 N. Chidambaram and Diane J. Burgess

1. Introduction . . . . 213

2. Manufacturing and Process Conditions . . . . 232

3. Lyophilization of Emulsions . . . . 239

4. Conclusions . . . . 240 References . . . . 241

8. Liposomes: Design and Manufacturing . . . . . . 249 Siddhesh D. Patil and Diane J. Burgess

1. Introduction . . . . 249

2. Liposomes: Definitions and Classes . . . . 250

3. Versatility of Drugs Delivered Using Liposomes . . . . 251

4. Advantages of Liposomal Delivery Systems . . . . 256

5. Liposome Composition: Choice of Lipids . . . . 260

6. Manufacture of Liposomes . . . . 265

7. Liposome Drug Encapsulation Techniques . . . . 271

8. Liposome Characterization and Compendial Requirements . . . . 275 8. Liposome Characterization and Compendial Requirements . . . . 275

9. Conclusions . . . . 283 References . . . . 284

9. Microspheres: Design and Manufacturing . . . 305 Diane J. Burgess and Anthony J. Hickey

1. Introduction . . . . 306

2. Microsphere Dispersions: Methods and Characterization . . . . 312

3. Tissue Targeting . . . . 325

4. Targeting Diseases . . . . 326

5. Commercial Prospects . . . . 326

6. Conclusions . . . . 338 References . . . . 339

SECTION III: Case Studies

10. Case Study: Development and Scale-Up of NanoCrystal Õ Particles . . . . . . . . . . . . . . . . . . . 355

Robert W. Lee

1. Introduction . . . . 355

2. Pharmaceutics . . . . 358

3. Formulation Development . . . . 360

4. Pharmacokinetics/Pharmacodynamics . . . . 363

5. Manufacturing Process . . . . 366

6. Scale-Up . . . . 366

7. Summary . . . . 369 Reference . . . . 370

11. Case Study: Formulation Development and Scale-Up Production of an Injectable Perfluorocarbon Emulsion . . . . . . . . . . . . . . . . 371 Robert T. Lyons

1. Introduction . . . . 371

2. Formulation Development . . . . 374

3. Process Optimization . . . . 379

4. Process Scale-Up . . . . 387

5. Conclusions . . . . 390 References . . . . 391

Contents xiii

12. Case Study: A Lipid Emulsion— Sterilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 Thomas Berger

1. Outline . . . . 393

2. Introduction . . . . 394

3. R&D Area . . . . 395

4. Production Environment . . . . 405

5. Regulatory Submission . . . . 409 References . . . . 412

13. Case Study: Formulation of an Intravenous Fat Emulsion . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 Bernie Mikrut

4. Filling/Packaging . . . . 422

5. Stability Evaluation . . . . 422 References . . . . 424

14. Case Study: DOXIL, the Development of Pegylated Liposomal Doxorubicin . . . . . . . . . . . . . . . . . . . 427 Frank J. Martin

1. Introduction . . . . 427

2. Background . . . . 428

3. Define Problem . . . . 429

4. Solutions to Problem: DOXIL (Pegylated Liposomal Doxorubicin) . . . . 435

5. Conclusions and Perspectives . . . . 469 References . . . . 472

15. Case Study: AmBisome—A Developmental Case

Study of a Liposomal Formulation of the Antifungal Agent Amphotericin B . . . . . . . . . . . . . . . . . . . . 481 Jill P. Adler-Moore and Richard T. Proffitt

1. Definition of the Problem . . . . 481

2. Overview of Amphotericin B/Lipid Formulations . . . . 484

3. Development of Ambisome Formulation . . . . 485 3. Development of Ambisome Formulation . . . . 485

4. Summary . . . . 514 References . . . . 515

16. Case Study: Optimization of a Liposomal Formulation with Respect to Tissue Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527 Gayle A. Brazeau

1. Introduction . . . . 527

2. Liposomal Formulations and Intramuscular Injections . . . . 530

3. Intramuscular Loxapine Formulation . . . . 530

4. Study Objectives . . . . 531

5. In Vitro Liposomal Myotoxicity Studies . . . . 532

6. Loxapine Liposomal Formulations and In Vitro

Myotoxicity Studies . . . . 534

7. In Vivo Myotoxicity of a Loxapine Liposomal Formulation . . . . 537

8. Concluding Remarks . . . . 540 References . . . . 541

17. Case Study: In Vitro/In Vivo Release from Injectable Microspheres . . . . . . . . . . . . . . . . . . 543 Brian C. Clark, Paul A. Dickinson, and Ian T. Pyrah

