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366 Cocrystals in Pharmaceutical Sciences
10(1) which states that no requirements for CTD and non-
CTD applications but the applicant should submit the mar-
ket authorization application for full access to the market.
3. Reection Paper: Another important parameter is the reec-
tion paper which EMA issued under directive 2001/83/EC.
Under the reection paper, EMA mentioned salt and API
should have the same regulatory status.
For the United States
USFDA published a directive named 21 U.S.C 505(j). In this directive,
those medicines and APIs that have the same quality and properties as
in RLD (Reference Listed Drug) are eligible for the application of ANDA.
For a better understanding, a comparison between the USFDA and EMA
requirements for generic cocrystal is represented in Table 12.3 below [34].
Table 12.3 EMA and USFDA requirements for generic cocrystals.
EMA USFDA
Reection
paper
EMA published FDA also published
Incorporation
of API
EMA gave permission for the
direct incorporation of API
in the European Union
USFDA’s statement was
unclear regarding the
incorporation of API in
the market
Denition EMA denition was a clear
point of view
But USFDA denition
was an unclear point
to view for that reason
they had to tolerate
criticism from scientic
community
Qna European medical agencies
statement was clear, and
they answered all the raised
questions
FDA cannot keep answer
which arose from
various regulatory
guidelines
Flexibility e European medical agency
gave exibility to their
guideline for generic drugs
containing cocrystal
But the FDA did not give
any exibility
Patents & Regulatory Concerns of Cocrystals 367
12.3 Data Consideration Using Pharmaceutical
Cocrystals for Abridged Application
A clinical trial is the most important parameter that both agencies carry out
to prove the product is safe and therapeutically eective. So, the agencies
issued regulatory guidelines for clinical trials. To get market authorization,
the clinical data reports are submitted in a xed format, which is a com-
mon technical document (CTD). e USA, EU, and Japan were the rst
countries to adopt the CTD structure. e CTD structure was developed
by the exertions of the International Conference on Harmonization (ICH)
of Technical Requirements for Registration of Pharmaceuticals for Human
Use for harmonizing application dossiers across dierent countries. CTD
is comprised of modules 2–5. Module 1 contains administration and coun-
try/regional information, hence is not a part of CTD. Modules 2–5 contain
all the scientic data gathered during the development and manufacturing
of the drug product. Module 2 summarizes the data within modules 3, 4,
and 5. Module 3 is composed of quality aspects during the development
of pharmaceutical drug products. Module 4 is composed of non-clinical
studies of pharmaceutical cocrystals and Module 5 contains data relating
to clinical studies of pharmaceutical products [35].
12.3.1 Module 3: Quality Aspects for Pharmaceutical
Cocrystals
Both agencies outlined quality aspects for pharmaceutical cocrystals and
coformers. Keeping in mind the information given by competent authority
some other quality aspects were craed during the development of medic-
inal products using pharmaceutical cocrystals as an API source.
As per EMA, cocrystals are formed from the acid-base reaction of API
and coformer and are linked via non-ionic interaction. e crystal lattice
is formed through ion transfer. For such type of reaction, the pKa value is
analyzed. However, this approach was not approved by EMA, but EMA
suggested certain spectroscopic analytical techniques that can help in the
determination of the formation of crystals. However, EMA did not sug-
gest any spectroscopic technique for the determination of interactions in
cocrystals, but generally, the X-ray diraction technique may be the best
technique to analyze the crystals. Other spectroscopic techniques like
Raman Spectroscopy, IR spectroscopy, and solid-state NMR. e data
obtained from such examinations should be mentioned in the drug sub-
stance section (3.2.S) of CTD. In addition, EMA states that the denition
368 Cocrystals in Pharmaceutical Sciences
of cocrystals is for theoretical implication but practically the characteriza-
tion of active solid substrate should be to nd out whether the active ingre-
dient meets proper quality, safety, and ecacy to be used for medicinal
applications. And does not focus on the classication of solids as salts or
cocrystals [36, 37].
As per the FDA regulatory perspective, a generic drug product developed
by cocrystals should be registered via ANDA. For approval, the applicant
should give supportive evidence for claiming that cocrystals are present
in the product. In comparison to EMA, the USFDA gave a more compre-
hensive and detailed data list that goes along with the ANDA application
of pharmaceutical cocrystals. e rst aspect is through investigation of
the presence of API and coformer in the crystal lattice. e applicant must
carefully examine whether both the API and coformer should be present
or not in the lattice.
e second aspect is that the cocrystal present in pharmaceutical prod-
ucts should be made up of non-ionic bonds but functional groups may
attach with API and coformers. For that, the FDA issued a guideline for
cocrystal determination. FDA outlined a statement for the analysis of the
pKa value. If
ΔpKa≥1, then the ingredient of the crystal lattice can form
an ionic bond. If ΔpKa ≤ 1, then it is considered the ingredient of a crys-
tal lattice that can form a non-ionic bond. In the third aspect, supportive
evidence should be given for the substantial dissolution of the active ingre-
dient before it reaches its target site. FDA also mentioned that the interac-
tions within the cocrystal lattice should behave like solvate and hydrate, as
cocrystals are regarded as special cases of solvates and hydrates. Based on
the dissolution results, the FDA determines that in vitro dissolution data
demonstrating crystal lattice dissociation before reaching the target site
is sucient for submitting an ANDA. e data collected from the clas-
sication and characterization of cocrystals should be provided in drug
substance format (3.2.S) of CTD.
