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257
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (257–292) © 2025 Scrivener Publishing LLC
9
Pharmaceutical Cocrystals
for Solubility Enhancement of Drugs
Mouli Das, Sk Habibullah, Tanisha Das and Subrata Mallick*
Department of Pharmaceutics, School of Pharmaceutical Sciences, Siksha ‘O’
Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India
Abstract
Cocrystallization is considered an ecologically and possibly active method
to improve the ability of a low water-soluble drug to be dissolved in an aque-
ous medium and consequently bioavailability without changing the physico-
pharmacological properties of the drug. In the eld of drug development and
research, cocrystallization is an appropriate, convenient, and green practice with
a small amount of solvent or without any solvent. In the world of chemistry, sol-
ubility plays a vital role in understanding the behavior of substances in various
solutions. Solubility denotes the capability of a material to dissolve in a solvent
and form a homogeneous mixture which remains inuenced by various factors
like solute-solvent nature, temperature, pressure and presence of another solute,
particle size, molecular size, and polymorphism. e rst key aspect to consider
is the nature of the solvent and solute involved in the dissolution process. Solvents
can be broadly classied into polar and nonpolar. Polar solvents, such as water,
have a positive and negative end, allowing them to interact with polar substances.
Weakly basic drugs with acidic coformers can improve solubility by altering the
pH. Cocrystallization involves combining multiple molecular components in pre-
cise ratios to form solid-phase materials through intermolecular interactions of
dispersion forces, dipole-dipole forces, dipole-induced dipole forces, and hydro-
gen bonds. Cocrystallization could also be utilized in pharmaceutical formulation
development of taste masking, controlled release dosage forms, targeted delivery
systems, etc. It can exhibit specic physical, chemical, and mechanical proper-
ties of various material science applications. Furthermore, cocrystallization nds
application beyond pharmaceuticals, extending to areas like nutraceuticals, food
science, and material engineering. Its versatility enables tailored solutions for taste
*Corresponding author: profsmallick@gmail.com; subratamallick@soa.ac.in
258 Cocrystals in Pharmaceutical Sciences
masking, controlled-release formulations, and targeted drug delivery systems.
As research progresses, the renement of cocrystallization strategies promises to
address the escalating demand for improved drug solubility.
Keywords: Bioavailability, cocrystallization, dissolution rate, polymorphism,
solubility
9.1 Introduction
e manufacturing of eective drug products inuences the successful
delivery of any active pharmaceutical ingredient (API) to patients. Generally,
the challenges faced in the successful delivery of drugs and manufacturing
include specic property decits, such as solubility, stability, organoleptic
properties, bioavailability, and mechanical characteristics [1]. Lack of sol-
ubility in pharmaceutical drug development is a major challenge for devel-
oping any dosage form as well as any other formulations. Dierent solid
pharmaceutical multi-components produced from API are shown in Figure
9.1. is section will comprise the various techniques related to cocrystalli-
zation in order to improve poor drug solubility thereby enhancing their bio-
availability. Consecutive administration of oral drugs, bioavailability studies,
and complexed inter-associated drug absorption deals with crucial factors
related to dosage forms. e primary factor includes the release of API from
the formulation which signicantly aects pharmacological actions. e
dissolution prole followed by the solubility studies of the drug enclosed
in the physiological environment of GIT also serves as another key factor
inuencing bioavailability. Any API transition from solid to dissolved state
is an important factor to be considered in the dissolution process for eective
absorption. Additionally, permeability also plays a signicant role in absorp-
tion at GIT. e drug’s ability to cross the mucosal barrier across the GI tract
and enter into the general circulation is highly inuenced by the permeabil-
ity factors depending upon specic characteristics of the site of absorption.
Fundamentally, the interplay of drug release, dissolution prole, and perme-
ability jointly rules the overall bioavailability, determining the rate and extent
at which the administered API reaches the systemic circulation and exerts
its therapeutic activity. Cocrystallization is considered likely to be a success-
ful approach in improving the aqueous solubility of weakly soluble drugs. It
encompasses the formation of a multicomponent solid crystalline substance
of a drug component and an appropriate conformer in a specic molar
ratio to form a crystal lattice. Cocrystals can enhance the physical charac-
teristics of the drug like solubility without hampering its pharmacological
Cocrystals for Solubility Enhancement 259
eectiveness [2–5]. Cocrystals of uoxetine hydrochloride with benzoic
acid and fumaric acid dissolve more sluggishly, while cocrystals with suc-
cinic acid dissolve more rapidly compared to the pure drug because of the
hydrogen bond formation between neutral carboxylic acid and chloride ion
of uoxetine hydrochloride [6]. e selection of a suitable coformer is a key
challenge in cocrystal development and can be done through trial and error,
supramolecular synthon, or virtual screening approaches. Drug material
and coformer are used to prepare cocrystals employing solvent vaporiza-
tion technique, solvent-drop grinding, and solution cooling crystallization.
