Co-Crystals in Pharmaceutical Sciences E-Book
188,99 €
Mehr erfahren.
- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
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.
Sie lesen das E-Book in den Legimi-Apps auf:
Seitenzahl: 592
Veröffentlichungsjahr: 2025
Ähnliche
Table of Contents
Cover
Table of Contents
Series Page
Title Page
Copyright Page
Preface
1 Pharmaceutical Cocrystals: Introduction, History and Applications
1.1 Introduction
1.2 History
1.3 Applications of Cocrystals in Pharmaceutical Sciences
1.4 Challenges in the Development of Cocrystals
1.5 Marketed Products
1.6 Future of Pharmaceutical Cocrystals
1.7 Conclusion
Acknowledgment
References
2 Design and Structural Characteristics of Pharmaceutical Cocrystals
2.1 Introduction
2.2 Design of Pharmaceutical Cocrystals
2.3 Structural Characteristics of Pharmaceutical Cocrystals
2.4 Challenges and Future Directions in Pharmaceutical Cocrystal
2.5 Conclusion
Acknowledgment
References
3 Advancements in Computational Screening Methods for Pharmaceutical Cocrystals
3.1 Introduction
3.2 Experimental Screening of Cocrystals
3.3 Computational Method for Screening Cocrystals
3.4 Recent Trends in Cocrystal Screening and Future Approach
3.5 Conclusion
Acknowledgments
References
4 Preparation Techniques of Pharmaceutical Cocrystals
4.1 Introduction
4.2 Cocrystal Preparation Techniques
4.3 Optimization Parameters for Cocrystal Formation
4.4 Future Perspectives and Challenges
Acknowledgments
References
5 A Brief on Analytical and Characterization Techniques for Evaluation of Pharmaceutical Cocrystals
5.1 Introduction
5.2 Analytical Techniques
5.3 Physicochemical Characterization of Cocrystals
5.4 Conclusion
Acknowledgment
References
6 Advancements and Applications of Herbal Cocrystals
6.1 Introduction
6.2 Benefits and Applications of Herbal Cocrystals
6.3 Challenges and Limitations of Herbal Cocrystals, Solubility Issues, and Incompatibilities
6.4 Reported Herbal Cocrystals
6.5 Future Perspectives and Trends
6.6 Conclusion
References
7 Drug-Drug Cocrystals: Advancements and Applications
7.1 Introduction
7.2 Reported Drug-Drug Cocrystals for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
7.3 Reported Drug-Drug Cocrystals for Anticancer Drugs
7.4 Reported Drug-Drug Cocrystals for Antituberculosis Drugs
7.5 Reported Drug-Drug Cocrystals for Diuretics
7.6 Reported Drug-Drug Cocrystals for Miscellaneous Drugs
7.7 Patent Perspectives
7.8 Marketed Product
7.9 Conclusion
Acknowledgment
References
8 Scaling Up Pharmaceutical Cocrystals: Exploring Commercial Opportunities and Industrial Prospective
8.1 Introduction
8.2 Challenges and Considerations in Cocrystal Scale-Up
8.3 Promising Methods for Cocrystal Scale-Up
8.4 Quality-By-Design Approaches (QbD) in Cocrystallization Manufacturing
8.5 Process Analytical Technology in Scale-Up Cocrystallization Process
8.6 Commercial Opportunities for Cocrystals
8.7 Future Directions and Outlook
8.8 Conclusion
Acknowledgment
References
9 Pharmaceutical Cocrystals for Solubility Enhancement of Drugs
9.1 Introduction
9.2 Why Solubility Enhancement is Important?
9.3 Factors Affecting Solubility
9.4 Solubility and Bioavailability
9.5 Permeability and Cocrystallization
9.6 Enhancing Solubility through Cocrystallization
9.7 Conclusion
Acknowledgment
References
10 Pharmaceutical Cocrystals for Improving Physicochemical Properties of Drugs: Enhancement of Therapeutic Efficacy
10.1 Introduction
10.2 Preparation and Characterization Methods for Cocrystals
10.3 Enhancement of Therapeutic Efficacy with Cocrystals
10.4 Regulatory Considerations for Cocrystal Approval
10.5 Conclusion and Future Aspects
Acknowledgment
References
11 Application of Pharmaceutical Cocrystals in Improving Mechanical Properties and Stability
11.1 Introduction
11.2 Pharmaceutical Cocrystals Improve Mechanical Properties
11.3 Pharmaceutical Cocrystals Improving Stability
11.4 Conclusion and Future Prospective
Acknowledgments
References
12 Patents and Regulatory Considerations of Pharmaceutical Cocrystals
12.1 Introduction
12.2 Generic Concept of Pharmaceutical Cocrystals
12.3 Data Consideration Using Pharmaceutical Cocrystals for Abridged Application
12.4 Patent on Cocrystals
12.5 Conclusion
Acknowledgment
References
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Drug-drug and nutraceuticals cocrystals developed to date [58].
Table 1.2 Some commercial pharmaceutical cocrystals.
Chapter 2
Table 2.1 Various techniques required for the combinatorial approach to cocrys...
Chapter 3
Table 3.1 Different techniques employed for the characterization of cocrystals...
Table 3.2 Recent publications on cocrystal screening using molecular electrost...
Table 3.3 Recent publications of cocrystal screening from Hirshfeld surface an...
Table 3.4 Recent publications of cocrystal screening from Cambridge structural...
Table 3.5 Recent publications of cocrystal screening from COSMO-RS approach me...
Table 3.6 Recent publications of cocrystal screening from crystal structure pr...
Chapter 4
Table 4.1 Various techniques employed for cocrystal synthesis.
Chapter 5
Table 5.1 The details regarding the characterization of pharmaceutical cocryst...
Chapter 6
Table 6.1 Description of herbal cocrystals and conformers with their methodolo...
Chapter 7
Table 7.1 Various methods of preparation techniques for drug-drug cocrystals.
Table 7.2 Various instrumental techniques for characterization of DDCs.
Table 7.3 Various physicochemical techniques for characterization of DDCs.
Table 7.4 Salient outcomes of NSAID-based cocrystals.
Table 7.5 Anticancer drug–based cocrystals for the management of various cance...
Table 7.6 Cocrystals of anti-TB drugs and their enhanced properties.
Table 7.7 Enhanced therapeutic efficacy of diuretics with cocrystals.
Table 7.8 Cocrystals of various drugs for the management of numerous disorders...
Table 7.9 Patents related to drug-drug cocrystals.
Table 7.10 Drug-drug cocrystals in the market, brands, combinations, and compa...
Chapter 8
Table 8.1 Comparison of batch and continuous process.
Table 8.2 Process analytical technology used in the scale-up of cocrystallizat...
Table 8.3 Examples of cocrystal drugs that are currently on the market.
Chapter 9
Table 9.1 Solubility enhancement of herbal drugs by cocrystallization techniqu...
Table 9.2 Cocrystallization of the anticancer drug for improved activity.
Table 9.3 Drug-drug cocrystal for enhancement of activity.
Chapter 10
Table 10.1 Role of cocrystals in enhancing therapeutic efficacy of drugs.
Chapter 11
Table 11.1 Reported cocrystals for improving tabletability.
Table 11.2 Reported cocrystals for improving stability.
Chapter 12
Table 12.1 Various preparation techniques of pharmaceutical cocrystals.
Table 12.2 Comparison between USFDA and EMA on pharmaceutical cocrystals based...
Table 12.3 EMA and USFDA requirements for generic cocrystals.
Table 12.4 Various cocrystals approved under different regulatory authorities.
List of Illustrations
Chapter 1
Figure 1.1 The evolution of cocrystals over the years.
Chapter 2
Figure 2.1 Solid state polymorphism.
Figure 2.2 Parameters to be considered in coformer selection (adopted from Sin...
Figure 2.3 Schematic representation of the coformer selection process for the ...
Figure 2.4 Methods for characterizing pharmaceutical cocrystals.
Chapter 3
Figure 3.1 Depiction of various computational methods for the screening of coc...
Figure 3.2 Depiction of experimental approach for screening cocrystals.
Figure 3.3 Depiction of cocrystal preparation by (a). Solvent evaporation tech...
Figure 3.4 Electrostatic potential scale.
Figure 3.5 Molecular electrostatic potential surfaces measurement process.
Figure 3.6 Hirshfeld surface analysis of seselin-thiourea cocrystal in 1:1 sto...
Figure 3.7 Molecular complementarity analysis in cocrystals using the Cambridg...
