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186 Cocrystals in Pharmaceutical Sciences
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189
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (189–230) © 2025 Scrivener Publishing LLC
7
Drug-Drug Cocrystals:
Advancements and Applications
Ritu Rathi
1
, Sushant Sharma
1
, Siddhartha Gautham Pal
1
, Rohil Panwar
2
,
Taruna
3
, Rakesh Pahwa
2
and Inderbir Singh
1
*
1
Chitkara College of Pharmacy, Chitkara University, Punjab, India
2
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra,
Haryana, India
3
Pt. C.L.S. Government College, Karnal, Haryana, India
Abstract
Drug-drug cocrystals (DDCs) are a combination of two or more drugs arranged
into a single crystalline structure. DDCs provide enormous benets such as
improved solubility, stability, and bioavailability without altering the chemical
integrity of the individual components. is method provides an avenue for refor-
mulating existing drugs but also facilitates the creation of synergistic therapeu-
tic combinations that may enhance ecacy and reduce adverse eects. ere are
numerous methods for the preparation of DDCs including solvent-based, solvent-
free approaches which are further classied in this chapter. During the prepa-
ration of DDCs, some of the parameters are most important to consider, such
as critical process parameters (CPP), and quality target product prole (QTPP),
which dene the desired properties of the nal product. It is crucial to consider the
ability of DDC to withstand dierent storage conditions. Various evaluation tests
for multiple drug cocrystals (MDC) are reviewed in this book chapter. Even with
their potential benets, the development of DDCs has several challenges. Some of
the challenges, such as the selection of appropriate drugs and their combinations,
require careful consideration of factors such as solubility proles, molecular inter-
actions, and compatibility between dosage forms. Additionally, there are a limited
number of marketed drug substances that restrict the available combinations for
DDC formation. To overcome these challenges, various strategies were explored,
including selecting appropriate techniques for preparing DDCs and investigat-
ing dierent stoichiometric ratios in cocrystal formation. Here, we review the
*Corresponding author: inderbir.singh@chitkara.edu.in
190 Cocrystals in Pharmaceutical Sciences
DDCs that were reported in the last decade along with their patents and marketed
products.
Keywords: Drug-drug cocrystal, multiple drug crystals, patents, marketed
7.1 Introduction
Monotherapies (i.e., targeting a specic receptor) are no longer eective
in treating many complicated disorders, including HIV/AIDS, cancer, dia-
betes, cardiovascular disease, and infectious diseases. As an outcome, the
combination of more than one therapeutic agent in unit dosage form has
gained popularity [1]. e successful development of bilayer tablet prod-
ucts addresses the challenges of drug incompatibility and enables both
rapid and slow drug release from a single tablet. However, this innovation
introduces new challenges in formulation design, manufacturing process
control, and product performance that are not seen in traditional mono-
lithic tablets [2]. erefore, it is necessary to develop new technologies to
overcome these problems. Hence, the need for drug-drug cocrystals (DDCs)
seems to be important. According to the FDA, cocrystals are dened as
“dissociable multi-component solid crystalline supramolecular complexes
composed of two or more components within the same crystal lattice
where the components are in a neutral state and interact via nonionic
interactions.” Generally, cocrystals consist of an API and a coformer; when
both the components of cocrystals are API (active pharmaceutical ingredi-
ent), it is called DDCs, also known as multiple drug cocrystals (MDCs) [3,
4]. DDCs can address the problems associated with traditional or conven-
tional combination drug therapies. e xed-dose combinations (FDC) of
the multi-targeted drugs are observed to de-escalate the associated adverse
outcomes, dosage frequency with good eciency, and medicinal eects. In
addition to this, DDCs decrease the occurrence of drug resistance which
culminates in more pronounced and simplied disease management [5].
e rst ever cocrystal was reported by Friedrich Wöhler in 1844, con-
sisting of quinone and hydroquinone. Many DDCs were then discov-
ered in the late 1800s and early 1900s reported in the book Organische
Molekulverbindungen, published by Paul Pfeier in 1922. roughout
the 1900s, more cocrystals originated, while some were found by acci-
dent, others were found through screening methods. By understanding
how intermolecular interactions impact crystal packing, cocrystals with
specic physical and chemical features can be engineered to alter the
Drug-Drug Cocrystals: Advancements and Applications 191
physicochemical properties of drugs [6]. erefore, the concept of DDCs
has generated massive interest in the pharmaceutical eld.
DDCs help to meet the criteria of innovation, as well as practicality for
pharmaceutical development, which are necessary for patent eligibility.