Overall, cocrystallization oers a promising strategy for enhancing not only
the solubility of drugs but also improving their pharmaceutical properties.
9.2 Why Solubility Enhancement is Important?
Drug solubility plays a crucial role in the eld of pharmacology as it has a
direct inuence on the bioavailability of the drug. Bioavailability denotes
the degree of availability of the drug in the bloodstream via the absorp-
tion process. erefore, enhancing the solubility of the material could be
of utmost importance as it determines how eciently the drug can be
absorbed and available in the body. When a drug is soluble, it can readily
dissolve in a solvent, typically water, and will be ready for absorption at the
absorption site. When a drug is poorly soluble, it is not readily available at
Drug molecule
Salts
Hydrate or Solvate
Cocrystal
Drug molecule
lons
Water or solvent
Co-former
Figure 9.1 Dierent solid pharmaceutical multi-components produced from API.
260 Cocrystals in Pharmaceutical Sciences
the absorption site which reduces the therapeutic ecacy due to long resi-
dence time near and around the site. Solubility enhancement improves the
dissolution rate of the drug allowing it to dissolve rapidly into the biologi-
cal uid and absorb more eciently. By increasing solubility, the therapeu-
tic concentration of a drug can be achieved more readily, leading to a faster
onset of action. e solubility enhancement method of cocrystallization
proposes to modify the solid-state properties of a drug without altering its
pharmacological activity. For example, in a study, cocrystal of atorvasta-
tin calcium with glucosamine hydrochloride and nicotinamide by solvent
vaporization method also exhibited an enhanced dissolution rate two to
three times faster than the pure atorvastatin and the physical mixture due
to weak inter-particular bonding with coformer and a higher degree of
drug crystallinity in a physical mixture [7].
9.3 Factors Aecting Solubility
Understanding the factors that inuence the capability of a material to dis-
solve in an assumed solvent is vital in enhancing solubility. Crucial vari-
ables that inuence solubility are discussed below:
9.3.1 Nature of Solute and Solvent
e major aspect is the nature of the solvent and solute participating in
the dissolution process. e two broad categories of solvents are polar sol-
vents and nonpolar solvents. Polar solvents, such as water, have a positive
and negative end, which allows them to interact with polar substances. On
the other hand, nonpolar solvents lack such polarity and interact more
readily with nonpolar substances. Understanding the nature of the solute
is equally important. Dierent substances have varying levels of solubility
based on their physicochemical properties. For example, polar substances
have a tendency to be soluble readily in polar liquids, whereas nonpolar
substances have greater solubility in nonpolar liquids.
9.3.2 Particle Size
e size of the solute particle and their surface area can inuence solubility.
Decreased particle size increases surface area and facilitates drug dissolu-
tion. Active surface area is directly related to the dissolution rate rather
than the entire external area of the material. Enhanced intimate contact of
the active solid external area with the aqueous medium enables augmented
Cocrystals for Solubility Enhancement 261
dissolution. e association between the material size and the solubility is
governed by the principle from physical chemistry specically the Noyes-
Whitney equation. It also exhibits dierent thermodynamic properties
compared to the larger particle size. It inuences solubility by aecting fac-
tors like Gibbs free energy and enthalpy of the same compound. Particle
agglomeration of hydrophobic drugs may form larger particles due to high
surface free energy resulting in a fall of dissolution. e use of a wetting
agent reduces interfacial tension and converts the total surface area of the
hydrophobic drug to active surface area and improves dissolution. e
reduction of size and crystallinity is eective in solubility as well as dis-
solution prole [8]. e preparation of nano-cocrystal formulation is still
in the investigative stage. e wet particulate milling crystallization tech-
nique was found more robust for the preparation of nano-cocrystals. In a
recent study, prepared nano-cocrystals (300 to 450 nm) exhibited better
physical stability and improved kinetic solubility by 6.6 and 51.5 times than
the solubility of itraconazole–succinic acid cocrystal and pure itraconazole
respectively [9].
9.3.3 Temperature
Temperature is a critical factor that inuences the solubility of solid drug
substances. Usually, a rise in temperature hints at increased solubility for
most solid solutes. is is because elevated temperatures extend additional
energy for the particulate materials to break down into individual pieces
and interact with the liquid molecules. However, the ability of the gas sol-
utes to be dissolved tends to decrease with increasing temperature. is is
due to the inverse relationship between temperature and the solubility of
gasses described by Henry’s law. In some cases, solubility may be relatively
constant with temperature changes. is is common for solutes where the
dissolution process is not signicantly aected by temperature or where
the exothermic and endothermic eects balance out each other.
