Insights of Dosage form Design: Polymorphs and Co-

crystals
Sonawane Aravind R*, Rawat Swati S, Janolkar Nandkishor N
Shri Bhagwan College of Pharmacy, Dr. Y. S. Khedkar Marg, N-6, CIDCO, Aurangabad,
431005, (M.S.), India

Abstract
Formulators are charged with the responsibility to formulate a
bioequivalent product (in case of ANDA) product which is physically and
Received on: 20-10-2013 chemically stable, manufacturable at commercial scale. Different crystal
Accepted on: 05-11-2013 structures in polymorphs arise when the drug substance crystallizes in
Published on: 15-11-2013
different crystal packing arrangements and/or different conformations.
Besides, Polymorphs cocrystallization is now important method to
Sonawane Aravind* achieve crystalline forms of molecules where alternative polymorphs or
1Shri Bhagwan College of Pharmacy,

Dr. Y. S. Khedkar Marg, N-6, CIDCO, salts or solvates are desired. Regulatory road map for polymorphs
Aurangabad, 431005, (M.S.), India approval is quite clear and for cocrystals draft guidance is on scientific
Email: aravindsonawane@gmail.com advisory form public. From Intellectual property perspectives
polymorphs and cocrystal patents are approved in different countries
within the meaning specified in the act. Overall the patentability of
polymorphs and cocrystals directly affects the business driven strategy
for research based Pharmaceuticals as well as collaborative research
universities for science updation for better health care.

Keywords: cocrystal, polymorph, dosage form, regulatory performs,

intellectual property.

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Cite this article as:

Sonawane Aravind R, Rawat Swati S, Janolkar Nandkishor N . Insights of Dosage form Design: Polymorphs and Co-crystals . Asian
Journal of Biomedical and Pharmaceutical Sciences; 03 (27); 2013; 1-8.
 Aravind Sonawane et al.: Asian Journal of Biomedical and Pharmaceutical Sciences; 3(27) 2013, 1-8.

Prologue: Insights of Dosage form Design Abbreviated new drug application (ANDA) a
Over the past number of years, the fraction of new bioequivalent version of innovator product, take
chemical entities (NCE) approaching the marketplace account of polymorphism as an important insight of
are very infrequent and steadily decreasing. dosage design and regulatory approval.
For the successful development and commercialization Polymorphs and Physicochemical properties
of NCEs (also called as API) it required that API should Different polymorphic forms of a drug have influence
possess adequate processability, stability, and on absorption of drug from its finished dosage form
bioavailability. Once the complete understanding of the and ultimately affecting the efficacy of dosage form.
physicochemical and biopharmaceutical properties of Typically, polymorphs, hydrates, solvates, and physical
the drug substance are known then the formulator can size of drug particles may have considerable impact on
design dosage of clinical relevance. Based on powder the rate and extent of drug absorption.
morphology; drugs are classified as amorphous and Substances that have no crystal structure are the
crystalline form; wherein each has its own set of merits amorphous forms, which have different physical
and demerits for design of dosage form. Crystal properties to that of crystalline forms. Amorphous
engineering is an emerging area which relates to forms usually dissolve faster than crystalline forms
molecular solids possess crystalline state. The field of because of high free energy, as no energy is needed to
Crystal modification is gaining an increased interest break up the crystal lattice. Amorphous form may
within the pharmaceutical industry because it enables however have stability problems and may have to
preparation of materials with modified and desirable evaluate crucially. During preparation of drug, organic
physical properties. There are few challenges solvents are used in preparation or purification which
associated with the nature of API in the development may get incorporated (one or more solvent molecules)
and manufacturing of solid dosage forms such as tablet within the crystal lattice and forms solvates. The most
is poor tabletting performance. In particular, usually common solvate utilized often is water. If water
the industry demands for crystals with stable and molecules get entrapped in a crystal structure,
better processing characteristics such as flow hydrates are formed. In hydrates, the tendency of the
properties and compressibility.1 Nowadays crystal to attract additional water to initiate the
pharmaceutical co-crystals have become an important dissolution process is reduced, and therefore solvated
part of a landscape that was previously occupied only (hydrated) crystals tend to dissolve more slowly than
by polymorphs, salts, and solvates/hydrates as it offers anhydrous forms (e.g. Esomeprazole magnesium, a
opportunity to diversify the number of crystal forms proton pump inhibitor exists in dihydrate form A, B
known for an API and to improve their physical and trihydrate form)3.
properties of clinical relevance with patent protection Thermodynamics of polymorphs
as a business driven strategy. Most drugs exhibit structural polymorphism and it is
Polymorphism and Dosage Design always preferable to develop the most
Polymorphism is the ability of substances to crystallize thermodynamically stable polymorph of the drug to
in more than one distinct crystal habit. Polymorphism assure reproducible bioavailability of the product over
has a great deal of impact on pharmaceuticals and is its shelf life under a variety of real-world storage
considered as an important factor during product conditions. Thermodynamically stable polymorph is
development. The differences in dissolution rate and more chemically stable than a metastable polymorph.
solubility that polymorphs can produce may have a The lowest energy polymorph is always the most
dramatic impact on bioavailability when dissolution is chemically stable form, and will not convert to another
the rate-limiting step in the absorption process. polymorph during storage and processing. Unexpected
Polymorphism is a dominating factor related to the appearance or disappearance of a polymorphic form
physicochemical and biological properties of API and may lead to serious pharmaceutical consequences.
dosage form design. There are several examples from In the case of a most thermodynamically stable
the pharmaceutical industry where a new crystal form polymorph of the drug whose absorption is solubility-
significantly affected the performance of a dosage form, limited and thus cannot achieve the systemic exposure
sometimes with serious clinical effects. However, any required for therapy. In this case, a more soluble form
subsequent alteration in the crystal form drastically of the drug is desired to deliver the therapeutic dose. A
affects the stability of the apparently stable metastable polymorph or amorphous form of such
polymorphic form and ultimately finished dosage drug is developed to get such benefits. Though the
form.2 Recent, intellectual property protection reflects metastable crystalline polymorphs are least chemically
number of granted patents and application filed by stable than the most physically stable crystalline form
innovator and generic developers related to but having a good solubility than stable form.
polymorphs, solvates, hydrates and salts for NCEs.

