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116 Cocrystals in Pharmaceutical Sciences
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121
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (121–152) © 2025 Scrivener Publishing LLC
5
A Brief on Analytical and Characterization
Techniques for Evaluation
of Pharmaceutical Cocrystals
Suraj R. Chaudhari
1
, Shashikant B. Bagade
2
, Sonali V. Chaudhari
3
and Atul A. Shirkhedkar
1
*
1
Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical
Education and Research, Shirpur, Maharashtra, India
2
SVKM’s NMIMS, School of Pharmacy & Technology Management, Shirpur,
Maharashtra, India
3
Department of Petrochemical Engineering, Dr. Babasaheb Ambedkar
Technological University, Lonere, Maharashtra, India
Abstract
Cocrystals are formed by energetically combining a molecular or ionic therapeu-
tic agent with another substance known as a cocrystal precursor. is precursor
remains in a solid state, which holds a signicant function. Understanding the
properties of cocrystals, including their thermal behavior and energy uctuations,
is really crucial in pharmaceutical and other elds. Research can enhance cocrys-
tal quality; specically, they are being extensively studied in industries like drug
administration. is study is focused on enhancing drug delivery and bioavail-
ability. Furthermore, when investigating solid-state transformations, for instance,
polymorphic transitions and amorphization, it provides valuable insights into
how cocrystals may evolve gradually over time, impacting their long-term
performance and stability, especially during storage. It is essential to employ var-
ious sophisticated and advanced characterization techniques to optimize a drug
formulation. is chapter oers an overview of vital analytical methods used to
characterize cocrystals and to detail and explain strategic approaches employed
for evaluating cocrystals. Also, physical parameters involved in the formulation’s
development phase may be monitored, investigated, and analyzed using these
approaches. General knowledge is obtained from exploring these analytical and
*Corresponding author: shirkhedkar@gmail.com
122 Cocrystals in Pharmaceutical Sciences
characterization techniques, which are vital in the development and utilization of
cocrystals across various scientic and industrial applications.
Keywords: Active pharmaceutical ingredient, cocrystal, thermal studies,
vibrational spectroscopy, x-ray diraction
5.1 Introduction
In the pursuit of advancing pharmaceutical innovation, the primary focus
of novel drug development research is to attain an active pharmaceutical
ingredient (API) that embodies optimal physiochemical, pharmaceutical,
and biological attributes [1]. It is signicant for progress in drug research
that APIs have greater attributes than just solubility, bioavailability, and
stability. e similarities in particle size, hygroscopicity, and crystallinity
are highly signicant drug substance properties. When drug properties
are improved, treatments work better, and the economy benets, leading
to enhanced patient outcomes, reduced healthcare costs, and increased
productivity [2]. Researchers and pharmaceutical companies are keen on
modifying APIs, oen by incorporating cocrystals. is is done to change
the quality of the drug so that it works better with the therapeutic solution
and, most importantly, for the person undergoing treatment [1, 3].
Pharmaceutical cocrystals involve an API co-formulated using a cocrys-
tallizing agent. ese are solid products, particularly at room temperature
(RT), and are usually bonded with noncovalent forces [2].
Due to the limited number of new drug discoveries in past years, phar-
maceutical makers and researchers have focused on modifying existing
active drug molecules into cocrystals [1–4]. A well-known challenge in
developing pharmaceutical formulations is the issue of insoluble drug
molecules. Studies have shown that more than 90% of drugs have been
approved since 1995, and approximately 40% of newly developed chem-
ical compounds encounter signicant challenges due to their poor water
solubility. is lack of solubility can lead to issues with drug absorption
and bioavailability, ultimately reducing their eectiveness and making it
dicult to achieve the desired therapeutic eects [5]. e bioavailability
of API taken orally is greatly inuenced by their solubility in water. As a
result, these drugs may not get absorbed well in the body as they are poorly
water-soluble [6, 7]. erefore, from a pharmaceutical and pharmacolog-
ical perspective, the main goal is to improve the characteristics of drugs,
particularly their solubility [5].
Characterization of Pharmaceutical Cocrystals 123
However, cocrystal formation is still highly benecial, oering signi-
cant improvements in solubility that can enhance drug performance and
bioavailability, making it a valuable alternative when salt formation is
unsuitable [1, 8].
is chapter discusses various analytical methods for evaluating solid-
state drug forms, such as cocrystals. Also, it discusses the few analytical
approaches implemented to characterize cocrystals. Many methods, such
as spectroscopy, crystallography, thermal analysis, microscopy, and other
physical techniques, are commonly used or combined to examine how
cocrystals are structured and work in solid form [9, 10]. is chapter pro-
vides comprehensive information on various commonly utilized methods,
encompassing conventional techniques and innovative approaches, to
gain insight into cocrystals. We provide a concise overview of these meth-
ods, emphasizing their application in gaining insights into the structure
and properties of cocrystals. ese techniques can also be used to keep
following up and exploring the physical characteristics of developing
formulations.
A complete analysis of cocrystals has been understood by exploring
analytical methodologies such as X-ray powder diraction (XRPD), sin-
gle-crystal X-ray diraction (SCXRD), dierential scanning calorimetry
(DSC), thermogravimetric analysis (TGA), infrared spectroscopy (IR),
nuclear magnetic resonance (NMR) spectroscopy, solid-state nuclear mag-
netic resonance (ssNMR), scanning electron microscopy (SEM), trans-
mission electron microscopy (TEM), Raman spectroscopy, powder X-ray
crystallography, and dynamic vapor sorption signicantly contributes to
the well-informed plan and application of cocrystals in miscellaneous sci-
entic and industrial domains.