9.3.4 Pressure
e pressure exerted on a gas solute can impact its solubility in a liquid sol-
vent. According to Henry’s law, the “solubility” of a gas is directly related to
the fractional pressure of the gas above the uid. erefore, an increase in
pressure leads to higher gas solubility, while a decrease in pressure reduces
solubility. is principle is vital in various applications such as carbonation
of beverages and gas absorption processes.
262 Cocrystals in Pharmaceutical Sciences
9.3.5 Molecular Size
Smaller molecules oen have higher solubility. is is because smaller
molecule experiences weaker intermolecular forces and can more easily
t between solvent molecules. Small molecules are more soluble in polar
solvents as they form favorable interactions with polar functional groups
in the solvent. e presence of polar or charged functional groups in a mol-
ecule can improve solubility in charged solvents. Bonding like hydrogen
bonding, dipole-dipole interaction, and ion-dipole interactions between
solute and solvent molecules can signicantly impact solubility.
9.3.6 Polymorphism
Polymorphs (having dierent molecular arrangements) can have a notable
impact on the solubility of a molecule. Variations in the crystal structure,
packing arrangement, and surface properties can aect the solubility of
any compound. ere are some factors about polymorphs that can aect
solubility. Dierent polymorphs can have distinct crystal packing arrange-
ments which lead to various molecular densities within the crystal lattice
that can inuence the exposure of functional groups and aect the solubil-
ity in a given solvent. Polymorphs having looser packing may have higher
solubility because solvent molecules can penetrate the crystal lattice very
easily. It is also seen that thermodynamically stable polymorphs play a cru-
cial role because they have lower solubility leads to less dissolution.
9.3.7 Polarity
Polarity is a fundamental factor that strongly inuences the solubility of
a substance. Polarity plays a crucial role in the interaction between mol-
ecules of the solvent and solute. In a general rule, a polar solvent tends
to dissolve in a polar solvent, i.e., “like dissolves like.” e polarity of the
solvent facilitates the breaking down of the intermolecular forces within
the solute. Similarly, nonpolar solutes tend to dissolve in nonpolar solvents
where van der Waals forces play a signicant role. For ionic compounds,
the interaction between ions and polar solvents is very crucial. Polar sol-
vents like water can enhance the dissolution of an ionic compound by sur-
rounding and stabilizing it through ion-dipole interaction.
9.3.8 Common-Ion Eect
e presence of a common ion in a solution can aect the solubility of a
given solute due to a shi in chemical equilibrium via the application of Le
Cocrystals for Solubility Enhancement 263
Chatelier’s principle of equilibrium reaction. A drug in salt form decreases
solubility when dissolved in a solution comprising one of its ions [10].
9.4 Solubility and Bioavailability
e amount and rate of any drug entering the systemic circulation is known
as bioavailability. When it comes to the development of any formulation,
a signicant challenge comes to its low solubility and oral bioavailability.
A cellular membrane is considered a combination of biological and phys-
icochemical barriers to drug transport. e solid drug present in solution
form is only readily available for permeation through the gastrointestinal
membrane. A limited factor in drug absorption is solubility in the early
stage of drug design. A common cause of poor solubility of any drug com-
pound is incomplete and erratic absorption of the drug aer oral adminis-
tration because of extreme lipophilicity.
e biopharmaceutical classication system (how well a drug dissolves
in aqueous media and how readily a drug diuses across the biomembrane)
categorizes four groups, but it has been claimed that the primary proper-
ties are not permeability and solubility but bonding (especially hydrogen
bonding) and molecular size [11]. Synthesizing and designing any phar-
maceutical cocrystal to increase aqueous solubility is the crucial work of
crystal engineering for possible improvement of oral bioavailability. One
report of a pharmacokinetic study conducted using apixaban-cocrystal
demonstrated more than 20-fold improvement in oral bioavailability when
compared with apixaban alone [12]. Another example of a cocrystal of bai-
calein with coformer nicotinamide showed 2.80- and 2.49-fold enhanced
area under the curve (AUC) and peak plasma concentration (Cmax) in rats
respectively as compared to pure API [13]. When tested in rats, meloxicam
cocrystal demonstrated signicantly higher bioavailability relative to the
drug alone [14]. Additionally, the anticancer compound 6-mercaptopu-
rine cocrystals exhibited 168.7% boosted oral bioavailability in rats when
compared to pure drugs [15]. Cocrystallization, a powerful technique that
can modify the drug’s crystal lattice can signicantly enhance the solubil-
ity and stability of various substances inuencing their physicochemical
properties and nally improving the bioavailability of the drug. By forming
complexes with two or more compounds, cocrystallization oers a unique
approach to overcoming challenges in drug formulation, material science,
and other elds including solubility properties leading to improved ther-
apeutic ecacy. Poorly soluble drugs oen face challenges in eective
absorption and consequent bioavailability.