© Asian Journal of Biomedical and Pharmaceutical Sciences, all rights reserved. Volume 3, Issue 27, 2013. 2
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Utilization of a metastable form of a drug for solid forms that are identified may be readily
processing would becomes advantageous only when transferred to the development chemist. Furthermore
undertaken drugs for which a very complete combinations or hybrids of these approaches are often
understanding exists with respect to polymorphic form used for effective polymorph screening.5
dependent chemical stability, physical stability, and Process induced Phase Transformation and its knock
most importantly, solubility and bioavailability of the The physical form (polymorphic form) of the active
drug. pharmaceutical ingredient (API) can significantly
Enalapril maleate is known to exist in two polymorphic influence the stability and performance of the dosage
modifications (I and II) with Form II being the more form, therefore a thorough understanding of the
thermodynamically stable. Both forms exhibit similar physicochemical properties of polymorphs is of
properties, as exemplified by their similar solubilities, primary importance to the selection of a suitable
dissolution characteristics, heats of solution, IR and crystalline form and development of a successful
Raman spectra, XRD data and DSC thermograms. pharmaceutical product.
Interestingly, although tablets manufactured via wet Even though an appropriate physical form of the API
granulation using Form I of enalapril maleate and one may be selected, it may not be retained in the final
molar equivalent of sodium bicarbonate are quite pharmaceutical product.
stable, tablets manufactured from Form II give rise to Physical characterization of the final product is
unacceptably high levels of the diketopiperazine necessary to detect the overall effect happened due to
degradation impurity. Hence, with the given drug of processing. However, multiple phase
product formulation, an inadvertent change in transformations may be able to also occur during the
polymorphic form would negatively impact drug sequence of pharmaceutical processing steps.
product stability, and it would be important to Monitoring the each phase of processing is the best
incorporate controls on the drug substance approach to detect phase transformation during
polymorphic forms. processing such as:6,7.
Conversely, tablets manufactured via wet granulation (a) Phase transformations during various
from either Form I or II and two molar equivalents of pharmaceutical unit operations,
sodium bicarbonate are equally stable.4 (b) The detection of such phase transformations, and
Polymorph Screening (c) Assessment of Potential impact of phase
Screening for polymorphs of APIs has become a transformations on the final product quality.
common practice. The extent and type of polymorph The potential advantages and disadvantages of such
screening performed depends on the stage of transitions are to be understood sometimes, a
development and the business strategy of the transition can be beneficial in some respects and
innovator or generic company. Since exhaustive disadvantageous in other aspects. While phase
polymorph screening is resource intensive and transformations of the API have a direct effect on the
attrition of early drug candidates is very high, stability and performance of the final product, any such
exhaustive screening would not be practical from a phase change affects product quality. Changes can be
business perspective for early drug candidates. divided as per
Polymorph screening approaches may be categorized (a) Solid-state manipulation intentionally brought
as rational design for resource saving and about by pharmaceutical processing
comprehensive design to discover all possible solid (b) Unintended transformations that may have a major
forms of a drug candidate. impact on product quality and stability8.
The goal of a rationally designed polymorph screen is Processing-related Stress
to discover all relevant forms of a drug candidate that During pharmaceutical processing, various
may be encountered during development, particularly formulation-specific processes are carried out using a
the thermodynamically most stable form, as early as wide variety of techniques and equipment. The major
possible while expending minimal resources. In a processing-related stresses include mechanical,
comprehensive polymorph screen, the objective is to thermal and those due to interaction with other
gain further confidence that all relevant forms have components. The thermal and mechanical stress,
been identified and to secure freedom to operate with, occurs during processing such as during the freezing of
or exclusive rights to, all possible solid forms of a drug aqueous solutions and during wet granulation
candidate. The solvents are those that are commonly respectively, can lead to phase transformations, the
used for scale-up and processing. These solvents are presence of water in both cases can cause hydrate
used in rational screening approaches because those crystallization Multiple operations can be carried out
screens are often used early in the drug-development using specialized equipment, as in a fluid-bed
process, and thus the methods for crystallizing any

