Handbook of Pharmaceutical Granulation Technology doc

Handbook of Pharmaceutical
Granulation Technology
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© 2005 by Taylor & Francis Group, LLC
DRUGS AND THE PHARMACEUTICAL SCIENCES
Executive Editor
James Swarbrick
PharmaceuTech, Inc.
Pinehurst, North Carolina
Advisory Board
Larry L. Augsburger
University of Maryland
Baltimore, Maryland
Jennifer B. Dressman
Johann Wolfgang Goethe University
Frankfurt, Germany
Jeffrey A. Hughes
University of Florida College of
Pharmacy
Gainesville, Florida
Trevor M. Jones
The Association of the
British Pharmaceutical Industry
London, United Kingdom
Vincent H. L. Lee
University of Southern California
Los Angeles, California
Jerome P. Skelly
Alexandria, Virginia
Geoffrey T. Tucker
University of Sheffield

Royal Hallamshire Hospital
Sheffield, United Kingdom
Harry G. Brittain
Center for Pharmaceutical Physics
Milford, New Jersey
Anthony J. Hickey
University of North Carolina School of
Pharmacy
Chapel Hill, North Carolina
Ajaz Hussain
U.S. Food and Drug Administration
Frederick, Maryland
Hans E. Junginger
Leiden/Amsterdam Center
for Drug Research
Leiden, The Netherlands
Stephen G. Schulman
University of Florida
Gainesville, Florida
Elizabeth M. Topp
University of Kansas School of
Pharmacy
Lawrence, Kansas
Peter York
University of Bradford School of
Pharmacy
Bradford, United Kingdom
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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
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© 2005 by Taylor & Francis Group, LLC

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
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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
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© 2005 by Taylor & Francis Group, LLC
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
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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
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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
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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 H. Nusim
152. Preclinical Drug Development,
edited by Mark C. Rogge and David 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
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© 2005 by Taylor & Francis Group, LLC
Handbook of Pharmaceutical
Granulation Technology

Second Edition
edited by
Dilip M. Parikh
Synthon Pharmaceuticals Inc.
Research Triangle Park, North Carolina, U.S.A.
Boca Raton London New York Singapore
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© 2005 by Taylor & Francis Group, LLC
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© 2005 by Taylor & Francis Group, LLC
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© 2005 by Taylor & Francis Group, LLC
Do not follow where the path may lead. Go instead where there is
no path and leave a trail.
— Ralph Waldo Emerson
© 2005 by Taylor & Francis Group, LLC
To
My wife, Leena Parikh, M.D. and
my son, Neehar Parikh, M.D.
for your support during this project
and
All of the co-workers at various companies and
friends from whom I have learned
over the last thirty years.
Thank you.
© 2005 by Taylor & Francis Group, LLC
Preface
It has been over eight years since the first edition of the Handbook of Pharmaceutical
Granulation Technology was published. The enthusiastic reception afforded by the
scientific community was heartwarming.
The basic science of granulation has not changed much over the last few years;
however, a better understanding of the theory of granulation and the proliferation of
different dosage forms has. The second edition seeks to improve and update the con-

tent of the first edition, as well as to enlarge the coverage by addition of new chapters
that reflect the current state of the technology and the regulatory environment.
The pharmaceutical industry has seen several waves of consolidation with each
successive year. The economic pressures on the industry have been increasing due to
political policies and dwindling supply of new chemical entities. The surge in expira-
tion of patents has given opportunities to the generic drug industry as never seen
before and the trend will continue for some time to come. The emergence of
biotechnology as the new resource for new drug candidates is exciting. To maintain
market share and remain in the forefront of technological advances, a number of dif-
ferent dosage forms utilizing different granulation technologies have been explored.
The technologies of interest include techniques for producing rapid release dosage
forms, the use of various meltable materials for melt pelletizations and the manufac-
ture of controlled release dosage forms. Thus, a new chapter on the rapid release
granulation techniques is included in this edition. A chapter on melt granulation
and pelletization is added toget her with another on effervescent granulation. These
additions provide pharmaceutical scientists a spectrum of granulation techni ques
reflecting the current state of the art. Additionally, the chapter on spray drying is
revised to include the spray congealing techni que, which is also becoming popular.
Regulatory requirements in the pharmaceutical industry have created the need
for an understanding of this unit operation at an early stage of product formulation,
method selection, and process development. Because the process and specifications
for the pivotal batches an d full-scale producti on batches ‘‘must be equivalent,’’ the
need for reliable control of the manufacturing process used to produce the test
and clinical batches cannot be overemphasized.
The FDA’s Process Analytical Technology (PAT) initiative is an effort to
facilitate the introduction of new manufa cturing technologies in the pharmaceutical
vii
© 2005 by Taylor & Francis Group, LLC
industry for achieving more efficient processes. PATs are systems that enhance
process understanding and assist in identifying and controlling critical points in a

