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356 Cocrystals in Pharmaceutical Sciences
of paracetamol cocrystal with 5-nitroisophthalic acid. Int. J. Pharm., 497,
1–2, 106–113, 2016.
78. Sanphui, P., Mishra, M.K., Ramamurty, U., Desiraju, G.R., Tuning mechan-
ical properties of pharmaceutical crystals with multicomponent crystals:
voriconazole as a case study. Mol. Pharmaceutics, 12, 3, 889–897, 2015.
357
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (357–378) © 2025 Scrivener Publishing LLC
12
Patents and Regulatory Considerations
of Pharmaceutical Cocrystals
Ritu Rathi
1
, Ritamay Sau
1
, Rakesh K. Sindhu
2
, Harpreet Singh
3
and Inderbir Singh
1
*
1
Chitkara College of Pharmacy, Chitkara University, Punjab, India
2
School of Pharmacy, Sharda University, Greater Noida, Uttar Pradesh, India
3
School of Pharmaceutical Sciences (Faculty of Pharmacy),
IFTM University, Moradabad, Uttar Pradesh, India
Abstract
Pharmaceutical cocrystals are a crystalline substance that is a new addition to
pharmaceutical drug design. Cocrystals oer improved physicochemical prop-
erties of drugs such as solubility, dissolution, mechanical properties, and more.
However, the development and commercialization of pharmaceutical cocrystals
have several legal and regulatory challenges. Hence, to preserve the innovative
approach for medicinal applications, the European Medicines Agency (EMA)
and the Food and Drug Administration (FDA) issued regulatory guidelines for
pharmaceutical cocrystals. e EU and FDA publish guidelines for the creation,
approval, and post-marketing surveillance of medicinal products based on cocrys-
tals. e regulatory guidelines covered matters relating to manufacturing proce-
dures, bioavailability, bioequivalence, and safety and quality aspects of both the
coformer as well as the nished product. e current book chapter provides a
brief overview of pharmaceutical cocrystals and their preparation techniques. e
descriptive overview of the USFDA and EMA starting from its evolution to the
current guidelines (NDA and ANDA applications) for pharmaceutical cocrystals
is also been discussed. Later, various patent licenses for pharmaceutical cocrys-
tals provided by the USFDA, EMA, and other countries are also mentioned.
Cocrystals. Pharmaceutical developers can eectively promote cocrystal-based
medicines while maintaining compliance with safety and legal norms by maneu-
vering through various regulatory and patent landscapes.
*Corresponding author: inderbir.singh@chitakra.edu.in
358 Cocrystals in Pharmaceutical Sciences
Keywords: Cocrystals, patents, regulatory, USFDA, EMA, CTD
12.1 Introduction
In this era of pharmaceutical development, the selection of a suitable solid
form of an active pharmaceutical ingredient (API) is the most crucial
phase during the design and development of a drug product. e devel-
oped product should be capable enough to possess desirable physico-
chemical properties such as improved solubility, dissolution, stability, and
bioavailability [1]. In this context, pharmaceutical cocrystals are a prom-
ising strategy that is capable of altering the physicochemical properties of
drugs without aecting their pharmacological properties. Cocrystals are
multicomponent systems consisting of an active pharmaceutical ingredient
(API) mixed with one or more cocrystal formers [2]. ese are solid prod-
ucts, particularly at room temperature, and usually form bonds through
noncovalent interactions such as hydrogen bonding, Pi stacking, and van
der Waals forces. As a result, cocrystals possess dierent physicochemi-
cal properties than pure drugs involving altered solubility, dissolution,
mechanical properties, etc. [3].
Researchers have extensively explored dierent methods for the prepa-
ration of pharmaceutical cocrystals. e selection of a suitable preparation
technique is one of the most important steps during cocrystallization. e
selection of technique is mainly based upon the solubility and thermal char-
acteristics of API and coformer [4]. e dierent methods for the prepa-
ration of cocrystals are majorly classied as solvent-based methods and
solvent-free methods. For the preparation of cocrystals, dierent methods
allow better control over the size, shape, and purity of the cocrystals. Some
methods are more suitable for large-scale production. e chemical nature
of the components can inuence the choice of method. Certain methods
are faster than others, Grinding, for example, can produce cocrystals in
a short time, whereas solution-based methods might take longer due to
the need for solvent evaporation [5]. Various advanced techniques that are
available for the preparation of cocrystals are solid-based cocrystal pro-
cessing methods, mechanochemical grinding, hot-melt extrusion, contact
formation, liquid-assisted cocrystal, liquid-assisted grinding, high shear
granulation, spray drying, antisolvent cocrystallization, supercritical car-
bon dioxide processing, freeze drying, microuidic and jet dispensing
approaches, and ultrasound crystallization [6, 7]. Some of the widely used
cocrystallization techniques are listed below in Table 12.1.
