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46 Cocrystals in Pharmaceutical Sciences
scanning calorimetry), solid-state NMR (nuclear magnetic resonance),
and FESEM (eld emission scanning electron microscopy). Due to the
usage of many novel techniques, each of which gives a unique view of the
molecular and crystal structures of the cocrystals, their organization can
be studied. e qualitative analysis of FTIR is perfectly well sorted for
functional group identication and considering intermolecular forces. e
technique used to achieve this goal is a quantication of the absorption of
light at the infrared spectrum, which provides valuable information on the
vibrational modes, as well as a means for the detection of hydrogen bond-
ing and other interactions [58, 59]. e principle of NMR spectroscopy is
based on the magnetic properties of the atomic nuclei, giving informative
insight into the spatial arrangement and motion of molecules. e ability
to monitor alterations in the chemical environment is linked to the for-
mation of cocrystals due to interactions, such as hydrogen bonding or π-π
stacking.
Recognizing crystal atomic arrangement within three dimensions is
challenging one and particularly well accomplished by SCXRD. X-rays
may image the atomic arrangement of crystalline lattice revealing interac-
tions such as van der Waals forces, π-π interactions, and hydrogen bonds
[58]. Application of FTIR to determine hydrogen bonds for coee and of
succinic acid, NMR to map out the chemical shi for coee and succinic
acid, and SCXRD to conrm the π-π interactions between two aromatic
rings and carboxyl groups for coee and succinic acid. H bonds present in
the carbamazepine and nicotinamide are conrmed by the NMR chemical
shis; FTIR reveals these bonds; SCXRD explains how these interactions
maintain and improve the cocrystal. ese enable identication of cocrys-
tal structures as well as bonding allowing for the rational design of the new
cocrystals with the right characteristics. ese results are useful for drug
delivery and cocrystal formation [60, 61].
2.4 Challenges and Future Directions
in Pharmaceutical Cocrystal
Pharmaceutical cocrystals are an area of promising research that can
enhance the solubility, stability, and biological availability of APIs. As a
developing area of expertise, a signicant problem in this realm is the
proper scaling of cocrystal synthesis. Furthermore, approval of these
products in dierent countries remains a challenge in this segment since
the regulatory authorities of dierent countries do not approve certain
Design and Characteristics of Pharmaceutical Cocrystals 47
products easily. Recent developments have been centered around contin-
uous manufacturing techniques, which hold the potential for maintain-
ing consistent quality and enabling real-time monitoring using process
analytical technology (PAT). Nevertheless, there remain challenges to be
addressed, including the need to improve the predictability of cocrystal
formation and the ability to control their physical properties on a larger
scale [62]. In anticipation of future developments, the industry is focused
on overcoming these obstacles by enhancing design approaches, selecting
appropriate coformers, and rening cocrystallization techniques. ere is
also a growing interest in exploring cocrystals for alternative dosage forms
beyond oral administration. e successful commercialization of cocrys-
tals, like the valsartan-sacubitril cocrystal (Entresto and Novartis), demon-
strates the potential for cocrystals to become a more mainstream option in
pharmaceutical development [63, 64].
e market success of pharmaceutical cocrystals depends on eectively
managing their strategic and regulatory aspects. Strategically, the design
and development process is crucial, requiring the careful selection of
coformers that enhance the desired properties of the API. is task neces-
sitates a strong understanding of molecular interactions and crystal engi-
neering principles [64].
e formation of cocrystals means a decent and cost-eective strategy
in drug design and development since the physicochemical properties
of APIs can be improved without profound chemical modications [25].
Both the US and European regulatory bodies have established criteria that
streamline the registration of pharmaceutical products to ease the use of
cocrystals to develop pharmaceutical products. e recommendations
given here detail the conditions for the registration of pharmaceutical
products containing cocrystals so as to meet safety, eectiveness, and qual-
ity requirements. e regulatory authorities appreciate the high potential
of cocrystals in enhancing the properties of APIs; therefore, they encour-
age new developments and advances in formulation and therapy. Current
research and development in the use of cocrystals as formulation tools in
developing pharmaceuticals largely depends on regulatory support [65].