process. These include appropriate measurement devices, which can be placed in- or
on-line, statistical and information technology tools, and a scientific systems approach
for data analysis to control processes that will ensure production of in-process mate-
rials and final products of the desired quality. A separate chapter on PAT covers this
important topic.
Every chapter in this edition is updated to reflect new developments in the
technologies and how these technologies are used to produce the desired granulation
end product.
This book is designed to give readers comprehensive knowledge of the subject.
As in the earlier edition, chapters include an appropriate level of theory on the fun-
damentals of powder characterization, granulation, an d state-of-the-art technology.
However, the emphasis is on the application of these basic principles to the industrial
practice of producing pharmaceutical granulation for subsequent processing into
dosage forms. The new regulatory requirements along with the new technologies
employed in the industry an d contemporary approaches to producing pharmaceuti-
cal granulation are important areas covered in this second edition.
Pharmaceutical professionals, such as research a nd development scientists,
process engineers, validation specialists, process specialists, quality assurance and
quality control professionals, and graduate students in industrial pharmacy pro-
grams will find the level of theory appropriate and the wealth of practical infor-
mation from renowned pharmaceutical professionals invaluable. The knowledge
provided will be invaluable for selecting the appropriate granulation technology,
while keeping in mind regulatory requirements and cost effectiveness.
I would like to acknowledge the support and cooperation of all the contribut-
ing authors throughout this process; to them I offer a most sincere thank you.
Without their dedication and timely submission of material, this book would not
have gone to print. I would also like to give special mention to Dr. Paul Heng
(National University of Singapore) and Dr. Gurvinder Singh Rekhi (Elan Drug
Delivery, Inc.) for their invaluable support during this project.
A special recognition goes to Ms. Sandra Beberman, Vice President of Taylor

& Francis Books. It was with her encouragement that I was driven to revise and
update the second edition of this book. I am overwhelmed by the wide acceptance
of the first edition throughout the worldwide pharmaceutical industry and acade-
mias. It is my hope that this second edition will continue to serve as a reference tool
and will provide useful knowledge in this important unit operation.
Dilip M. Parikh
viii Preface
© 2005 by Taylor & Francis Group, LLC
Contents
. . . . vii
Contributors . . . . xv
1. Introduction . . . . . . 1
Dilip M. Parikh
References . . . . 6
2. Theory of Granulation: An Engineering Perspective . . . 7
Bryan J. Ennis
1. Introduction . . . . 7
2. Wetting . . . . 19
3. Granule Growth and Consolidation . . . . 34
4. Granule Strength and Breakage . . . . 55
5. Controlling Granulation Processes . . . . 60
References . . . . 77
3. Drug Substance and Excipient Characterization . . . . . 79
L. W. Chan and P. W. S. Heng
1. Introduction . . . . 79
2. Particle Shape, Size, and Surface Area . . . . 80
3. Solubility . . . . 89
4. Crystal Properties and Polymorphism . . . . 95
5. Other Physical Properties . . . . 100
6. Commonly Used Excipients in Granulation . . . . 102

