Polymorphism in cocrystals

CrystEngComm

HIGHLIGHT

Cite this: DOI: 10.1039/c3ce42008f

Received 4th October 2013,Accepted 11th February 2014

DOI: 10.1039/c3ce42008f

www.rsc.org/crystengcomm

Polymorphism in cocrystals: a review andassessment of its significance†

Srinivasulu Aitipamula,*a Pui Shan Chowa and Reginald B. H. Tan*ab

Cocrystals have gained much interest in recent years owing to their potential to improve the

physicochemical properties of the parent compounds. It was once thought that cocrystals could be a

means to prevent polymorphism but many recent examples of cocrystal polymorphism have been

discovered and reported. Similar to single component crystals, polymorphs of cocrystals can display

significantly different properties. In this contribution, we present a survey of polymorphic cocrystals. The

different types of polymorphs, namely synthon, conformational, packing, and tautomeric, are identified

and discussed with representative examples. In addition, polymorphs of cocrystals that showed distinct

physicochemical properties are highlighted.

1. IntroductionDesign and synthesis of multi-component crystals, such ascocrystals,1 have gained significant interest in recent timesdue to the ability of cocrystals to alter the material propertiesfor pharmaceutical and materials sciences applications.In pharmaceuticals, cocrystals of several important active

pharmaceutical ingredients (APIs) have been shown to offerproperty enhancement compared to their native drugs.2 Inmaterials science, properties such as photoluminescence,mechanical strength, etc. have been modified usingcocrystals.3 Despite the recent widespread popularity of thecocrystals, there is not yet a universally accepted definition ofcocrystals. This has spurred a significant scientific debate,4

and different authors have used different parameters todefine what constitutes a cocrystal and how the cocrystalcomponents are interacting with each other.4h,5 However,most authors agree with the definition that defines cocrystalsas crystalline materials composed of at least two differentneutral components that are solids under ambient conditionsand present in definite stoichiometric amounts.5e,g A broaderdefinition of cocrystals that also encompasses salts has beenrecently proposed.4h

CrystEngCommThis journal is © The Royal Society of Chemistry 2014

Srinivasulu Aitipamula

Srinivasulu Aitipamula obtainedhis PhD in 2006 from the Universityof Hyderabad, India, on struc-tural and thermochemical stud-ies of some host–guest systemsand polymorphs under thesupervision of Prof. AshwiniNangia. After a short industrialstint as a manager-R&D at theShasun Research Centre, India,he joined the Institute of Chemicaland Engineering Sciences (ICES),Singapore, as a scientist in 2007.His research interests include

crystal engineering, polymorphism, pharmaceutical cocrystals andsolid form screening of active pharmaceutical ingredients.

Pui Shan Chow

Pui Shan Chow obtained herPhD (2000) in chemical engi-neering from the University ofCambridge, UK, under thesupervision of Professor LynnGladden and Professor JohnDavidson. Upon graduation,she joined the Chemical andProcessing Engineering Centre(predecessor of ICES) to set upa crystallization research team.She is now the team leader ofcrystallization at the ICES andhas research interests in the

crystallization fundamentals, cocrystal development, and theapplication of PAT in crystallisation processes.

a Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science,Technology and Research), 1 Pesek Road, Jurong Island, Singapore, 627833.E-mail: [email protected] of Chemical & Biomolecular Engineering, National University ofSingapore, 4 Engineering Drive 4, Singapore 117576.E-mail: [email protected]† Electronic supplementary information (ESI) available: A table listing all ofthe polymorphic cocrystals and overlay diagrams of the cocrystal components.See DOI: 10.1039/c3ce42008f

Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article OnlineView Journal

http://dx.doi.org/10.1039/c3ce42008f

http://pubs.rsc.org/en/journals/journal/CE

CrystEngComm This journal is © The Royal Society of Chemistry 2014

Polymorphs refer to crystalline forms with distinct crystalstructures of the same chemical compound.6 Polymorphsoffer a unique opportunity to study the structure–propertyrelationships of the same compound formed in differentsupramolecular environments. Investigating the polymorphicbehaviour of an API is a critical part of the drug developmentprocess.6 This is because polymorphism can greatly influencepharmaceutical properties, such as stability, solubility,bioavailability, hygroscopicity, etc., and the economic signifi-cance of novel polymorphs as intellectual property.7

Therefore, solid form screening to identify novel polymorphsof APIs is a rigorous exercise in pharmaceutical drug develop-ment. Studies aimed at understanding the origin of polymor-phism in single component crystals and APIs are ubiquitous.It is estimated that more than 50% of drug molecules arepolymorphic.8 Although serendipity plays a greater role inidentifying novel polymorphs, recent advances in experimentalstrategies have paved ways for successful polymorph screen-ing.9 In contrast to single component crystals and APIs, studiesconcerning polymorphism in cocrystals are not so widelyreported and there have been very few studies devoted toidentifying novel polymorphs of cocrystals.5f,10 However, due tothe increasing interest in the development of cocrystals, thenumber of polymorphic cocrystals being reported has signifi-cantly increased in recent years.11 As cocrystals are beingconsidered as promising and patentable new solid forms forthe development of drugs and materials, investigation of thepolymorphic behaviour of cocrystals is as important as that ofsingle component crystals and APIs.12

The aim of this highlight is to provide an overview of thereported examples of polymorphic cocrystals, the differentexperimental screening methods and the distinct physico-chemical properties of some of these polymorphs. We restrictourselves to polymorphic systems that contain at least twoneutral organic solid components (under ambient conditions),such that polymorphs of solvates and hydrates that contain asingle solid component and salts resulting from acid–basereactions are not included.13 We are aware that salt formationis an inadvertent outcome of some of the cocrystallization

experiments and polymorphism in salts is not uncommon.14

Polymorphic cocrystals that are highlighted in this article wereretrieved from the Cambridge Structural Database (CSD, May2013 update) and from the major crystallographic, physical,and pharmaceutical journals (ESI†). As is true for any reviewarticle on a contemporary topic, there may be inadvertentomissions due to oversight; we present our apologies to theauthors of those articles.

2. CocrystallizationIn cocrystal design, crystal engineering principles15 are gener-ally employed to select a suitable cocrystal former (CCF)to form a cocrystal with the active compound in order todeliver the desired physical and chemical properties. Identify-ing potential hydrogen bonding sites in the parent com-pound and selecting the right CCF that has complementaryhydrogen bonding groups are critical in the cocrystal designstrategy. Besides crystal engineering considerations, thesuccess of a cocrystallization experiment depends also onseveral controlling factors, such as the composition of thecocrystal components, solvent of crystallization, temperature,solubility of the components, etc. Fig. 1 shows a typical threecomponent phase diagram involving an API, a CCF, and asolvent. According to this, a pure cocrystal in equilibriumwith the solution of the API and the CCF is formed only ina limited range of compositions. In other domains of thephase diagram, either a pure CCF, a pure API or mixtures ofthe cocrystal with the API or the CCF are obtained. Recentwork by Zhang and Rasmuson has further shown that poly-morphism in the pure components of a cocrystal candramatically affect the phase diagram and the cocrystalstability region.16 Therefore, knowledge of the phase diagramis essential for successful cocrystallization development.

The outcome of cocrystallization is not often as expectedand sometimes leads to serendipitous discovery of alternativesolid forms such as polymorphs, solvates, and hydrates

Reginald B. H. Tan

Reginald Tan holds a PhD inchemical engineering from theUniversity of Cambridge. He iscurrently the Principal Scien-tist, Director of Research andHead of Crystallization andParticle Science at the ICESand, concurrently, a Professorin the Department of Chemicaland Biomolecular Engineeringat the National University ofSingapore (NUS). He was aTechnology Projects Engineer atthe ICI Engineering in UK

before joining the NUS in 1990.

Fig. 1 Example of a three component phase diagram involving an API,a CCF, and a solvent. The solid-state outcomes in the different regionsof the phase diagram are designated.