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 Aravind Sonawane et al.: Asian Journal of Biomedical and Pharmaceutical Sciences; 3(27) 2013, 1-8.

granulator, wherein granulation and drying are the constituent free base molecule or vice versa is
simultaneously accomplished. applicable, whereas in co-crystals no such transfer
The material may therefore be exposed to several occurs11.
stress–relaxation Processes in a single step. Formulation development of nonionisable or poor salt
The final physical form of the material is expected to be forming APIs, there are few options for developing
influenced by the type, intensity and duration of each faster dissolving more soluble crystalline forms. In the
stress9. pharmaceutical co-crystals, the co-crystal formation is
potentially employed with all APIs including acidic,
Mechanical Thermal Interaction with Other basic, and nonionic molecules. This has been an
Stress Stress Components advantage of co-crystals over salt form. Also in the salt
formation there is generally a single acidic or basic
Milling Freezing Hydrate Formation
Compression Drying Complexation functional group is involved but the co-crystals can
simultaneously address multiple functional groups in a
Melting Salt–Free-acid/Base single drug molecule12. The cocrystallization is now
Conversion recognized as an important method to achieve
Metastable Phase
Formation crystalline forms of molecules where alternative
Multiple Interactions polymorphs or salts or solvates are desired13.
Benefits of Co-crystals:
Co-crystals and dosage form design: Co-crystals are more thermodynamically stable than
Formulators are charged with the responsibility to amorphous form of API. Cocrystalization technique is
formulate a bioequivalent product (in case of ANDA) suitable for all ionic, weakly ionic and nonionic APIs.
product which is physically and chemically stable, Co-crystals of API overcomes various undesirable
manufacturable at commercial scale. properties of API such as low aqueous solubility, poor
Hence, the prior assessments of all physical & oral bioavailability, less stability, poor compressibility,
physicochemical characteristics of API are of great flowability and hygroscopicity. Recent year’s number of
importance for effective and bioequivalent (in the case patent grants and applications has been seen for API
of ANDA) dosage form. physicochemical modification along with increased
Hence selection of the crystal form in formulation efficacy.
development process is crucial for the performance of Cocrystallization techniques
dosage form because the crystal form acts as a barrier Solid Based Solvent based Electrically
Methods methods Assisted method
to drugs product performance by showing low aqueous Neat Solvent drop grinding Sonocrystallization
solubility, slow dissolution rate, flow related troubles, grinding/cogrinding
performance and stability related issues. Hence the Hot melt extrusion Antisolvent addition Microwave
nature of physical form of API tends to exhibit greatest assistance
effect on formulation development strategy. Solvent evaporation
Approaches are developed for such API which includes Slurry conversion
salt preparation, solvates, hydrates, solid dispersion, Sonocrystallization
polymorphs, cyclodextrin complexation, etc.
Solvent mediated
In recent years co-crystal approach has been emerged phase
as a promising valuable crystal engineering approach transformations(SMP)
for improving the solubility and dissolution rate and
also improving other properties of API with low Regulatory performs: Polymorphs and cocrystals
aqueous solubility and stability. Pharmaceutical co- Polymorphic forms of a drug substance differ in
crystals are the crystalline materials comprised of an internal solid-state structure, but not in chemical
API, one or more unique co-crystal formers both of structure. Section 505(j) (2) of the act specifies that an
which are solids at room temperature. Pharmaceutical ANDA must contain, among other things, information
co-crystals comprises of an API (Host, neutral or in to show that the active ingredient in the generic drug
ionic form) and pharmaceutically accepted compounds product is the "same as" that of the reference listed
(Guest)10. The co-crystals are formed because of drug (RLD). When a United States Pharmacopeia (USP)
several types of interactions including hydrogen monograph exists for a particular drug substance,
bonding, π-staking, Vander walls forces, etc. Co- standards for identity generally refer to the definition
crystals may include one or more solvent / water (e.g. chemical name, empirical formula, molecular
molecule in crystal lattice. The main difference structure, description) at the beginning of the
between co-crystals and salts is that in salts, a proton is monograph. However, FDA may prescribe additional
transformed from acidic to the basic functionality of

