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 Therapy 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
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 Theoretical Methods 37
2.2.3.2 GRAS Coformer Libraries 38
2.2.3.3 High-Throughput 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 Thakur, Mansi Prashar, Sukhvir Kaur, Neelima Dhingra, Manish Kumar, Ritu Rathi, Inderbir Singh and Poonam Arora
4.1 Introduction 94
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 Diffraction (XRPD) 123
5.2.2 Single-Crystal X-Ray Diffraction (SCXRD) 124
5.2.3 Differential Scanning Calorimetry (DSC) 126
5.2.4 Thermogravimetric 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
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 Definition 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 Benefits 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 Therapeutics 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
7.2 Reported Drug-Drug Cocrystals for Non¿Steroidal Anti-Inflammatory 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
9.2 Why Solubility Enhancement is Important? 259
9.3 Factors Affecting Solubility 260
9.3.1 Nature of Solute and Solvent 260
9.3.2 Particle Size 260
9.3.3 Temperature 261
9.3.4 Pressure 261
9.3.5 Molecular Size 262
9.3.6 Polymorphism 262
9.3.7 Polarity 262
9.3.8 Common-Ion Effect 262
9.4 Solubility and Bioavailability 263
9.5 Permeability and Cocrystallization 264
9.6 Enhancing Solubility through Cocrystallization 265
9.6.1 Hot-Melt Extrusion Technique of Cocrystallization to Enhance Solubility 265
9.6.2 Amino Acid in Cocrystal to Enhance Solubility 266
9.6.3 Polymeric Effect on Cocrystallization 266
9.6.4 Cocrystals of Herbal Bioactive to Enhance Solubility 267
9.6.5 Solubility Enhancement of Anticancer Drug via Cocrystallization 272
9.6.6 Drug-Drug Cocrystallization to Enhance Solubility 281
9.6.7 Cocrystallization for Food Encapsulation 281
9.7 Conclusion 282
Acknowledgment 283
References 283
10 Pharmaceutical Cocrystals for Improving Physicochemical Properties of Drugs: Enhancement of
Therapeutic Efficacy 293
Debabrata Ghosh Dastidar, Arpan Datta, Sanchari Bhattacharya and Moumita Chowdhury
10.1 Introduction 294
10.2 Preparation and Characterization Methods for Cocrystals 295
10.3 Enhancement of Therapeutic Efficacy with Cocrystals 297
10.3.1 Improving the Physicochemical Properties of Drugs 302
10.3.1.1 Melting Point 302
10.3.1.2 Hygroscopicity 303
10.3.1.3 Solubility and Dissolution 303
10.3.1.4 Mechanical Behavior 305
10.3.1.5 Optical Properties 306
10.3.2 Enhancing Stability and Shelf Life 307
10.3.2.1 Changing the Reaction Cavity/ Environment 308
10.3.2.2 Alteration of Solid-State Properties 309
10.3.2.3 Manipulation of Hydrogen Bonding Pattern 309
10.3.2.4 Influencing Solid-State Microenvironment 310
10.3.2.5 Increased Thermal Stability 311
10.3.3 Improving Bioavailability and Pharmacokinetics 312
10.3.3.1 The Mechanism for Enhancing the Bioavailability and Improve Pharmacokinetics of Drugs 312
10.3.4 Combination Therapy 316
10.3.5 Improving the Targeted Delivery of Drugs 318
10.4 Regulatory Considerations for Cocrystal Approval 319
10.5 Conclusion and Future Aspects 322
Acknowledgment 323
References 323
11 Application of Pharmaceutical Cocrystals in Improving Mechanical Properties and Stability 329
Sushant Sharma, Ritu Rathi, Ayushi Taneja, Poonam Arora and Inderbir Singh
11.1 Introduction 330
11.2 Pharmaceutical Cocrystals Improve Mechanical Properties 332
11.3 Pharmaceutical Cocrystals Improving Stability 341
11.4 Conclusion and Future Prospective 344
Acknowledgments 350
References 350
12 Patents and Regulatory Considerations of Pharmaceutical Cocrystals 357
Ritu Rathi, Ritamay Sau, Rakesh K. Sindhu, Harpreet Singh and Inderbir Singh
12.1 Introduction 358
12.1.1 Comparison Between USFDA and EMA on the Aspects of Cocrystal 363
12.2 Generic Concept of Pharmaceutical Cocrystals 365
12.3 Data Consideration Using Pharmaceutical Cocrystals for Abridged Application 367
12.3.1 Module 3: Quality Aspects for Pharmaceutical Cocrystals 367
12.3.1.1 Quality Aspects During Development of Generic Cocrystal API 369
12.3.2 Module 4: Non-Clinical Safety Toxicological Studies 369
12.3.3 Module 5: Clinical Studies 370
12.4 Patent on Cocrystals 370
12.5 Conclusion 373
Acknowledgment 374
References 374
Index 379