CrystEngCommHighlight

Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



of cocrystals or APIs.17 Different possible outcomes of acocrystal experiment, more specifically from a solvent-basedcocrystallization experiment, are schematically shown inFig. 2. Although obtaining a physical mixture of single com-ponent crystals is an undesirable outcome if a cocrystal is thetarget, the serendipitous discovery of new polymorphs ofsingle component crystals could be of advantage in expandingthe solid form diversity and providing patent life protection.For example, attempted cocrystallization of aspirin, curcumin,and nicotinamide (NCT) resulted in the serendipitous discoveryof novel polymorphs of single component crystals.18 Inaddition, formation of solvates and hydrates of the cocrystalsand their components is not uncommon in an attemptedcocrystallization experiment; several such alternative solids havebeen reported recently.17,19 Solid solutions20 and eutectics21 aretwo other alternative outcomes of cocrystallization experiments.While the solid solution is formed between materials that areisomorphous or isostructural, eutectics are formed betweennon-isomorphous materials. A recent review by Cherukuvadaand Nangia provided a comprehensive understanding of thestructural aspects and potential applications of these solids inpharmaceutical and materials science fields.22

3. Screening of polymorphsof cocrystalsDespite the few reports aimed specifically at polymorphscreening of cocrystals, they provide useful reference on thedifferent methods for cocrystal polymorph screening. There-fore, we highlight here some of the significant contributionson the topic.

Crystallization from solution is the most common methodfor polymorph screening because it generally yields single

crystals that can be analyzed by single crystal X-ray diffraction.The wide range of experimental conditions during solutioncrystallization may improve the chances of identifying newpolymorphs. For example, cocrystallization experiments can beconducted from solvents of different polarities and solventmixtures. The rate of evaporation of the solvent can also bevaried by changing the experimental temperature. A number ofrecent polymorphs of cocrystals have been obtained by conven-tional crystallization experiments. For example, of the fivepolymorphs reported for a cocrystal involving a loop diureticdrug, furosemide, and NCT, four polymorphs were obtainedby cocrystallization experiments from solvents of differentpolarities.23 The fifth polymorph has been obtained bydehydration of the cocrystal hydrate. In another study, Kaurand Row reported four anhydrous polymorphs of a 1 : 1cocrystal of gallic acid with acetamide (ACT) which wereobtained under similar experimental conditions from methanol(Fig. 3).24 All polymorphs were characterized by single crystalX-ray analysis and found to feature different hydrogen bondingpatterns that helped to explain the polymorphic phase transfor-mation to the stable 1 : 3 cocrystal.

Lammerer et al. performed a polymorph screening studyto investigate if cocrystals are less or more prone to polymor-phism than their individual components.10a In their study,four sets of cocrystals were found to be polymorphic viasolution crystallization experiments. It is interesting to notethat all of the components of the reported cocrystals arepolymorphic in their pure forms. The study not only reportsnovel polymorphs of the reported cocrystals, but also supportsthe fact that cocrystals do exist in polymorphic forms.

Parallel to solvent-based cocrystallization technique, solid-state grinding has been extensively used for cocrystal screening.25

In this method, the constituents of a cocrystal are groundtogether using either a mortar and pestle or an electric mill. Arecent modification to this technique is solvent-drop grindingwherein a minor quantity of a solvent is added to the reactantsprior to grinding. The technique has been proven to signifi-cantly improve the kinetics of cocrystal formation and provide

Fig. 2 Various possible outcomes of an attempted cocrystallizationexperiment.

Fig. 3 Phase transformation pathways to the final stable 1 : 3 cocrystalof gallic acid and ACT. Reprinted with permission from ref. 24.Copyright 2012, The American Chemical Society.

CrystEngComm Highlight

Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



quantitative yields of highly crystalline cocrystal products.26

There are many examples in the literature in which novelpolymorphs of cocrystals were discovered by grinding experi-ments. A second polymorph of a 1 : 1 cocrystal of ethenzamidewith ethylmalonic acid was first observed by grinding.27 Thepolymorphic outcome of a cocrystallization experiment couldalso be controlled by using different grinding methods asdemonstrated by Trask et al. on a 1 : 1 cocrystal of caffeine andglutaric acid.26 While forms I and II of the 1 : 1 cocrystalof caffeine–glutaric acid crystallized concomitantly fromevaporative crystallization, form I could be obtained by neatgrinding or grinding with a few drops of non-polar solventsand form II could be obtained by grinding with a few drops ofpolar solvents (Fig. 4). This observation has been rationalizedby the fact that form I has a non-polar cleavage plane betweenthe stacks of ribbons formed by caffeine and glutaric acid andthat non-polar solvents may preferentially stabilize thisexposed plane. Bysouth et al. recently modified a planetary millcapable of performing up to 48 experiments at a time.28 Themachine has been found to be effective in producing notonly known cocrystals of the model systems but also a novelpolymorph of the cocrystal involving caffeine and maleic acid.Using this machine for cocrystal screening enables more exper-imental variables to be investigated in less time and providesan opportunity for identifying cocrystal polymorphs.

Solvent-mediated transformation has been suggested asone of the ways to screen cocrystal polymorphs. Using acarbamazepine (CBZ)–isonicotinamide (1 : 1) cocrystal as a modelsystem, ter Horst and Cains demonstrated the applicationsof a solvent-mediated transformation method for polymorphscreening of cocrystals.29 Hydrothermal or solvothermal syn-thesis, a widely used technique for inorganic or metal–organicmaterial preparation,30 has also been used for cocrystal poly-morph screening. Wang et al. recently applied this techniqueto prepare a cocrystal involving 1,2-bis(4-pyridyl)ethylene(BPE) and 4,4′-dihydroxybenzophenone (DHB).31 Interestingly,while conventional solvent evaporative crystallization resulted

only in a single 1 : 1 cocrystal form, the hydrothermal methodresulted in concomitant crystallization of three polymorphsof the 1 : 1 cocrystal. The crystal structures of all of thethree forms have been determined and it was found that theDHB molecule adopts distinct conformations in the cocrystalpolymorphs (Fig. 5).

Applications of high pressure in exploring new polymorphshave been elegantly reviewed recently by Pulham and coworkers.32

From a thermodynamic perspective, the polymorph obtainedat a low pressure will be less dense, and this means that theapplication of high pressure to metastable polymorphs caninduce phase transformation to a more stable polymorph.Successful application of high pressure on a number of organiccompounds has resulted in novel polymorphs. Zakharov et al.demonstrated pressure induced polymorphic phase transfor-mation in a cocrystal involving glycine and glutaric acid.33 Ithas been found that at a very low pressure (0.1 GPa), thecocrystal undergoes a first order reversible phase transition toa low temperature phase.

Ideally, it is necessary to employ different methods toidentify a maximum number of polymorphs. The advantage ofusing multiple screening methods to identify cocrystal poly-morphs has been demonstrated by Jones and co-workers.10c

Methods such as solution crystallization, neat and solvent-dropgrinding, sublimation, melt crystallization, and cocrystallizationat the interface between two immiscible solvents have beenapplied to obtain polymorphs of a 1 : 1 cocrystal involvingphenazine and mesaconic acid. Table 1 summarizes the differentpolymorph screening methods that generated each form of thecocrystal. The thermodynamically stable form II (at ambienttemperature) was obtained by cocrystallization at the interfacebetween two immiscible solvents, while the conventionalsolution based cocrystallization resulted only in the metastableforms I and III. The fact that no single method yielded all ofthe observed polymorphs highlights the importance ofusing multiple screening methods for a comprehensive under-standing of the polymorphic behavior of cocrystals. This workalso demonstrated cocrystallization at the interface of two

Fig. 4 Powder X-ray diffraction patterns of the polymorphs of the 1 : 1cocrystal of caffeine and glutaric acid: (a) a simulated pattern from thesingle crystal structure of form I, (b) the result of solvent-drop grindingof caffeine and GA with cyclohexane, (c) a simulated pattern from thesingle-crystal structure of form II, (d) the result of solvent-drop grindingof caffeine and GA with chloroform. Reproduced from ref. 26.

Fig. 5 A layer structure formed by O–H⋯N strong hydrogen bondsand C–H⋯O weak hydrogen bonds in one of the three polymorphs ofthe cocrystal of BPE and DHB. Notably, all of the three polymorphsfeature a similar hydrogen bonding pattern. Reproduced from ref. 31.


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



immiscible solvents as a useful alternative technique to tradi-tional solution based approaches that are limited by the differ-ences in solubility of the API and the CCF.

Polymorphism is an elusive phenomenon and it is diffi-cult to find conditions under which polymorphs can beobtained. For example, despite a thorough investigationusing high-throughput screening, neat grinding, and solvent-drop grinding with several solvents, there was no evidence ofpolymorphism in the cocrystals of CBZ with saccharin (SAC)and NCT.34 However, a novel polymorph of the cocrystals wasfound when functionalized cross-linked polymers wereutilized as heteronuclei for crystal growth (Fig. 6).10d Thefindings reiterate the fact that a successful polymorph screenshould involve diverse nucleation conditions for comprehen-sive understanding of the polymorphic behavior of cocrystals.

