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326 Cocrystals in Pharmaceutical Sciences
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329
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (329–356) © 2025 Scrivener Publishing LLC
11
Application of Pharmaceutical
Cocrystals in Improving Mechanical
Properties and Stability
Sushant Sharma, Ritu Rathi, Ayushi Taneja, Poonam Arora and Inderbir Singh*
Chitkara College of Pharmacy, Chitkara University, Punjab, India
Abstract
Cocrystals, dened as crystalline complexes formed by two or more constituents,
usually involving a drug and a coformer, present a promising strategy to improve
the physicochemical characteristics of pharmaceuticals. ese solid-state materi-
als can enhance stability, bioavailability, and solubility, addressing common chal-
lenges in drug formulation. One of the signicant advantages of cocrystals lies in
their ability to change the mechanical properties of active pharmaceutical ingredi-
ents (APIs). Many drugs face issues such as poor compressibility and low stability,
which can hamper their ecacy and manufacturability. By integrating cocrystals,
these limitations can be mitigated. For instance, the formation of a cocrystal can
stabilize an API that is otherwise prone to degradation under environmental con-
ditions, thereby prolonging its shelf life. Furthermore, cocrystals oen exhibit
improved mechanical properties, which are critical for tablet formulation. e
incorporation of coformers can lead to a more favorable solid-state structure,
enhancing owability and compressibility, ultimately resulting in a lower risk of
brittleness and better tablet hardness. Additionally, cocrystals can enable better
dissolution rates, enhancing bioavailability and therapeutic outcomes. By optimiz-
ing the physicochemical characteristics of drugs, cocrystals serve as a vital tool in
pharmaceutical development, providing a strategic approach to overcoming sta-
bility issues and improving mechanical properties. is innovation not only fosters
more ecient drug formulations but also opens pathways for re-evaluating exist-
ing medications, ensuring that they can meet contemporary therapeutic demands
with greater ecacy. Here we review the cocrystals and their mechanism that led
to enhanced stability and mechanical properties of various drugs.
*Corresponding author: inderbir.singh@chitkara.edu.in
330 Cocrystals in Pharmaceutical Sciences
Keywords: Tablets, hygroscopicity, compressibility, plasticity, cocrystals,
tabletability
11.1 Introduction
Pharmaceutical cocrystals are multicomponent systems comprising at
least one API and other components (called coformer) in a stoichiomet-
ric ratio that are held together through noncovalent interactions (e.g.,
hydrogen bonding or van der Waals interactions) [1]. Cocrystals oer
improved drug performance by combining the pharmacological qualities
of the drug molecule with a hydrogen-bonded coformer in the crystal lat-
tice [2]. e ionization of both the components inside the cocrystal can
be neutral, ionic, or zwitterion and can have its own set of polymorphs
and solvates. With such structural diversity, cocrystals are benecial in
improving the physicochemical properties of drugs. Cocrystallization is a
promising technique for enhancing the physicochemical characteristics of
APIs without changing their chemical structure [3]. Drugs physicochem-
ical characteristics, including their melting point, tabletability, solubility,
stability, bioavailability, and permeability, can be improved by pharma-
ceutical cocrystals [4]. At present, the BCS Class II and IV comprise
40% of already marketed medications and about 90% of new chemical
entities. ese classes suer from issues of low bioavailability and poor
water solubility [5]. is limits the drug absorption in the gastrointestinal
tract, which in turn limits the therapeutic ecacy of the drug. e phys-
icochemical characteristics of pharmaceutical solids have a signicant
impact on how well medicinal products work [6]. Poor mechanical and
physicochemical qualities, such as the solubility, permeability, bioavail-
ability, dissolving rate, hygroscopicity, tabletability, compressibility, and
stability of APIs and excipients, are a common cause of medication failure
in the clinical development stages [7, 8].
e study of the mechanical properties of pharmaceutical APIs is critical
for understanding the nature of the material and developing tablets with
suitable tensile strength. Poor mechanical properties can lead to several
tablet defects such as capping, fragmentation, and cracking, which would
be dicult for scale-up as well. erefore a powder should have sucient
mechanical properties, which include elasticity, plasticity, and hardness.