Figure 3.8 COSMO-RS screening method.
Figure 3.9 Results of the COSMO-RS approach and another method of minoxidil wi...
Figure 3.10 Flowchart of the major component of FLEXCRYST software used for cr...
Figure 3.11 Recent trends in computational cocrystal screening in the scientif...
Figure 3.12 Data-driven machine learning algorithm for advanced cocrystal scre...
Chapter 4
Figure 4.1 Various techniques for the preparation of cocrystals.
Chapter 5
Figure 5.1 Various analytical approaches explored for the characterization of ...
Chapter 6
Figure 6.1 Herbal API and coformer forming the cocrystal formation.
Figure 6.2 Various methods of production of cocrystals.
Figure 6.3 Characterization method of cocrystals.
Chapter 8
Figure 8.1 Schematic of cocrystal manufacturing by fluid bed drying and contin...
Figure 8.2 Hot-melt extrusion for cocrystal manufacturing.
Figure 8.3 CMAs, CPPs, CQAs, and QTPP in cocrystallization manufacturing.
Chapter 9
Figure 9.1 Different solid pharmaceutical multi-components produced from API.
Chapter 10
Figure 10.1 Cocrystal preparation methods. Various techniques are used for the...
Figure 10.2 Schematic representation of the cocrystallization process and the ...
Figure 10.3 Coformer-drug interactions are the key to enhancing drug stability...
Figure 10.4 From discovery to delivery: The workflow of coformer selection and...
Guide
Cover Page
Table of Contents
Series Page
Title Page
Copyright Page
Preface
Begin Reading
Index
WILEY END USER LICENSE AGREEMENT
Pages
ii
iii
iv
xiii
xiv
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
Scrivener Publishing 100 Cummings Center, Suite 541J Beverly, MA 01915-6106
Publishers at Scrivener Martin Scrivener ([email protected]) Phillip Carmical ([email protected])
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
This edition first 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 For more information about Scrivener publications please visit www.scrivenerpublishing.com.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.
Wiley Global Headquarters 111 River Street, Hoboken, NJ 07030, USA
For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.
Limit of Liability/Disclaimer of Warranty While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials, or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read.
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
Preface
Pharmaceutical cocrystals represent an expanding field that has the potential to enhance drug safety, efficacy, and patient compliance. Cocrystals are multicomponent crystalline materials composed of two or more compounds, typically a drug and a coformer, held together by non-covalent interactions such as hydrogen bonding or van der Waals forces. Cocrystals offer numerous advantages, including improved solubility, bioavailability, stability, taste masking, drug release, hygroscopicity, and mechanical properties. However, the utilization of cocrystals requires careful consideration of factors such as scalability, regulatory compliance, and industrial feasibility. Addressing these challenges can help bridge the gap between laboratory research and commercialization.
This book provides a comprehensive overview of pharmaceutical cocrystals, addressing fundamental principles, practical considerations, and the regulatory landscape. The content is organized into distinct chapters covering the historical background, design, structural characteristics, and preparation techniques of cocrystals. Additionally, a designated chapter discusses computational methods for screening and characterizing pharmaceutical cocrystals. The book also explores the concept of herbal cocrystals and the commercialization of pharmaceutical cocrystals.
Various applications of pharmaceutical cocrystals—such as enhancing solubility, stability, mechanical properties, and therapeutic efficacy of active pharmaceutical ingredients—are thoroughly discussed using the latest updated literature. Moreover, the regulatory perspectives surrounding cocrystals are also examined in detail.
We would like to extend our heartfelt thanks to Martin Scrivener and Scrivener Publishing for their belief in this project and their kind cooperation throughout the process. We also gladly acknowledge all the sources utilized in the curation of this book. Furthermore, we extend our gratitude to the authors, colleagues, and others who contributed to and supported the compilation of this book. The content has been deliberately chosen to cater to a diverse audience, including academics, pharmaceutical experts, and students interested in drug formulation and delivery. We hope this book will inspire further study and innovation in the field of pharmaceutical cocrystals.
Prof. (Dr.) Inderbir Singh
Prof. (Dr.) Subrata Mallick
Ms. Ritu Rathi
1Pharmaceutical Cocrystals: Introduction, History and Applications
Oluwatoyin A. Odeku* and Olufunke D. Akin-Ajani
Department of Pharmaceutics and Industrial Pharmacy, University of Ibadan, Ibadan, Nigeria
Abstract
Cocrystals represent an expanding field of pharmaceutical sciences that offers an innovative approach to improving the physicochemical properties of active pharmaceutical ingredients (APIs). Cocrystals are a unique type of solid-state crystalline substance created by the interaction of two or more molecular species, usually an API and a coformer, joined together by noncovalent interactions, without forming chemical bonds. Unlike traditional drug formulations, cocrystals use purposeful molecular design to manufacture precise interactions between components, resulting in distinct crystal shapes and characteristics. Cocrystals offer the potential to increase drug solubility, bioavailability, and stability, mask taste, boost flavor, and control the release of drugs from formulations. In addition, cocrystals can facilitate the co-formulation of multiple drugs with complementary pharmacological activities, and they serve as versatile carriers or excipients in drug delivery systems such as nanoparticles, liposomes, or microspheres, enabling drug targeting. This chapter gives a background of cocrystals and their application in various aspects of drug development and delivery, as well as some marketed cocrystal formulations.
Keywords: Cocrystals, bioavailability, solubility, stability, marketed cocrystal formulations
1.1 Introduction
Cocrystal is a supramolecular chemistry idea that is gaining popularity among pharmaceutical and chemical researchers, as well as drug regulatory bodies. The primary reason for this is its capacity to affect the physicochemical characteristics of active medicinal components [1]. During pharmaceutical product development, formulators must maximize the physicochemical qualities of active medicinal components.
The European Medicines Agency (EMA) has defined cocrystals as “homogenous (single phase) crystalline structures made up of two or more components in a definite stoichiometric ratio where the arrangement in the crystal lattice is not based on ionic bonds (as with salts) and the components of a cocrystal may nevertheless be neutral as well as ionized” [2]. Cocrystals have been defined by the United States Food and Drug Administration (USFDA) as “Crystalline materials composed of two or more different molecules, typically API and cocrystal formers (coformers), in the same crystal lattice in a defined stoichiometric ratio” [3]. They were characterized as a discrete category of innovative, crystalline compounds that may affect the physicochemical properties of APIs, signifying the start of a new era in the domains of crystal engineering and manufacture [4]. Cocrystals consist of an active pharmaceutical ingredient and one or more distinct coformers that are solid at ambient temperature [5]. They are preferred over amorphous API forms or solid dispersions because they offer the solubility benefits of high-energy solids and a crystalline structure with strong thermal stability [6].
A coformer is described as “a component that interacts non-ionically with the active medicinal substance in the crystal lattice, which is typically non-solvent and is not volatile” [7]. The coformer selection has a significant impact on the final cocrystal properties. When synthesized as a cocrystal, the coformers can alter the API’s stability and solubility by causing modifications to the structure of its crystals [8]. Unlike traditional drug formulations, cocrystals use purposeful molecular design to manufacture precise interactions between components, resulting in distinct crystal shapes and characteristics. Cocrystals can be formed by interactions, including van der Waals forces, p-stacking, and hydrogen bonding. This excludes API solvates and hydrates from the category of cocrystals. However, cocrystals may comprise one or more water molecules or solvents in the crystal lattice [9]. Cocrystals frequently rely on hydrogen-bonded assemblies formed by neutral drug molecules and additional components [4]. For nonionizable substances, cocrystals increase medicinal qualities by modifying their mechanical behavior, solubility, water absorption, dissolution rate, bioavailability, and stability [10–12].
The major distinction between solvates and cocrystals rests in the physical condition of their constituents [13]. Crystals are known as solvates if one of the constituents is liquid at ambient temperature and cocrystals if both constituents are solid at ambient temperature. Solvates are prevalent because they develop as an accidental outcome of crystallization from solution and can boost the medicine dissolution rate, as demonstrated by spironolactone solvate [14]. Cocrystals have a more stable crystalline form without having to make or break covalent bonds, and both weakly ionizable and nonionizable drug molecules can be combined to form cocrystals. They have several potential commercial pharmaceutical and food applications [15]. Cocrystals have the potential to improve medication solubility, stability, bioavailability, and other essential properties important for medicinal efficacy [16].