7. Compatibility of Drug and Excipient . . . . 103
8. Conclusion . . . . 105
References . . . . 106
4. Binders and Solvents 109
Ehab Hamed, Derek Moe, Raj Khankari, and John Hontz
1. Introduction . . . . 109
2. Types of Binders . . . . 109
3. Factors Influencing Binder Efficiency . . . . 115
ix
Preface
© 2005 by Taylor & Francis Group, LLC
4. Processing Parameters for Commonly Used Binders . . . . 119
References . . . . 125
5. Spray Drying and Pharmaceutical Applications . . . . . . 129
Metin C¸ elik and Susan C. Wendel
1. Introduction . . . . 129
2. Spray Drying Process Stages . . . . 130
3. Process Layouts . . . . 138
4. Theory of Spray Drying Fundamentals . . . . 139
5. Spray Drying Applications . . . . 146
6. Conclusion . . . . 154
References . . . . 155
6. Roller Compaction Technology . . . 159
Ronald W. Miller
1. Introduction . . . . 159
2. Powder Granulation and Compaction . . . . 159
3. Background . . . . 160
4. Benefits of Roller Compaction . . . . 161
5. Compaction Theory . . . . 162
6. Design Features of Roller Compactors . . . . 166

7. Roll Configuration . . . . 167
8. Feed Screw Design . . . . 170
9. Future Trends in Granulation Technology . . . . 172
10. New Findings . . . . 173
11. Deaeration Theory . . . . 178
12. Roller Compaction and Near-Infrared
Spectroscopy . . . . 182
13. Roller Compaction and PAT . . . . 185
References . . . . 188
7. High-Shear Granulation . 191
Rajeev Gokhale, Yichun Sun, and Atul J. Shukla
1. Introduction . . . . 191
2. High-Shear Granulators . . . . 192
3. High-Shear Granulation Process . . . . 195
4. Mechanism of High Shear Wet Granulation . . . . 200
5. Factors Affecting the Granulation Process
and Granule Properties . . . . 204
6. Granulation End-Point Determination . . . . 212
7. Formulation Development (Optimization) . . . . 217
8. Process Scale-Up . . . . 219
9. Conclusion . . . . 224
References . . . . 224
x Contents
© 2005 by Taylor & Francis Group, LLC
8. Low-Shear Granulation . . . . . . . . 229
Tom Chirkot and Cecil Propst
1. Introduction . . . . 229
2. Mechanical Agitator Granulators . . . . 231
3. Rotating Shape Granulators . . . . 235
4. Scale-Up . . . . 240

5. End-Point Determination and Control . . . . 243
6. Conclusions . . . . 244
References . . . . 244
9. Batch Fluid Bed Granulation . . . . 247
Dilip M. Parikh and Martin Mogavero
1. Introduction . . . . 247
2. Fluidization Theory . . . . 248
3. System Description . . . . 251
4. Particle Agglomeration and Granule Growth . . . . 261
5. Fluid Bed Drying . . . . 265
6. Process and Variables in Granulation . . . . 268
7. Process Controls and Automation . . . . 276
8. Process Scale-Up . . . . 282
9. Safety in Fluid Bed . . . . 286
10. Material Handling Options . . . . 291
11. Fluid Bed Technology Progress . . . . 294
References . . . . 304
10. Single-Pot Processing . . . . . . . . . 311
Harald Stahl and Griet Van Vaerenbergh
1. Introduction . . . . 311
2. Typical Single-Pot Process . . . . 313
3. Drying Methods for Single-Pot Processors . . . . 315
4. Other Processes and Applications . . . . 321
5. Scale-Up of Drying Processes . . . . 324
6. Cleaning . . . . 326
7. Product Stability . . . . 326
8. Regulatory Considerations . . . . 326
9. Validation of Single-Pot Processors . . . . 327
10. Control Systems and Data Acquisition Systems . . . . 328
11. Safety . . . . 328