Cocrystallization is one of the leading approaches that can improve the
mechanical properties of powders which also results in improved tablet-
ability [9]. Cocrystal-based tablets can display variable tensile strength,
which can either increase or decrease. is variability is oen due to
Cocrystals and Physicomechanical Properties 331
changes in elasticity and plasticity introduced by the cocrystal formation.
Cocrystals can improve powder tableting performance through appreci-
ation of their unique structural features, including the presence of salts,
strong and weak hydrogen bonds, and at layers. ese structural advan-
tages lead to enhanced mechanical qualities in cocrystals, highlighting the
potential of crystal engineering to optimize pharmaceutical solids. e
formation of cocrystals is therefore essential for improving the mechan-
ical properties and processing characteristics of xenobiotics, surpassing
the capabilities of drugs that do not form cocrystals [10]. Various research
studies have already been conducted to examine the eect of cocrystals on
mechanical properties. Research conducted by Chow et al. for exploring
the mechanical properties, dissolution performance, and hygroscopicity of
urbiprofen. e urbiprofen was cocrystallized with nicotinamide using
a rapid-solvent evaporation technique. e resulting cocrystals showed
improved tableting performance, dissolution behavior, and reduced
hygroscopicity [11]. is research indicated the potential of cocrystals to
improve the mechanical properties of pharmaceutical APIs.
In addition to mechanical properties, cocrystals have applications in
altering the stability of pharmaceutical APIs. Crystallization can improve
chemical stability, which includes resistance to degradation and preserves
the drug’s ecacy over time; physical stability, which maintains the drug’s
structural integrity and prevents undesirable transformations; and thermal
stability, which ensures the cocrystal can withstand heat without decom-
posing. Traditional drugs oen face challenges like polymorphic trans-
formations, hygroscopicity, and poor compaction, leading to instability
and reduced ecacy. Cocrystals address these issues by enhancing chem-
ical stability through protective interactions that shield the active phar-
maceutical ingredient (API) from environmental degradation. ey also
improve physical stability by maintaining a consistent crystal structure,
which helps prevent unwanted phase changes. Furthermore, the robust
bonding in cocrystals increases thermal stability, allowing drugs to endure
higher temperatures without losing ecacy. Overall, cocrystals oer a
more reliable and eective solution for drug tablets by overcoming many
of the stability challenges associated with simple drugs. Dapagliozin, an
anti-hyperglycemic drug is unstable due to its highly hygroscopic nature
and exposure to high temperatures. e preparation of 1:1 cocrystals of
dapagliozin and citric acid was capable of solving the issue. e cocrys-
tals showed improved stability over high temperatures and high relative
humidity, while compromising the dissolution performance and tableting
performance [12]. is indicated the signicance of cocrystals in enhanc-
ing the stability of pharmaceutical APIs.
332 Cocrystals in Pharmaceutical Sciences
11.2 Pharmaceutical Cocrystals Improve Mechanical
Properties
Mechanical properties show a signicant role in the manufacture of solid
dosage forms that have all of the features required for a pharmaceutical API
to be compressed in tablet form, such as compaction, tabletability, and ten-
sile strength. e mechanical characteristics of crystalline constituents are
essential as they are important in various manufacturing processes, includ-
ing milling, granulation, tableting, coating, and blending. Pharmaceutical
APIs exhibiting low elastic recovery and increased plastic deformation are
predicted to oer good tableting behavior. In the case of solid materials,
mechanical deformation includes fragmentation, plastic, elastic, and plas-
tic. Elastic deformation allows a material to gain to its original shape aer
the deforming force is removed, due to the alterable stretching of intermo-
lecular bonds, though this is typically restricted to minor strains. Plastic
deformation, on the other hand, results in irreversible changes to the
shape and size of the solid due to stress, caused by irreversible dislocation
movement within the crystal structure [13]. Viscoelastic deformation is
partially reversible and depends on the amount and rate of applied stress.
Fragmentation occurs when the material fractures due to external stress if
elastic, viscoelastic, or plastic deformations are insucient to accommo-
date the strain, forming fragments.