© Asian Journal of Biomedical and Pharmaceutical Sciences, all rights reserved. Volume 3, Issue 27, 2013. 4
 Aravind Sonawane et al.: Asian Journal of Biomedical and Pharmaceutical Sciences; 3(27) 2013, 1-8.

standards that are material to the sameness of a drug

substance.
Therefore, differences in drug substance polymorphic
forms do not render drug substances different active
ingredients for the purposes of ANDA approvals within
the meaning of the Act and FDA regulations. FDA
demonstrates that, among other things, the drug
product exhibits sufficient stability and is bioequivalent
to the RLD. While the polymorphic form can affect drug
product stability and bioequivalence, these
performance characteristics are also dependent on the
formulation, the manufacturing process, and other Steps of regulatory performs of Co-crystallized NDA or ANDA
physicochemical properties (e.g. particle size, Polymorphism in Co-crystals – Unique
moisture) of both the drug substance and formulation characteristics
excipients. Using a drug substance polymorphic form Pharmaceutical co-crystals may be polymorphic.
that is different from that of the RLD may not preclude Aitipamula et al analyzed for the co-crystals deposited
an ANDA applicant from formulating a generic drug in the Cambridge Structural Database (CSD). There
product that exhibits bioequivalence and stability, and were a total of 3624 co-crystals present in the CSD, of
the drug substance in the generic drug product need which 44 co-crystals are polymorphic. A total of 46
not have the same polymorphic form as the drug polymorphic co-crystals were reported to date. Of
substance in the RLD. these 46 co-crystals, 33 co-crystals were sustained by
Over the years, FDA has approved a number of ANDAs strong hydrogen bonding and the remaining 13 co-
in which the drug substance in the generic drug crystals are sustained only by weak interactions.
product had a different polymorphic form from the Interestingly analysis of the co-crystals deposited into
drug substance in the respective RLD (e.g. warfarin the CSD suggests that the number of co-crystal
sodium, famotidine, and ranitidine). FDA also has polymorphs being added to the database is increasing
approved some ANDAs in which the drug substance in in recent year16. Recent research findings address
the generic drug product differed in solvate or hydrate toward occurrence of polymorphism in co-crystals17.
forms from the drug substance in the corresponding The different crystal structures in polymorphs arise
RLD (e.g. terazosin hydrochloride, ampicillin, and when the drug substance crystallizes in different
cefadroxil).14 crystal packing arrangements and/or different
For Co-crystals at present no regulatory prototype conformations. In co-crystals, polymorphism is either
exists for governing co-crystals. The issue of whether a true polymorphism in which the different polymorphs
new co-crystal of a marketed API may be eligible for of same compound have precisely the same
regulatory approval via the NDA or ANDA system is not stoichiometry. In distinction, pseudo-polymorphism,
clear till date but it will impact the overall utility of co- there are different polymorphs with different
crystal technology towards the generic pharmaceutical stoichiometries and different crystal structures. The
industry, and may possibly in the future marketplace. polymorphism in co-crystals comes too often under the
In draft guidance for industry published by US FDA15, later class.
co-crystals should be classified as dissociable “API- In co-crystals the polymorphism is governed by
excipient” molecular complexes (with the neutral guest variations in the hydrogen bonding schemes of the
compound being the excipient) because of the fact that coformers in the crystal lattice. In order to control the
the molecular association of API and its excipient(s) extent of polymorphism in co-crystals, designing the
occurs within the crystal lattice of co-crystals. Co- co-crystals by crystal engineering strategies which
crystal is treated as a drug product intermediate in relies on developing an understanding and
which API that has been processed with a co- rationalization of intermolecular interactions in the
crystallizing excipient to generate an “API-excipient”. context of crystal packing to design predictable
Therefore when going for NDA or ANDAs containing or structural motifs, followed by the subsequent
claiming to contain co-crystal, the one has to consider utilization and exploitation of this understanding in the
the following things (represented pictorially) carefully design of new solids with specific desired structural
and to submit appropriate data. properties which offers at least a partial solution to the
problem18. The concepts of supramolecular synthesis
and crystal engineering have gained prime importance
in recent years when there is a clear need for better

