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x Contents
9.2 Why Solubility Enhancement is Important?
259
9.3 Factors Aecting 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 Eect 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 Eect 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 erapeutic Ecacy 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 erapeutic Ecacy 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
Contents xi
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 Inuencing Solid-State
Microenvironment 310
10.3.2.5 Increased ermal Stability 311
10.3.3 Improving Bioavailability and Pharmacokinetics 312
10.3.3.1 e Mechanism for Enhancing
the Bioavailability and Improve
Pharmacokinetics of Drugs 312
10.3.4 Combination erapy
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
xii Contents
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
xiii
Preface
Pharmaceutical cocrystals represent an expanding eld that has the poten-
tial to enhance drug safety, ecacy, and patient compliance. Cocrystals
are multicomponent crystalline materials composed of two or more com-
pounds, typically a drug and a coformer, held together by non-covalent
interactions such as hydrogen bonding or van der Waals forces. Cocrystals
oer numerous advantages, including improved solubility, bioavailability,
stability, taste masking, drug release, hygroscopicity, and mechanical prop-
erties. However, the utilization of cocrystals requires careful consideration
of factors such as scalability, regulatory compliance, and industrial feasi-
bility. Addressing these challenges can help bridge the gap between labora-
tory research and commercialization.
is book provides a comprehensive overview of pharmaceutical
cocrystals, addressing fundamental principles, practical considerations,
and the regulatory landscape. e content is organized into distinct chap-
ters covering the historical background, design, structural characteristics,
and preparation techniques of cocrystals. Additionally, a designated chap-
ter discusses computational methods for screening and characterizing
pharmaceutical cocrystals. e book also explores the concept of herbal
cocrystals and the commercialization of pharmaceutical cocrystals.
Various applications of pharmaceutical cocrystals—such as enhanc-
ing solubility, stability, mechanical properties, and therapeutic ecacy of
active pharmaceutical ingredients—are thoroughly discussed using the lat-
est updated literature. Moreover, the regulatory perspectives surrounding
cocrystals are also examined in detail.
xiv Preface
We would like to extend our heartfelt thanks to Martin Scrivener and
Scrivener Publishing for their belief in this project and their kind cooper-
ation 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. e 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 eld of pharmaceu-
tical cocrystals.
Prof. (Dr.) Inderbir Singh
Prof. (Dr.) Subrata Mallick
Ms. Ritu Rathi
1
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (1–28) © 2025 Scrivener Publishing LLC
1
Pharmaceutical 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 eld of pharmaceutical sciences that oers
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 spe-
cies, usually an API and a coformer, joined together by noncovalent interactions,
without forming chemical bonds. Unlike traditional drug formulations, cocrys-
tals use purposeful molecular design to manufacture precise interactions between
components, resulting in distinct crystal shapes and characteristics. Cocrystals
oer the potential to increase drug solubility, bioavailability, and stability, mask
taste, boost avor, and control the release of drugs from formulations. In addition,
cocrystals can facilitate the co-formulation of multiple drugs with complemen-
tary pharmacological activities, and they serve as versatile carriers or excipients in
drug delivery systems such as nanoparticles, liposomes, or microspheres, enabling
drug targeting. is 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
*Corresponding author: pejuodeku@yahoo.com; o.odeku@ui.edu.ng
2 Cocrystals in Pharmaceutical Sciences
1.1 Introduction
Cocrystal is a supramolecular chemistry idea that is gaining popularity
among pharmaceutical and chemical researchers, as well as drug regula-
tory bodies. e primary reason for this is its capacity to aect the phys-
icochemical characteristics of active medicinal components [1]. During
pharmaceutical product development, formulators must maximize the
physicochemical qualities of active medicinal components.