Furthermore, many organic substances exhibit poor mechanical char-
acteristics, which is an obstacle to manufacturing tablet formulations. It
was found that material with improved plasticity properties can display
superior compressibility, which remains irreversible even aer stress elim-
ination. Cocrystallization is the method that has been shown to success-
fully improve the mechanical characteristics of xenobiotics by changing
the crystal packing and providing the necessary stability and mechanical
strength. For organic constituents, low elastic recovery and increased plas-
tic deformation are predicted by good tableting behavior. e behavior
of bulk compaction would eventually be improved by crystal formations
having slip planes, which would facilitate plastic deformation. Roy et al.
reported one of the examples explained the mechanical behaviors of chlor-
zoxazone. Chlorzoxazone shows poor compressibility, so chlorzoxazone
and picolinic acid cocrystals were developed, followed by tablet produc-
tion. e tensile strength of tablets comprising chlorzoxazone only was less
than 0.8 MPa at a compaction force of y MPa. Chlorzoxazone-picolinic
acid cocrystals’ tensile strength was on the other much higher reaching
approx. 1 6 MPa at even with no cap or lamination (250 MPa). e higher
Cocrystals and Physicomechanical Properties 333
adhesion strength is related to the more closely packed cocrystals compared
with pure chlorzoxazone. Furthermore, the cocrystal structure’s slip planes
promote better plastic deformation in the material, which enhances com-
pressibility [14]. One of the reasons that cocrystals advance the mechanical
properties of drugs is due to the presence of slip planes which are crystal-
lographic planes that have the weakest interplanar interaction in a given
crystal and have been related with the highest molecular density and the
major separation amid adjacent planes [15]. e existence of slip planes in
crystal assembly enables sliding motion, hence providing better plasticity
to the crystal which results in an enhanced inter-particulate bonding area
of the compact. Kale et al. reported improved tableting performance of
rivaroxaban-malonic acid (2:1) cocrystal than that of rivaroxaban due to
the occurrence of a at slip plane that enhanced the plasticity of rivarox-
aban-malonic acid cocrystal [16].
A drug’s “tabletability” refers to its ability to be transformed from bulk
powder at a specic compaction pressure into tablets with a specic ten-
sile strength [17]. High-speed tableting can be achieved by adequate blend
owability, mechanical strength, friability, and appropriate dissolving
performance [18]. Cocrystal formation can be used to modify compac-
tion characteristics and, consequently, the manufacturability of solid-state
pharmaceuticals [19]. It has been found that crystallization improves
tabletability, compressibility, packability, and powder owability of drugs.
e salt and cocrystals’ compressibility and owability are crucial to assess-
ing tabletability more precisely. In the eld of pharmaceutical research, the
optimal formulation should be engineered to be stable, compact, and ow-
able at low punch force, and it should require as little excipient addition as
possible [20].
Flowability in the context of cocrystals refers to the ease with which
cocrystal powders can move and be handled during processes like mixing,
granulation, and tablet compression. Good owability ensures uniformity
in dosage forms and prevents issues like segregation during processing.
Favipiravir exhibited poor owability at higher angles of repose, as demon-
strated by Xinyuan et al. In comparison, its cocrystals displayed superior
ow characteristics at lower angles of repose and outstanding compress-
ibility of these samples [21]. e results of powder tableting supported
the poor uidity and compressibility of favipiravir. Favipiravir cocrystals
have dramatically improved permeability and tabletability as a result of a
characteristic layered structure and a decrease in molecular polarity [22].
e molecular congurations and packing techniques of the crystals also
aect how tabletable crystalline powders are. Jie et al. showed that hes-
peretin cocrystals of temozolomide, have superior tableting behavior, and
334 Cocrystals in Pharmaceutical Sciences
have better compaction properties than temozolomide powder. Over the
whole compaction pressure range, they can be formed into intact tablets
without the need for any excipients. Molecular congurations and pack-
ing techniques of crystals aect how tabletable crystalline powders are.