264 Cocrystals in Pharmaceutical Sciences
9.5 Permeability and Cocrystallization
One of the key factors of absorption and distribution of API depends on
the drug’s permeability through the cellular membrane. e permeability
of any pharmaceutical compound is mostly dependent on the “octanol-
water partition coecient” (K
o/w
) measuring its lipophilicity/hydrophilic-
ity of the unmodied API. One study investigated the permeability of
hydrochlorothiazide and cocrystals with various coformers using Franz
diusion cells and it showed higher drug ow levels as compared to pure
drugs. Permeability enhanced due to the development of hetero-synthon
formation between API and the coformer [16]. In a cocrystal formation
between drug and coformer, the properties and structure of the coformer
play an important role. Coformer selection is based on its hydrophilicity
and hydrophobicity to prepare cocrystals with higher solubility and pene-
trability [17]. Likewise, API and coformer interaction, molecular packing,
and interaction with solvent play an important part in modifying pene-
trability to select an optimal formulation [18]. Previous literature suggests
that cocrystallization can alter the polarity of the relevant chemical entity
which results in altering the permeability of the drug compound [16].
Coformers like glutaric acid, lactic acid, tartaric acid, and fumaric acid are
used to improve the permeability, particularly of highly lipophilic drugs.
Membrane permeability and/or diusion could potentially be improved
by cocrystallization without modifying the molecule’s structure or disturb-
ing membrane integrity. Pharmaceutical cocrystallization is known as a
novel and modied method to improve penetrability as it is well repro-
ducible, free of tissue harm, and can be shaped on a big scale related to
other methods [16, 19, 20]. Ferretti and colleagues conducted the study
on indomethacin for solubility as well as permeability enhancement with
three dierent coformers, i.e., 2-methoxy-5-nitroaniline, 2-hydroxy-4-
methyl-pyridine, and saccharine. eir result demonstrated that there is
a 2-fold and 2.5-fold increase in permeability with 2-hydroxy-4-methyl-
pyridine and saccharine and no remarkable change with 2-methoxy-5-
nitroaniline. is dierence in results may be due to the anity of API
for protein being induced by specic weak interaction [20]. BCS class IV
drug hydrochlorothiazide with coformers piperazine and picolinamide
gave 6.6-fold and 3-fold higher solubility along with permeability respec-
tively using cellulose nitrate membrane, and cocrystals using TMP, isonia-
zid, and malonamide also contributed higher cumulative permeation [21].
A similar study on hydrochlorothiazide with succinic acid (4.7-fold lower
solubility, lower permeability), nicotinic acid (1.4-fold decreased solubility,
Cocrystals for Solubility Enhancement 265
two-time increased penetrability), resorcinol (2.4-folds enhanced solubil-
ity, 1.6-fold enhanced penetrability), nicotinamide (solubility enhanced by
1.3-fold, penetrability enhanced by 1.8 times), and 4-aminobenzoic acid
(increased solubility by 2.4 times and increased permeability by 1.3-fold),
and all cocrystal exhibit altered solubility as well as permeability [16].
9.6 Enhancing Solubility through Cocrystallization
Several methods to prepare cocrystals have been investigated like sol-
vent vaporization method, reaction crystallization, fusion, and grinding
method, etc. Drug solubility increases by the preparation of cocrystals by
altering original molecular arrangements or by reducing the lattice energy
of the packing of drug molecules [22]. Nevertheless, supersaturation is
achieved on the surface of the cocrystal diusion layer due to the increase
in the drug concentration. Crystal growth and nucleation coincide with
the dissolution of the cocrystal and that transforms into the real crys-
tal structure which precipitates on “the cocrystal surface,” consequently
avoiding the fast procedure of dissolution and losing the benet of the sol-
ubility of the cocrystal [23]. Several techniques have been introduced for
the improvement of solubility of API such as hot-melt extrusion (HME),
SE, ultrasonic preparation, high-pressure homogenization, supercritical
uid process, freeze drying, ultrasonic precipitation, and spray drying.
Apart from the preparation method, the nature of the materials is another
factor in developing a formulation, having improved solubility leading to
improved bioavailability [24–27].
9.6.1 Hot-Melt Extrusion Technique of Cocrystallization
to Enhance Solubility
HME is a widely used technology not only in the food and polymer industry
but also in cocrystallization for the development of various types of drug
delivery systems. HME is advantageous because it is a solvent-free tech-
nique, a readily scalable process, and a continuous or single-step method
[28–30]. Cocrystal agglomerates prepared with ibuprofen and nicotin-
amide (1:1) using HME showed an enhanced dissolution rate compared to
ibuprofen alone [31]. In another study, Soluplus matrix-assisted cocrystal-
lization of carbamazepine using nicotinamide as a coformer by the HME
method presented a very fast dissolution prole [32]. Drugs with compati-
ble coformers are used to create a “supramolecular synthon”-type cocrystal.