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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5460_Библиотеки_им_академика_М_И_Перельмана.pdf
Cocrystals in
Pharmaceutical Sciences
Scrivener Publishing
100 Cummings Center, Suite 541J
Beverly, MA 01915-6106
Publishers at Scrivener
Martin Scrivener (martin@scrivenerpublishing.com)
Phillip Carmical (pcarmical@scrivenerpublishing.com)
Cocrystals in
Pharmaceutical Sciences
Design to Applications
Edited by
Inderbir Singh
Chitkara College of Pharmacy, Chitkara University, Punjab, India
Subrata Mallick
School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be
University), Odisha, India
and
Ritu Rathi
Chitkara College of Pharmacy, Chitkara University, Punjab, India
is edition rst published 2025 by John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA
and Scrivener Publishing LLC, 100 Cummings Center, Suite 541J, Beverly, MA 01915, USA
© 2025 Scrivener Publishing LLC
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While the publisher and authors have used their best eorts in preparing this work, they make no rep-
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Library of Congress Cataloging-in-Publication Data
ISBN 978-1-394-30247-5
Front cover image courtesy of Inderbir Singh
Cover design by Russell Richardson
Set in size of 11pt and Minion Pro by Manila Typesetting Company, Makati, Philippines
Printed in the USA
10 9 8 7 6 5 4 3 2 1
v
Contents
Preface xiii
1 Pharmaceutical Cocrystals: Introduction, History
and Applications 1
Oluwatoyin A. Odeku and Olufunke D. Akin-Ajani
1.1 Introduction
2
1.2 History 3
1.3 Applications of Cocrystals in Pharmaceutical Sciences 4
1.3.1 Enhanced Solubility
5
1.3.2 Improved Bioavailability 5
1.3.3 Stability Enhancement 6
1.3.4 Taste Masking and Palatability 7
1.3.5 Controlled Release 8
1.3.6 Increased Tabletability 8
1.3.7 Combination erapy 9
1.4 Challenges in the Development of Cocrystals 12
1.5 Marketed Products 17
1.6 Future of Pharmaceutical Cocrystals 17
1.7 Conclusion 18
Acknowledgment 18
References 19
2 Design and Structural Characteristics of Pharmaceutical
Cocrystals
29
Harpreet Singh, Bhuvnesh Kumar Singh, Anil Kumar,
Arvind Kumar, Arun Kumar Mishra, Ritu Rathi
and Inderbir Singh
2.1 Introduction
30
2.1.1 Polymorphism 33
2.1.2 Salt Cocrystal Continuum 34
2.2 Design of Pharmaceutical Cocrystals 34
vi Contents
2.2.1 Molecular Recognition and Supramolecular
Interactions 35
2.2.2 Hansen Solubility Parameters (HSPs) 36
2.2.3 Coformers Selection and Combinatorial Approaches 37
2.2.3.1 eoretical Methods
37
2.2.3.2 GRAS Coformer Libraries 38
2.2.3.3 High-roughput Experimentation 38
2.2.3.4 Coformer Selection
38
2.2.4 Combinatorial Approaches 40
2.3 Structural Characteristics of Pharmaceutical Cocrystals 44
2.3.1 Crystal Structure Analysis
44
2.3.2 A Perspective on Cocrystal Hydrogen Bonding 44
2.3.3 Characterization Techniques
45
2.4 Challenges and Future Directions in Pharmaceutical
Cocrystal 46
2.5 Conclusion 48
Acknowledgment 48
References 49
3 Advancements in Computational Screening Methods
for Pharmaceutical Cocrystals 55
Maan Singh, Abhishek Mali, Madhukiran Dhondale,
Ashish Kumar Agrawal, Amrit Paudel and Dinesh Kumar
3.1 Introduction
56
3.2 Experimental Screening of Cocrystals 59
3.3 Computational Method for Screening Cocrystals 62
3.3.1 Molecular Electrostatic Potential Surfaces (MEPS)
Measurement
62
3.3.2 Hirshfeld Surface Analysis (HSA) 66
3.3.3 Cambridge Structural Database (CSD) 69
3.3.4 COSMO-RS Approach 72
3.3.5 Crystal Structure Prediction (CSP) 76
3.4 Recent Trends in Cocrystal Screening and Future Approach 78
3.5 Conclusion
81
Acknowledgments 82
References 82
4 Preparation Techniques of Pharmaceutical Cocrystals 93
Nikita akur, Mansi Prashar, Sukhvir Kaur,
Neelima Dhingra, Manish Kumar, Ritu Rathi, Inderbir Singh
and Poonam Arora
4.1 Introduction
94
Contents vii
4.2 Cocrystal Preparation Techniques 95
4.2.1 Solid-State Approach 96
4.2.1.1 Neat-Grinding Method 96
4.2.1.2 Liquid-Assisted Grinding Method 97
4.2.1.3 Hot-Melt Extrusion Approach
98
4.2.2 Solution-Based Method 99
4.2.2.1 Solvent Evaporation Approach 99
4.2.2.2 Slurry Conversion Approach 100