1.2 History
Cocrystals have a history dating back to the early nineteenth century, yet their notion and understanding have developed greatly over time (Figure 1.1). The development of cocrystals may be traced back to 1844 when Friedrich Wöhler mixed quinone and hydroquinone solutions to create quinhydrone, a green solid with a 1:1 stoichiometry between the reactants [17, 18]. For several decades, there remained debate regarding the actual nature of the chemical composition of Wöhler’s product, and it took more than a century to verify the content and structure of this crystalline substance using single-crystal X-ray diffraction [19]. The introduction of X-ray crystallography in the early 20th century transformed the study of crystal structures, revealing insights into the molecular configurations inside cocrystals.
Figure 1.1 The evolution of cocrystals over the years.
A close evaluation of the literature from the latter part of the 19th and early 20th centuries reveals the existence of practically hundreds of cocrystals (even though they would continually appear under various names). The concept of cocrystals evolved in the later part of the 20th century when researchers defined them as “solid-state structures made up of two or more components held together by noncovalent interactions.” The area of crystal engineering sprang to prominence, with an emphasis on designing and manipulating crystal formations to attain certain qualities and functionality. Researchers investigated the use of cocrystals in medicines, noting their capacity to increase medication solubility, stability, and other characteristics. Stahly has published an excellent comprehensive summary of cocrystals reported before the year 2000 [18].
The 21st century saw an increase in research on cocrystals, notably in the pharmaceutical business. The emphasis on cocrystals as an easily recognized research owes a great deal to Etter’s foundational work in the late 1980s and early 1990s [20, 21]. In 1984, Desiraju and Steiner presented a systematic definition of hydrogen-bonded molecular complexes, which helped to formalize cocrystal notions in a book on “crystal engineering” [22].
Cocrystals attracted attention for their capacity to handle issues such as medication solubility, bioavailability, polymorphism, and intellectual property protection [15]. Several successful examples of cocrystal-based pharmaceuticals hit the market, emphasizing the practical applicability of cocrystals in pharmaceutical sciences.
1.3 Applications of Cocrystals in Pharmaceutical Sciences
Cocrystals have a wide range of pharmaceutical uses, providing answers to difficulties in standard medication formulations. Some important pharmaceutical uses of cocrystals include the following.
1.3.1 Enhanced Solubility
Many drugs have been revealed to have low solubility, which can reduce their bioavailability and therapeutic effectiveness. Approximately 70% of new drugs belong to the class II Biopharmaceutical Classification System (BCS; low solubility/high permeability) or class IV BCS (poor solubility/low permeability) [23, 24]. Since the gastrointestinal (GI) system has varied pH in different parts, drugs taken orally exhibit varying solubility in GI fluids at different pH, resulting in unpredictable and variable absorption and the inability to evaluate the drug’s efficacy and safety appropriately. Hence, restricted drug solubility is a key challenge in developing oral drug delivery systems [25].
Cocrystallization with proper coformers can improve API solubility by changing the crystal lattice structure, resulting in faster dissolution and greater absorption in the body [26]. Synthesizing salts and cocrystals boosted the solubility of ketoconazole, an antifungal medication, by 53 and 100 times, respectively, compared to ketoconazole [27]. Thus, cocrystals resulted in better drug solubility than the salt form.
The formulation of pterostilbene cocrystals with piperazine resulted in a sixfold increase in solubility, while pterostilbene-glutaric acid cocrystals led to the fast precipitation of the drug due to glutaric acid’s high solubility [28]. Cocrystals of the anticancer drug 6-mercaptopurine with nicotinamide exhibited two times greater solubility than pure drug [29]. Apixaban cocrystals exhibited improved solubility of about twofold, and the cocrystals showed a faster dissolution rate when compared to pure drugs [30]. Studies have shown that combining curcumin with resorcinol and pyrogallol enhanced its solubility significantly [31]. Curcumin-resorcinol and curcumin-pyrogallol cocrystals were shown to dissolve 5 and 12 times faster than pure curcumin, respectively.
1.3.2 Improved Bioavailability
Currently, several newly marketed drugs experience the challenges of poor water solubility as well as poor bioavailability [32, 33]. The limited oral bioavailability of medications makes developing new drugs a considerable issue. Crystal engineering is critical in developing and manufacturing pharmaceutical cocrystals with increased oral bioavailability and aqueous solubility, leading to therapeutic efficacy [34].
In vivo studies of the bioavailability of baicalein in rats showed that the formation of cocrystals of baicalein with nicotinamide resulted in increased oral bioavailability of baicalein [35]. The peak plasma concentration (Cmax) and area under the curve (AUC) for the baicalein-nicotinamide cocrystals were 2.49 and 2.80 times higher, respectively, than the pure drug [36]. The hydrotropic solubilization of nicotinamide improves the bioavailability of cocrystals as a result of the concurrent improvement in solubility and dissolution of baicalein. In a pharmacokinetic investigation carried out on beagle dogs, apixaban-oxalic acid cocrystals demonstrated better oral bioavailability than pure drugs [30]. Meloxicam-aspirin cocrystals exhibited a 12-fold increase in onset of action compared to the pure drugs in rats, as well as higher oral bioavailability [37]. Furthermore, cocrystals of 6-mercaptopurine, categorized as a BCS class II medicine, with isonicotinamide, exhibited faster dissolution and greater oral bioavailability (168.7%) than the pure drug in rats [29].
1.3.3 Stability Enhancement
Cocrystallization can increase an API’s physical stability, eliminating polymorphism concerns such as unwanted phase shifts during storage and processing. Cocrystals can improve the chemical stability of APIs, shielding them from deterioration caused by environmental variables such as moisture, heat, and light.
Stability studies are usually conducted throughout the development of cocrystals, including solution, chemical, and thermal stability, relative humidity (RH) stress, and photostability. Indomethacin-saccharin cocrystals demonstrated negligible water sorption in RH investigations, and theophylline cocrystals also showed RH stability at varied RH with distinct coformers (maleic, glutaric, malonic, and oxalic acid) for diverse periods. The study confirmed an increase in the physical quality and stability of the drugs, particularly by avoiding hydrate formation [38].
The chemical stability of the cocrystal is usually done using accelerated stability conditions to investigate whether there are any changes or chemical deteriorations in the formulation. There were very few publications on cocrystals’ chemical stability. Cocrystals of glutaric with API exhibited no degradation and high physical and chemical stability under thermal stress and RH for 2 months [39]. Indomethacin-saccharin cocrystals also demonstrated negligible moisture sorption during stability studies, and no separation or conversion arose under trial circumstances [40].
Solution stability is a crucial parameter for cocrystal growth and it provides a better knowledge of cocrystal behavior in the release medium [41]. A study of the stability of carbamazepine cocrystals in water showed that cocrystals made with poorly water-soluble coformers stayed as such in the solution for 20 to 48 hours, whereas cocrystals with highly water-soluble coformers transformed to dihydrates [42]. Caffeine/oxalic acid cocrystals demonstrated superior stability at all RH up to 98% for 7 days with no noticeable change occurring in the physical structure compared to when the materials were suspended in aqueous medium for two days at ambient temperature [43]. Carbamazepine and saccharine cocrystals suspended in equal parts in water for 24 hours showed good stability as indicated by the presence of only the cocrystals in the solution, and no other form was discovered [44]. Nitrofurantoin cocrystals prepared with various coformers showed greater photostability than pure drug and physical mixtures. Cocrystallization can minimize the photodegradation of light-sensitive drugs since all cocrystals demonstrated little deterioration (<3%) after 168 hours [45].
1.3.4 Taste Masking and Palatability
Taste-masking methods are utilized to mask or overcome the bitter or unpleasant taste of active medicinal constituents/drugs, resulting in patient acceptance and compliance, particularly for pediatric and geriatric patients [46]. Sweetener-based coformers have been used to mask the taste of bitter drugs. The coformer interacts with medicinal molecules to produce single-phase crystalline assemblies via intermolecular interactions [47]. An innovative cocrystal of paracetamol and trimethylglycine with a sweeter taste enhanced compressibility, and dissolution rate than pure paracetamol has been reported [48]. Likewise, the sweetness of theophylline was boosted by saccharin by producing a cocrystal, thereby enhancing stability and assuring continuous drug release [49]. However, increased sweetness does not always indicate excellent masking of bitter taste; rather, the flavor is a mix of bitter and sweet, which could be of inferior quality. Ogata et al. discovered that certain acids that are not sweeteners can have beneficial effects on the taste masking of bitter drugs like propiverine [50]. Hence, cocrystals can mask the taste of bitter drugs due to the inability of human taste receptors to register the taste of cocrystals formed from the molecular aggregation of drug and coformer [51]. As a result, some coformers, despite their lack of sweetness, may successfully conceal the bitter taste of medications due to their propensity to form tiny transitory clusters with drug particles when dissolved in the mouth.