Multidrug cocrystals oer advantages such as increased bioavailability [7],
enhanced solubility and dissolution of component drugs [8–10], potential
stabilization through intermolecular interactions [11], synergistic or addi-
tive therapeutic eects [12], and opportunities for the life cycle manage-
ment of existing pharmaceutical products [13]. Along with physiochemical
properties, DDCs can enhance biological activities as well by adding an
appropriate, therapeutically useful component without requiring any
chemical alteration [14]. Another study comprising meloxicam and aspi-
rin reported a 12-time decrease in the Tmax, which resulted in bioavail-
ability enhancement fourfold [15]. Palash et al. reported DDC of curcumin
with resorcinol and pyrogallol that showed improved drug solubility [16].
DDCs have also gained a new form of intellectual property protection that
nanoparticles, microspheres, liposomes, and niosomes currently lack. is
IP protection provides a regulatory and competitive advantage for DDC
products over other novel drug delivery technologies in the market. DDCs
can overcome the challenges of xed-dose combinations and could over-
come the additional indications by drug-drug interactions with modied
physicochemical properties of each drug [17]. DDCs have many benets
and have outstanding development in the eld of pharmaceutical sciences
but they still have major challenges due to lack of commercial viability and
economic factors and are dicult to evaluate [18]. ere are limited drug-
drug combinations available until now, which leads to challenges in the
development of MDCs. One of the major factors is limited solubility; they
possess less solubility than the parent drug, and their therapeutic eect is
not reversible. However, DDCs cover the majority of challenges that are
not present in traditional drugs. DDCs are explored in various therapeutic
areas such as DDCs of nonsteroidal anti-inammatory drugs (NSAIDs),
DDCs of anti-tubercular drugs, and DDCs of diuretic drugs [19–21].
Despite having so many advantages, DDCs face their own development
challenges. One of the challenges is its synthesizing and designing. DDCs
mainly prepared to provide a synergistic eect because it is made up of the
combination of two APIs but the combination of two drugs will not always
provide a guarantee that DDCs will be eective and provide a better thera-
peutic eect than monolithic therapy. erefore, it will not ensure that our
combination is pharmaceutically acceptable. For example, a scientist named
Tomita synthesized DDC in 1977 consisting of theophylline and phenobar-
bital. A combination of phenobarbital (a nervous system depressant) and
192 Cocrystals in Pharmaceutical Sciences
theophylline (antiasthmatic) should provide a synergistic eect but there is
no supporting evidence for synergism or any practical application in ther-
apy. Furthermore, phenobarbital is a cytochrome P450 (CYP) inducer and
theophylline undergoes rst-pass metabolism, which can lead to decreased
plasma concentration of theophylline [22]. Moreover, cocrystals consist of
xed stoichiometric ratios but the dose ratio obtained from DDCs may not
be in accordance with the clinical applications. For example, among scien-
tists, Desiraju et al. developed a DDC consisting of zidovudine and lamivu-
dine as both of the drug substances are antiviral agents, so it may provide
some benet. However, the mass ratio of DDC consisting of lamivudine
and zidovudine (1:1.2) was dissimilar from their oral dosage form having
a mass ratio of 1:2 which could result in its diculty in clinical application
[23]. Another challenge is the quantication of multiple drugs, especially in
the case of nutraceuticals having poor solution state stability. Furthermore,
challenges are represented in the gure. Primarily, we can use three aspects
to overcome these disadvantages. Firstly, it is important to select cocrystal-
lization techniques that align with the properties, nature, and morphology
of drugs involved. erefore, choosing the most suitable method will result
in more eective screening procedures and may increase the success rate of
DDC preparation. Secondly, one of the problems associated with DDCs is
dierent stoichiometric ratios which may be overcome if more emphasis is
given to exploring DDCs with dierent stoichiometric ratios, which could
be applied to triumph over the dosage problem. irdly, we can think of
expanding the DDCs to drug- drug-drug-nutraceutical cocrystals, which
may be benecial and can ease the task of development.
At last, we need to consider several strategic methods such as inves-
tigating varied stoichiometric ratios, cocrystallization techniques, and
also considering the combination of drug-drug nutraceutical cocrystals.
ese actions are critical for getting at most from DDCs, nally leading to
improved patient care, treatment, safety, and eectiveness [24].