Patents & Regulatory Concerns of Cocrystals 359
Table 12.1 Various preparation techniques of pharmaceutical cocrystals.
Techniques Description Advantage Disadvantage
Solvent
evaporation
Dissolving API
and coformer
in a common
solvent, followed
by evaporation
to induce
crystallization
Simple, versatile,
suitable for a
wide range of
compounds
Solvent choice
can aect
crystal growth,
may require
optimization
Grinding (neat
grinding)
Manually grinding
API and coformer
together in a mortar
and pestle
Simple, cost-
eective, does
not require
solvents
Lack of control
over particle
size, potential
for polymorphic
forms, scalability
challenges
Solvent drop
grinding
Mixing API and
coformer with a
small amount of
solvent, followed by
grinding to induce
crystallization
Combines
advantages
of grinding
and solution
methods
Similar limitations to
grinding methods,
such as lack
of particle size
control
Antisolvent
crystallization
Injecting a non-
solvent into a
solution containing
API and coformer
to induce
precipitation and
crystallization
Rapid
crystallization,
better control
over crystal
size
Requires careful
selection of
solvents and
antisolvents,
optimization
of process
parameters
Slurry
conversion
Mixing suspension
of API and
coformer in a
solvent, followed
by controlled
crystallization
Good control
over crystal
size and
morphology
Time-consuming,
may require
optimization
(Continued)
360 Cocrystals in Pharmaceutical Sciences
Cocrystals have been known for a long time but have received relatively
little attention in research. In 1844, Wohler created the rst cocrystal, a
1:1 ratio of benzoquinone and hydroquinone, known as quinhydrone. e
denition of crystal engineering, as provided by Desiraju in 1989, entails
understanding intermolecular interactions in crystal packing and utilizing
this knowledge to design new solids with desired physical and chemical
properties [7]. Over the past ten years, pharmaceutical cocrystals have
attracted considerable interest from researchers. e growing attention
to cocrystallization primarily arises from the advantages it oers, wherein
supramolecular synthons and noncovalent interactions are utilized for
accurately controlling the molecular arrangement within the crystal lat-
tice. As a result, cocrystals oer better thermal stability, processing, and
purity characteristics as compared to amorphous solids [8]. In 2004, a
widely accepted denition of cocrystals was proposed by Almarsson and
Zaworotko, describing them as solid formations involving an API and
a coformer under ambient conditions. Multicomponent cocrystals are
included in this denition, which highlights the importance of interactions
such as hydrogen bonding, along with other noncovalent and non-ionic
interactions like H-bonding or π-π interactions [9].
In 2011, a broadly accepted denition of cocrystals was established
during a consensual meeting sponsored by the Indo-U.S. Science and
Technology Forum (IUSSTF). Cocrystals were dened as single-phase
Table 12.1 Various preparation techniques of pharmaceutical cocrystals.
(Continued)
Techniques Description Advantage Disadvantage
Coprecipitation Simultaneous
precipitation of
API and coformer
from a solution
under controlled
conditions
Good control
over crystal
size and
morphology
Requires careful
selection
of solvents,
optimization
of process
parameters
Hydrothermal/
solvothermal
Crystallization of API
and coformer under
high-temperature
and high-pressure
conditions in a
closed vessel
Allows for
synthesis of
crystalline
materials not
easily obtained
by other
methods
Requires specialized
equipment,
careful control
of reaction
conditions
Patents & Regulatory Concerns of Cocrystals 361
crystalline materials composed of two or more dierent molecular and/
or ionic compounds in a stoichiometric ratio, explicitly excluding sol-
vates and simple salts. is denition was provided by the participants
[10]. Cocrystals, as dened by the USFDA, are crystalline materials com-
prising two or more molecules within the same crystal lattice, linked via
non-ionic and noncovalent interactions. In pharmaceutical cocrystals,
one component acts as the API, while the other, known as the coformer,
generally comprises a substance acknowledged as safe for use in drugs
or food. ese components interact within the crystal lattice through
noncovalent interactions, such as hydrogen bonding, in specic stoichio-
metric ratios [11, 12]. Crystal engineering is rooted in supramolecular
chemistry, emphasizing molecular recognition between complementary
fragments that drive self-organization and enable the development of
supramolecular functions. Cocrystallization, a pivotal aspect of crystal
engineering, markedly alters the physicochemical properties of drug
substances. is modication inuences factors including solubility, dis-
solution, compaction, tableting, permeability, bioavailability, physical
form, biochemical and hydration stability, and melting point [13].
e utilization of crystal engineering to fabricate cocrystals has emerged
as a viable approach for formulating chemicals encompassing low water
solubility, garnering signicant attention [14]. e terminology and pre-
cise denition of cocrystal have been the subjects of ongoing disclosure
and scrutiny for a signicant period. In a collaborative eort involving the
FDA, United States Department of Health and Human Services (HHS),
and CDER (Center for Drug Evaluation and Research), a comprehen-
sive description of cocrystals was established. e FDA issued a guid-
ance document in April 2013, titled “Guidance for Industry; FDA 2013”
which provided an ocial categorization and denition of pharmaceutical
cocrystals [15]. According to this document, a cocrystal is a type of crys-
talline substance that consists of several molecules organized in the same
crystal lattice structure. A pharmaceutical cocrystal is precisely described
as a molecular complex comprised of a dissociable mixture consisting of
an active pharmaceutical ingredient and an excipient, with the excipient
acting as a neutral guest element [16].