12. Conclusion . . . . 330
References . . . . 330
11. Extrusion/Spheronization as a Granulation Technique . 333
Ketan A. Mehta, Gurvinder Singh Rekhi, and Dilip M. Parikh
1. Introduction . . . . 333
2. Applications . . . . 335
3. General Process Description . . . . 336
Contents xi
© 2005 by Taylor & Francis Group, LLC
4. Equipment Description and Process Parameters . . . . 337
5. Formulation Variables . . . . 352
6. Compression of Pellets . . . . 357
7. Conclusions . . . . 359
References . . . . 360
12. Effervescent Granulation 365
Guia Bertuzzi
1. Introduction . . . . 365
2. The Effervescent Reaction . . . . 366
3. Formulation . . . . 366
4. Raw Materials . . . . 367
5. Manufacturing of Effervescent Forms . . . . 371
References . . . . 382
13. Melt Granulation and Pelletization 385
T. W. Wong, W. S. Cheong, and P. W. S. Heng
1. Introduction . . . . 385
2. Mechanism of Melt Agglomeration . . . . 389
3. Factors Affecting Melt Agglomeration . . . . 393
4. Control of Melt Agglomeration . . . . 395
5. Conclusions . . . . 400
References . . . . 401

14. Rapid Release Granulation . . . . . . 407
P. W. S. Heng, Anthony Yolande, and Lee Chin Chiat
1. Introduction . . . . 407
2. Formulation-Related Factors . . . . 409
3. Granulation-Related Factors . . . . 417
4. Solid Dispersion . . . . 419
5. Conclusions . . . . 423
References . . . . 424
15. Continuous Granulation Technologies . . . . . . 431
Rudolf Schroeder and Klaus-Ju
¨
rgen Steffens
1. Introduction . . . . 431
2. Comparison of Different Modes of Processing . . . . 431
3. Fluid Bed Systems . . . . 433
4. Mechanical Wet Granulation Systems . . . . 437
5. Roller Extrusion System . . . . 441
References . . . . 456
16. Scale-Up Considerations in Granulation . . . . 459
Y. He, L. X. Liu, and J. D. Litster
1. Introduction . . . . 459
2. General Considerations in Process Scale-Up: Dimensional Analysis
and the Principle of Similarity . . . . 460
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© 2005 by Taylor & Francis Group, LLC
3. Analysis of Granulation Rate Processes
and Implications for Scale-Up . . . . 462
4. Scale-Down, Formulation Characterization, and Formulation Design
in Pharmaceutical Granulation . . . . 473
5. Scale-Up of Fluidized Bed Granulators . . . . 475

6. Scale-Up of High-Shear Mixer Granulators . . . . 480
7. Concluding Remarks . . . . 487
Nomenclature . . . . 487
References . . . . 488
17. Sizing of Granulation 491
Gurvinder Singh Rekhi and Richard Sidwell
1. Introduction . . . . 491
2. Theory of Comminution or Size Reduction . . . . 492
3. Properties of Feed Materials Affecting
the Sizing Process . . . . 493
4. Criteria for Selection of a Mill . . . . 494
5. Classification of Mills . . . . 495
6. Wet Milling . . . . 499
7. Variables Affecting the Sizing Process . . . . 502
8. Scale-Up . . . . 507
9. Case Studies . . . . 509
10. List of Equipment Suppliers . . . . 510
References . . . . 511
18. Granulation Characterization . . . . 513
Raj Birudaraj, Sanjay Goskonda, and Poonam G. Pande
1. Introduction . . . . 513
2. Physical and Chemical Characterization
of Granules . . . . 513
3. Conclusion . . . . 531
References . . . . 531
19. Bioavailability and Granule Properties . . . . . 535
Sunil S. Jambhekar
1. Introduction . . . . 535
2. Bioavailability Parameters . . . . 536
3. Conclusion . . . . 541