1. Introduction . . . . 543

2. In Vitro Studies . . . . 544

3. In Vivo Study . . . . 560

4. Conclusions . . . . 570 Reference . . . . 570

18. Case Study: Biodegradable Microspheres for the

Sustained Release of Proteins . . . . . . . . . . . . . 571 Mark A. Tracy

1. Introduction . . . . 571

2. Guideline #1: Minimize Molecular Mobility to

Maximize Stability . . . . 572

3. Guideline #2: Understand the Role of Particle

Structure and Morphology in Product Function and Stability . . . . 576

4. Conclusions . . . . 579 References . . . . 579

Contents xv

SECTION IV: Quality Assurance and Regulation

19. Injectable Dispersed Systems: Quality and Regulatory Considerations . . . . . . . . . . . . . . . . 583 James P. Simpson and Michael J. Akers

1. Introduction and Scope . . . . 583

2. Regulatory Requirements . . . . 584

3. Quality During the Product Development Phase . . . . 591

4. Raw Materials . . . . 598

5. Scale Up and Unit Processing . . . . 602

6. Finished Product Considerations . . . . 602

7. Summary . . . . 616 References . . . . 616 Appendix 1. ICH Guidelines . . . . 617

20. Regulatory Considerations for Controlled Release Parenteral Drug Products: Liposomes and Microspheres . . . . . . . . . . . . . . . . . . . . . . . . . . . 621 Mei-Ling Chen

1. Introduction . . . . 621

2. Liposomes . . . . 622

3. Microspheres . . . . 631 References . . . . 640

Acknowledgments

I wish to express my sincere gratitude to all the contributors to this work. Their patience and perseverance throughout this process is greatly appreciated. I wish to acknowledge Dr. Paula Jo Stout who was involved in the initial stages of the writing of this book. I would also like to say a big thank you to Mr. Jean-Louis Raton who encouraged me to make it to the finish line and always with a big smile.

xvii

Contributors

Jill P. Adler-Moore Department of Biological Sciences, California State Polytechnic University–Pomona, Pomona, California, U.S.A.

Michael J. Akers Pharmaceutical Research and Development, Baxter Pharmaceutical Solutions LLC, Bloomington, Indiana, U.S.A.

Thomas Berger Pharmaceutical Research & Development, Hospira, Inc., Lake Forest, Illinois, U.S.A.

Gayle A. Brazeau Departments of Pharmacy Practice and Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, U.S.A.

Diane J. Burgess Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, U.S.A.

xix xix

Mei-Ling Chen Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland, U.S.A.

N. Chidambaram Senior Scientist, Research & Development, Banner Pharmacaps Inc., High Point, North Carolina, U.S.A.

Brian C. Clark Pharmaceutical and Analytical R&D, AstraZeneca, Macclesfield, U.K.

Paul A. Dickinson Pharmaceutical and Analytical R&D, AstraZeneca, Macclesfield, U.K.

Colm Farrell GloboMax Division of ICON plc, Hanover, Maryland, U.S.A.

Anthony J. Hickey School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, U.S.A.

Jim Jiao Pharmaceutical Research and Development, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut, U.S.A.

F. Kadir Postacademic Education for Pharmacists, Bunnik, Utrecht, The Netherlands

Robert W. Lee Elan Drug Delivery, Inc., King of Prussia, Pennsylvania, U.S.A.

Robert T. Lyons Allergan, Inc., Irvine, California, U.S.A. Frank J. Martin ALZA Corporation, Mountain View,

California, U.S.A. Bernie Mikrut Pharmaceutical Research & Development,

Hospira, Inc., Lake Forest, Illinois, U.S.A. Steven L. Nail Lilly Research Labs, Lilly Corporate

Center, Indianapolis, Indiana, U.S.A.

Contributors xxi

C. Oussoren Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands

Siddhesh D. Patil Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, U.S.A.

Richard T. Proffitt RichPro Associates, Lincoln, California, U.S.A.

Ian T. Pyrah Safety Assessment, AstraZeneca, Macclesfield, U.K.

Theresa Shepard GloboMax Division of ICON plc, Hanover, Maryland, U.S.A.

James P. Simpson Regulatory and Government Affairs, Zimmer, Inc., Warsaw, Indiana, U.S.A.