7.1.1 Preparation Techniques
Various methods are used for preparing DDCs, including solvent-based
and solvent-free approaches with miscellaneous methods, as listed in
Table 7.1. Solvent-based methods utilize high solvent consumption, with
the choice of solvent impacting the cocrystallization outcome [25]. On
the other hand, solvent-free (solid-state) methods oer the potential to
eliminate the need for solvents in cocrystal synthesis. Solvent-based meth-
ods include solvent evaporation, vapor diusion, slurry transformation
Drug-Drug Cocrystals: Advancements and Applications 193
Table 7.1 Various methods of preparation techniques for drug-drug cocrystals.
Methods of cocrystallization Description
Solvent-based techniques
Solvent evaporation API and coformer are dissolved
in a common solvent. en, the
solution slowly evaporates over
time. As the solvent evaporates,
the drug and coformer molecules
come together and form a
cocrystal.
Slurry conversion In this method, API and coformer
are mixed in a liquid solvent for
the formation of slurry. en, the
slurry is stirred, and the solvent
is allowed to evaporate to get the
cocrystals.
Vapor diusion API and coformer are dissolved
in a common solvent. en, the
solution is placed in a closed
container. Aer that, a vapor of a
dierent solvent is added to the
container. As the vapor diuses
into the solution, the formation of
cocrystals takes place.
High-pressure
homogenization (HPH)
With high-pressure drug and
coformer mixed. en, the mixture
is passed through a narrow nozzle
under controlled pressure, which
results in the nanosized cocrystal
formation.
High shear granulation
(HSG)
e drug and coformer are mixed
with a binder and placed in high
shear force within the granulator.
e speed of the impeller and
chopper are maintained constant
during granulation. e high-shear
mixing results in the formation of
granules of cocrystals.
(Continued)
194 Cocrystals in Pharmaceutical Sciences
Table 7.1 Various methods of preparation techniques for drug-drug cocrystals.
(Continued)
Ultrasound-assisted e drug and the coformer are
dissolved in a solvent. en, the
solution is exposed to ultrasound
waves, which results in crystal
growth by increasing mass transfer
and disrupting agglomerates. e
formation of cocrystals takes place.
Solvent-free techniques
Neat grinding With the application of manual or
mechanical pressure, the API and
coformer are combined with their
dry solid form.
Liquid-assisted
grinding(LAG)
e API and coformer are combined
in their solid forms. A catalytic
quantity of liquid is added to the
mixture by applying pressure
through manual or mechanical
means to promote cocrystal
preparation.
Hot-melt extrusion (HME) Cocrystallization is formed by
pressure and heat to melt API and
coformer. Cocrystals developed
without the use of solvents make it
an eco-friendlier option.
Matrix-assisted
cocrystallization (MAC)
Equimolar amounts of the API
(drug) and the coformer are
mixed with a matrix material in
the solid state. en, the mixture
is fed into a hot-melt extruder
that is responsible for forming a
cocrystal.
Polymer-assisted grinding
(POLAG)
API and the coformer are blended
with a polymer in their solid state.
e grinding process promotes the
cocrystal formation.
(Continued)
Drug-Drug Cocrystals: Advancements and Applications 195
crystallization, high-shear granulation, high-pressure homogenization,
and ultrasound-assisted cocrystallization [26]. In contrast, solid-based
approaches consist of methods like pure grinding crystallization, liquid-
assisted grinding, hot-melt extrusion, matrix-assisted cocrystallization,
Table 7.1 Various methods of preparation techniques for drug-drug cocrystals.
(Continued)
Methods of cocrystallization Description
Miscellaneous techniques
Microwave-assisted In this technique with or without
the use of solvent, the drug
with the coformer is taken in
equimolar ratios. en, it is placed
in microwave irradiation in a
microwave reactor.
Freeze drying (lyophilization) In the freeze-drying process, the
drug and the coformer are
dissolved in a solvent. en, the
solution is frozen to form a solid
mass. When the frozen solid is
placed in the vacuum, it undergoes
a sublimation process, and the
cocrystals collect as a dry powder.
Electrospray e drug and the coformer are
dissolved in a solvent. en, the
solution passed through a nozzle
with the inuence of an electric
eld, and ne droplets formed. e
solvent evaporation method results
in the formation of cocrystals.
Laser irradiation In the laser irradiation process, the
drug and the coformer are used
in powder form. With the help
of a high-power CO
2
laser, this
process results in the formation of
cocrystals.
Resonant acoustic mixing
(RAM)
It involves subjecting a mixture of the
drug and the coformer to resonant
acoustic waves. ese pressure
waves stimulate ecient mixing
and cocrystal formation.