In addition to the previously described methods of poly-morph screening of cocrystals, the unconventional crystal-lization techniques described below have facilitated theidentification of cocrystal polymorphs. Bag et al. proposed

fast evaporation of a solvent by a rotary evaporator as a rapidmethod for screening of new cocrystal forms.35 The authorsdemonstrated the preparation of the metastable polymorphof the cocrystal involving CBZ and SAC. The possibility ofhigher supersaturation levels and enhanced crystallizationkinetics seems to facilitate the formation of metastablepolymorphs of the cocrystals. A similar method of kineticallycontrolled cocrystallization using spray drying has been dem-onstrated by Alhalaweh and Velaga.36 The authors found thatspray drying of an ethanol solution of a 1 : 1 molar ratio ofcaffeine to glutaric acid selectively produces the metastablepolymorph of the cocrystal (form I). Similarly, Eddlestonet al. used freeze-drying to reproduce several previouslyreported cocrystals; in addition, a novel hydrate of a cocrystalinvolving theophylline and oxalic acid and a solid solution ofcaffeine and theophylline have been identified.37 Interest-ingly, the solid solution was found to be converted to anew polymorph of the 1 : 1 cocrystal involving caffeine andtheophylline, which the authors successfully predicted bycomputational methods.

On the other hand, it should be stressed here thatemploying thorough screening does not guarantee the dis-covery of cocrystal polymorphs. For example, Abourahma et al.recently noted that despite thorough polymorph screeningemploying solvent-drop grinding and slurry, solution and meltcrystallization, the search for polymorphism in the cocrystalsof pyrazinamide with six benzenecarboxylic acids yieldedonly a single crystal form for each of the cocrystalsobtained.38 In another study, Martí-rujas et al. did not observepolymorphism in a homologous family of urea cocrystals withα,ω-dihydroxyalkanes, although the observed cocrystals showeda significant structural diversity among this class of cocrystals.39

4. Classification of cocrystalpolymorphsIn general, polymorphs can be classified into different types.As cocrystals contain two or more different molecules in thecrystal lattice, classification of polymorphs in these systemsshould consider not only the conformational differences ofconstituents, but also the intermolecular interactionsbetween two or more different molecules. It should becautioned that these classifications are not applied in thestrictest sense because polymorphs may belong to one ormore different classes. The advantage of these classificationsis that the nature of polymorphism and the differencesbetween alternative crystal structures are easily identified.

4.1. Synthon polymorphs

Polymorphs that differ in their primary hydrogen bondmotifs or synthons can be classified as synthon polymorphs.Polymorphs of tetrolic acid represent a classic example ofsynthon polymorphs in single component crystals: the α-formcontains the acid–acid dimer synthon and the β-form containsa catemer synthon.40 Synthon polymorphism arising from

Table 1 Summary of the results from polymorph screening with the1 : 1 phenazine–mesaconic acid cocrystal (reproduced from ref. 10c)

Cocrystal form Method of cocrystallization

Form I Solution crystallization, grinding, sublimation,thermal methods, desolvation of hydrate

Form II Cocrystallization at the interface of two saturatedsolutions, solvent-drop grinding, desolvation of thedimethyl sulfoxide (DMSO) solvate

Form III Thermal methodsMonohydrate Cocrystallization at the interface between two

saturated solutionsDMSO solvate Solvent-drop grinding

Fig. 6 Powder X-ray diffraction patterns of the new polymorphsof the cocrystals of CBZ with NCT (top) and SAC (bottom). ThePXRD patterns represented in red correspond to the results ofcocrystallization experiments using crosslinked polymers as heteronuclei.Reprinted with permission from ref. 10d. Copyright 2008, The AmericanChemical Society.


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



different hydrogen bond synthons has also been reported incocrystals. For example, Sreekanth et al. reported synthon poly-morphs of a 2 : 1 cocrystal of 4-hydroxybenzoic acid (4HBA) and2,3,5,6-tetramethylpyrazine (TMP).41 Whereas form I consistsof acid–acid dimer and hydroxyl–pyridine synthons, form II issustained by acid–pyridine and hydroxyl–carbonyl synthons.Interestingly, form I, which does not follow the hydrogen bondhierarchy, converts to form II that follows the hydrogen bondhierarchy (Fig. 7).

A similar synthon polymorphism has also been observedrecently in a cocrystal involving 4HBA and 4,4′-bipyridine(BP) (Fig. 8).42 While one of the polymorphs features acid–acid dimer and hydroxyl–pyridine synthons, the other poly-morph is sustained by acid–pyridine and hydroxyl–carbonylsynthons. The observed polymorphism resulting from the dif-ferences in synthons has been attributed to the comparableacidities of the two OH groups in 4HBA.

Molecules that contain multiple hydrogen bonding capa-bilities appear to be more prone to form synthon poly-morphs. Fig. 9 shows some selected examples of cocrystalsystems that feature different supramolecular synthons intheir polymorphs.

4.2. Conformational polymorphs

Conformational polymorphism refers to the occurrence ofdifferent molecular conformations in different polymorphs.50

In general, flexible molecules with several degrees of tor-sional freedom and low-energy conformers are more prone to

exhibit conformational polymorphism. The high occurrenceof polymorphism in APIs has been attributed to their flexiblemolecular structures. Conformationally flexible moleculesmay possess a greater propensity to exhibit polymorphism asenergies required for rotation about single bonds are oftencomparable to the lattice energy differences between poly-morphs. With respect to cocrystals, a number of reportedpolymorphic cocrystals feature different conformers of oneor more of the cocrystal components and, therefore, can beclassified as conformational polymorphs. For example, ourrecent polymorphic cocrystals of NCT–pimelic acid (1 : 1),51

ethenzamide–gentisic acid (1 : 1),52 and ethenzamide–ethylmalonic acid (1 : 1)27 all feature different conformers ofone or more of the cocrystal components. Interestingly, bothpolymorphs of the cocrystal of ethenzamide–ethylmalonicacid feature a similar hydrogen bond motif and a commonsecondary level architecture but contain significantly differentconformers of ethylmalonic acid (Fig. 10).27

Fig. 7 Supramolecular synthons in (4HBA)2–(TMP) polymorphs. (a) Thehomosynthon and heterosynthon in form I. (b) Heterosynthons in form II.Reproduced from ref. 41.

Fig. 8 Hydrogen bonding schemes in polymorphs 1 and 2 of 4HBAand BP. Note the different synthons in the crystal structures.Reproduced from ref. 42.

Fig. 9 Selected examples of cocrystals that show synthon polymorphs.The differences in hydrogen bond synthons in the polymorphs areidentified.


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



A similar conformational polymorphism has beenobserved recently by Braga et al. in a 1 : 1 cocrystal of pimelicacid with BP, which forms three polymorphs that show minordifferences in their overall crystal packing but feature differ-ences in the conformations of pimelic acid (Fig. 11).53

Conformational reorganization leading to concertedmovement akin to rack-and-pinion gears at the molecular levelhas been observed by Sokolov et al. in a cocrystal of all-trans-2,5-bis(4-ethenylpyridyl)thiophene and 4-hexylresorcinol.54 Thecocrystal undergoes reversible single crystal to single crystal(SCSC) phase transformation to three distinct polymorphicforms. All of the three forms were characterized by singlecrystal X-ray diffraction. The phase transitions occur due toconformational changes resulting from expansions and com-pressions of the alkyl chains, rotations of the carbon–carbondouble bonds, and tilts of the aromatic rings of the cocrystalcomponents.

Conformational polymorphism appears to be more com-mon than synthon polymorphism as is evidenced by a numberof recent examples that show considerable conformational dif-ferences in their constituents (ESI†). In addition, the fact thatthere is a possibility of some flexibility in the supramolecularunit formed and in the interactions that they are stabilized bymay further facilitate the polymorphism in cocrystals. Fig. 12shows some selected examples of cocrystal systems that repre-sent conformational polymorphs in cocrystals.

Conformational differences in the components of thepolymorphic cocrystals were analyzed and provided in the ESI.†It suggests that a majority of the polymorphic cocrystals featuredifferent conformers of one or more of the cocrystalcomponents.

4.3. Packing polymorphs

Polymorphs can be classified as packing polymorphs whenthey differ in their overall three-dimensional crystal packing.Although there is no clear distinction between packing poly-morphs and other classes of polymorphs, the former is morecommon for totally rigid molecules or molecules with weakconformational flexibility. For example, p-nitrophenol,57a

chlordiazepoxide,57b and sulfathiazole57c all show minordifferences in their conformations but show differences intheir overall crystal packing.