Mary P. Stickelmeyer Lilly Research Labs, Lilly Corporate Center, Indianapolis, Indiana, U.S.A.

H. Talsma Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands

Mark A. Tracy Formulation Development, Alkermes, Inc., Cambridge, Massachusetts, U.S.A.

David Young GloboMax Division of ICON plc, Hanover, Maryland, U.S.A.

J. Zuidema Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands

SECTION I: BASIC PRINCIPLES

Physical Stability of Dispersed Systems

DIANE J. BURGESS Department of Pharmaceutical Sciences,

School of Pharmacy, University of Connecticut, Storrs, Connecticut, U.S.A.

1. INTRODUCTION AND THEORY Injectable dispersed systems (emulsions, suspensions, lipo-

somes, and microspheres) have unique properties, that are related to their size, interfacial area, and dispersion state. The physicochemical principles governing their behavior include thermodynamics, interfacial chemistry, and mass transport. The stability of these dosage forms is a major issue and is a function of thermodynamics, interfacial chemistry, and particle size. Drug release from such systems is governed by mass transport principles, interfacial chemistry, and size.

2 Burgess

Principles of thermodynamics and interfacial chemistry as applied to dispersed systems are detailed in this chapter. Although the principles of particle size are discussed here, they are reviewed in greater detail in the chapter by Jiao and Burgess on characterization. Due to the unique factors asso- ciated with release of drugs from the different dispersed sys- tem dosage forms mass transport issues are addressed in the individual dosage form (suspensions, emulsions, liposomes, and microspheres) chapters.

Injectable dispersed systems are often colloidal in nature and therefore the principles of colloidal chemistry are also reviewed here. Dispersed systems for intravenous (i.v.) admini- stration are almost always colloids, since their particle size is restricted to blockage that can occur with larger particles. Dispersed sys- tems administered via other parenteral routes can be much lar- ger and their size is restricted by performance criteria (such as drug release rates, biopharmaceutical considerations, and potential for irritation) and needle size (larger needles are required for larger particles and can result in more painful injections).

2. COLLOID AND INTERFACIAL CHEMISTRY Colloids are systems containing at least two components, in

any state of matter, one dispersed in the other, in which the dispersed component consists of large molecules or small particles. These systems possess characteristic properties that are related mainly to the dimensions of the dispersed phase. The colloidal size range is approximately 1 nm to

1 mm and is set by the following lower and upper limits: The particles or molecules must be large relative to the mole- cular dimensions of the dispersion media so that the disper- sion media can be assigned continuous properties; and they must be sufficiently small so that thermal forces dominate gravitational forces and they remain suspended. To qualify as a colloid, only one of the dimensions of the particles must

be within this size range. For example, colloidal behavior is observed in fibers in which only two dimensions are in the

Physical Stability of Dispersed Systems 3

colloidal size range. There are no sharp boundaries between colloidal and non-colloidal systems, especially at the upper size range. For example, an emulsion system may display col- loidal properties, yet the average droplet size may be larger than 1 mm.

2.1. Classification of Colloids Based on interaction between the dispersed and continuous

phases, colloidal systems are classified into three groups: (i) lyophilic or solvent ‘‘loving’’ colloids, the dispersed phase is dissolved in the continuous phase; (ii) lyophobic or solvent ‘‘hating’’ colloids, the dispersed phase is insoluble in the con- tinuous phase; and (iii) association colloids, the dispersed phase molecules are soluble in the continuous phase and spontaneously ‘‘self-assemble’’ or ‘‘associate’’ to form aggre- gates in the colloidal size range.

This book focuses mainly on lyophobic systems: emulsions, suspensions, and microspheres. Liposomes may

be classified as association colloids, although larger liposomes can be outside the colloidal range. In some instances, lipo- somes are surface-treated and =or polymerized rendering them irreversible; they are then considered lyophobic colloids. Often, lyophobic nanospheres, microspheres, liposomes, and emulsions are surface-treated with hydrophilic polymers to improve their stability and =or to avoid=delay interaction with the reticular endothelial system following i.v. injection.