Ensuring quality and consistency while meeting the industrial needs
for pharmaceutical cocrystals presents a great diculty. Mechanochemical
developments provide promise for scalable, solvent-free cocrystal synthe-
sis, therefore providing the means of more aordable and environmentally
friendly manufacture [66–70]. Apart from raising solubility, cocrystals
are attracting more and more use in taste masking, mechanical property
improvement, and intellectual property generation. Researchers are look-
ing at many methods to create cocrystals with enhanced physicochemical
48 Cocrystals in Pharmaceutical Sciences
qualities. Among other things, better bioavailability, owability, solubility,
and tabletability could emerge from these advancements [71]. Researchers
are investigating cocrystals, especially for young and elderly patients as
they can enhance the taste of specic APIs, therefore considerably boost-
ing the palatability of medications [72].
2.5 Conclusion
In this chapter, we provide a comprehensive analysis of the developments
and advantages that pharmaceutical cocrystals have brought to the eld
of drug development. One of the most promising approaches to enhanc-
ing the eectiveness of drugs is represented by these cocrystals. e e-
cacy of the medicine is much enhanced by the structural elements and
design ideas. In the realm of medical research, the usage of pharmaceutical
cocrystals presents an interesting opportunity to surpass the restrictions
imposed by conventional drug forms and to transform drug generation.
is creative solution opens the path for major developments as it can e-
ciently address solubility and stability problems. e potential of cocrystals
is driving studies on them. Future use and manufacturing of medicinal
cocrystals should be much improved by ongoing research and develop-
ment. Combining pharmacology, materials science, and chemistry gives
a fascinating eld. Emphasizing the relevance of these molecules in the
pharmaceutical industry, this work presents a thorough study of the many
characteristics of medicinal cocrystals. Further improvements will be
shaped by the use of advanced characterization techniques, environmen-
tally friendly synthesis methods, customized medication, combination
therapies, and legislative framework construction. Constant research, cre-
ativity, and industry-wide cooperation among pharmaceutical companies
will help us to fully appreciate the advantages of cocrystals for patients all
around. Whatever challenges have been overcome; the future seems bright.
Researchers and doctors are quite interested in them as they have the abil-
ity to improve the quality of drugs.
Acknowledgment
We extend our heartfelt gratitude to IFTM University, Moradabad, and
Moradabad Educational Trust Group of Institutions, Faculty of Pharmacy
for providing the necessary facilities and resources to complete this chapter.
Design and Characteristics of Pharmaceutical Cocrystals 49
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55
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (55–92) © 2025 Scrivener Publishing LLC
3
Advancements in Computational
Screening Methods for
Pharmaceutical Cocrystals
Maan Singh
1
, Abhishek Mali
1
, Madhukiran Dhondale
1
,
Ashish Kumar Agrawal
1
, Amrit Paudel
2
* and Dinesh Kumar
1†
1
Department of Pharmaceutical Engineering and Technology, Indian Institute of
Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, India
2
Research Centre Pharmaceutical Engineering GmbH (RCPE), University of
Technology, Institute of Process and Particle Engineering, Graz, Austria
Abstract
In crystal engineering, pharmaceutical cocrystals are designed as co-systems com-
posed of an active pharmaceutical ingredient (API) and a coformer held together
by noncovalent interaction. Cocrystallization is a commonly employed technique
to enhance the solubility and bioavailability of drugs. e selection of a suitable
coformer has a paramount role in cocrystal development. A vast range of coform-
ers is currently available for cocrystallization experiments. Coformer selection
is either done by experimental- or computational-based methods. Experimental
methods predominantly rely on the traditional empirical approach and are thus
extremely tedious. Computational methods can boost the cocrystal research
capabilities by providing information about the API-coformer complex even
before experimentation by considering the structural features of the components.
Computational-based screening methods can screen libraries of compounds in a
relatively short time. Molecular electrostatic potential surfaces (MEPS), Hirshfeld
surface analysis (HSA), Cambridge structure database (CSD), COSMO-RS (con-
ductor-like screening model for real solvents), and Crystal structure prediction
(CSP) are the prominent cocrystal screening tools employed by the researchers.
ese methods can also save signicant time and resources. Apart from assisting
the screening, the physical and chemical properties of formed cocrystals can also
*Corresponding author: amrit.paudel@rcpe.at
†
Corresponding author: dinesh.phe@itbhu.ac.in