The reported polymorphic cocrystals containing rigid com-ponents were analyzed to identify the packing differences orsimilarities. This analysis was aimed at identifying the packingpolymorphs that contain similar conformations of the cocrystalcomponents and hydrogen bond synthons. Two of thecocrystals reported by Skovsgaard and Bond best representpacking polymorphism in cocrystals.58 A 2 : 1 cocrystal of

Fig. 10 A hydrogen bonded four-component unit that was found inboth the polymorphs of ethenzamide–ethylmalonic acid (1 : 1) (top).Overlay diagrams of the cocrystal components (bottom). Note thedifferent conformations of ethylmalonic acid. Reproduced from ref. 27.

Fig. 11 Conformations of the two, four and one independent pimelicacid molecules in crystalline forms I, II and III, respectively. Reproducedfrom ref. 53 with permission from Wiley-VCH.

Fig. 12 Overlay of the different conformers of the components ofselected cocrystals that show conformational polymorphism.


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



benzoic acid with 2-aminopyrimidine was found to exist in twopolymorphic forms (forms I and II).58 Both polymorphs arecomposed of a trimeric unit involving two molecules of benzoicacid and one molecule of 2-aminopyrimidine connected viaN–H⋯O hydrogen bonds. However, the trimeric unit is approx-imately planar in form I, but the benzoic acid molecules forma dihedral angle of 42.6° to the 2-aminopyridine molecule inform II. Furthermore, while the planar trimers form herring-bone arrangements in the crystal lattice, the non-planar trimersare “nested” together in the crystal lattice of form II (Fig. 13).

Similarly, the crystal packing in the polymorphs (forms Iand II) of a 2 : 1 cocrystal of salicylic acid and N,N′-diacetylpiperazine is found to be significantly different whilethe hydrogen bonding in both polymorphs is similar.58

Whereas form I is a layered structure with the salicylic acidmolecules lying almost within the plane of the layer, form IIis not a layered structure (Fig. 14).

The polymorphs of a 1 : 1 cocrystal involving4-cyanophenol (4CP) and BPE present an interesting packingpolymorphism.5f A monoclinic polymorph, which was found tocrystallize concomitantly with a triclinic polymorph, featurestwo distinct supramolecular entities. The first is a non-centrosymmetric 2 : 1 adduct of 4CP2–BPE sustained byhydroxyl–pyridine heterosynthons while the second is a non-hydrogen bonded BPE that is sandwiched by the 2 : 1 adducts.On the contrary, the triclinic form is composed of two crystallo-graphically independent 1 : 1 supramolecular adducts that aresustained by hydroxyl–pyridine heterosynthons (Fig. 15).

The same authors have also reported a polymorphic 2 : 1cocrystal involving 4-cyanopyridine and 4,4′-biphenol.5e Thepolymorphs not only show differences in their intermolecularinteractions, but also feature different conformers of the 4,4′-biphenol molecule and hence can also be considered as con-formational and synthon polymorphs.

4.4. Tautomeric polymorphs

When different tautomers of a compound crystallize in differ-ent crystal forms, they are termed as tautomeric polymorphs.In general, tautomerism occurs when the constitutional isomers of different hydrogen-atom connectivities are in

dynamic equilibrium with one another. Tautomers that inter-convert in solution or in melt are considered to be the samechemical compound and hence the crystal forms that containthese tautomers can be classified as polymorphs.59 APIs suchas omeprazole,60a sulfasalazine,60b and triclabendazole60c

have been reported to contain different tautomers in theirpolymorphic forms. A 1 : 1 cocrystal of a nonsteroidal anti-inflammatory drug, piroxicam, with 4HBA represents a rarecase of tautomeric polymorphism in cocrystals.61 One of thepolymorphs contains the piroxicam molecule as the zwitter-ionic tautomer, whereas the other contains the piroxicammolecule as the non-ionized tautomer. As shown in Fig. 16,the polymorph that contains the non-ionized tautomer fea-tures the acid–acid dimer and phenol–pyridine synthons,whereas the polymorph that contains the zwitterion tautomerfeatures acid–sulfonyl and phenol–enolate oxygen synthons.

Fig. 13 Packing polymorphs of the 2 : 1 cocrystal of benzoic acid with2-aminopyrimidine. Left: the herringbone arrangement of planar trimericunits, and right: view of non-planar trimeric units “nested” togetheralong the c axis. Reproduced from ref. 58.

Fig. 14 Packing diagrams of the 2 : 1 cocrystal of salicylic acid andN,N′-diacetylpiperazine, (a) form I, (b) form II. Reproduced from ref. 58.

Fig. 15 Crystal structure of 4CP–BPE. Top: monoclinic form;non-centrosymmetric 2 : 1 supramolecular adducts sustained byhydroxyl–pyridine heterosynthons that engage in π⋯π interactions withBPE molecules. Bottom: triclinic form; 1 : 1 supramolecular adductssustained by hydroxyl–pyridine heterosynthons that stack in a face-to-face fashion parallel to the a-axis. Reprinted with permission from ref.5f. Copyright 2007, The American Chemical Society.


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



4.5. Polymorphic cocrystal hydrates and solvates

Polymorphism in crystalline hydrates that contain a singlesolid component is not uncommon. For example, hydratesof zoledronic acid,62a niclosamide,62b gallic acid,62c andnitrofurantoin62d show polymorphism. As in the case withpolymorphs of anhydrous solids, different polymorphs of ahydrate are also found to exhibit different properties, andhence studies concerning polymorphism in hydrates are criti-cal for the development of hydrate solids. Similar to hydratesof single solid component systems, polymorphism in solvateshas also been reported. For example, methanol and ethanolsolvates of indantrione-1,2-dioxime63a and trifluoroaceticacid solvates of caffeine63b have been shown to exist in poly-morphic forms.

In contrast to crystals of single solid components,polymorphism in cocrystal hydrates and solvates is a rarephenomenon and to the best of our knowledge only twopolymorphic cocrystal hydrates and a polymorphic cocrystalsolvate have been reported to date.

We have recently shown that a cocrystal of an anti-tuberculosis drug, isoniazid, with 4HBA exists in two poly-morphic forms in its monohydrate form.64 Single crystalX-ray diffraction analysis of the two polymorphs revealeddifferent hydrogen bonding motifs as shown in Fig. 17.

A cocrystal hydrate that involves 18-crown-6 and3,5-dichloropicric acid (DCPA) has also been shown to existin two polymorphic forms by Britton et al.65 It was found thatthe association of 18-crown-6, DCPA and water moleculesthrough hydrogen bonding is essentially the same in bothpolymorphs and the polymorphs differ mainly in the overall(molecular) packing (Fig. 18).

For a polymorphic cocrystal solvate, Bhattacharya andSaha recently reported a methanol solvate of a cocrystal of1,3,5-benzenetricarboxylic acid (BTA) with 4,4′-methylenebis-(2,6-dimethylaniline) (MBDA) in a 1 : 1 : 1 molar ratio whichexists in two polymorphic forms.66 Interestingly, the crystalstructures of the polymorphs show some significant differ-ences. In form I, the crystal structure is composed of a hexa-gonal network, but devoid of acid–acid dimers; instead twoacid groups are bridged by hydroxyl or amine groups andhence the hexagon is expanded (Fig. 19). On the other hand,form II features chains of BTA molecules connected viacommonly observed acid–acid dimer synthons and the leftover carboxylic acid group of BTA interacts with MBDA andmethanol molecules via O–H⋯N and O–H⋯O hydrogenbonds. The fact that these polymorphs show differences in thehydrogen bonding synthons suggests that these polymorphscan also be classified as synthon polymorphs.

As the data concerning the polymorphism in cocrystalsolvates and hydrates are very limited, it is difficult to makeany generalizations or classifications in this class of cocrystals.

4.6. Polymorphism in ternary cocrystals

A rare case of polymorphism in a ternary cocrystal hasbeen reported by Ma et al.67 The authors found thatcocrystallization of C-methylcalix[4]resorcinarene (CMCR)

Fig. 16 Tautomeric polymorphs of the 1 : 1 cocrystal of piroxicam and4HBA. Notice that piroxicam exists as the neutral form in (a) and as thezwitterionic form in (b). Only the sulfonamide group that accepts ahydrogen bond from the carboxylic acid of 4HBA is shown in (b).Reprinted with permission from ref. 61. Copyright 2007, The AmericanChemical Society.