2.1.1. Lyophilic Colloids The dispersed phase usually consists of soluble macromole-

cules, such as proteins and carbohydrates. These are true solutions and are best treated as a single phase system from

a thermodynamic viewpoint. The dispersed phase has a sig- nificant contribution to the properties of the dispersion med- ium and introduces an extra degree of freedom to the system. Lyophilic colloidal solutions are thermodynamically stable and form spontaneously on adding the solute to the solvent. There is a reduction in the Gibbs free energy (DG) on disper- sion of a lyophilic colloid. DG is related to the interfacial

4 Burgess

area (A), the interfacial tension (g), and the entropy of the system (DS):

DG where T is the absolute temperature.

The solute =solvent interaction is usually sufficient to break up the dispersed phase. In addition, there is an increase in the entropy of the solute on dispersion and this is generally greater than any decrease in solvent entropy. The interfacial tension (g) is negligible if the solute has a high affinity for the solvent; thus, the gDA term approxi- mates zero. The shape of macromolecular colloids will vary depending on their affinity for the solvent. The shape of these therapeutics is important as it can affect their activ- ity. Proteins will take on elongated configurations in sol- vents for which they have a high affinity and will tend to decrease their total area of contact with solvents for which they have little affinity. Since the molecular dimensions of protein molecules are large compared to those of the solvent, the pro- tein effectively has an ‘‘interface’’ with the solvent. Proteins contain both hydrophilic and hydrophobic moieties and conse- quently shape changes can result in different moieties being exposed to the solvent. Following from this are physical instability and aggregation problems associated with protein solutions. The use of a solvent for which the protein has a high affinity can reduce these problems, as can the addition of sur- factants that adsorb onto the protein and thus alter its ‘‘inter- face’’ with and affinity for the solvent. (Refer to Sec. 3 in this Chapter.)

2.1.2. Lyophobic Colloids The dispersed phase consists of tiny particles that are distrib-

uted more or less uniformly throughout the solvent. The dispersed phase and the dispersion medium may consist of solids, liquids, or gases and are two-phase or multiphase systems with a distinct interfacial region. As a consequence of poor dispersed phase–dispersion media interactions,

Physical Stability of Dispersed Systems 5

lyophobic colloids are thermodynamically unstable and tend to aggregate. The DG increases when a lyophobic material is dispersed and the greater the extent of dispersion, the greater the total surface area exposed, and, hence, the greater the increase in the free energy of the system. When a particle is broken down, work is required to separate the pieces against the forces of attraction between them (DW). The resultant increase in free energy is proportional to the area of new surface created (A):

DG ¼ DW ¼ 2gA Molecules that were originally bulk molecules become surface

molecules and take on different configurations and energies. An increase in free energy arises from the difference between the intermolecular forces experienced by surface and bulk molecules. Lyophobic colloids are aggregatively unstable and can remain dispersed in a medium only if the surface is treated to cause a strong repulsion between the particles. Such treated colloids are thermodynamically unstable yet are kinetically stable since aggregation can be prevented for long periods.

Emulsions Emulsion systems can be considered a subcategory of

lyophobic colloids. Their preparation requires an energy input, such as ultrasonication, homogenization, or high-speed stirring. The droplets formed are spherical, provided that the interfacial tension is positive and sufficiently large. Sponta- neous emulsification may occur if a surfactant or surfactant system is present at a sufficient concentration to lower the interfacial tension almost to zero. Spontaneously forming emulsions usually have very small particle size ( <100 nm) and are referred to as microemulsions.

2.1.3. Association Colloids Association colloids are aggregates or ‘‘associations’’ of amphi-

pathic surfactant molecules. Surfactants are soluble in the solvent, and their molecular dimensions are below the

6 Burgess

Figure 1 Different types of association colloids (micelles): a) sphe- rical micelle; b) disc-shaped micelle; c) cylindrical micelle; d) micro- tubular micelle; e) lipid soluble drug in a swollen micelle; f) inverted micelle.

colloidal size range. However, when present in solution at concentrations above the critical micelle concentration, these molecules tend to form association colloids (also known as micelles) (Fig. 1). Surfactants have a region that has a high affinity for the medium (lyophilic), and a region that has a low affinity for the medium (lyophobic). These molecules adsorb at interfaces to reduce the energy between their lyophobic region(s) and the medium. On micellization, the

Physical Stability of Dispersed Systems 7

surfactants associate such that their lyophobic regions are in the interior, their lyophilic regions are at the surface, and the solvent is excluded from the hydrophobic core. Not all surfactants form micelles since a subtle balance between the lyophilic and lyophobic portions of the surfactant molecule is required. A charged, zwitterionic, or bulky oxygen-containing hydrophilic group is required to form micelles in aqueous media (1). These moieties are able to undergo significant hydro- gen bonding and dipole interactions with water to stabilize the micelles. Micelle formation in strongly hydrogen-bonded solvents is very similar to that in water (1). Micellization occurs spontaneously, depending on the lyophilic–lyophobic balance of the surfactant, surfactant concentration, and temperature.

