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86 Cocrystals in Pharmaceutical Sciences
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93
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (93–120) © 2025 Scrivener Publishing LLC
4
Preparation Techniques
of Pharmaceutical Cocrystals
Nikita akur
1
, Mansi Prashar
2
, Sukhvir Kaur
1
, Neelima Dhingra
2
,
Manish Kumar
3
, Ritu Rathi
3
, Inderbir Singh
3
and Poonam Arora
3
*
1
Chitkara University School of Pharmacy, Chitkara University,
Himachal Pradesh, India
2
University Institute of Pharmaceutical Sciences, Panjab University,
Chandigarh, India
3
Chitkara College of Pharmacy, Chitkara University, Punjab, India
Abstract
Academic and industrial scientists are becoming more concerned with novel solid
forms, i.e., pharmaceutical cocrystals, emerging as an innovative class of solid
pharmaceuticals with enhanced physicochemical properties. By incorporating
APIs with pharmaceutically acceptable coformers, cocrystals oer improved solu-
bility, stability, dissolution rates, and bioavailability. e preparation of cocrystals
can be achieved using various techniques, broadly categorized into solid-based
and solution-based methods. Solid-based methods, such as dry grinding, wet
grinding, and hot-melt extrusion, involve minimal solvents and are advantageous
for solvent-sensitive compounds. On the other hand, solution-based methods—
including solvent evaporation, cooling crystallization, antisolvent crystallization,
and supercritical uids—provide a versatile approach to producing cocrystals,
allowing better control over crystal morphology and purity. Optimization of these
techniques requires a systematic understanding of several critical parameters.
A quality-by-design framework is essential for identifying critical quality attri-
butes and critical process parameters, ensuring consistency and reproducibility in
cocrystal production. e kinetics of crystallization, particularly nucleation and
crystal growth, are crucial for regulating particle size distribution, crystal habit,
and yield. Moreover, the selection of an appropriate coformer is of paramount
importance; it should be based on molecular complementarity, hydrogen bonding
potential, and compatibility with the API to achieve the desired physicochemical
*Corresponding author: poonamarora0803@gmail.com
94 Cocrystals in Pharmaceutical Sciences
enhancements. is chapter provides a comprehensive overview of the prepara-
tion techniques and the key optimization parameters that inuence cocrystal for-
mation, emphasizing their signicance in developing cocrystals with enhanced
therapeutic ecacy for pharmaceutical applications.
Keywords: Optimization, quality-by-design, green chemistry, eciency, PAT,
innovation
4.1 Introduction
Over the past two decades, cocrystals have gained noteworthy interest
from academia and industry for their ability to enhance API properties
without changing pharmacological eects. Cocrystals, which contain more
than two coformer in a xed stoichiometric ratio, oer a strategic approach
to improving the chemical and physical properties, such as stability,
apparent bioavailability, and solubility studies, of active pharmaceutical
ingredients (APIs) [1]. Research has highlighted the importance of crys-
tal engineering and supramolecular synthons in designing pharmaceuti-
cal cocrystals, which advanced the use of cocrystal strategies to enhance
drug properties. Various vigorous supramolecular synthons are key fac-
tors in driving pharmaceutical cocrystal formation. Functional groups like
carboxylic acids, amides, and alcohols are particularly suitable for form-
ing these synthons [2]. Supramolecular synthons are classied into two
types: homosynthons and heterosynthons. Homosynthons are formed by
self-complementary collections, such as amide dimers or carboxylic acid,
while heterosynthons arise from dierent but complementary groups, like
hydrogen bonding between pyridines and carboxylic acids or alcohols and
aromatic nitrogen ring [3].
Historically, cocrystal preparation methods were limited and oen relied
on trial-and-error approaches. Early techniques primarily involved solvent
evaporation or mechanical grinding. While eective in some cases, lacked
consistency and eciency. As research progressed, solid-state methods,
such as ball milling and extrusion were introduced. ese techniques gen-
erally use little or no solvent, making them more environmentally friendly
and simpler to implement. However, they oen required extensive experi-
mentation to ne-tune the process and achieve desirable cocrystal qualities.
Moreover, recent research has emphasized optimizing various parameters,
including temperature, pressure, and solvent choice, to achieve the desired
cocrystal characteristics. e ability to manipulate these factors has led
to the development of new cocrystals with tailored properties, further
Preparation Techniques of Pharmaceutical Cocrystals 95
expanding their potential applications in pharmaceuticals and beyond
[4]. is chapter explores various techniques commonly used for cocrys-
tallization, including liquid-assisted and solid-state approaches. It also
evaluates several novel approaches, such as spray drying and supercritical
CO
2
-assisted and ultrasound-assisted cocrystallization, for their potential
in cocrystal preparation [5]. It also provides a comprehensive conversa-
tion on continuous manufacturing and scale-up eorts undertaken over
the past 15 years. Finally, it addresses the regulatory aspects of solid forms
(pharmaceutical cocrystals), focusing on the perspectives and classica-
tions provided by regulatory agencies regarding their manufacturing.
4.2 Cocrystal Preparation Techniques
Cocrystal preparation approaches can be categorized into three main types:
solid-state approach, solution-based approach, and miscellaneous techniques.
Solid-state approaches, such as hot-melt extrusion, solvent-assisted grinding,
and dry grinding, use little to no solvent and rely on mechanical forces to
promote cocrystal formation [6]. Solution-based methods, involving cooling
crystallization, solvent drop grinding, antisolvent crystallization, and solvent
Cooling Crystallization Technique
Twin Screw Extrusion
Ultra Sonication Method
Neat Grinding
Solvent Evaporation Method
Liquid Assisted Grinding
Supercritical Fluid Method
Coformer A
API + Coformer
ATR-FTIR Probe
Overhead stirrer
Thermocouple
Physical Mixture
of materials
Feeder
Liquid Phase
Peristaltic Pump
Mixing and melting
of the components
Different Zone for Injection
Collection of semi-solid
product
Baffle
Coformer B
Hot Melt Extrusion
Preparation of
cocrystals
CO2
PROBE
Figure 4.1 Various techniques for the preparation of cocrystals.