Fig. 17 Hydrogen bonding in the polymorphic hydrate of thecocrystal of isoniazid with 4HBA: form I (left) and form II (right).Reproduced from ref. 64.

Fig. 18 Molecular associations in the polymorphic cocrystal hydrateof 18-crown-6 and DCPA. Reproduced from ref. 65 with permissionfrom the International Union of Crystallography.

Fig. 19 Crystal structures of polymorphs of BTA–MBDA–MeOH. Left:form I; right: form II. Notice the different hydrogen bond synthons inthe crystal structures. Reprinted with permission from ref. 66.Copyright 2011, The American Chemical Society.


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



with BP in the presence of benzil resulted in concomitantcrystallization of two polymorphs of a 1 : 1 : 1 ternarycocrystal, CMCR–BP–benzil. In both polymorphs, the CMCRmolecule adopts a boat conformation and the association ofCMCR with BP molecules through O–H⋯O and O–H⋯Nhydrogen bonds results in skewed brick-wall sheets (Fig. 20).Although the topological architecture of both crystal struc-tures is essentially the same, the crystal structures can bedistinguished by the way the brick-wall sheets are slanted. Inaddition, the cavities in form I contain two benzil moleculesrelated by an inversion center, but form II contains two inde-pendent benzil guests in the cavities. The overlay of differentconformers of cocrystal components revealed that there isonly a minor difference in the conformations of CMCR andBP, but the conformers of benzil are different (ESI†). There-fore, these polymorphs can be classified as conformationalpolymorphs.

5. Concomitant crystallization ofcocrystal polymorphsConcomitant polymorphs are those that crystallize simulta-neously from the same crystallization batch under identicalcrystallization conditions. In general, polymorphs crystallizetogether when there are two or more local minima on thefree energy curve with relatively equal energies. Concomitantpolymorphism in several organic, inorganic, and proteinsamples has been reviewed by Bernstein et al.,68 and thethermodynamic and kinetic factors that govern competitive andconcomitant crystallization of polymorphs were highlighted.Interestingly, the earliest reported organic compound to showpolymorphism, benzamide, crystallizes in two concomitantpolymorphs from a hot saturated aqueous solution asfeatherlike needles and blocks.69

An analysis of the reported polymorphic cocrystalsrevealed that the concomitant crystallization of two or moreof the cocrystal polymorphs is also not uncommon. Of the114 polymorphic cocrystals reported (ESI†), polymorphs of17 cocrystals have been found to crystallize concomitantly.These are listed in Table 2. Concomitant cocrystal poly-morphs that contain energetically different supramolecularsynthons provide challenging model systems to understandthe relationship between nucleation and crystal growth ofcocrystal polymorphs. Future studies along these lines areexpected to shed light on the intriguing phenomenon ofconcomitant polymorphism in cocrystals.

6. Polymorphs of cocrystals displayingdistinct physicochemical propertiesThe effect of polymorphism on materials' properties has beenvery well documented. As mentioned before, polymorphismis known to impact properties such as solubility, dissolutionrate, stability, bioavailability, mechanical properties, etc. Inthe case of cocrystals, it is reasonable to expect that thechanges in the crystal structure may lead to specific andsignificant differences in the performance of the cocrystals.

Goud and Nangia have recently reported two polymorphsof a cocrystal of a sulfonamide antibiotic, SACT, with ACT.44

Crystal structure analysis revealed that the two polymorphscan be distinguished by N–H⋯Osulfonamide and N–H⋯Ocarbonyl

hydrogen bonds and thus can be classified as synthon poly-morphs. Dissolution studies suggest that the dissolution ratesof the metastable form I and the stable form II of SACT–ACTare 1.6 times and 1.3 times, respectively, faster than thedissolution rate of SACT (2.18 (mg cm−2) min−1) in aqueousbuffer medium of pH 7 (Fig. 21).

Caffeine is known to exhibit instability with respect tohumidity, with the formation of a crystalline nonstoichiometrichydrate.75 Various caffeine cocrystals have been reported toaddress this issue.76 Trask et al. have shown that the twopolymorphs of the cocrystal of caffeine with glutaric acid showdifferences in their physical stability under elevated relativehumidity (RH) conditions.76 Form II of the cocrystal exhibitsremarkable resistance to hydration under high RH conditions;on the contrary, form I converts to form II at low RH andcompletely converts to caffeine hydrate under high RHconditions.

MacGillivray and co-workers77,78 demonstrated the photo-activity difference in two polymorphs of a cocrystal ofresorcinol (res) and BPE. The first polymorph contains discretefour-component molecular assemblies held together by fourO–H⋯N hydrogen bonds,77 while the second polymorph fea-tures one-dimensional chains connected via O–H⋯N hydrogen

Fig. 20 Brick-wall network in polymorphs of the ternary cocrystal,CMCR–BP–benzil. Reproduced from ref. 67.

Table 2 A list of cocrystals that form polymorphs concomitantly

S. no. Cocrystal (molar ratio)

1 4CP + BPE (1 : 1)5f

2 4-Cyanopyridine + 4,4′-biphenol (1 : 0.5)5f

3 Trimesic acid + BPET (2 : 3)55

4 4,4′-Dihydroxybenzophenone + BPE (1 : 1)31

5 Sulfamethazine + 4-hydroxybenzamide (1 : 1)48

6 Gallic acid + ACT (1 : 1)24

7 Triphenylsilanol + BP (4 : 1)70

8 Isoniazid + 4HBA + water (1 : 1 : 1)64

9 Isoniazid + fumaric acid (1 : 0.5)64

10 4HBA + BP (2 : 1)42

11 Caffeine + glutaric acid (1 : 1)26

12 Theophylline + p-coumaric acid (1 : 1)71

13 1-Iodo-3,5-dinitrobenzoic acid + 1,4-diazabicyclo[2.2.2]octane (1 :1)72

14 1,3-Adamantanedicarboxylic acid + 1,7-phenanthroline (1 : 2)73

15 2,4-Dihydroxybenzoic acid + NCT (1 : 1)10a

16 Malonic acid + NCT (1 : 2)10a

17 Caffeine + 4-chloro-3-nitrobenzoic acid (1 : 1)74


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



bonds.78 The olefinic double bonds in the second polymorphare separated by 4.6 Å and therefore lie outside the rangerequired for a photoreaction. As expected, the second polymorphis photostable but the first polymorph completely converts to(res)·(4,4′-tpcb) (4,4′-tpcb = rctt-tetrakis(4-pyridyl)cyclobutane).MacGillivray and co-workers79 also reported the difference in thephotoactivity of two polymorphs of a 1 : 2 cocrystal involvingrctt-cyclobutanetetracarboxylic acid (CBTA) and BPE. Form I ofthe CBTA·2BPE cocrystal was obtained by cooling crystallizationfrom DMSO–methanol (v/v 1 : 1); form II was obtained similarlybut from pure DMSO. Upon UV irradiation of form II, BPE wascompletely converted to 4,4′-tpcb after only 40 min in a SCSCmanner. In contrast, the same photodimerization reactionrequired 2 h to complete in form I, during which the crystalsexperienced widespread cracking before disintegrating to apowder. Based on the crystal structures of the polymorphs, itwas concluded that the differences in both CC stacking andtilts of adjacent chains likely contribute to the resulting SCSCbehavior, as well as the shorter time for the photodimerizationof form II versus form I (Fig. 22).

In another study, MacGillivray and co-workers reportedtwo polymorphs of a cocrystal involving 5-cyanoresorcinol(5-CN-res) and 4,4′-tpcb.80 Whereas one of the polymorphs(form I) was obtained from the [2 + 2] photodimerization ofBPE molecules by irradiating a 2 : 2 cocrystal of 5-CN-res andBPE, the second polymorph (form II) was obtained byconventional cocrystallization of 5-CN-res and 4,4′-tpcb fromsolution. 5-CN-res adopts a syn,syn-conformation in form I,but a syn,anti-conformation in form II. While 5-CN-res andTPCB molecules form hydrogen bonded chains in form II,form I features discrete three component units formed bytwo molecules of 5-CN-res and one molecule of 4,4′-tpcb.AFM nanoindentation measurements on the (101) faceshowed that form I has a higher Young's modulus than formII, indicating that form II is softer than form I.