References . . . . 542
Recommended Reading . . . . 543
20. Process Analytical Technology . . . 545
D. Christopher Watts and Ajaz S. Hussain
1. Introduction . . . . 545
2. Background . . . . 546
3. PAT and Process Understanding . . . . 548
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© 2005 by Taylor & Francis Group, LLC
4. PAT Tools and Their Application . . . . 549
5. Conclusion . . . . 552
References . . . . 552
21. Granulation Process Modeling . . . 555
I. T. Cameron and F. Y. Wang
1. Modeling of Granulation Systems . . . . 555
2. Key Factors in Granulation Modeling . . . . 560
3. Representing Granulation Processes Through
Population Balances . . . . 562
4. Solving and Using Population Balances . . . . 570
5. Application of Modeling Techniques . . . . 577
6. Conclusion . . . . 590
References . . . . 591
22. Regulatory Issues in Granulation . . 595
Prasad Kanneganti
1. Introduction . . . . 595
2. Pharmaceutical Quality Management . . . . 595
3. Postapproval Change Considerations . . . . 597
4. Validation of Granulation Processes . . . . 609
5. Conclusion . . . . 613
References . . . . 613

xiv Contents
© 2005 by Taylor & Francis Group, LLC
Contributors
Guia Bertuzzi IMA S.p.A., Solid Dose Division, Bologna, Italy
Raj Birudaraj Roche Palo Alto, Palo Alto, California, U.S.A.
I. T. Cameron Particle and Systems Design Centre, School of Engineering,
The University of Queensland, Queensland, Australia
L. W. Chan National University of Singapore, Singapore
W. S. Cheong National University of Singapore, Singapore
Lee Chin Chiat International Specialty Products (ISP) Asia Pacific Pte. Ltd.,
Singapore
Tom Chirkot Patterson-Kelly Co., East Stroudsburg, Pennsylvania, U.S.A.
Metin C¸ elik Pharmaceutical Technologies International, Inc., Belle Mead,
New Jersey, U.S.A.
Bryan J. Ennis E&G Associates, Inc., Nashville, Tennessee, U.S.A.
Rajeev Gokhale
Ã
Incyte Corporation, Wilmington, Delaware, U.S.A.
Sanjay Goskonda Durect Corp., Cupertino, California, U.S.A.
Ehab Hamed CIMA Labs Inc., Eden Prairie, Minnesota, U.S.A.
Y. He Particle and Systems Design Centre, Division of Chemical Engineering,
School of Engineering, The University of Queensland, Queensland, Australia
P. W. S. Heng National University of Singapore, Singapore
John Hontz Biovail, Chantilly, Virginia, U.S.A.
Ã
Present Address: Merck Research Laboratories, West Point, Pennsylvania, U.S.A.
xv
© 2005 by Taylor & Francis Group, LLC
Ajaz S. Hussain Office of Pharmaceutical Science, Center for Drug Evaluation and
Research, Food and Drug Administration, Bethesda, Maryland, U.S.A.

Sunil S. Jambhekar South University School of Pharmacy, Savannah,
Georgia, U.S.A.
Prasad Kanneganti Quality Operations, Pfizer Global Ma nufacturing,
Pfizer Asia Pacific Pte. Ltd., Singapore
Raj Khankari CIMA Labs Inc., Eden Prairie, Minnesota, U.S.A.
J. D. Litster Particle and Systems Design Centre, Division of Chemical
Engineering, School of Engineering, The University of Queensland,
Queensland, Australia
L. X. Liu Particle and Systems Design Centre, Division of Chemical Engineering,
School of Engineering, The University of Queensland, Queensland, Australia
Ketan A. Mehta RO
¨
HM Pharma, Degussa Corp., Piscataway, New Jersey, U.S.A.
Ronald W. Miller Bristol-Myers Squibb Company, New Brunswick,
New Jersey, U.S.A.
Derek Moe CIMA Labs Inc., Eden Prairie, Minnesota, U.S.A.
Martin Mogavero Niro Pharma Systems, Columbia, Maryland, U.S.A.
Poonam G. Pande Synthon Pharmaceuticals Inc., Research Triangle Park,
North Carolina, U.S.A.
Dilip M. Parikh Synthon Pharmaceuticals Inc., Research Triangle Park,
North Carolina, U.S.A.
Cecil Propst SPI Pharma, Norton Shores, Michigan, U.S.A.
Gurvinder Singh Rekhi Elan Drug Delivery Inc., Gainesville, Georgia, U.S.A.
Rudolf Schroeder
Ã
L.B. Bohle Maschinen und Verfahren GmbH, Ennigerloh,
Germany
Atul J. Shukla College of Pharmacy, University of Tennessee, Memphis,
Tennessee, U.S.A.
Richard Sidwell Elan Drug Delivery Inc., Gainesville, Georgia, U.S.A.