The strongly unpalatable and bitter taste of nevirapine, an antiretroviral drug, used in newborns and children, particularly in sub-Saharan Africa, has been masked with the cocrystals using maleic acid, benzoic acid, and glutaric acid as coformers [51]. The data showed that the taste of the pure coformer and solution aggregation play essential roles in taste masking.
1.3.5 Controlled Release
Cocrystals can be designed to alter drug release rates, enabling controlled or sustained release formulations that have improved therapeutic outcomes. Cocrystallization has been shown as a promising strategy for producing controlled-release formulations of olaparib, a PARP1/2 inhibitor with blockbuster anticancer activity, that have a shorter half-life and limited dose-limiting toxicity than marketed immediate-release formulations [52]. Sustained-release cocrystals of olaparib with kaempferol and the cocrystal solvate of olaparib with quercetin showed 21.4% and 18.6% reduction in the dissolution rate, respectively, in comparison to the original drug. Furthermore, the cocrystals exhibited increased pharmacological activity and inhibited ovarian cancer cells significantly more effectively than the pure drug.
Human insulin has been cocrystallized at predetermined proportions with octanoyl-Nε-LysB29-human insulin (C8-HI), a lipophilic modified insulin derivative [53]. The cocrystal mimics the neutral protamine Hagedorn (NPH) cocrystals generated by human insulin, generally used as a long-acting insulin element in diabetes treatment. The release rates of the cocrystal can be controlled, in vitro and in vivo, by altering the quantities of the two insulin contents. The cocrystal ratio-dependent release rate provides a successful method to regulate insulin pharmacodynamics, suggesting that a crystalline protein matrix is capable of supporting a chemical alteration that changes the rate of dissolution of the crystals in an intensely beneficial manner while remaining adequate to maintain the medicinal quality and the therapeutic effects of the parent drug.
1.3.6 Increased Tabletability
Tabletability denotes a material’s capacity to be converted to a compact. Tabletability, compatibility, and crystal packing are critical characteristics in preformulation. Cocrystallization with appropriate coformers can alter these characteristics to improve the tabletability of poorly compressible pharmaceutical powders. The tabletability of resveratrol, a poorly compressible drug, has been increased by cocrystallization [54]. Resveratrol cocrystals with coformers 4-amino benzamide and isoniazid exhibited improved tabletability, leading to the formation of tablets with acceptable tensile strength even at low compression pressure.
Cocrystallization can be used to alter the mechanical characteristics of medicinal compounds. Vanillin isomers cocrystals with the coformer have demonstrated greater tabletability than single materials [55]. Paracetamol is poorly compressible, and wet granulation which is a tedious process requiring the use of binders is used to overcome this problem. Studies have shown that paracetamol cocrystals prepared using caffeine as a coformer using techniques such as solvent evaporation, liquid-assisted grinding, dry grinding, and the addition of anti-solvent improved the compression and the mechanical properties of paracetamol tablets [56].
1.3.7 Combination Therapy
Cocrystals allow for the formulation of multiple drugs in a unit dosage form, facilitating combination therapy and synergistic outcomes. Cocrystals consisting of two or more active ingredients, generally known as drug-drug, multi-drug, or multi-API cocrystals, are made feasible by noncovalent connections between the active drugs, which enables the drugs to retain their activity [57]. The two or more therapeutically useful elements are bound in a stoichiometric equilibrium in a single crystal lattice structure where they can interact primarily through nonionic interactions and, on some occasions, through a hybrid interaction with or without the inclusion of solvate molecules [58].
Furthermore, drug-drug cocrystals provide possible answers to restrictions like solubility, stability, and chemical instabilities between the APIs, which are frequently encountered in standard combination therapy [57]. Table 1.1 presents some multi-drug cocrystals developed to date, as well as their preparation techniques and uses.
Table 1.1 Drug-drug and nutraceuticals cocrystals developed to date [58].
Drug combination
Method of preparation
Indication
Refs
Theophylline–phenobarbital (2:1)
Distillation
Sedativehypnotic and Antiasthmatic
[
58
]
Sulfadimidine–aspirin (1:1)
Solvent evaporation
NSAID and Antibacterial
[
74
]
Sulfadimidine–4-ASA (1:1)
Antibacterial
[
74
]
Theophylline–5-FU (2:1)
Antiasthmatic and anticancer
[
75
]
Trimethoprim–sulfadimidine (1:1, 1:2)
Antibacterial
[
76
,
77
]
Trimethoprim–sulfamethoxypyridazine (1:1)
Heating at boiling point followed by instant cooling
Antibacterial
[
78
]
Tetroxoprim–sulfametrole (1:1)
Cogrinding and solvent evaporation
Antibacterial
[
79
,
80
]
Piracetam–gentisic acid (1:1)
Co-grinding and solvent evaporation
Nootropic agent and NSAID
[
81
]
Amoxicillin trihydrate–potassium clavulanate (3:7, 5:5, 7:3)
Melting at 50°C for 30 min
Antibacterial and β-lactamase inhibitor
[
82
]
Lamivudine–zidovudine (1:1)
Solvent evaporation
Antiviral
[
83
]
Theophylline–gentisic acid (1:1)
Thermal-assisted solvent evaporation
Antiasthmatic and NSAID
[
84
]
Ethenzamide–gentisic acid (1:1)
Solvent evaporation
Both drugs are NSAIDs, the latter also has anti-ageing properties
[
49
]
Sulfamethazine–theophylline (2:1)
Antibacterial and antiasthmatic
[
85
]
Meloxicam–aspirin (1:1)
Solution crystallization, solvent and slurry drop grinding methods
NSAIDs
[
37
]
Isoniazid–4-ASA (1:1)
Solvent drop grinding
Antitubercular drugs
[
86
]
Pyrazinamide–4-ASA (1:1)
Carbamazepine–salicylic acid (1:1)
Unexpected in the presence of moisture
Antiepileptic and antiinflammatory
[
87
]
Pyrazinamide–diflunisal (1:1)
Ball mill grinding
Antitubercular and NSAID
[
88
]
Curcumin–pyrogallol (1:1)
Liquid-assisted manual grinding
Anticancer
[
83
]
Aceclofenac–paracetamol (1:1)
Various methods
NSAIDs
[
89
]
Isoniazid–2-chloro-4-nitro benzoic acid (1:1)
Solvent evaporation
Antitubercular and antiviral compounds
[
90
]
Piracetam–lithium chloride (1:1)
Solvent evaporation and grinding
Nootropic agent and moodstabilizing agent
[
91
]
Furosemide–pentoxifylline (1:1)
Solvent evaporation
Loop diuretic; the latter is used for the treatment of intermittent claudication
[
92
]
Pyrimethamine–carbamazepine (1:1)
Antimalarial and antiepileptic
[
93
]
Pyrimethamine–theophylline (1:1)
Solvent evaporation
Antimalarial and antiasthmatic
Ciprofloxacin–norfloxacin (1:1)
Antibacterial
[
94
]
Paracetamol–indomethacin and mefenamic acid (1:1)
NSAIDs
[
95
]
Sildenafil–aspirin (1:1)
Antihypertensive and NSAID
[
96
]
Diclofenac and Diflunisal–Theophylline (1:1)
Solvent evaporation and Solvent drop grinding
Antiasthmatic and NSAID
[
97
]
Dapsone–sulfanilamide flavone, luteolin, caffeine and benzothiazolone (1:1)
Solution crystallization
Antileprotic, antibacterial and antioxidants
[
98
]
Carbamazepine–ibuprofen
Solution crystallization
Antiepileptic and NSAID
[
99
]
Abbreviations: 4-ASA, 4-aminosalicyic acid; NSAID, Non-steroidal anti-inflammatory agent.
1.4 Challenges in the Development of Cocrystals
The fundamental problem in developing therapeutic cocrystals is the choice of appropriate coformers. Given the vast number of potential coformers, it is necessary to design an approach to screening that can predict the most probable coformers [59]. The prospective coformers should subsequently be evaluated experimentally to see whether cocrystals occur [60]. Owing to the expanded study on the subject of cocrystals over the past few decades, enough evidence has been amassed to estimate the likely coformers.