© Asian Journal of Biomedical and Pharmaceutical Sciences, all rights reserved. Volume 3, Issue 27, 2013. 5
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understanding and control of crystalline forms in the Polymorphic forms are the new forms of existing APIs
context of pharmaceutical development. and such new forms can be patented by simply proving
Sr. Example Details Reference its novelty over existing one. Since every substances
No. represent different properties associated with every
1 Carbamazepine- CBZ-SAC form I 19
Saccharin; CBZ-SAC form II
different crystal structures achieved by crystal
carbamazepine- CBZ-NCT form I modifications, which creates an opportunity to claim an
nicotinamide CBZ-NCT form II invention over the new properties of new form.
2 Carbamazepine- CBZ-INA form I 20 Therefore, in current scenario polymorphism is one of
Isonicotinamide CBZ-INA form II the exigent issues in patent hierarchy. Development of
3 carbamazepine- CBZ-NCT form I 21
nicotinamide (CBZ- CBZ-NCT form II
novel crystal forms i.e. new polymorphs becomes a
NCT) strategy tool for seeking additional patent protection
4 Carbamazepine- CBZ-MA form A 22 over a new chemical entity, however only in few cases
Malonic acid CBZ-MA form B polymorph patent proved beneficial to sustain the
CBZ-MA form C market exclusivity of the product where the
5 Caffeine-GA Caffeine-GA form I 23
Caffeine-GA form II polymorphic form is genuinely the key factor for
6 Caffeine- Co-crystal E Form I 24 products presence in market as the other polymorphs
Trifluoroacetic Acid Co-crystal E Form II are not having specified activity or efficacy, hence even
7 4-hydroxybenzoic acid (4HBA)- (TMP) 25 a new polymorph patent of such API will have a distinct
-2,3,5,6-tetramethyl (2:1) form I commercial advantage with respect to market
pyrazine (4HBA)- (TMP)
(2:1) form II exclusivity. There are numerous instances where
8 Chlorzoxazone:2,4- Form I 26 innovator and non-innovator companies have acquired
dihydroxybenzoic patents on particular polymorphic forms of API, in few
acid cases patent protections of particular polymorph
9 Ethenzamide- EA-SAC form I 27 extends beyond the expiry of basic molecules patent
Saccharin EA-SAC form II
10 Ethenzamide- 3,5- EA-DNBA form I 28
thereby helping to extent product life32.
Dinitrobenzoic Acid EA-DNBA form II Among one the routes of filing of ANDA with paragraph
IV certification that USFDA allows, which involves
Pharmaceutical co-crystals show a strong tendency to ANDA filing provided the solid form discovered by the
form polymorphs furthermore their interconversion generic manufacturer bypasses innovators patent. On
from one form to another or into other undesirable successful paragraph IV filling and approval, generic
forms during the manufacturing processes can also be manufacturer gets market exclusivity rights for 180
seen. Therefore investigating the general occurrence of days to market his generic product accompanied by
polymorphism in existing co-crystals is subject of innovator product.33
growing interest. Polymorphs are patented in US and Europe after
It has been also proposed that formulation as a co- proving its novelty, non-obviousness and utility and
crystal would reduce the impact of polymorphism for exemplified in various review articles, also can be
highly polymorphic compounds29 although this searched at patent web site of respective country.
conclusion is based on assumption that fewer In US, “New” refers to anything under the sun that is
polymorphic arrangements are available when two made by man, such as a new composition of matter or
compounds are present in the unit cell. Furthermore any new and useful improvement (35 USC & 101).
another assumption is that co-crystals are less prone to Patent protection is normally granted only on
polymorphism30. Still no strong evidences were individual polymorphic forms that have been
available to prove such hypotheses therefore needs identified, characterized, and differentiated, so there is
more attention and research in this area.31 a powerful incentive to identify and protect alternative
McCrone stated that: “every compound has different forms that may otherwise be identified and developed
polymorphic forms” and that, .in general, the number of by a competitor or a generics manufacturer.
forms known for a given compound is proportional to In the United Kingdom, a new crystal modification is
the time and energy spent in research on that not prima facia patentable; the inventor must
compound” demonstrate that it is an unobvious. New crystal forms
In co-crystals arena, studies concerning polymorphism can be patented without showing unexpected
are in ongoing phase and needs more time and properties, since one of ordinary skill cannot predict
research to upend any strong conclusion. the structure, properties, or method of preparation of
Intellectual Property rights for Polymorphs, Co- that crystal form prior to its discovery variant of the
crystals and Business driven strategy previously known material.
Polymorphs and Patentability: Co-crystals and Patentability:

