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293
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (293–328) © 2025 Scrivener Publishing LLC
10
Pharmaceutical Cocrystals for Improving
Physicochemical Properties of Drugs:
Enhancement of erapeutic Ecacy
Debabrata Ghosh Dastidar*, Arpan Datta, Sanchari Bhattacharya
and Moumita Chowdhury
Guru Nanak Institute of Pharmaceutical Science and Technology, Panihati,
Kolkata, West Bengal, India
Abstract
Cocrystallization has emerged as a crucial technique in pharmaceutical sciences
for enhancing the physicochemical and therapeutic properties of drugs. A cocrys-
tal, dened as a crystalline complex of two or more molecules in a non-ionic
association, held together by weaker noncovalent intermolecular forces such as
hydrogen bonding, oers opportunities for modulating the important proper-
ties of active pharmaceutical ingredients (APIs). Many APIs face challenges like
poor solubility, dissolution rate, bioavailability, and stability, which impact drug
development and commercialization. Traditional techniques have limitations, but
cocrystallization provides a unique opportunity to enhance properties like solu-
bility, dissolution, permeability, and stability without altering the chemical identi-
ties of the molecules. By optimizing physicochemical properties like crystallinity,
particle size, and crystal habit early in drug development, cocrystals can acceler-
ate development timelines and lower costs. is chapter provides an overview of
the science of cocrystallization and its applications in enhancing the therapeutic
ecacy of drugs. It covers topics such as cocrystal formation fundamentals, char-
acterization methods, and the inuence of cocrystals on pharmacokinetic proper-
ties. Additionally, industrially relevant cocrystallization techniques and examples
of marketed cocrystal-based pharmaceutical products are discussed, showcasing
the potential and impact of cocrystals in drug development.
*Corresponding author: debabrata.ghoshdastidar@gnipst.ac.in
294 Cocrystals in Pharmaceutical Sciences
Keywords: Solubility enhancement, crystal engineering, biopharmaceutical
properties, combinatorial approaches, therapeutic ecacy
10.1 Introduction
Cocrystallization is emerging as an important technique in pharmaceuti-
cal sciences for improving the physicochemical and therapeutic proper-
ties of drugs. A cocrystal is dened as a crystalline complex comprising
two or more dierent molecules in a non-ionic association held together
by weaker noncovalent intermolecular forces such as hydrogen bonding.
In cocrystals, the component molecules interact through supramolecular
synthons resulting in new crystalline forms with properties distinct from
their individual components [1]. Many pharmaceutical active pharma-
ceutical ingredients (APIs) suer from poor solubility, dissolution rate,
bioavailability, and stability issues, which pose challenges for drug devel-
opment and commercialization. Traditionally, techniques such as salt for-
mation, polymorphism, and solvates/hydrates have been utilized to modify
the physicochemical properties of APIs. However, these approaches have
limitations and cannot be universally applied. Cocrystallization provides a
unique opportunity to modulate important properties like solubility, dis-
solution, permeability, and stability of APIs without altering their chemical
identities [2].
e ultimate goal of drug development is to deliver safe and eective
therapeutics to patients. However, many promising drug candidates fail
due to poor solubility, dissolution, and bioavailability issues leading to
a lack of therapeutic ecacy. It is estimated that over 40% of new drug
candidates exhibit poor aqueous solubility, a key determinant of oral bio-
availability. Dissolution of the drug is the rate-limiting step for systemic
absorption and attainment of pharmacological concentrations at the site
of action. Low bioavailability translates to diculties in achieving the
intended pharmacological response even at higher doses, increasing tox-
icity risks [3]. Enhancing solubility, dissolution and oral bioavailability of
drug compounds during early development phases is therefore critical for
improving therapeutic ecacy and enabling successful commercialization
[3]. is requires optimization of physicochemical properties like crystal-
linity, particle size, and habit without altering the molecular structure or
pharmacological activity of the drug molecule. Strategic modications at
the preformulation stage can signicantly accelerate development time-
lines and lower costs by eliminating candidates with inherent poor solu-
bility or dissolution properties early on [4]. Properties like stability also
Cocrystals for Enhancing Therapeutic Efficacy 295
impact the treatment ecacy and safety over time. Drugs with stability
issues may degrade during manufacturing, storage, or in vivo, reducing
potency and consistency of therapeutic outcome [5]. Unstable forms also
face challenges in commercial scale-up due to diculties in process opti-
mization and validation. Designing stable solid forms of compounds early
provides an advantage in manufacturing.
Over the past two decades, signicant advances have been made in the
fundamental understanding of cocrystal formation and characterization. A
wide range of pharmaceutical cocrystals have been reported with improved
solubility, dissolution, and stability proles relative to their parent mol-
ecules [1]. Recent industrial and regulatory acceptance of cocrystals has
validated their potential for commercial applications [6]. is chapter aims
to provide an overview of cocrystallization science and its pharmaceutical
applications in enhancing the therapeutic ecacy of drugs. Key topics that
will be covered include fundamentals of cocrystal formation, screening
and characterization methods, the inuence of cocrystals on pharmaco-
kinetic properties, and industrially relevant cocrystallization techniques.
Representative examples of marketed cocrystal-based pharmaceutical
products will also be discussed.
10.2 Preparation and Characterization Methods
for Cocrystals
Several experimental and computational techniques have been devel-
oped for the synthesis and screening of pharmaceutical cocrystals (Figure
10.1). e selection of an appropriate method is governed by the intrin-
sic properties of the components as well as objectives such as laboratory-
scale synthesis versus industrial-scale production [7]. e commonly
used cocrystal formation methods include solution-mediated methods
involving solvent evaporation, spray drying, slurry conversion, and ther-
mal treatment. Solutions of components are employed for cocrystal nucle-
ation and growth. While eective for smaller-scale synthesis, issues arise
with solvent residuals and hydrate/solvate formation during scale-up [8].
e solvent-free methods for cocrystal preparation include neat/grind-
ing cocrystallization, melt-mediated methods, mechanical activation,
and gas antisolvent technique. Neat/grinding cocrystallization involves
grinding or grinding with little or no solvent. is technique mimics the
solution process on the surfaces. It is simple, requiring only mortar/pestle
[9] but may induce undesired phases and lack reproducibility at the