Some of the effective methods for screening coformers include hydrogen bond propensity, Hansen solubility parameter, Cambridge Structural Database, pKa rule, and supramolecular synthon approach. However, there is a need to develop more efficient screening techniques for the fruitful implementation of the use of cocrystals in drug development in the pharmaceutical sector [61].
A variety of cocrystallization procedures can be employed to screen cocrystals. Solvent-based cocrystallization procedures present obstacles, such as the selection of the proper solvent, adjustments in the solubility of active drug and coformer in the selected solvent (compatible and incompatible), concentration effects, and the selection of appropriate cooling and heating profiles [62]. The solid-state grinding approach of screening cocrystals outperforms solvent-based methods. However, occasionally phase transitions in medicinal cocrystals occur in cocrystals prepared by solid-state grinding [63].
The chance of cocrystal separation owing to the contact with other excipients, the substitution of coformers by excipients, alteration of the cocrystal stoichiometry, and its transformation to a poorly soluble form of the parent drug during dissolution needs to be addressed during the cocrystal preparation [64, 65].
Sometimes, the selected coformers may not generate cocrystals with appropriate processability, and physical, chemical, and pharmacokinetic qualities [41]. The obstacles encountered in the production and evaluation of cocrystals include the formation of hybrids, salts, or solvates, polymorphism of cocrystals, and alteration to the less soluble form of the parent drug [66–68]. In addition, pH, surface active agent concentration, solubility and dissolution rates, and inherent instability of cocrystals in the solution phase can hinder the successful formulation [69, 70].
Industrial cocrystallization processes must be scalable, flexible, and environmentally friendly, and the cocrystal quality should not be jeopardized by commercial-scale manufacture. However, there are no recognized strategies for scaling up the production of medicinal cocrystals. Methods such as hot-melt extrusion, supercritical fluid technologies spray congealing, and spray drying are now being used for commercial scale-up of cocrystal production. An additional obstacle in the large-scale production of cocrystals is the reliable regulation of stoichiometry [71] and the lack of correlation features in vitro and in vivo, which can drastically shorten the development period [72, 73].
Table 1.2 Some commercial pharmaceutical cocrystals.
Commercial name
Approval
API
Coformer
Improved property
Indication
Manufacturer
References
Suglat
®
Japan 2014
Ipragliflozin
l-Prolin
Stability against hydrate formation
Diabetes
Kotobuki Pharmaceuticals, Nishina, Shizuoka, Japan, and Astellas Pharma, Tokyo, Japan
[
100
]
Cafcit
®
USFDA 1999
Caffeine
Citric acid
Improved dissolution behavior and lower hygroscopicity
Infantile apnoea
Hikma Pharmaceuticals Plc, London, UK
[
100
–
102
]
Entresto
®
USFDA 2015
Valsartan
Sacubitril
Improved pharmacokinetics and bioavailability
Heart failure
Novartis, Basel, Switzerland
[
103
,
104
]
Lamivudine/zidovudine Teva
®
EMA 2011
Lamivudine
Zidovudine
Improved solubility, stability, and bioavailability
HIV infection
Teva Pharma B.V., Tel Aviv-Yafo, Israel
[
76
,
102
,
105
]
Steglatro
®
USFDA 2017
Ertugliflozin
Z-Pyroglutamic acid
Improved stability
Diabetes
Pfizer, New York, USA
[
106
,
107
]
Depakote
®
USFDA 1983
Valproic acid
Valproate sodium
Improved stability
Epilepsy
Abbott Laboratories, Illinois, USA
[
100
,
108
]
Lexapro
®
USFDA 2002
Escitalopram
Oxalate
Improved stability of API
Anxiety and depression
Allergan Inc., Dublin, Ireland
[
109
]
ESIX-10
®
USFDA 2009
Escitalopram
Oxalate
Improved stability of API
Anxiety and depression
Sag Health Science Pvt Ltd., New Delhi, India
[
59
,
83
]
Beta-chlor
®
USFDA 1963
Chloral hydrate
Betaine
Improved thermal stability
Sedation
Mead Johnson, Illinois, USA
[
100
,
110
]
Abilify
®
USFDA 2002
Aripiprazole
Fumaric acid
Improved the dissolution rate and solubility
Schizophrenia
Otsuka Pharmaceuticals, Tokyo, Japan
[
111
,
112
]
Odomzo
®
USFDA 2015
Sonidegib
Phosphoric acid
Improve its solubility and bioavailability
Basal cell carcinoma
Sun Pharma Global, Mumbai, India
[
83
,
113
,
114
]
Mayzent
®
USFDA 2019
Siponimod
Fumaric acid
Improved bioavailability and aqueous solubility
Multiple sclerosis
Novartis, Basel, Switzerland
[
115
,
116
]
Seglentis
®
USFDA 2021
Celecoxib
Tramadol
Improved stability
Acute pain
Kowa Pharmaceuticals, Alabama, USA
[
116
,
117
]
Dimenhydrinate
USFDA 1982 (ANDA)
Diphenhydramine
8-Chlorotheophylline
Enhanced solubility and pharmacokinetics
Motion sickness
Watson Laboratories Inc., New Jersey, USA
[
37
,
118
]
Mobic
®
USFDA 2000
Meloxicam
Aspirin
Enhanced solubility, improved bioavailability, stabilized the API, and provided synergistic therapeutic effects
Osteoarthritis and rheumatoid arthritis.
Boehringer Ingelheim Pharmaceuticals
[
37
]
Zafatek
®
Japan 2015
Trelagliptin
Succinic acid
Improved solubility
Diabetes
Takeda Pharmaceutical Company Limited, Tokyo, Japan
Ibrutinib
Tentative approval
Ibrutinib
Fumaric acid
Improved stability
Anticancerchronic lymphocytic leukemia
Teva Pharmaceutical Industries Ltd., Tel Aviv-Yafo, Israel
[
59
]
1.5 Marketed Products
The market acceptance of cocrystallized pharmaceuticals demonstrates the effective implementation of cocrystallization in the pharmaceutical business. Some of the marked products are presented in Table 1.2.
1.6 Future of Pharmaceutical Cocrystals
The research conducted over the previous decade has helped to shape several elements of cocrystallization, including cocrystal screening, characterization, manufacturing processes, and development. The versatility of cocrystals offers opportunities beyond traditional pharmaceuticals. Exploring their use in nutraceuticals, cosmetics, and agrochemicals can open new markets and applications. Tailor-made cocrystals can find applications in customized medicines for individual patients based on their unique genetic and metabolic profiles, improving personalized treatment plans. Cocrystals could be used in precision medicine to create more precise dosing regimens and drug combinations, thereby optimizing therapeutic outcomes and minimizing side effects. It could also be used as a multifunctional carrier that can deliver multiple drugs simultaneously, improving treatment efficacy for complex diseases. They can also be integrated into advanced drug delivery systems like nanoparticles, liposomes, and microspheres for targeted and controlled release.
In addition, the recent advances in green and sustainable chemistry can be utilized to develop sustainable green and eco-friendly synthesis methods for cocrystals, thereby reducing the environmental impact of pharmaceutical manufacturing. These innovative processes minimize waste and energy consumption, contributing to a more sustainable pharmaceutical industry.
While the potential of cocrystals is immense, regulatory hurdles and market acceptance remain significant challenges. A continuous dialog with regulatory bodies and transparent clinical data can help mitigate these challenges. The regulatory strategies from agencies (USFDA and EMA) on medicinal cocrystals demonstrate their recognized significance in the creation of better candidates with superior properties [59]. There is a need to establish comprehensive regulatory guidelines for the approval and commercialization of cocrystals, thereby facilitating their entry into the market.
The pharmaceutical manufacturing and investigations of cocrystals should also focus on the standardization of the synthetic procedures, identification, and improvement of the properties that impact the quality of cocrystals including the reproducibility, yield and purity, and integration of cocrystal screening and research into the drug development process. Technological advancements in crystallography, computational chemistry, and material science will continue to drive the evolution of cocrystals, enabling more sophisticated and effective drug formulations. Cocrystals have the potential to make a global impact by improving drug accessibility and efficacy in developing regions. Addressing affordability and production scalability will be crucial for this vision.
The future of cocrystals in pharmaceutical sciences is promising, with the potential to revolutionize drug development and delivery. By embracing interdisciplinary collaboration, leveraging advanced technologies, and addressing regulatory and market challenges, the pharmaceutical industry can harness the full potential of cocrystals to improve patient outcomes and create a more sustainable and innovative future in drug development.