In addition to quality aspects of pharmaceutical cocrystals, the USFDA
and EMA provide quality considerations for coformers as well. A huge
number of chemical substances, with dierent chemical characteristics,
can act as a coformer. EMA states within their reection paper that coform-
ers should be pharmaceutical-acceptable to be used in medicinal prod-
ucts. EMA developed a citation to the ICH guideline Q11 (Development
and Manufacture of Drug Substances-Chemical and Biotechnological/
Biological Entities) and took a stand on behalf of the coformer which
should be regarded as a reagent for the production of the drug substance.
e European medical agency included all Q11 sections for coformers,
as cocrystals have the same regulatory status as salts. Pharmaceutical
Patents & Regulatory Concerns of Cocrystals 369
cocrystals are discussed in guidelines materials from the FDA and the
European Medicines Agency (EMA), but it is unclear how they are regu-
lated. Meanwhile, the FDA categorized coformers as excipients, the EMA
dictates that coformers must be pharmaceutically approved for use in a
medicinal product. Coformers can be removed from categories like start-
ing material and raw materials, as they are not required for the synthesis of
active substances. A coformer may be deemed to have sucient rationale
if it has been used in a medicinal product before. If not, the applicant must
present dierent data to justify its usage as a coformer. Excipients that have
been previously approved by the FDA for use in medications or that are
classied as generally regarded as safe (GRAS) are accepted. It is important
to review all viable approaches with the FDA before ANDA application for
any drug containing cocrystals [38–40].
12.3.1.1 Quality Aspects During Development of Generic
Cocrystal API
As previously mentioned, the USFDA and EMA gave regulatory guide-
lines for the usage of pharmaceutical cocrystals. However, despite that
guideline, some points should be mentioned in the guidelines. Both the
regulatory authorities mentioned that the physiochemical properties of
cocrystals should be thoroughly evaluated, whether the cocrystals are suit-
able for development of generic medicinal products. Since melting point
is an important property for determining the purity and identication of
can create a huge dierence between API and pharmaceutical cocrystals.
Hence, the melting point should be checked as there might be a large dif-
ference between the pure API and cocrystals. Other properties like stability
and dissolution study should also be checked properly. Stability studies are
necessary for determining the Shelf life of the pure drug and nished prod-
uct. Dissolution studies are one of the important parameters that should
be checked properly during cocrystal development and the dissolution of
API in the reference medicinal product should match with the dissolution
observed in cocrystals [41–43].
12.3.2 Module 4: Non-Clinical Safety Toxicological Studies
Non-clinical studies like toxicological and pharmacological safety stud-
ies are not necessary to be conducted for generic medicinal products. e
applicant for Market Access Authorization (EU) or an ANDA (US) makes
references to non-clinical studies conducted by the innovator. e same
370 Cocrystals in Pharmaceutical Sciences
approach applies to pharmaceutical cocrystals as well. However, the lit-
erature available circumvents the need for non-clinical studies but the
need for toxicological and safety pharmacological studies applies to novel
coformers.
12.3.3 Module 5: Clinical Studies
During the production of the generic medicinal product, the manufactur-
ers need not perform the whole clinical trials to dene the safety and eec-
tiveness of their product. e important parameters are the bioavailability
study and bioequivalence study. By doing this study, the generic product
manufacturer accumulates the data and proves that their product is equiv-
alent to the innovator’s product. Bioavailability studies show that the rate
and extent of the drug in the unchanged form reaches systemic circulation
for showing pharmacological activity. e bioequivalence study deter-
mines the pharmacokinetic parameter which helps to determine whether
the product is bioequivalent or not. e pharmacokinetic parameters are
C
max
, AUC, and T
max
. Apart from that factor, there is another factor that
helps to demonstrate whether the product is clinically signicant or not.
e factor is the BCS classication system, both the regulatory authorities
should outline the guidance on the data type that investigates the BCS class
of API [44–46].
12.4 Patent on Cocrystals
Aer the successful evolution of cocrystal formulation, the regulatory
authority took over for required approval to access the market. Regulatory
procedures need to be improved to speed up patent ling, granting, and
regulatory approval. e Patent should be novel, non-obviousness, and
utility. ere are two processes to le a patent, one is the national appli-
cation and another is the international application. Currently, there are
two ways available for approval of cocrystals, one is NDA(505(b)(2)) and
another is ANDA(505(j)). For the NDA application, it is not required
for the cocrystal to contain an API that is listed in the references listed
drug, and for the ANDA application, the cocrystals should have contained
the previously approved drug. Many research papers on pharmaceutical
cocrystals and licenses that have been registered as pharmaceutical cocrys-
tals are evolving daily. A few approved drug cocrystal licenses in the USA,
EU, and other countries are listed in Table 12.4 below.