Upon successful development of a pharmaceutical cocrystal yielded pos-
itive outcomes, the subsequent step involved securing regulatory approval,
and facilitating the pathway to commercialization. For development to qual-
ify for a patent, it must satisfy three conditions: novelty, non-obviousness,
and utility/convenience [17]. To use pharmaceutical cocrystals in drugs
marketed for the United States and the European Union, should strictly
comply with stated regulatory laws. From a regulatory point of view, the
362 Cocrystals in Pharmaceutical Sciences
dierent salt form of the drug is considered as a separate active pharma-
ceutical ingredient but a new cocrystal is not. us, to get approval for a
drug product that includes either salt or an authorized active pharmaceu-
tical ingredient, it is essential to le an Abbreviated New Drug Application
[ANDA 505(b)(2)]. ANDA necessitates the regulatory body in assessing
clinical data, to ascertain the safety and ecacy of the associated drug [18].
Nevertheless, if an individual intends to acquire authorization for a medic-
inal product that includes a cocrystal of a previously proved API, they just
need to le an Abbreviated New Drug Application (ANDA) under section
505(j) [19]. e application does not need the FDA to assess clinical data.
In 2013, the USFDA became the inaugural regulatory agency to issue
explicit guidelines about pharmaceutical cocrystals. As per the guidelines,
pharmaceutical cocrystals are classied as drug product intermediates and
are handled similarly to molecular complexes of APIs and excipients [20].
e standards demand that both API and the coformer must be in a state
of neutrality, and their interaction must be noncovalent and non-ionic. If
the pKa values of both API and its coformer are greater than 1 (pKa (acid)
- pKa (the conjugate acid of base), there will be a signicant transfer of
protons, leading to ionization and possible formation of salt rather than
cocrystal [21]. On the other hand, if both have a ΔpKa dierence of less
than 1, the transfer of protons will have little or no eect. On fullling this
condition, the API coformer product must be characterized as a cocrystal.
Before reaching the site of pharmacological activity, it is essential for both
the API and the coformer to completely separate.
e FDA reclassied pharmaceutical cocrystals as a separate class of
solvates and hydrates in their 2016 updated guidance. Pharmaceutical
cocrystals were classied in the same regulatory category as a polymorph
of the active pharmaceutical ingredient [22]. In addition, the FDA requires
an in-vitro evaluation that specically examines the ability of a substance
to dissolve or to be dissolved. is evaluation is typically considered suf-
cient in demonstrating that the active medicine fully separates from the
coformer. According to the latest denition by the FDA, cocrystals are
crystalline substances consisting of two or more distinct molecules, usually
a drug and coformers, arranged in the same crystal lattice [23]. Moreover, a
cocrystal containing two or more APIs must be categorized as a xed-dose
combination product by the FDA rather than a new API [24].
e European Medicines Agency (EMA) holds a notably distinct view-
point on pharmaceutical cocrystals in comparison to the Food and Drug
Administration. According to the European Medicines Agency, the doc-
umentation of cocrystals entails identifying commonalities between the
cocrystals and salts. erefore, the guidelines outlined for documenting
Patents & Regulatory Concerns of Cocrystals 363
salts should be followed by the cocrystals also [25]. According to the EMA,
the cocrystal dossier should include documents related to quality, manufac-
turing, reference standards, control, characterization, control, mechanism
of container-closure, and stability of the drug ingredient. Ensuring the phar-
macological suitability for coformers is essential, with commonly utilized
components regarded as reagents in ICH Q11 [26]. Additionally, any com-
plex unique coformers should be elucidated, accompanied by safety data.
e approval process for the European Medicines Agency (EMA) includes
a decentralized procedure, facilitating a mutual recognition procedure [27].
A “full application” is submitted for newer active substances (NAS).
