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Full Description
Ten proven strategies to overcome solubility challenges in drug development
Poor water solubility prevents drug candidates from reaching their therapeutic targets, causing promising compounds to fail during development. Drug Development Approaches for Poorly Soluble Compounds presents ten distinct strategies for overcoming this challenge, from altering drug structure and creating prodrugs to formulation techniques using nanosuspensions, microemulsions, micelles, co-crystals, and co-solvents. Each approach includes case studies from current pharmaceutical industry projects.
This reference covers strategies applicable to virtually every drug type, regardless of molecular size or chemical composition. Beyond formulation science, the book addresses solubility-related commercial and regulatory considerations essential for bringing drugs to market. Special attention is given to animal study requirements for poorly soluble compounds. Each chapter demonstrates approaches through examples from recent pharmaceutical development projects across small and large companies.
Readers will also find:
Detailed explanations of ten formulation strategies including nanosuspensions, microemulsions, micelles, co-crystals, and co-solvent approaches for enhancing drug solubility
Practical case studies drawn from recent pharmaceutical industry drug development projects demonstrating real-world applications of each solubility enhancement strategy
Guidance on regulatory considerations specific to poorly soluble compounds, helping developers navigate approval pathways more efficiently throughout the development process
Coverage of special requirements for conducting animal studies with compounds that exhibit poor solubility in biological fluids
Commercial considerations for solubility enhancement strategies that reduce required drug substance amounts, lowering costs and minimizing potential side effects
Designed for medicinal chemists, pharmaceutical chemists, pharmacologists, and pharmaceutical industry professionals, this book ensures no drug candidate fails due to solubility challenges. The strategies presented here apply across compound types and development stages, providing practitioners with proven solutions for this common development obstacle.
Contents
Series Editors Preface xvii
Preface xix
1 Impact of Poor Solubility on Drug Development 1
Preshita Desai
1.1 Introduction 1
1.2 Drug Solubility 2
1.3 Impact of Poor Drug Solubility on Drug-Like Properties 4
1.4 Addressing Poor Drug Solubility Challenge 5
1.5 Poor Drug Solubility—Is It Always a Challenge? 13
1.6 Conclusion 14
2 Design and Development of Amorphous Solid Dispersion as Enabling Formulation Strategies of Poorly Soluble Drugs 19
Amrit Paudel and Sarah Stryeck
2.1 Basics of Amorphous Solid Dispersion (ASD) 19
2.2 Analytical Characterization of ASDs 28
2.3 Preformulation and Screening of ASD 38
2.4 Manufacturing Processes of ASD 40
2.5 Biopharmaceutics of ASD 46
2.6 Stability Considerations of ASD 50
2.7 Computational Tools for ASD Development 54
2.8 Emerging Innovations in ASD 59
3 Nanosizing of Drugs to Improve the Apparent Dissolution and Bioavailability 81
Yalamanda Varla, Vishvesh Joshi, Rikin Patel, and Derajram Benival
3.1 Introduction 81
3.2 Techniques for Nanosizing 87
3.3 Formulation Strategies for Nanosized Drugs 93
3.4 Challenges and Limitations in Nanosizing 96
3.5 Future Perspectives 98
3.6 Conclusion 99
4 Pharmaceutical Cocrystals 115
Ghaida Mustafa, Shahzeb Khan, and Anant Paradkar
4.1 Introduction 115
4.2 Synthon Theory and Prediction Tools in Cocrystal Design 119
4.3 Synthesis of Pharmaceutical Cocrystals 124
4.4 Characterization Techniques of Pharmaceutical Cocrystals 132
4.5 Solubility Aspects of Pharmaceutical Cocrystals 139
4.6 Pharmaceutical Cocrystals: Physicochemical Properties and Applications 141
4.7 Regulatory Considerations and Approval Pathways 151
4.8 Commercially Available Cocrystals-Based Pharmaceuticals 153
4.9 Challenges and Future Perspectives 153
4.10 Conclusion 156
5 Self-Microemulsifying and Self-Emulsifying Drug Delivery Systems to Improve Solubility and Bioavailability 173
Dipak B. Bari, Rakhee Kapadia, Raju O. Sonawane, Kamalesh D. Mali, Vivek P. Rajkule, Mahesh G. Umbarkar, and Chandrakantsing V. Pardeshi
5.1 Introduction 173
5.2 Self-Emulsifying Drug Delivery Systems 174
5.3 Advantages and Disadvantages of SEDDS/SMEDDS 175