Patents & Regulatory Concerns of Cocrystals 371
Table 12.4 Various cocrystals approved under dierent regulatory authorities.
Date Publication no. Title Attorney References
2014-
01-02
US20140004051A1 Cocrystals and
salts of contrast
agents and
imaging
University Of
Iowa Research
Foundation
[47]
2022-
11-17
US 2022/0363661
A1
Cocrystals,
pharmaceutical
compositions
thereof, and
methods of
treatment
involving the
same
Servier
Pharmaceuticals
LLC
[48]
2019-
05-21
US10292951B2 Treatment
methods and
formulations
for illnesses
involving an
inappropriate
inammatory
response
First Wave Bio, Inc. [49]
2021-
02-04
WO/2021/022103 Cocrystals of
posaconazole,
methods of
making and
using the same
e Regents of the
University of
Michigan
[50]
2007-
05-03
US20070100143A1 Crystalline
alfuzosin base
Hetero Drugs
Limited
[51]
2019-
08-29
Wo 2019/162429 Cocrystals of
ubiquinone and
compositions
comprising
them
Center for
Intelligent
Research
in Crystal
Engineering
[52]
(Continued)
372 Cocrystals in Pharmaceutical Sciences
Table 12.4 Various cocrystals approved under dierent regulatory authorities.
(Continued)
Date Publication no. Title Attorney References
2018-
06-27
EP3339292A1 Cocrystals of
apremilast
Zaklady
Farmaceutyczne
Polpharma
SA 83-200
Starogard
Gdanski (PL)
[53]
2016-
03-23
EP2688575B1 Lithium
compositions
University of South
Florida
[54]
2011-
07-06
EP2340818A1 Cocrystals of
venlafaxine and
celecoxib
Laboratories Del.
Dr. Esteve, S.A.
[55]
2009-
05-13
EP2056798A2 Sorbic acid analog
cocrystals
Amgen, Inc [56]
2015-
08-13
AU2013201664B2 Intravenous
formulation
including
water-soluble
acetylsalicylic
acid and
theanine
cocrystals.
eaprin
Pharmaceuticals
Inc.
[57]
2007-
06-21
JP2007516259A Method for
preparing
mixed phase
cocrystal with
activator
Med Crystal
Forms, LLC
[58]
2017-
02-24
NZ710780A New forms of
rifaximin and
uses thereof
Salix
Pharmaceuticals
Ltd
[59]
(Continued)
Patents & Regulatory Concerns of Cocrystals 373
12.5 Conclusion
According to various studies, cocrystals are crystalline substances that are a
new addition to pharmaceutical drug design. According to some research-
ers, cocrystals can be a game changer for upcoming pharmaceutical drug
design challenges. e major drug encounters issues with physiochemical
properties so as with its absorption, distribution, metabolism, and excre-
tion. Keeping this in mind, this problem can be resolved by cocrystal for-
mation which can easily bypass the physicochemical issue of drugs. For
this, authorized regulation of cocrystals is very important. In this scenario,
the momentousness of cocrystals was accepted by the USFDA and EMA.
However, the dissimilarities between both agencies regarding the classi-
cation of cocrystals are dicult for professionals working in the eld of
regulatory aairs.
Pharmaceutical cocrystals are of interest as they can help with phar-
maceutical manufacturing processes by oering desirable manufacturing
characteristics and avoiding parent API. Due to their non-infringement,
generic industries are able to develop and market products ahead of the
expiration of polymorph patents. Since the debut of these solids, regulatory
aairs have facilitated plenty of discussion that has resulted in new regu-
latory strategies for novel pharmaceutical products as well as their possi-
ble inclusion into the USA and EU’s existing legal frameworks. Given the
regulatory challenges they will face, the future of novel drugs and generic
goods containing cocrystal APIs will be fascinating. Cocrystals’ debut
Table 12.4 Various cocrystals approved under dierent regulatory authorities.
(Continued)
Date Publication no. Title Attorney References
2016-
07-06
CN102952138B e salt of a kind
of pyrazole-
pyrimidinone
compound,
polymorph and
pharmaceutical
composition,
preparation
method, and
application
Shanghai Tehua
Pharmaceutical
Technology Co.,
Ltd.
[60]
374 Cocrystals in Pharmaceutical Sciences
shows how the pharmaceutical sciences and the regulatory landscape are
always changing and how new APIs are attempting to nd a home.
Acknowledgment
e authors are thankful to Chitkara College of Pharmacy, Chitkara
University, Punjab, India for providing infrastructure and library facilities.
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