Organizations must provide a comprehensive dossier for approval, which
comprises information about the clinical trials, pharmaceutical tests, and
preclinical tests. e EMA classied solid-state compounds according to
their intrinsic structures. Cocrystals are dened as highly ordered crystal-
line structures composed of two or more components in a specic stoichio-
metric ratio [28]. In contrast to salts, the arrangement of these structures
in the crystal lattice is not determined by ionic bonding. It is also crucial to
follow good manufacturing procedures when producing active compounds
or nished pharmaceutical products that include the in-situ creation of
cocrystals throughout the manufacturing process [29]. e submission
of an active substance master le encompassing both cocrystals and API
[30]. In such instances, it may be essential to create cocrystals consisting of
many therapeutic entities. However, to conrm this potential, it is essential
to present evidence based on a thorough examination of the dosage ratio,
constituents of the cocrystals, and their inuence on biopharmaceutical
characteristics and therapeutic eectiveness.
is chapter will look into the complex system of patents and regulatory
diculties surrounding pharmaceutical cocrystals. It examines the fun-
damental principles, synthesis methods, and characterization techniques
of cocrystals, providing a comprehensive understanding of their potential
applications in the pharmaceutical industry. Furthermore, it will investi-
gate the complex regulatory frameworks and intellectual property con-
cerns that inuence the development, manufacturing, and marketing of
cocrystal-based medicinal products.
12.1.1 Comparison Between USFDA and EMA
on the Aspects of Cocrystal
ere are only two regulatory bodies, namely, the USFDA and EMA, to
recognize the signicance of cocrystals. e USFDA and EMA both stated
364 Cocrystals in Pharmaceutical Sciences
cocrystals are composed of one or two components that are held together
by non-ionic bonds in the same crystal lattice. Although on comparing
the USDA and EMA regulatory guidelines we can spot several dierences
based on the API and co former’s properties.
According to EMA’s point of view, neither neutral nor charged mole-
cules can develop crystals. On the other side, the FDA had not issued any
remarks on that point. Additionally, some assertions are missing from the
old proposed guideline. Some gaps throughout their guideline can create
an issue for developing cocrystals. EMA also states that API and coformer
can be neutral or charged (either positive or negative). However, as per
FDA guidelines, all the components present in a crystal lattice should be in
Table 12.2 Comparison between USFDA and EMA on pharmaceutical
cocrystals based on regulatory aspects.
EMA USFDA
Denition Monophasic crystal
structures are
fabricated by two or
more elements in a
stoichiometric ratio
Crystal is made up
of two or more
molecules. One is
API, and the other is
coformer
Coformer role Act as reagent Act as excipient
Regulatory category API Polymorphism of API
Coformer Non-active compound
reagents
Neutral compound
Interaction Non-ionic interaction Non-ionic interaction
*Resemblance
with active
pharmaceutical
ingredient
Cocrystals depends on
safety and ecacy
Ye s
GMP regulation and
guidelines
According to GMP
regulation, part two
of EU GMP guideline
and ICH Q7 and in
rare cases, part one of
EU GMP guideline
cGMP for drug product
USDMF/ASMF Can be led Non-practicable being
DPI
Patents & Regulatory Concerns of Cocrystals 365
a neutral state. Even the latest FDA guidelines do not mention any change
in their document [31].
Similar to disagreement on the absence or presence of charges within
the crystal, EMA and USFDA fail to agree on API and coformer aggregate
state. In EMA’s point of view, the aggregate state of API and coformer has
less scientic value. e Food and Drug Administration (FDA) emphasizes
that cocrystals are specic examples of hydrates and solvates in its latest
guidance statement. Consequently, one could draw the conclusion that
since the US agency distinguishes between hydrates, solvates, and cocrys-
tals, each cocrystal component needs to be solid at room temperature.
In addition to these, the USFDA and EMA share disagreements over
the scientic point of view of cocrystals. As per EMA, solvates, hydrates,
and cocrystals allocate the same general principles for crystal curation.
Hence, they did not classify them as all three belonging to the same sol-
id-state class family. However, in accordance with the USFDA cocrystals
are referred to as a special case of solvates and hydrates [32, 33]. For a
better understanding, the comparison between the USFDA and EMA is
represented in Table 12.2.
12.2 Generic Concept of Pharmaceutical Cocrystals
For European Union
Aer the establishment of EU legislation, EMA achieved a big accomplish-
ment and focused on medicinal and pharmaceutical products. Aer that,
a guideline is framed for the regulation of pharmaceutical products and
post-marketing surveillance. All the EU member states took a resolution
for market authorization which can be procured in a centralized, decen-
tralized way, at that moment EMA easily executed the scientic evaluation
and the commission gave access to the market. EMA issued a directive
2001/83/EC For generic products to get access to the market through a
principal legislative document Directive 2001/83/EC.
Requirement for generic requisition using cocrystal API within EU:-
1. Regulatory Compliance: Aer the formation of cocrys-
tal guidelines, the generic application for cocrystal should
be under regulatory compliance as written in Directive
2001/83/EC.
2. Market Access: e generic application for cocrystals can
enter the market under the directive 2001/83/EC. However,
Article 10(1) gives relaxation for the application Under