1.7 Conclusion
Cocrystals exhibit promising outcomes in altering and enhancing the physicochemical properties of API. Several cocrystal formation techniques are available, ranging from lab-scale synthesis to continuous operations at the industrial level. This article provides a brief overview of several approaches for cocrystal formation, coformer selection, and cocrystal characterization, along with appropriate examples. Cocrystals are gaining popularity in the pharmaceutical industry owing to their enhanced physicochemical qualities, as well as the availability of patent rights for cocrystals, which is critical for huge pharma businesses to earn money. Pharmaceutical cocrystals are projected to become a more common method of pharmaceutical research once the way for their creation is established and their advantages have been demonstrated.
Acknowledgment
The authors are very thankful to the Department of Pharmaceutics and Industrial Pharmacy, University of Ibadan for providing infrastructural and library facilities.
References
1. Rathi, R., Kaur, S., Singh, I., A Review on Co-crystals of Herbal Bioactives for Solubility Enhancement: Preparation Methods and Characterization Techniques.
Cryst. Growth Des.
, 22, 3, 2023–42, 2022.
2. E. M. Agency, European Medicines Agency, Amsterdam, The Netherlands, 2015.
3. USFDA, 2015,
https://www.fda.gov/files/drugs/published/Regulatory-Classification-of-Pharmaceutical-Co-Crystals.pdf
.
4. Almarsson, O. and Zaworotko, M.J., Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines?
Chem. Commun. (Camb.)
, 7, 1889–1896, 2004.
5. Yadav, A.V., Shete As Fau - Dabke, A.P., Dabke Ap Fau - Kulkarni, P.V., Kulkarni Pv Fau - Sakhare, S.S., Sakhare, S.S., Co-crystals: a novel approach to modify physicochemical properties of active pharmaceutical ingredients.
Indian J. Pharm. Sci.
, 71, 359–370, 2009.
6. Issa, N., Barnett, S.A., Mohamed, S., Braun, D.E., Copley, R.C., Tocher, D.A., Price, S.L., Screening for cocrystals of succinic acid and 4-aminobenzoic acid.
CrystEngComm
, 14, 2454–2464, 2012.
7. Bhutani, P., Joshi, G., Raja, N., Bachhav, N., Rajanna, P.K., Bhutani, H., Paul, A.T., Kumar, R., US FDA approved drugs from 2015–June 2020: a perspective.
J. Med. Chem.
, 64, 2339–2381, 2021.
8. Singh, M., Barua, H., Jyothi, V., Dhondale, M., Nambiar, A.G., Agrawal, A., Kumar, P., Shastri, N.R., Kumar, D., Cocrystals by Design: A Rational Coformer Selection Approach for Tackling the API Problems.
Pharmaceutics
, 15, 1161, 2023.
9. Peterson, M.L., Hickey Mb Fau - Zaworotko, M.J., Zaworotko Mj Fau - Almarsson, O., Almarsson, O., Expanding the scope of crystal form evaluation in pharmaceutical science.
J. Pharm. Pharm. Sci.
, 9, 317–326, 2006.
10. Rodríguez-Hornedo N, Nehm SJ, Jayasankar A, Cocrystals: design, properties and formation mechanisms, in:
Encyclopedia of Pharmaceutical Technology, 3rd ed
, pp 615–635, Taylor & Francis, London, 2007.
11. Taylor, L.S. and Zografi, G., Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions.
Pharm. Res.
, 14, 1691–1698, 1997.
12. Tong, P. and Zografi, G., A study of amorphous molecular dispersions of indomethacin and its sodium salt.
J. Pharm. Sci.
, 90, 1991–2004, 2001.
13. Morissette, S.L., Fau, A.O., Peterson, M.L., Remenar, J.F., Read, M.J., Lemmo, A.V., Ellis, S., Cima, M.J., Gardner, C.R., High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids.
Adv. Drug Deliv. Rev.
, 56, 275–300, 2004.
14. Hickey, M.B., P.M.L., S.L.A., M.S.L., V.A., Guzmán, H., Remenar, J.F., Zhang, Z., Tawa, M.D., Haley, S., Zaworotko, M.J., Almarsson, O., Performance comparison of a co-crystal of carbamazepine with marketed product.
Eur. J. Pharm. Biopharm.
, 67, 112–119, 2007.
15. Steed, J.W., The role of co-crystals in pharmaceutical design.
Trends Pharmacol. Sci.
, 34, 185–193, 2013.
16. Gadade, D.D. and Pekamwar, S.S., Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development.
Adv. Pharm. Bull.
, 4, 479–494, 2016.
17. Wohler, F., Untersuchungen über das Chinon.
Ann. Chem. Pharm.
, 51, 145–163, 1844.
18. Stahly, G.P., A Survey of Cocrystals Reported Prior to 2000.
Cryst. Growth Des.
, 9, 4212–4229, 2009.
19. Matsuda, H., Osaki, K., Nitta, I., Crystal Structure of Quinhydrone, C12H10O4.
Bull. Chem. Soc. Jpn.
, 31, 611–620, 1958.
20. Etter, M.C., Urbanczyk-Lipkowska, Z., Zia-Ebrahimi, M., Panunto, T.W., Hydrogen bond-directed cocrystallization and molecular recognition properties of diarylureas.
J. Am. Chem. Soc.
, 112, 8415–8426, 1990.
21. Aakeröy, C.B. and Sinha, A.S.,
Co-crystals: Preparation, Characterization and Applications
, C.B. Aakeröy and A.S. Sinha (Eds.), pp. 1–32, The Royal Society of Chemistry, London, UK. 2018.
22. Desiraju, G.R. and Parshall, G.W., Crystal engineering: the design of organic solids.
Mater. Sci. Monogr.
, 54, XIV–312, 1989.
23. Babu, N.J. and Nangia, A., Solubility advantage of amorphous drugs and pharmaceutical cocrystals.
Cryst. Growth Des.
, 11, 2662–2679, 2011.
24. Fong, S.Y.K., Ibisogly, A., Bauer-Brandl, A., Solubility enhancement of BCS Class II drug by solid phospholipid dispersions: Spray drying versus freeze-drying.
Int. J. Pharm.
, 496, 382–391, 2015.
25. Hisada, N., Takano, R., Takata, N., Shiraki, K., Ueto, T., Tanida, S., Kataoka, M., Yamashita, S., Characterizing the dissolution profiles of supersaturable salts, cocrystals, and solvates to enhance
in vivo
oral absorption.
Eur. J. Pharm. Biopharm.
, 103, 192–199, 2016.
26. Kumar, S. and Nanda, A., Pharmaceutical Cocrystals: An Overview.
Indian J. Pharm. Sci.
, 79, 858–871, 2017.
27. Martin, F.A., Pop, M.M., Borodi, G., Filip, X., Kacso, I., Ketoconazole salt and co-crystals with enhanced aqueous solubility.
Cryst. Growth Des.
, 13, 4295–4304, 2013.
28. Bethune, S.J., Schultheiss, N., Henck, J.-O., Improving the poor aqueous solubility of nutraceutical compound pterostilbene through cocrystal formation.
Cryst. Growth Des.
, 11, 2817–2823, 2011.
29. Wang, J.-R., Yu, X., Zhou, C., Lin, Y., Chen, C., Pan, G., Mei, X., Improving the dissolution and bioavailability of 6-mercaptopurine via co-crystallization with isonicotinamide.
Bioorg. Med. Chem. Lett.
, 25, 1036–1039, 2015.
30. Chen, Y., Li, L., Yao, J., Ma, Y.-Y., Chen, J.-M., Lu, T.-B., Improving the solubility and bioavailability of apixaban via apixaban–oxalic acid cocrystal.
Cryst. Growth Des.
, 16, 2923–2930, 2016.
31. Sanphui, P., Goud, N.R., Khandavilli, U.B.R., Nangia, A., Fast dissolving curcumin cocrystals.
Cryst. Growth Des.
, 11, 4135–4145, 2011.
32. Guo, M., Sun, X., Chen, J., Cai, T., Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications.
Acta Pharm. Sin. B
, 11, 2537–2564, 2021.
33. Kalepu, S. and Nekkanti, V., Insoluble drug delivery strategies: Review of recent advances and business prospects.
Acta Pharm. Sin. B
, 5, 442–453, 2015.