Distinct mechanical behavior of two structurally similarconcomitant polymorphs of a caffeine cocrystal with4-chloro-3-nitrobenzoic acid has been reported recently by

Ghosh et al.74 Crystal structures of both polymorphs featurea common 2D layer packing, but show some differences inintralayer C–H⋯O and interlayer π⋯π stacking interactions.Form I was found to be brittle and converted to form II uponmechanical grinding. Form I possesses relatively weak intra-layer C–H⋯O interactions and is resistant to shearing; hencethe crystals are brittle. On the contrary, form II has relativelytighter 2D sheets due to more specific intralayer C–H⋯Ointeractions and sliding of layers along certain crystallo-graphic directions is possible. Nanoindentation experimentsshowed that the average values of elastic modulus (E) andhardness (H) of form II are much lower than form I; thereforeit is easier to deform form II than form I (Table 3).

7. Crystal structure prediction (CSP)of cocrystal polymorphsThe prediction of the crystal structure of a small organicmolecule, given only the structural formula, is still a difficulttask,81 although improved methodologies and sophisticatedcomputational abilities to predict the crystal energy landscapehave facilitated successful structure predictions in recenttimes.82 The main aim of CSP is to find, by computationalmethods, a set of crystal structures which are low in energythat can correspond to stable/metastable polymorphs. As thereliable prediction of a practically useful polymorph has

Fig. 21 Comparison of intrinsic dissolution rate curves of SACT andSACT–ACT polymorphs in pH 7 buffer medium. Reproduced from ref. 44. Fig. 22 Hydrogen-bonded chains in (a) form I and (b) form II

polymorphs of CBTA·BPE cocrystals. Reprinted with permission fromref. 79b. Copyright 2013, The American Chemical Society.

Table 3 Average values of elastic modulus (E) and hardness (H) offorms I and II of the cocrystal of caffeine–4-chloro-3-nitrobenzoicacid. Reproduced with permission from ref. 74. Copyright 2013, TheAmerican Chemical Society

Polymorph Orientation E (Mpa) H (MPa)

Form I (001) 7860 ± 28 175 ± 5Form II (01̄1) 6715 ± 9 106 ± 3

(011) 4920 ± 5 96 ± 3


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



tremendous implications in drug development and materialsscience, interest in the CSP of polymorphic forms hasincreased significantly over the years.83

CSP of multi-component crystals is even more challengingbecause of the additional need to predict the relative orienta-tion of the components and the increased number of potentialstructures to be considered. However, there have been recentsuccesses in the CSP of these systems.84,85 With respect topolymorphism in cocrystals, a CSP study by Habgood et al. ona 1 : 1 cocrystal of CBZ and isonicotinamide resulted in twostructures with lattice energies lower or comparable to the sumof the pure component lattice energies.84 These two structureswere found to correspond to the known polymorphs ofthe cocrystal. The successful prediction of both polymorphsof the cocrystal underscores the importance of CSP in thepolymorph screening of cocrystals. A synthon-based approachhas been recently proposed by Desiraju and Thakur that helpsto include some kinetic information in the CSP.86 The infor-mation obtained from the analysis of the arrangement ofmolecules in cocrystals of similar molecules in the CSD wasconsidered in the final ranking of crystal structures of thecocrystals. The approach successfully predicted the hydrogenbonding motif present in the crystal structure of a cocrystalinvolving 2-methylbenzoic acid and 2-amino-4-methylpyrimidine.86

Using such a synthon-based approach can give valuable predic-tive information which not only includes kinetic informationin the CSP but also identifies the structures that feature themost probable hydrogen bonding synthons which may paveways to the successful prediction of polymorphs of cocrystals.

8. Statistical analysis of cocrystalpolymorphs: are cocrystals less ormore prone to polymorphism?From a recent exhaustive search, there were a total of 114neutral polymorphic cocrystals in the literature at the end ofSeptember 2013 (ESI†). Our recent database analysis of thecrystal structures deposited in the CSD revealed that thepercentage of polymorphs in cocrystals is comparable to thepercentage of polymorphs in crystals that contain a singlesolid component.11 Our observations were also validated byanother database study conducted in the same year byZaworotko and co-workers.87 The authors found that thepercentage of polymorphic cocrystals that are sustained bystrong hydrogen bonds is approximately the same as thepercentage of polymorphic crystals that contain a single solidcomponent. We have also concluded from our database analysisthat the number of cocrystal polymorphs reported after the year2000 is significantly higher than the number of cocrystalsreported before.11 As cocrystals continue to find applications indiverse areas of interest over the past few years, there is a suddenincrease in the number of polymorphic cocrystals reported.

Besides the growing interest in the development ofcocrystals and curiosity to understand the origin of poly-morphism in cocrystals, the question of whether cocrystals are

less or more prone to polymorphism has attracted greatattention.4,10a,d,11,53,88 This is undoubtedly a difficult questionto answer based on the data that are available to date.However, as is presented in this article, polymorphism is notlimited to any particular type of compound or cocrystal. Asin crystals that contain a single solid component, polymor-phism has been observed in cocrystals that contain flexibleor rigid molecules with or without functional groups thatform strong hydrogen bonds. In addition, polymorphism hasalso been found in cocrystal solvates and hydrates and evenin higher order cocrystals such as ternary cocrystals. Ouranalysis of the reported polymorphic cocrystals did notreveal any conclusive evidence to answer whether cocrystalsare less or more prone to polymorphism. However, it shouldbe emphasized that a number of recent polymorph screenshave been reported to yield one or more cocrystal poly-morphs.5f,10 It should also be emphasized that, as in singlecomponent crystals, there have been reported examples ofcocrystals that exist only in a single form even after exhaustivepolymorph screening.38,39 Therefore, it is not appropriate todistinguish cocrystals from single component crystals withrespect to polymorphism, and finding a polymorph of acocrystal solely relies on our ability to find the right experimen-tal conditions. A recent comment by Mukherjee and Desirajuon the polymorphism in cocrystals is quite appropriate in thisregard: “…it is possible that any compound may be inducedto form a co-crystal and under the conditions of McCrone'sextremum, polymorphs may be isolated for both a moleculeand for any of its co-crystals”.42

9. ConclusionsCocrystals have opened up new avenues for fine tuning vari-ous material properties. The past decade has seen an explo-sion of interest in the design, synthesis, and development ofcocrystals for various applications. In pharmaceuticals,cocrystals offer a rational approach to address several impor-tant issues in the development of an API. Polymorphism isan important aspect that is equally important in single com-ponent crystals and in cocrystals. While most of the reportedcocrystal polymorphs have been discovered serendipitouslyduring cocrystallization experiments, systematic screeningmethods to discover new polymorphs of cocrystals are anemerging activity. In addition to conventional cocrystallizationtechniques such as solvent evaporative crystallization andsolid-state grinding, techniques such as slurry conversion,melt crystallization, high-throughput screening, hydro-thermal crystallization, spray drying, and crystallization athigh pressures have been used for the discovery of cocrystalpolymorphs. The effect of polymorphism on the performanceof cocrystals has only been evaluated in a very few examples;however, these studies emphasize the impact of poly-morphism on the performance of cocrystals. Therefore, under-standing the structure–property relationships in cocrystalpolymorphs is valuable in an attempt to select a suitablepolymorph.


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



In this review, we have made an attempt to provide anoverview of reported examples of polymorphic cocrystals. Allof the polymorphic cocrystals were retrieved from varioussources. As of September 2013, there are a total of114 cocrystals existing in two or more polymorphic forms. Asdiscussed in the previous sections, different classes ofpolymorphs, namely synthon, packing, and conformational,were identified and representative examples were highlighted.Notably, most of the cocrystal polymorphs feature differentconformers of one or more of the cocrystal componentssuggesting that conformational flexibility of the cocrystalcomponents greatly contribute to the polymorphism in thisclass of solids. It is also important to highlight here that asignificant number of cocrystals (15%) form polymorphsconcomitantly.

As cocrystals continue to attract greater attention in phar-maceuticals, it is reasonable to foresee a greater significancefor polymorphism studies in cocrystal screening. In thisregard, systematic investigations dealing with understandingof polymorphism in cocrystals are desired. It is also importantto attempt different approaches for polymorph screening.As illustrated by Chadwick et al., utilization of ternary phasediagrams provides valuable information on the operatingconditions for obtaining cocrystal forms.89 Robotics aidedpolymorph screening methods, such as high-throughputscreening, are yet to be fully applied to cocrystals, and therecent work by Shi et al. highlighted the significance of suchtools in the identification of cocrystal polymorphs.10b Exploringnovel techniques to monitor polymorphic transformationssheds light on the fundamental understanding of the origin ofpolymorphism. In this regard, recent attempts to monitor thepolymorphic phase transformations of a caffeine–glutaric acidcocrystal by in situ atomic force microscopy are noteworthy.90

AcknowledgementsWe greatly acknowledge financial support from the Scienceand Engineering Research Council of A*STAR (Agency forScience, Technology and Research), Singapore. We also thankMs. Annie B. H. Wong for helping in the preparation of somefigures presented in this article.