4.2.2.3 Cooling Crystallization 101
4.2.2.4 Antisolvent Method 102
4.2.3 Miscellaneous Approaches 103
4.2.3.1 Spray Drying and Supercritical CO
2
-Assisted
Spray Drying
103
4.2.3.2 Twin-Screw Extruder 104
4.3 Optimization Parameters for Cocrystal Formation 108
4.3.1 Choice of Coformer
108
4.3.2 Kinetics of Cocrystallization 109
4.3.3 Application of Modeling and Process Analytical
Technology
110
4.4 Future Perspectives and Challenges 112
Acknowledgments 113
References 114
5 A Brief on Analytical and Characterization Techniques
for Evaluation of Pharmaceutical Cocrystals 121
Suraj R. Chaudhari, Shashikant B. Bagade,
Sonali V. Chaudhari and Atul A. Shirkhedkar
5.1 Introduction
122
5.2 Analytical Techniques 123
5.2.1 X-Ray Powder Diraction (XRPD) 123
5.2.2 Single-Crystal X-Ray Diraction (SCXRD) 124
5.2.3 Dierential Scanning Calorimetry (DSC) 126
5.2.4 ermogravimetric Analysis (TGA)
127
5.2.5 Spectroscopic Methods (Infra-red, Raman,
and Nuclear Magnetic Resonance) 128
5.3 Physicochemical Characterization of Cocrystals 131
5.3.1 Assessment of Solubility and Dissolution
Characteristics 131
5.3.2 Cocrystal Stability 132
viii Contents
5.3.3 Discussion on Exploration of Analytical Techniques
for Characterization of Cocrystals 133
5.4 Conclusion 143
Acknowledgment 144
References 144
6 Advancements and Applications of Herbal Cocrystals 153
Rajat Goyal, Pankaj Popli, Kashish Wilson, Hitesh Chopra,
Sonia Dhiman and Sumeet Gupta
6.1 Introduction
154
6.1.1 Denition and Overview 154
6.1.2 Fundamentals of Cocrystal Formation 155
6.1.3 Selection of Coformer 157
6.1.4 Methods of Cocrystal Synthesis 158
6.1.4.1 Solid-State Methods 159
6.1.4.2 Solvent-Based Methods 160
6.1.4.3 Solvent Evaporation Method 160
6.1.4.4 Miscellaneous Methods 160
6.1.5 Characterization Techniques 161
6.2 Benets and Applications of Herbal Cocrystals 163
6.2.1 Enhanced Solubility and Bioavailability 163
6.2.2 Improved Stability and Shelf Life
164
6.3 Challenges and Limitations of Herbal Cocrystals, Solubility
Issues, and Incompatibilities
164
6.3.1 Scale-Up and Manufacturing Challenges 164
6.3.2 Safety Concerns
165
6.3.3 Quality Control 165
6.3.4 Regulatory Considerations 166
6.4 Reported Herbal Cocrystals 166
6.5 Future Perspectives and Trends 166
6.5.1 Advances in Cocrystal Technology 166
6.5.2 Potential for New Herbal erapeutics 177
6.6 Conclusion 178
References 179
7 Drug-Drug Cocrystals: Advancements and Applications 189
Ritu Rathi, Sushant Sharma, Siddhartha Gautham Pal,
Rohil Panwar, Taruna, Rakesh Pahwa and Inderbir Singh
7.1 Introduction
190
7.1.1 Preparation Techniques 192
7.1.2 Characterization of DDCS 196
Contents ix
7.2 Reported Drug-Drug Cocrystals for Non-Steroidal
Anti-Inammatory Drugs (NSAIDs) 199
7.3 Reported Drug-Drug Cocrystals for Anticancer Drugs 202
7.4 Reported Drug-Drug Cocrystals for Antituberculosis Drugs 206
7.5 Reported Drug-Drug Cocrystals for Diuretics 209
7.6 Reported Drug-Drug Cocrystals for Miscellaneous Drugs 212
7.7 Patent Perspectives
214
7.8 Marketed Product 218
7.9 Conclusion 218
Acknowledgment 218
References 219
8 Scaling Up Pharmaceutical Cocrystals: Exploring Commercial
Opportunities and Industrial Prospective
231
Kampanart Huanbutta, Tanikan Sangnim, Ritu Rathi
and Inderbir Singh
8.1 Introduction
232
8.2 Challenges and Considerations in Cocrystal Scale-Up 233
8.2.1 Process Control and Consistency
233
8.2.2 Kinetics of Cocrystallization 233
8.2.3 Selection of Appropriate Scale-Up Method 234
8.2.4 Regulatory Compliance
235
8.3 Promising Methods for Cocrystal Scale-Up 235
8.3.1 Solution-Mediated Cocrystallization 235
8.3.2 Solid/Slurry Cocrystallization 240
8.4 Quality-By-Design Approaches (QbD)
in Cocrystallization Manufacturing 243
8.5 Process Analytical Technology in Scale-Up
Cocrystallization Process 244
8.6 Commercial Opportunities for Cocrystals 246
8.7 Future Directions and Outlook 246
8.7.1 Machine Learning and AI 246
8.7.2 Advanced Process Analytical Technology (PAT) 248
8.7.3 Green Chemistry
248
8.8 Conclusion 249
Acknowledgment 250
References 250
9 Pharmaceutical Cocrystals for Solubility Enhancement
of Drugs 257
Mouli Das, Sk Habibullah, Tanisha Das and Subrata Mallick
9.1 Introduction
258