34. Rathi, R., Kushwaha, R., Goyal, A., Singh, I., Oxaliplatin-flavone pharmaceutical co-crystal-CN111205332A: patent spotlight.
Pharm. Pat. Anal.
, 11, 5, 147–154, 2022.
35. Chettri, A., Subba, A., Singh, G.P., Bag, P.P., Pharmaceutical co-crystals: A green way to enhance drug stability and solubility for improved therapeutic efficacy.
J. Pharm. Pharmacol.
, 76, 1–12, 2023.
36. Huang, Y., Zhang, B., Gao, Y., Zhang, J., Shi, L., Baicalein–nicotinamide cocrystal with enhanced solubility, dissolution, and oral bioavailability.
J. Pharm. Sci.
, 103, 2330–2337, 2014.
37. Cheney, M.L., Weyna, D.R., Shan, N., Hanna, M., Wojtas, L., Zaworotko, M.J., Coformer selection in pharmaceutical cocrystal development: A case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics.
J. Pharm. Sci.
, 100, 2172–2181, 2011.
38. Trask, A.V., Motherwell, W.S., Jones, W., Physical stability enhancement of theophylline via cocrystallization.
Int. J. Pharm.
, 320, 114–123, 2006.
39. McNamara, D.P., Childs, S.L., Giordano, J., Iarriccio, A., Cassidy, J., Shet, M.S., Mannion, R., O’Donnell, E., Park, A., Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API.
Pharm. Res.
, 23, 1888–1897, 2006.
40. Basavoju, S., Boström, D., Velaga, S.P., Indomethacin–saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization.
Pharm. Res.
, 25, 530–541, 2008.
41. Schultheiss, N. and Newman, A., Pharmaceutical cocrystals and their physicochemical properties.
Cryst. Growth Des.
, 9, 2950–2967, 2009.
42. Childs, S.L., Rodríguez-Hornedo, N., Reddy, L.S., Jayasankar, A., Maheshwari, C., McCausland, L., Shipplett, R., Stahly, B.C., Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine.
CrystEngComm
, 10, 856–864, 2008.
43. Trask, A.V., Motherwell, W.S., Jones, W., Pharmaceutical cocrystallization: engineering a remedy for caffeine hydration.
Cryst. Growth Des.
, 5, 1013–1021, 2005.
44. Oswald, I.D., Allan, D.R., McGregor, P.A., Motherwell, W.S., Parsons, S., Pulham, C.R., The formation of paracetamol (acetaminophen) adducts with hydrogen-bond acceptors.
Acta Crystallogr., Sect. B: Struct. Sci
, 58, 1057–1066, 2002.
45. Vangala, V.R., Chow, P.S., Tan, R.B., Co-crystals and co-crystal hydrates of the antibiotic nitrofurantoin: structural studies and physicochemical properties.
Cryst. Growth Des.
, 12, 5925–5938, 2012.
46. Mohamed, M.A., Nasr, M., Elkhatib, W.F., Eltayeb, W.N., Elshamy, A.A., El-Sayyad, G.S., Nanobiotic formulations as promising advances for combating MRSA resistance: susceptibilities and post-antibiotic effects of clindamycin, doxycycline, and linezolid.
RSC Adv.
, 11, 39696–39706, 2021.
47. Vishweshwar, P., McMahon, J.A., Bis, J.A., Zaworotko, M.J., Pharmaceutical co-crystals.
J. Pharm. Sci.
, 95, 499–516, 2006.
48. Maeno, Y., Fukami, T., Kawahata, M., Yamaguchi, K., Tagami, T., Ozeki, T., Suzuki, T., Tomono, K., Novel pharmaceutical cocrystal consisting of paracetamol and trimethylglycine, a new promising cocrystal former.
Int. J. Pharm.
, 473, 179–186, 2014.
49. Aitipamula, S., Wong, A.B., Kanaujia, P., Evaluating suspension formulations of theophylline cocrystals with artificial sweeteners.
J. Pharm. Sci.
, 107, 604–611, 2018.
50. Ogata, T., Tanaka, D., Ozeki, T., Enhancing the solubility and masking the bitter taste of propiverine using crystalline complex formation.
Drug Dev. Ind. Pharm.
, 40, 1084–1091, 2014.
51. Shen, Y., Aucamp, M., Abdelhakim, H.E., Li, X., Ghazali, Y., Edkins, K., Exploring co-crystallisation as a technique for taste-masking of nevirapine.
RSC Pharm.
, 1, 132–140, 2024.
52. Duan, C., Chen, Y., Zhang, Y., Liang, F., Liu, W., Xiao, X., Xu, C., Zhuang, T., Hao, C., Chen, Y., Two Cocrystals of Olaparib with Flavonoids toward Sustained Release: Structure, Dissolution Behavior, and Anticancer Activity Analysis.
Cryst. Growth Des.
, 22, 4885–4894, 2022.
53. Brader, M.L., Sukumar, M., Pekar, A.H., McClellan, D.S., Chance, R.E., Flora, D.B., Cox, A.L., Irwin, L., Myers, S.R., Hybrid insulin cocrystals for controlled release delivery.
Nat. Biotechnol.
, 20, 800–804, 2002.
54. Zhou, Z., Li, W., Sun, W.-J., Lu, T., Tong, H.H., Sun, C.C., Zheng, Y., Resveratrol cocrystals with enhanced solubility and tabletability.
Int. J. Pharm.
, 509, 391–399, 2016.
55. Rathi, R. and Singh, I., Multicomponent crystal compromising dasatinib and selected co-crystals formers: a patent evaluation of EP2861589B1.
Pharm. Pat. Anal.
, 11, 1, 15–21, 2021.
56. Latif, S., Abbas, N., Hussain, A., Arshad, M.S., Bukhari, N.I., Afzal, H., Riffat, S., Ahmad, Z., Development of paracetamol-caffeine co-crystals to improve compressional, formulation and
in vivo
performance.
Drug Dev. Ind. Pharm.
, 44, 1099–1108, 2018.
57. Srivastava, D., Fatima, Z., Kaur, C.D., Multicomponent Pharmaceutical Cocrystals: A Novel Approach for Combination Therapy.
Mini-Rev. Med. Chem.
, 18, 1160–1167, 2018.
58. Thipparaboina, R., Kumar, D., Chavan, R.B., Shastri, N.R., Multidrug co-crystals: towards the development of effective therapeutic hybrids.
Drug Discov. Today
, 21, 481–490, 2016.
59. Rathi, R., Guggal, Y., Twinkle, Sandhu, V., Singh, I., Exploring the Patent Landscape and Regulatory Prospective on Pharmaceutical Cocrystals.
J. Pharm. Technol. Res. Manag.
, 11, 49–61, 2023.
60. Jones, W., Motherwell, W.S., Trask, A.V., Pharmaceutical cocrystals: An emerging approach to physical property enhancement.
MRS Bull.
, 31, 875–879, 2006.
61. Kumar, S. and Nanda, A., Approaches to design of pharmaceutical cocrystals: A review.
Mol. Cryst. Liq. Cryst.
, 667, 54–77, 2018.
62. Chow, P.S., Lau, G., Ng, W.K., Vangala, V.R., Stability of pharmaceutical cocrystal during milling: a case study of 1: 1 caffeine–glutaric acid.
Cryst. Growth Des.
, 17, 4064–4071, 2017.
63. Kaur, N., Duggirala, N.K., Thakral, S., Suryanarayanan, R., Role of lattice disorder in water-mediated dissociation of pharmaceutical cocrystal systems.
Mol. Pharmaceutics
, 16, 3167–3177, 2019.
64. Qiu, S. and Li, M., Effects of coformers on phase transformation and release profiles of carbamazepine cocrystals in hydroxypropyl methylcellulose based matrix tablets.
Int. J. Pharm.
, 479, 118–128, 2015.
65. Duggirala, N.K., Vyas, A., Krzyzaniak, J.F., Arora, K.K., Suryanarayanan, R., Mechanistic insight into caffeine–oxalic cocrystal dissociation in formulations: Role of excipients.
Mol. Pharmaceutics
, 14, 3879–3887, 2017.
66. Porter Iii, W.W., Elie, S.C., Matzger, A.J., Polymorphism in carbamazepine cocrystals.
Cryst. Growth Des.
, 8, 14–16, 2008.
67. Rathi, R., Guggal, Y., Twinkle, Sandhu, V., Singh, I., Exploring the Patent Landscape and Regulatory Prospective on Pharmaceutical Cocrystals.