At room temperature, micellization of surfactants in aqu- eous media is driven by entropy. The hydrophobic part of the surfactants induces a degree of structuring of water, which disturbs the hydrogen bond pattern and causes a significant decrease in the entropy of the water. This is known as the ‘‘hydrophobic’’ effect. The effect of temperature and pressure on micellization is dependent on surfactant properties (1,2). Ionic surfactants generally exhibit a ‘‘Krafft’’ point. In these systems, micelles form only at temperatures above a certain critical temperature, the Krafft temperature. This is a conse- quence of a marked increase in surfactant solubility at this temperature, whereas, non-ionic surfactants tend to aggre- gate and phase separate above a certain temperature (the cloud point) (3).

Micellar shape ( Fig. 1 ) is concentration dependent. At low concentrations, micelles are usually spherical with well- defined aggregation numbers, and are monodisperse. At high concentrations, micellar shape becomes distorted and cylindri- cal rods or flattened discs form (4). At very high concentrations, the surfactants arrange as liquid crystals (5–7). Surfactants can also form two-dimensional membranes or bilayers separat- ing two aqueous regions under specific conditions. If this bilayer is continuous and encloses an aqueous region, then vesicles result, which are known as liposomes. Micelles are used pharmaceutically to solubilize insoluble drug substances. The drug is solubilized within the micellar core (Fig. 1).

8 Burgess

Micellar solubilization allows the preparation of water-insolu- ble drugs within aqueous vehicles (8). This is advantageous, particularly for i.v. delivery of water-insoluble drugs. Entrap- ment within a micellar system may increase the stability of poorly stable drug substances and can enhance drug bioavail- ability (9). Liposomes can have hydrophobic and hydrophilic regions and therefore can be used to solubilize both water solu- ble and water insoluble drugs.

2.2. Properties of Colloids Characteristic properties of colloids include: particle size and

shape, scattering of radiation, and kinetic properties.

2.2.1. Particle Size and Shape The colloidal size range is approximately 1 nm to 1 mm and

most colloidal systems are heterodisperse. Solid dispersions usually consist of particles of very irregular shape. Particles produced by dispersion methods have shapes that depend partly on the natural cleavage planes of the crystals and partly on any points of weakness (imperfections) within the crystals. The shape of solid dispersions produced by condensation methods depends on the rate of growth of the different crystal faces. Treatments of particle shape are given by Beddow (10), Allen (11), and Shutton (12). Both liquid and solid dispersions often have wide size distribu- tions. (Refer to the chapters by Chidambaram and Burgess and by Nail and Stickelmeyer in this book for methods of preparation of liquid and solid dispersions, respectively. Refer to the chapter by Jiao and Burgess for details on particle size analysis.)

2.2.2. Scattering of Radiation The scattering of a narrow beam of light by a colloidal system

to form a visible cone of scattered light is known as the Faraday–Tyndall effect. The reader is referred to the text of Heimenz (13) for a full account of light scattering by colloidal systems. Electromagnetic radiation induces oscillating dipoles

Physical Stability of Dispersed Systems 9

in the material and these act as secondary sources of emission of scattered radiation. The scattered light has the same wavelength (l) as the incident light. The intensity of the scat- tered light depends on the intensity of the original light, the polarizability of the material, the size and shape of the mate- rial, and the angle of observation. The scattering intensity increases with increase in particle radius, reaching a maxi- mum, and then decreasing. This maximum in scattering inten- sity coincides with the colloidal size range. Small particles (l =20 In larger particles, different regions of the same particle may behave as scattering centers and these multiple scattering cen- ters interfere with one another, either constructively or destructively. As particle size increases, the number of scatter- ing centers increases, and the resultant destructive interfer- ence causes a reduction in the intensity of the scattered light.

2.2.3 Kinetic Properties The kinetic properties of colloids are characterized by slow

diffusion and usually negligible sedimentation under gravity.

2.3. Thermal Motion Colloidal particles display a zigzag-type movement as a