Harald Stahl Niro Pharma Systems, Muellheim, Germany
Ã
Present Address: Abbott GmbH & Co. KG, Ludwigshafen, Germany.
xvi Contributors
M
e
U.
S
© 2005 by Taylor & Francis Group, LLC
Klaus-Ju
¨
rgen Steffens Department of Pharmaceutical Technology,
University of Bonn, Bonn, Germany
Yichun Sun College of Pharmacy, University of Tennessee, Memphis,
Tennessee, U.S.A.
Griet Van Vaerenbergh Collette N.V., Wommelgren, Belgium
F. Y. Wang Particle and Systems Design Centre, School of Engineering,
The University of Queensland, Queensland, Australia
D. Christopher Watts Office of Pharmaceutical Science, Center for Drug
Evaluation and Research, Food and Drug Administration, Bethesda, Maryland,
U.S.A.
Susan C. Wendel Elan NanoSystems, King of Prussia, Pennsylvania, U.S.A.
T. W. Wong Faculty of Pharmacy, University of Technology MARA, Selangor,
Malaysia
Anthony Yolande International Specialty Products (ISP) Asia Pacific Pte. Ltd.,
Singapore
Contributors xvii
© 2005 by Taylor & Francis Group, LLC
1
Introduction

Dilip M. Parikh
Synthon Pharmaceuticals Inc., Research Triangle Park, North Carolina, U.S.A.
Perry’s Chemical Engineer’s Handbook (1) defines the granulation process as ‘‘any
process whereby small particles are gathered into larger, permanent masses in which
the original particles can still be identified.’’ This definition is of course particularly
appropriate to a pharmaceutical granu lation where the rapid breakdown of agglom-
erates is important to maximize the available surface area and aid in solution of the
active drug. The granulation process of size enlargement used within the pharmaceu-
tical industry has its roots in ancient times. The practice of delivering medicinal pow-
der by hand rolling into a pill by using honey or sugar has been used for centuries.
It is still the practice to deliver the botanical and herbal extract in homeopathic and
ayurvedic branches of medicine, which are still practiced in India along with allo-
pathic medicine. The term ‘‘granulated’’ material is derived from the Latin word
‘‘granulatum,’’ meaning grained. The granulated material can be obtained by direct
size enlargement of primary parti cles, or size reduction from dry compacted mate-
rial. In modern times, granulation technology has been widely used by a wide range
of industries, such as coal, mining, and agrochemical. These industries employ
agglomeration techniques to reduce dust, provide ease of handling, and enhance
the material’s ultimate utility.
The development of pharmaceutical granulation was driven by the invention of
the tablet press by W. Brockedon in 1843. Subsequent improvements in the tablet
machinery were patented in the United States by J. A. McFerran (1874), T. J. Young
(1874), and J. Dunton (1876). The demands on the granulation properties were further
enhanced in the 1970s as high-speed tablet and capsule filling machines with auto-
mated controls were introduced. The continuous refinements in the regulatory require-
ments such as low-dose products requiring blend uniformity/content uniformity
necessitated knowledge and technology to produce the required granule characteris-
tics. The high-speed compression and capsule filling machines require a uniform flow
of material to the dies or filling stations that produce pharmaceutical dosage form.
Granulation is an example of particle design. The desired attributes of the

granule are controlled by a combinat ion of the formulation and the process.
Granulation methods can be divided into two major types: wet methods which
utilize some form of liquid to bind the primary particles, and dry methods which do
1
not utilize any liquid (Fig. 1).
© 2005 by Taylor & Francis Group, LLC