Notes and references1 (a) Ö. Almarsson and M. J. Zaworotko, Chem. Commun.,

2004, 1889; (b) R. D. B. Walsh, M. W. Bradner, S. G. Fleischman,L. A. Morales, B. Moulton, N. Rodríguez-Hornedo andM. J. Zaworotko, Chem. Commun., 2003, 186.

2 (a) N. Schultheiss and A. Newman, Cryst. Growth Des., 2009,9, 2950; (b) N. J. Babu and A. Nangia, Cryst. Growth Des.,2011, 11, 2662; (c) R. Thakuria, A. Delori, W. Jones,M. P. Lipert, L. Roy and N. Rodríguez-Hornedo, Int. J. Pharm.,2013, 453, 101; (d) D. P. Elder, R. Holm and H. P. de Diego,Int. J. Pharm., 2013, 453, 88.

3 (a) D. Yan, A. Delori, G. O. Lloyd, T. Friščić, G. M. Day,W. Jones, J. Lu, M. Wei, D. G. Evans and X. Duan, Angew.

Chem., Int. Ed., 2011, 50, 12483; (b) S. Karki, T. Friščić,L. Fábián, P. R. Laity, G. M. Day and W. Jones, Adv. Mater.,2009, 21, 3905.

4 (a) G. R. Desiraju, CrystEngComm, 2003, 5, 466; (b)J. D. Dunitz, CrystEngComm, 2003, 5, 506; (c) S. L. Childs,G. P. Stahly and A. Park, Mol. Pharmaceutics, 2007, 4, 323; (d)J. Zukerman-Schpector and E. R. T. Tiekink, Z. Kristallogr.,2008, 223, 233; (e) M. J. Zaworotko, Cryst. Growth Des., 2007, 7,4; ( f ) H. G. Brittain, Cryst. Growth Des., 2012, 12, 5823; (g)G. R. Desiraju, Pharmaceutical salts and co-crystals: retrospectand prospects, in Pharmaceutical salts and co-crystals, ed.J. Wouters and L. Quere, Royal Society of Chemistry, London,2011, pp. 1–8; (h) S. Aitipamula, R. Banerjee, A. K. Bansal,K. Biradha, M. L. Cheney, A. R. Choudhury, G. R. Desiraju,A. G. Dikundwar, R. Dubey, M. Duggirala, P. P. Ghogale,S. Ghosh, P. K. Goswami, N. R. Goud, R. K. R. Jetti,P. Karpinski, P. Kaushik, D. Kumar, V. Kumar, B. Moulton,A. Mukherjee, G. Mukherjee, A. S. Myerson, V. Puri,A. Ramanan, T. Rajamannar, C. M. Reddy, N. Rodriguez-Hornedo, R. D. Rogers, T. N. G. Row, P. Sanphui, N. Shan,G. Shete, A. Singh, C. C. Sun, J. A. Swift, R. Thaimattam,T. S. Thakur, R. K. Thaper, S. P. Thomas, S. Tothadi,V. R. Vangala, N. Variankaval, P. Vishweshwar, D. R. Weynaand M. J. Zaworotko, Cryst. Growth Des., 2012, 12, 2147–2152.

5 (a) B. R. Bhogala and A. Nangia, New J. Chem., 2008, 32, 800;(b) G. Stahly, Cryst. Growth Des., 2007, 7, 1007; (c) S. Childsand K. Hardcastle, Cryst. Growth Des., 2007, 7, 1291; (d)A. V. Bond, CrystEngComm, 2007, 9, 833; (e) C. B. Aakeroyand D. J. Salmon, CrystEngComm, 2005, 7, 439; ( f ) J. A. Bis,P. Vishweshwar, D. Weyna and M. J. Zaworotko, Mol.Pharmaceutics, 2007, 4, 401; (g) N. Shan and M. J. Zaworotko,Drug Discovery Today, 2008, 13, 440; (h) W. Jones,W. D. Motherwell and A. V. Trask, MRS Bull., 2006, 341, 875;(i) L. J. Barbour, D. Das, T. Jacobs, G. O. Lloyd and V. J. Smith,Concepts and nomenclature in chemical crystallography, inSupramolecular Chemistry from Molecules to Nanomaterials,ed. P. A. Gale and J. W. Steed, Wiley-Blackwell, 2012,p. 2869; ( j) Guidance for Industry: Regulatory Classification ofPharmaceutical Co-crystals, Food and Drug Administration,Silver Spring, MD, December 2011.

6 J. Bernstein, Polymorphism in Molecular Crystals, Clarendon,Oxford, 2002.

7 (a) H. G. Brittain, Polymorphism in Pharmaceutical Solids,Marcel Dekker, New York, 1999; (b) R. Hilfiker, Polymorphismin the Pharmaceutical Industry, Wiley, Weinheim, 2006; (c)J. Berstein, Organic Solid State Chemistry, Elsevier, Amsterdam,1987, pp. 471–518.

8 J. O. Henck, U. J. Griesser and A. Burger, Pharm. Ind., 1997,59, 165.

9 S. L. Morissette, Ö. Almarsson, M. L. Peterson, J. F. Remenar,M. J. Read, A. V. Lemmo, S. Ellis, M. J. Cima andC. R. Gardner, Adv. Drug Delivery Rev., 2004, 56, 275.

10 (a) A. Lammerer, A. Adsmond, C. Esterhuysen andJ. Bernstein, Cryst. Growth Des., 2013, 13, 3935; (b) X. Shi,S. Y. Wong, X. Yang and A. S. Myerson, CrystEngComm,2013, 15, 7450; (c) M. D. Eddleston, S. Sivachelvam and


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



W. Jones, CrystEngComm, 2013, 15, 175; (d) W. W. Porter III,S. C. Elie and A. J. Matzger, Cryst. Growth Des., 2008, 8, 14.

11 S. Aitipamula, P. S. Chow and R. B. H. Tan, Cryst. GrowthDes., 2010, 10, 2229.

12 A. V. Trask, Mol. Pharmaceutics, 2007, 4, 301.13 Polymorphic cocrystals wherein a cocrystal contains a

conventional salt and a neutral CCF, S. Dong, Y. Tao,X. Shen and Z. Pan, Acta Crystallogr., Sect. C: Cryst. Struct.Commun., 2013, 69, 896, and an ionic cocrystal consistingof sodium benzoate and benzoic acid, C. Butterhof,K. Bärwinkel, J. Senker and J. Breu, CrystEngComm, 2012, 14,6744, were considered.

14 For some recent polymorphic salts, see (a) J. B. Nanubolu,B. Sridhar, K. Ravikumar, K. D. Sawant, T. A. Naik,L. N. Patkar, S. Cherukuvada and B. Sreedhar, CrystEngComm,2013, 15, 4448; (b) Y. Yan, C. E. Hughes, B. M. Kariuki andK. D. M. Harris, Cryst. Growth Des., 2013, 13, 27; (c)A. Lemmerer, J. Bernstein and M. A. Spackman, Chem.Commun., 2012, 48, 1883; (d) V. André, M. T. Duarte, D. Bragaand F. Grepioni, Cryst. Growth Des., 2012, 12, 3082; (e)L. Loots, H. Wahl, L. van der Westhuizen, D. A. Haynes andT. le Roex, Chem. Commun., 2012, 48, 11507; ( f ) W. Yin,X. Huang, X. Xu and X. Meng, Acta Crystallogr., Sect. C: Cryst.Struct. Commun., 2010, 66, o508; (g) S. L. Childs, L. J. Chyall,J. T. Dunlap, D. A. Coates, B. C. Stahly and G. P. Stahly, Cryst.Growth Des., 2004, 4, 441.

15 G. R. Desiraju, Crystal engineering: The design of organicsolids, Elsevier, Amsterdam, 1989.

16 S. Zhang and A. C. Rasmuson, Cryst. Growth Des., 2013,13, 1153.

17 S. Aitipamula, P. S. Chow and R. B. H. Tan, CrystEngComm,2012, 14, 2381.

18 Selected examples: (a) N. K. Nath and A. Nangia,CrystEngComm, 2011, 13, 47; (b) P. Sanphui, N. R. Goud,U. B. R. Khandavilli, S. Bhanoth and A. Nangia, Chem.Commun., 2011, 47, 5013; (c) R. Thakuria and A. Naniga,Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 2011, 67,o461; (d) P. Vishweshwar, J. A. McMahon, M. Oliveira,M. L. Peterson and M. J. Zaworotko, J. Am. Chem. Soc., 2005,127, 16802.