© Asian Journal of Biomedical and Pharmaceutical Sciences, all rights reserved. Volume 3, Issue 27, 2013. 6
 Aravind Sonawane et al.: Asian Journal of Biomedical and Pharmaceutical Sciences; 3(27) 2013, 1-8.

In recent time an article by Andrew Trask, provided an or to predict the properties of any, as yet unknown,
open eyed landscape on how the developing field of crystal forms.
cocrystallization may impact the pharmaceutical Utility /Industrial applicability: When generic
intellectual property domain34. According to the article pharmaceutical companies use polymorphs and
co-crystals are eligible for patent protection when hydrates they file Abbreviated New Drug Applications
screened through the eyes of novelty, non-obviousness (ANDAs), which requires the submission of minimal
and utility (Industrial applicability). In any case where bioavailability and clinical data and does not require
the solid form offers a commercial advantage over the proving safety or efficacy. New salts of an API, however,
original form, whether it is a polymorph or solvate or use a slightly different regulatory pathway, a so-called
hydrate of co-crystal, the solid form patent would 505(b) (2) application, and require more testing and
provide significant patent protection even after the clinical data than an ANDA submission. The
expiration of the new chemical entity patent. classification of co-crystals as a generic has not yet
As the new polymorphs are novel and non-obvious and been addressed and still a clear path for co-crystals
can be patented. Unlike polymorphs and salts, co- from the viewpoint of regulatory is not clear36.
crystals are new compositions of matter and equally Currently in the area of co-crystals several patents in
patentable as well. Co-crystals also show US, Europe and other countries has been granted such
polymorphism and so can opt for patent. There will not as US6570036 (Co-crystallization Processes),
be any surprise when we will see number of co-crystals US7452555 (Cocrystallization), US7803786
getting patent protection in upcoming future35. (Pharmaceutical co-crystal compositions and related
However, a solid form that was not found by the methods of use), US7935817 (Salt form and co-crystals
innovator, but was found and patented by a competitor, of adefovir dipivoxil and processes for preparation
could significantly alter this strategy. Similarly co- thereof), EP1608339B1 (Pharmaceutical co-crystal of
crystal screens for potential drugs could generate new celecoxib-nicotinamide), EP1962600B1 (Metronidazole
solid forms which can be protected, not only the co- cocrystals), EP2488169B1 (Co-crystals of Tramadol
crystals found, but also any polymorphs, hydrates, and Coxibs) etc.37,38 and can be cited at Patent web site
solvates, or other solid forms of the individual co- of respective country. At present number of patent
crystals. applications claiming co-crystals are in prosecution
Novelty and non-obviousness: phase. Besides of this many more applications are also
In new polymorph patent application the first question being filed day-after-day.
arises that is the crystalline form novel? In such case Section 3 (d) of India Patent act and patentability of
anticipation with respect to novelty is the deciding polymorphs:
factor for patentability, similarly in co-crystals the As per section 3 (d) salts, esters, ethers, polymorphs,
same question surges to decide the novelty of metabolites, pure form, particle size, isomers, mixtures
invention. For a new solid form of existing compound of isomers, complexes, combinations and other
to be novel irrespective of that it is either polymorph or derivatives of known substance shall be considered to