Temozolomide’s crystal structure is packed in a reticular pattern with-
out any possible slip planes, which hinders its capacity to be plastically
deformed and results in poor tabletability. Hesperetin exhibits signi-
cantly greater tabletability than temozolomide because its crystal structure
is lled with two-dimensional layered structures that can generate slip
planes. Consequently, the tabletability of the cocrystal is in between that
of hesperetin and pure temozolomide [23]. When stress is detached, con-
stituents with higher plasticity properties classically display greater com-
pressibility, which is permanent. Nevertheless, a task in producing tablet
preparations is the weak mechanical characteristics of many organic sub-
stances. It has been shown that cocrystallization can signicantly enhance a
drug’s mechanical qualities by changing the crystal packing [24, 25] exam-
ple here. For organic materials, better tableting behavior predicts greater
plastic deformation and less elastic regaining. e mechanical character-
istics and compaction performance of caeine cocrystal polymorphs were
assessed by Singaraju et al. Caeine-3-nitrobenzoic acid cocrystal form I
exhibits superior plastic deformation (compared to form II) which may be
explained by its two-dimensional layered crystal structure, according to
data from the mechanical and energy framework [26]. Mishra et al. used
nanoindentation to examine the mechanical characteristics of caeine-
glutaric acid cocrystals on various crystalline faces. It was discovered that
the anisotropic mechanical responses of polymorphs were contingent on
the number of potential slip planes and the potency of intermolecular
interactions within the crystal structure concerning the indentation path
[27]. Its maximum plasticity and tabletability are congruent. Since the slip
planes with the corrugated sheet structure only interact extremely weakly,
hardness and plasticity are inversely related. is is also the fundamental
cause of its distortion due to bending. e maximum tabletability indicates
that bending crystals are signicantly more appropriate for tableting than
shearing crystals [28]. In a study, Malonic acid had a fairly excellent bond-
ing strength, but due to its lesser exibility, it showed “lower” tabletability.
is behavior was inuenced by the “intermediate” bonding stability and
the lack of a slip plane. e primary reason for Rivaroxaban’s “interme-
diate” tabletability was identied as dierential surface topologies of slip
planes. Because of its greater exibility and bonding strength, rivaroxaban-
malonic acid cocrystal solids had a noticeably “higher” tabletability. e
enhanced mechanical behavior of rivaroxaban-malonic acid cocrystals
Cocrystals and Physicomechanical Properties 335
was attributed to at-layered topological slip through the plane, a higher
degree of intermolecular contact, and a bigger spacing among neighbor-
ing crystallographic layers [29]. Deformation of organic molecule solids
that is irreversible and pliable leads to increased BA; this type of defor-
mation behavior is referred to as plasticity [30]. Slip systems and other
crystallographic characteristics are what give single- and multicomponent
cocrystals their plasticity (a rise in BA). Two factors that aect the BS of
the crystal form are the degree of intermolecular contacts besides actual
density [31]. It is important to note that “plasticity” only aects BA; hence,
while assessing bulk deformation (compaction) behavior, one must also
take into account the impact of BS. “Compressibility” is a term used to
describe a powder material’s capacity to experience a volume reduction
upon the application of compaction pressure. Porosity versus compac-
tion pressure is plotted to show compressibility, and the plot indicates the
degree of the interparticulate bonding area (BA) increase. e capacity of
powder material to form tablets with adequate tensile strength when den-
sication occurs is known as compactibility [37]. It is shown as a plot of
tablet porosity versus tensile strength, where the plot represents the bond-
ing strength (BS) of a particular material. Plots showing compactibility
reveal that the cocrystal (RIV-MAL Co) has a stronger bonding strength
than both RIV and MAL at all compaction pressures. Higher BA and BS
combined to give RIV-MAL Co a higher tabletability [31]. Signicantly
higher tabletability was shown by the cocrystal with the highest bond angle
and bond strength. e porosity is another factor that inuences tabletabil-
ity. A study showed that porosity as a function of applied pressure makes
up the powder compressibility prole. Beneath a certain stress, more
compressible materials have a greater solid fraction besides a lower nal
porosity. e tensile strength of tablets is shown as a function of porosity
in the compactibility prole. erefore, powdered materials are said to be
more compactible if they produce tougher compacts at a given porosity.
Plotting the tablet’s tensile strength against the applied compression pres-
sure results in the creation of a tabletability prole. All materials experi-
ence initial fragmentation and particle rearrangement at mild stress (< 20
MPa). All materials rst show elastic deformation as pressure rises beyond
20 MPa, with the observed strain being linearly proportional to the stress.
e material will give and start to plastically ow or irrevocably deform
if a critical pressure is reached [32]. erefore, it is crucial to note in the
conclusion that cocrystallization is an eective method for improving the
API’s tabletability. More examples of dierent drugs whose stability is
enhanced by the formation of cocrystals are enumerated below in Table
11.1.