Co-Crystals in Pharmaceutical Sciences

The book is essential for anyone in the pharmaceutical field, as it offers invaluable insights into the innovative world of cocrystals, their design principles, experimental techniques, and practical applications that can significantly enhance drug development and address critical industry challenges. Co-Crystals in Pharmaceutical Sciences: Design to Applications is a comprehensive exploration of pharmaceutical cocrystals that introduces their scope and potential impact on drug development. This volume highlights the structural characteristics influencing cocrystals and delves into design principles and molecular interactions. Focus is placed on the advantages and challenges of integrating in-silico techniques for screening, which accelerates cocrystal discovery. Detailed coverage of experimental techniques, validation, and process optimization provides a solid foundation for readers. The book uniquely explores herbal and drug-drug cocrystals, showcasing synergies between traditional herbal medicine and modern pharmaceuticals. Scaling up cocrystal synthesis and potential commercial opportunities are examined in depth. Chapters on pharmaceutical applications emphasize how cocrystals address solubility, stability, and therapeutic challenges, with real-world examples illustrating their impact. The role of cocrystals in enhancing mechanical properties for more efficient formulations is discussed, and insights into the patent landscape and regulatory considerations round out the book, making it an indispensable resource for researchers and industry professionals alike. Audience Botanists, biologists, pharmaceutical professionals, drug delivery experts, and materials scientists studying pharmaceutical sciences.

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