e European Medicines Agency (EMA) has dened cocrystals as
“homogenous (single phase) crystalline structures made up of two or more
components in a denite 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 dened by the United States Food and Drug
Administration (USFDA) as “Crystalline materials composed of two or
more dierent molecules, typically API and cocrystal formers (coformers),
in the same crystal lattice in a dened stoichiometric ratio” [3]. ey were
characterized as a discrete category of innovative, crystalline compounds
that may aect 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]. ey are pre-
ferred over amorphous API forms or solid dispersions because they oer
the solubility benets 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]. e coformer selection has a signicant
impact on the nal cocrystal properties. When synthesized as a cocrystal,
the coformers can alter the API’s stability and solubility by causing modi-
cations to the structure of its crystals [8]. Unlike traditional drug formu-
lations, 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. is 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
Pharmaceutical Cocrystals 3
mechanical behavior, solubility, water absorption, dissolution rate, bio-
availability, and stability [10–12].
e major distinction between solvates and cocrystals rests in the phys-
ical 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 ioniz-
able and nonionizable drug molecules can be combined to form cocrystals.
ey have several potential commercial pharmaceutical and food applica-
tions [15]. Cocrystals have the potential to improve medication solubil-
ity, stability, bioavailability, and other essential properties important for
medicinal ecacy [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). e 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
1844 Friedrich
Wohler's first
cocrystal
"Quinhydrone"
20th century
revealed molecular
configurations of
cocrystals
1990's Margret Etter
reported rules of
hydrogen bonding
of organic cocrystal
2003 Desiraju
supramolecular
synthon concept of
hydrogen bond
formation in crystal
structure
2004 Era of crystal
engineering &
crystal formation
Figure 1.1 e evolution of cocrystals over the years.
4 Cocrystals in Pharmaceutical Sciences
[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 sub-
stance using single-crystal X-ray diraction [19]. e introduction of
X-ray crystallography in the early 20th century transformed the study of
crystal structures, revealing insights into the molecular congurations
inside cocrystals.
A close evaluation of the literature from the latter part of the 19th and
early 20th centuries reveals the existence of practically hundreds of cocrys-
tals (even though they would continually appear under various names).
e concept of cocrystals evolved in the later part of the 20th century when
researchers dened them as “solid-state structures made up of two or more
components held together by noncovalent interactions.” e area of crys-
tal engineering sprang to prominence, with an emphasis on designing and
manipulating crystal formations to attain certain qualities and function-
ality. Researchers investigated the use of cocrystals in medicines, noting
their capacity to increase medication solubility, stability, and other char-
acteristics. Stahly has published an excellent comprehensive summary of
cocrystals reported before the year 2000 [18].
e 21st century saw an increase in research on cocrystals, notably in
the pharmaceutical business. e emphasis on cocrystals as an easily rec-
ognized 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 denition 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
diculties in standard medication formulations. Some important pharma-
ceutical uses of cocrystals include the following.
Pharmaceutical Cocrystals 5
1.3.1 Enhanced Solubility
Many drugs have been revealed to have low solubility, which can reduce
their bioavailability and therapeutic eectiveness. Approximately 70% of
new drugs belong to the class II Biopharmaceutical Classication System
(BCS; low solubility/high permeability) or class IV BCS (poor solubility/
low permeability) [23, 24]. Since the gastrointestinal (GI) system has var-
ied pH in dierent parts, drugs taken orally exhibit varying solubility in GI
uids at dierent pH, resulting in unpredictable and variable absorption
and the inability to evaluate the drug’s ecacy 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]. us, cocrystals
resulted in better drug solubility than the salt form.
e 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 nicotin-
amide exhibited two times greater solubility than pure drug [29]. Apixaban
cocrystals exhibited improved solubility of about twofold, and the cocrys-
tals showed a faster dissolution rate when compared to pure drugs [30].
Studies have shown that combining curcumin with resorcinol and pyrogal-
lol enhanced its solubility signicantly [31]. Curcumin-resorcinol and cur-
cumin-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]. e limited oral
bioavailability of medications makes developing new drugs a consider-
able issue. Crystal engineering is critical in developing and manufacturing
pharmaceutical cocrystals with increased oral bioavailability and aqueous
solubility, leading to therapeutic ecacy [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]. e peak plasma concentration