5.2 Analytical Techniques
5.2.1 X-Ray Powder Diraction (XRPD)
It has been explored to investigate the structural characteristics of crys-
talline materials. It works by aiming X-rays at a nely ground powder
sample and measuring its diraction pattern. It delivers essential insights
regarding the atomic layout inside the matrix. By analyzing the peaks in
the pattern, researchers can determine how well the atoms are organized
in the crystal structure. e XRPD helps determine the structures of pow-
dered samples, learn about new crystals, and comprehend the transitions
between materials’ phases. It is utilized for component identication,
124 Cocrystals in Pharmaceutical Sciences
crystal structure determination, quantitative analysis, stability and poly-
morphism, interaction research, and phase transitions in various domains,
including geology, medicine, and materials science. Herein, the single
crystal and powder methods need the diraction condition met, as Bragg’s
law suggested [10–12].
nλ = 2d.sin θ
(5.1)
where “n” is the integer, “d” is the distance relating crystal planes, “θ” is the
striking angle, and “λ” is the X-ray frequency wavelength.
Various literature reports consider it the “gold standard” method for
identifying and conrming cocrystal forms. Yuta Otsuka and Satoru Goto
investigated the eects of mechanochemical synthesis (dry and wet) on
mixtures comprised of piroxicam and saccharin. XRPD analysis showed
that grinding reduced the crystallinity of both compounds without causing
peak shis or new peaks, indicating no transition to an amorphous state
aer 4 hours. However, grinding an equimolar mixture resulted in peak
broadening and signicant intensity reduction, suggesting the amorphiza-
tion of most particles. e study concludes that while individual grinding
did not amorphized the samples, mixed grinding led to amorphization,
requiring further thermal analysis to dierentiate cocrystallization from
individual amorphization [13].
e cocrystal of ketoprofen was made with succinic acid and saccharin
conformers in 1:1:1 and 2:1:1 molar ratios and subsequently characterized.
e diraction peak intensity of the cocrystal is reduced compared to the
reference standard (RS) owing to a change in crystal structure. In the dif-
fractograms of RS-ketoprofen and the cocrystal compound of interest, an
attenuation in strength was recorded at 6.3126°, 18.3094°, and 22.9618°,
indicating a structural alteration [14]. In another study, Urszula Maciołek
and Iwona Budziak-Wieczorek synthesized and characterized a cocrystal
of (−)-epicatechin and barbituric acid. X-ray crystallography was explored
to elucidate the structure and intermolecular relationship. Insights from
the analysis of the crystal lattice packing and interactions suggested that
the molecules were aligned into tapes through O−H···O contacts involving
(−)-epicatechin and coformers [15].
5.2.2 Single-Crystal X-Ray Diraction (SCXRD)
It is helpful to researchers from many dierent disciplines. Researchers can
crystallize the overall crystal structure of cocrystals at the atomic level. is
Characterization of Pharmaceutical Cocrystals 125
will help determine the specicity of the cocrystal’s properties and func-
tions. It will give a clear picture of the molecular structure and their place-
ment pattern, essential for the formation of cocrystals in which a specic
shape and function prevail. is technique lets us see where each atom is
within the structure, making the atomic arrangement in crystals of cocrys-
tal. Measuring bond length and angle is vital for scientists to understand
molecules’ stability and geometric arrangement. In addition, the lattice cell
size is the fundamental reproducible element of the crystal, another essen-
tial detail that SCXRD provides. is provides valuable insights into the
structure and geometry of the cocrystal.
Further understanding of the general structure and organization of the
cocrystal can be obtained by examining the diraction pattern, which can
reveal the lattice symmetry of the crystal. Researchers can analyze the dif-
fraction pattern and create an electron density map showing the distribution
of electrons within the crystal. is map provides a more comprehensive
view of the molecular structure. Furthermore, crystal XRD oers knowl-
edge about the molecular scaolding in the crystal structure, including
details about vacancies and intermolecular interactions. is information
helps us understand crystal packing. Finally, the method detects anomalies
in atomic arrangement and isolates uctuations in the thermal motion of
atoms because it is sensitive to disorder and anisotropy [16–19].
A one-pot, three-component Betti reaction created a cocrystal of
8-hydroxyquinoline and acetone-(2,4-dinitrophenyl) hydrazone. The
chemical was analyzed, revealing that noncovalent interactions are the
primary forces driving the development of the cocrystal [20].
In another approach, a cocrystal of nateglinide was prepared to address
its poor water solubility, signicantly limiting its oral bioavailability.
Although various techniques exist to enhance drug solubility, each method
has limitations. According to SCXRD results, the newly developed crystal
material is classied as associated with the P21 monoclinic crystal arrange-
ment, formed from nateglinide and isonicotinamide in a stoichiometric
ratio of 2:2 [21]. e slow solvent evaporation technique synthesized a
novel energetic cocrystal of trinitrotoluene and pyrene in a 1:1 molar ratio.
SCXRD analysis and noncovalent interaction calculations revealed that the
donor primarily governs the structure of the trinitrotoluene and pyrene
cocrystal–acceptor π-π interactions [22].
In a vital effort aiming to enhance X-ray absorption efficiency in
pure luminescent materials, a highly fluorescent dye, 2,5-di(4-pyr-
idyl)thiazolo[5,4-d]thiazole (Py
2
TTz), was produced. Following that,
cocrystals were produced with 1,4-diiodotetrafluorobenzene (I
2
F
4
B)
and 1,3,5-trifluoro-2,4,6-triiodobenzene (I
3
F
3
B), yielding Py2TTz-I2F4