5.4 Formulation of SEDDS and SMEDDS 175
5.5 Challenges in Formulation Development of SEDDS/SMEDDS 182
5.6 Mechanism of Self-Emulsification 187
5.7 Self-Emulsification and Uptake of Drugs In Vivo 187
5.8 Applications of SEDDS 188
5.9 Regulatory Updates on SMEDDS/SNEDDS 194
5.10 Commercial SEDDS 194
5.11 Patents on SEDDS 195
5.12 Clinical Status of SEDDS Formulations 195
5.13 Conclusion 195
6 Liposomes and Mixed Micelles for Improvement of Drug Solubility 209
Chukwuebuka E. Umeyor, Diksha Narula, Ankita Anure, Andrew Ezegbe, Prafull Kolekar, and Vandana B. Patravale
6.1 Introduction 209
6.2 Drug Carrier Solubility Enhances Drug Bioavailability 210
6.3 Process Development of Liposomes 211
6.4 Mixed Micelles for Enhanced Drug Solubility 228
6.5 In vivo Safety of Liposomes and Mixed Micelles Drug Carriers 233
6.6 Benefits and Limitations of Liposomes and Mixed Micelles 234
6.7 Marketed Micellar and Liposomal Products 237
6.8 Regulatory Guidelines for Liposomes and Mixed Micelles Use 237
6.9 Clinical Application of Liposomes and Mixed Micelles 241
6.10 Patent Landscape of Liposomes and Mixed Micelles 244
6.11 Future Research and Conclusion 244
7 Improvement of Solubility and Bioavailability of Poorly Soluble Drugs Using Mesoporous Silica Particles 257
Jitendra Wankar and Sonia Gera
7.1 Introduction 257
7.2 Different Techniques for Synthesis of Silica Particles 258
7.3 Characterization of MSN 260
7.4 Mesoporous Silica for Drug Dissolution and Dosage Form Development 261
7.5 Drug-Loading Methods in Mesoporous Silica Particles to Improve Drug Solubility 262
7.6 Mesoporous Silica Particles as a Potential Option to Improve Bioavailability (BA) 267
7.7 Commercial Success and Clinical Pipeline Using This Technology 269
7.8 Challenges Toward Clinical Translation of Mesoporous Silica Particles 270
7.9 Future Prospects and Conclusions 271
8 Gastrointestinal Dissolution and Absorption of BCS Class II Drugs 277
Almog Eliyahu Dahan and Arik Dahan
8.1 Introduction 277
8.2 Drug Absorption and the BCS 277
8.3 GI Physiological Variables Affecting BCS Class II Drug Dissolution 280
8.4 In vitro Dissolution Tests for Class II Drugs 284
8.5 Biowaiver Extension Potential 285
8.6 Advanced Simulation Models for FDA Biowaiver Submission 286
8.7 Conclusions 288
9 Cyclodextrin-Based Formulations to Improve Solubility of Poorly Soluble Drugs 297
Ganesh Shevalkar, Shradhha Tiwari, Deepak Bari, Chandrakantsing Pardeshi, and Sarika Kamble
9.1 Introduction 297
9.2 CD Structure and Types 298
9.3 Approved CD-Based Pharmaceutical Formulations 304
9.4 Drug Delivery Applications of CD-Based Formulations 306
9.5 Current Landscape Post Approval of Captisol 311
9.6 Regulatory and Clinical Landscape of Cyclodextrin-Based Biomaterials 312
9.7 Toxicological Considerations of CDs with Emphasis on Renal Safety 314
9.8 Patent Scenario Regarding the Use of CD 316
9.9 Conclusion 318
10 Cosolvent-Based Formulations to Improve Solubility and Bioavailability 327
Nilam Bhusare, Chetana Eknure, Yogeshwar Bachhav, and Maushmi S. Kumar
10.1 Background of the Cosolvent-Based Formulations 327
10.2 Cosolvency 328
10.3 Types of Cosolvents Allowed and Their IIG Limits 334
10.4 Possible Adverse Events Due to the Use of Cosolvents—Case Studies 336
10.5 Challenges in Selecting a Formulation in the Preclinical Studies Using Cosolvents 337
10.6 Design of Formulations Using Cosolvents for First-in-Man Studies or Late Clinical Phases 339
10.7 Regulatory Aspects 339
10.8 Selected Examples of Cosolvent-Based Formulations Using 505(b)(2) Pathway and Intellectual Property (IP) Protection 340
10.9 Clinical Pipeline 344
10.10 Future Prospects 345
10.11 Conclusion 345
11 First-in-Animal Studies and Formulation Considerations 353
Dnyaneshwar N. Kapote and Vandana Gawande-Kapote
11.1 Introduction 353
11.2 Steps in Preclinical Studies 355
11.3 Pre-Formulation Considerations for First-in-Animal Studies (Preclinical Formulations) 356
11.4 Formulation Considerations for First-in-Animal Formulations 363
11.5 Bridging the Gap of First-in-Animal Studies with First-in-Human Studies 377
11.6 Conclusions 378
12 Improving Aqueous Solubility of Drug Candidates Through Structural Modifications 389
Kamal Kumar
12.1 Introduction 389
12.2 Enhancing Drug Solubility and Bioavailability: A Key to Effective Therapy 391
12.3 Chemical Modification as a Strategy to Enhance Solubility 394
12.4 Conclusion 410
References 411
Index 419