J. Pharm. Technol. Res. Manag.
, 11, 49–60, 2023.
68. Guerain, M., Guinet, Y., Correia, N., Paccou, L., Danède, F., Hédoux, A., Polymorphism and stability of ibuprofen/nicotinamide cocrystal: The effect of the crystalline synthesis method.
Int. J. Pharm.
, 584, 119454, 2020.
69. Lange, L., Schleinitz, M., Sadowski, G., Predicting the effect of pH on stability and solubility of polymorphs, hydrates, and cocrystals.
Cryst. Growth Des.
, 16, 4136–4147, 2016.
70. Ren, S., Liu, M., Hong, C., Li, G., Sun, J., Wang, J., Zhang, L., Xie, Y., The effects of pH, surfactant, ion concentration, coformer, and molecular arrangement on the solubility behavior of myricetin cocrystals.
Acta Pharm. Sin. B
, 9, 59–73, 2019.
71. Rathi, R., Sanshita, Singh, I., Hot Melt Extrusion Technique for Developing Pharmaceutical Co-crystals: A Review.
Drug Deliv. Lett.
, 14, 2, 97–108, 2024.
72. González-García, I., Mangas-Sanjuán, V., Merino-Sanjuán, M., Bermejo, M.,
In vitro
–
in vivo
correlations: general concepts, methodologies and regulatory applications.
Drug Dev. Ind. Pharm.
, 41, 1935–1947, 2015.
73. Yousef, M.A. and Vangala, V.R., Pharmaceutical cocrystals: molecules, crystals, formulations, medicines.
Cryst. Growth Des.
, 19, 7420–7438, 2019.
74. Desiraju, G.R., Supramolecular synthons in crystal engineering—a new organic synthesis.
Angew. Chem. Int. Ed. Engl.
, 34, 2311–2327, 1995.
75. Khan, M., Enkelmann, V., Brunklaus, G., O– H··· N heterosynthon: a robust supramolecular unit for crystal engineering.
Cryst. Growth Des.
, 9, 2354–2362, 2009.
76. Bhatt, P.M., Azim, Y., Thakur, T.S., Desiraju, G.R., Co-crystals of the anti-HIV drugs lamivudine and zidovudine.
Cryst. Growth Des.
, 9, 951–957, 2009.
77. Delori, A., Galek, P.T., Pidcock, E., Patni, M., Jones, W., Knowledge-based hydrogen bond prediction and the synthesis of salts and cocrystals of the anti-malarial drug pyrimethamine with various drug and GRAS molecules.
CrystEngComm
, 15, 2916–2928, 2013.
78. Fábián, L., Cambridge structural database analysis of molecular complementarity in cocrystals.
Cryst. Growth Des.
, 9, 1436–1443, 2009.
79. Issa, N., Karamertzanis, P.G., Welch, G.W., Price, S.L., Can the formation of pharmaceutical cocrystals be computationally predicted? I. Comparison of lattice energies.
Cryst. Growth Des.
, 9, 442–453, 2009.
80. Bhogala, B.R., Basavoju, S., Nangia, A., Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4,4′-bipyridines and isonicotinamide. From binary to ternary cocrystals.
CrystEngComm
, 7, 551–562, 2005.
81. Chadha, R., Saini, A., Arora, P., Jain, D.S., Dasgupta, A., Guru Row, T.N., Multicomponent solids of lamotrigine with some selected coformers and their characterization by thermoanalytical, spectroscopic and X-ray diffraction methods.
CrystEngComm
, 13, 6271–6284, 2011.
82. Suresh, K., Minkov, V.S., Namila, K.K., Derevyannikova, E., Losev, E., Nangia, A., Boldyreva, E.V., Novel Synthons in Sulfamethizole Cocrystals: Structure-Property Relations and Solubility.
Cryst. Growth Des.
, 15, 3498–3510, 2015.
83. Sanphui, P., Bolla, G., Nangia, A., Chernyshev, V., Acemetacin cocrystals and salts: Structure solution from powder X-ray data and form selection of the piperazine salt.
IUCrJ
, 1, 136–150, 2014.
84. Sarma, B., Nath, N.K., Bhogala, B.R., Nangia, A., Synthon competition and cooperation in molecular salts of hydroxybenzoic acids and aminopyridines.
Cryst. Growth Des.
, 9, 1546–1557, 2009.
85. Lu, J. and Rohani, S., Synthesis and preliminary characterization of sulfamethazine-theophylline co-crystal.
J. Pharm. Sci.
, 99, 4042–4047, 2010.
86. Childs, S.L., Stahly, G.P., Park, A., The salt-cocrystal continuum: The influence of crystal structure on ionization state.
Mol. Pharmaceutics
, 4, 323–338, 2007.
87. Cruz-Cabeza, A.J., Acid-base crystalline complexes and the pKa rule.
CrystEngComm
, 14, 6362–6365, 2012.
88. Mohammad, M.A., Alhalaweh, A., Velaga, S.P., Hansen solubility parameter as a tool to predict cocrystal formation.
Int. J. Pharm.
, 407, 63–71, 2011.
89. Chandel, N., Gupta, V., Pandey, A., Saxena, S., Sciences, L., Co-crystalization of aceclofenac and paracetamol and their characterization.
Int. J. Pharm.
, 2, 1020–1028, 2011.
90. Lu, E., Rodríguez-Hornedo, N., Suryanarayanan, R., A rapid thermal method for cocrystal screening.
CrystEngComm
, 10, 665–668, 2008.
91. Braga, D., Grepioni, F., Maini, L., Capucci, D., Nanna, S., Wouters, J., Aerts, L., Quéré, L., Combining piracetam and lithium salts: Ionic co-crystals and co-drugs?
Chem. Commun.
, 48, 8219–8221, 2012.
92. Friščić, T., Childs, S.L., Rizvi, S.A., Jones, W., The role of solvent in mechanochemical and sonochemical cocrystal formation: a solubility-based approach for predicting cocrystallisation outcome.
CrystEngComm
, 11, 418–426, 2009.
93. Hong, C., Xie, Y., Yao, Y., Li, G., Yuan, X., Shen, H., A novel strategy for pharmaceutical cocrystal generation without knowledge of stoichiometric ratio: myricetin cocrystals and a ternary phase diagram.
Pharm. Res.
, 32, 47–60, 2015.
94. Chiarella, R.A., Davey, R.J., Peterson, M.L., Making co-crystals - The utility of ternary phase diagrams.
Cryst. Growth Des.
, 7, 1223–1226, 2007.
95. Nehm, S.J., Rodríguez-Spong, B., Rodríguez-Hornedo, N., Phase solubility diagrams of cocrystals are explained by solubility product and solution complexation.
Cryst. Growth Des.
, 6, 592–600, 2006.
96. Žegarac, M., Lekšić, E., Šket, P., Plavec, J., Bogdanović, M.D., Bučar, D.-K., Dumić, M., Meštrović, E., A sildenafil cocrystal based on acetylsalicylic acid exhibits an enhanced intrinsic dissolution rate.
CrystEngComm
, 16, 32–35, 2014.
97. Surov, A.O., Voronin, A.P., Manin, A.N., Manin, N.G., Kuzmina, L.G., Churakov, A.V., Perlovich, G.L., Pharmaceutical cocrystals of diflunisal and diclofenac with theophylline.
Mol. Pharmaceutics
, 11, 3707–3715, 2014.
98. Jiang, L., Huang, Y., Zhang, Q., He, H., Xu, Y., Mei, X., Preparation and solid-state characterization of dapsone drug-drug co-crystals.
Cryst. Growth Des.
, 14, 4562–4573, 2014.
99. Abramov, Y.A., Current computational approaches to support pharmaceutical solid form selection.
Org. Process Res. Dev.
, 17, 472–485, 2013.
100. Kavanagh, O.N., Croker, D.M., Walker, G.M., Zaworotko, M.J., Pharmaceutical cocrystals: from serendipity to design to application.
Drug Discov. Today
, 24, 796–804, 2019.
101. Gromila, R., Mooibroek, T., Frontera, A.,
Hot Topics in Crystal Engineering
, Elsevier Amsterdam, The Netherlands, 2021.
102. Rissanen, K.,
Hot Topics in Crystal Engineering
, Elsevier, Amsterdam, 2021.
103. Emami, S., Siahi-Shadbad, M., Adibkia, K.A.-O., Barzegar-Jalali, M., Recent advances in improving oral drug bioavailability by cocrystals.
Bioimpacts
, 8, 305–320, 2018.