co-crystal, it should not appear in the prior art be the same substance, unless they differ significantly
expressly or inherently. If such happens in the prior art in properties with regard to efficacy”39. Hence,
then invention is expected to be obvious. In co-crystals, polymorphs patentability should pass this significantly
prior art references are limited since prior art differed efficacy. Recently a research disclosure for
reference for the specific compound with the specific anti-cancer molecule imatinib mesylate (Glivec) for
the coformer would likely not be published in crystalline form has not been successful to obtain
connection with the crystallization of the API. Such lack patent in India40.
of prior art is an advantage from the IP perspective in Till date in India there is no clear methodology to
connection with novelty. patentability of co-crystals, however few patents were
The inventive step in co-crystals can be summarized filed in Indian patent office, some of them are granted
by these two statements; and some still are under prosecution. For example-
i) If the co-crystal composition carries patentability, it IN864MUM2005 (Novel cocrystallization),
claim as new composition; IN3073KOL2006 (Gossypolco-crystals and the use
ii) If the crystalline form carries patentability, same thereof), IN818CHE2008 (O-desmethyl venlafxine
considerations as with polymorphs. cocrystals), IN2303CHE2009 (Stable cocrystals of
However another criterion of patentability is non- temozolomide), IN3190CHE2010 (Novel polymorphs
obviousness. The subject matter should not be obvious and cocrystals of curcumin), IN8827DEL2010 (New co-
to a person having ordinary skill in the art. It is not crystal compounds of rivaroxaban and malonic acid),
possible to predict- how many different co-crystal IN2454DEL2011 (Novel choline cocrystal of
forms can be prepared, as yet unknown, crystal forms, epalrestat), etc. Furthermore IN4367KOL2008

© Asian Journal of Biomedical and Pharmaceutical Sciences, all rights reserved. Volume 3, Issue 27, 2013. 7
 Aravind Sonawane et al.: Asian Journal of Biomedical and Pharmaceutical Sciences; 3(27) 2013, 1-8.

(Cocrystal of c-glycoside derivative and l-proline) and 3,5-Dinitrobenzoic Acid. Cryst. Growth Des. 2010, 10 (5), 2229-
received grant of patent which is IN256260 on May 2238.
16. a) Aitipamula, S.; Chow, P. S.; Reginald B. H. Tan. Dimorphs of a
201341. However co-crystals will also likely to face 1:1 cocrystal of ethenzamide and saccharin: solid-state grinding
hurdle of section 3(d) of Indian patent act, which methods result in metastable polymorph. CrystEngComm. 2009, 11,
describes the things which are not inventions within 1823.; b) Aitipamula, S.; Chow, P. S.; Reginald B. H. Tan. Trimorphs
the meaning of this act. In US and Europe the numbers of a pharmaceutical cocrystal involving two active pharmaceutical
ingredients: potential relevance to combination drugs.
of granted patents of co-crystals are more which CrystEngComm. 2009, 11, 1823-1827.; c) Porter, W. W., III.; Elie, S.
reflects the successful intellectual property protection C.; Matzger, A. J. Polymorphism in Carbamazepine Cocrystals. Cryst.
for co-crystals. Overall the patentability of polymorphs Growth Des. 2008, 8, 14-16.; d) J. H. Ter Horst, J. H.; Cains, P. W. Co-
and cocrystals directly affects the business driven Crystal Polymorphs from a Solvent-Mediated Transformation. Cryst.
strategy for research based Pharmaceuticals as well as Growth Des. 2008, 8, 2537-2542.
18. Ahn, S.; Kariuki, B.M.; Harris, K.D.M. Polymorphs of a 1:1 Co-
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