19 (a) S. Aitipamula, P. S. Chow and R. B. H. Tan,CrystEngComm, 2012, 14, 691; (b) E. J. C. de Vries,D. C. Levendis and H. A. Reece, CrystEngComm, 2011, 13,3334; (c) M. Wenger and J. Bernstein, Mol. Pharmaceutics,2007, 4, 355; (d) S. Roy, N. R. Goud, N. J. Babu, J. Iqbal,A. K. Kruthiventi and A. Nangia, Cryst. Growth Des., 2008, 8,4343; (e) A. Jayasankar, L. Roy and N. Rodríguez-Hornedo,J. Pharm. Sci., 2010, 99, 3977; ( f ) A. Lammerer, J. Bernsteinand V. Kahlenberg, CrystEngComm, 2011, 13, 5692; (g)H.-R. Xu, Q.-C. Zhang, Y.-P. Ren, H.-X. Zhao, L.-S. Long,R.-B. Huang and L.-S. Zheng, CrystEngComm, 2011, 13, 6361.

20 (a) M. A. Oliveira, M. L. Peterson and D. Klein, Cryst. GrowthDes., 2008, 8, 4487; (b) M. Dabros, P. L. Emery andV. R. Thalladi, Angew. Chem., Int. Ed., 2007, 46, 4132.

21 (a) S. Cherukuvada and A. Nangia, CrystEngComm, 2012, 14,2579; (b) N. R. Goud, K. Suresh, P. Sanphui and A. Nangia,

Int. J. Pharm., 2012, 439, 63; (c) E. Lu, N. Rodríguez-Hornedoand R. Suryanarayanan, CrystEngComm, 2008, 10, 665; (d)J. Lu, Y.-P. Li, J. Wang, Z. Li, S. Rohani and C.-B. Ching,J. Cryst. Growth, 2011, 407, 63.

22 S. Cherukuvada and A. Nangia, Chem. Commun., 2014, 50, 906.23 T. Ueto, N. Takata, N. Muroyama, A. Nedu, A. Sasaki,

S. Tanida and K. Terada, Cryst. Growth Des., 2012, 12, 485.24 R. Kaur and T. N. G. Row, Cryst. Growth Des., 2012, 12, 2744.25 A. Delori, T. Friščić and W. Jones, CrystEngComm, 2012, 14, 2350.26 A. V. Trask, W. D. S. Motherwell and W. Jones, Chem.

Commun., 2004, 890.27 S. Aitipamula, P. S. Chow and R. B. H. Tan, CrystEngComm,

2010, 12, 3691.28 S. R. Bysouth, J. A. Bis and D. Igo, Int. J. Pharm., 2011, 411, 169.29 J. H. ter Horst and P. W. Cains, Cryst. Growth Des., 2008, 8, 2537.30 O. M. Yaghi, M. O'Keeffe, N. W. Ockwig, H. K. Chae,

M. Eddaoudi and J. Kim, Nature, 2003, 423, 705.31 J. Wang, L. Ding and C. Yang, CrystEngComm, 2007, 9, 591.32 F. P. A. Fabbiani, D. R. Allan, W. I. F. David, S. A. Moggach,

S. Parsons and C. R. Pulham, CrystEngComm, 2004, 6, 504.33 B. A. Zakharov, E. A. Losav and E. V. Boldyreva,

CrystEngComm, 2013, 15, 1693.34 (a) M. B. Hickey, M. L. Peterson, L. A. Scoppettuolo,

S. L. Morrisette, A. Vetter, H. Guzmán, J. F. Remenar,Z. Zhang, M. D. Tawa, S. Haley, M. J. Zaworotko andÖ. Almarsson, Eur. J. Pharm. Biopharm., 2007, 67, 112; (b)S. G. Fleischman, S. S. Kuduva, J. A. McMahon, B. Moulton,R. D. B. Walsh, N. Rodríguez-Hornedo and M. J. Zaworotko,Cryst. Growth Des., 2003, 3, 909.

35 P. P. Bag, M. Patni and C. M. Reddy, CrystEngComm, 2011,13, 5650.

36 A. Alhalaweh and S. P. Velaga, Cryst. Growth Des., 2010, 10, 3302.37 M. D. Eddleston, B. Patel, G. M. Day and W. Jones, Cryst.

Growth Des., 2013, 13, 4599.38 H. Abourahma, D. S. Cocuzza, J. Melendez and J. M. Urban,

CrystEngComm, 2011, 13, 6442.39 J. Martí-rujas, B. M. Kariuki, C. E. Hughes, A. Morte-Ródenas,

F. Guo, Z. Glavcheva-Laleva, K. Taştemür, L. Ooi, L. Yeo andK. D. M. Harris, New J. Chem., 2011, 35, 1515.

40 S. Parveen, R. J. Davey, G. Dent and R. G. Pritchard, Chem.Commun., 2005, 1531.

41 B. R. Sreekanth, P. Vishweshwar and K. Vyas, Chem.Commun., 2007, 2375.

42 A. Mukherjee and G. R. Desiraju, Chem. Commun., 2011, 47, 4090.43 S. Aitipamula, P. S. Chow and R. B. H. Tan, CrystEngComm,

2009, 11, 889.44 N. R. Goud and A. Nangia, CrystEngComm, 2013, 15, 7456.45 P. Sanphui, N. J. Babu and A. Nangia, Cryst. Growth Des.,

2013, 13, 2208.46 S. Tothadi and G. R. Desiraju, Cryst. Growth Des., 2012, 12, 6188.47 S. Zhang, I. A. Guzei, M. M. de Villiers, L. Yu and

J. F. Krzyzaniak, Cryst. Growth Des., 2012, 12, 4090.48 S. Ghosh, P. P. Bag and C. M. Reddy, Cryst. Growth Des.,

2011, 11, 3489.49 N. J. Babu, L. S. Reddy, S. Aitipamula and A. Nangia, Chem.–

Asian J., 2008, 3, 1122.


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online



50 A. Nangia, Acc. Chem. Res., 2008, 41, 595.51 (a) S. Aitipamula, A. B. H. Wong, P. S. Chow and

R. B. H. Tan, CrystEngComm, 2012, 14, 8193; (b) S. Karki,T. Friščić and W. Jones, CrystEngComm, 2009, 11, 470.

52 S. Aitipamula, P. S. Chow and R. B. H. Tan, CrystEngComm,2009, 11, 1823.

53 D. Braga, G. Palladino, M. Polito, K. Rubini, F. Grepioni,M. R. Chierotti and R. Gobetto, Chem.–Eur. J., 2008, 14, 10149.

54 A. N. Sokolov, D. C. Swenson and L. R. MacGillivray, Proc.Natl. Acad. Sci. U. S. A., 2008, 105, 1794.

55 T. R. Shattock, P. Vishweshwar, Z. Wang and M. J. Zaworotko,Cryst. Growth Des., 2005, 5, 2046.

56 G. Bolla, S. Mittapalli and A. Nangia, CrystEngComm, 2014,16, 24.

57 (a) G. U. Kulkarni, P. Kumardas and C. N. R. Rao, Chem. Mater.,1998, 10, 3498; (b) D. Singh, P. V. Marshall, L. Shields andP. York, J. Pharm. Sci., 1998, 87, 655; (c) N. Blagden, R. J. Davey,L. Lieberman, R. Williams, R. Payne, R. Roberts, R. Rowe andR. Docherty, J. Chem. Soc., Faraday Trans., 1998, 94.

58 S. Skovsgaard and A. D. Bond, CrystEngComm, 2009, 11, 444.59 G. R. Desiraju, J. J. Vittal and A. Ramanan, Crystal

Engineering: A Textbook, IISC Press and World ScientificPublishing, Singapore, 2011.

60 (a) P. M. Bhatt and G. R. Desiraju, Chem. Commun., 2007, 2057;(b) A. J. Blake, X. Lin, M. Schroder, C. Wilson and R. X. Yuan,Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 2004, 60,o226; (c) S. Tothadi, B. R. Bhogala, A. R. Gorantla, T. S. Thakur,R. K. R. Jetti and G. R. Desiraju, Chem.–Asian J., 2012, 7, 330.

61 S. L. Childs and K. I. Hardcastle, Cryst. Growth Des., 2007, 7, 1291.62 (a) R. Ruscica, M. Bianchi, M. Quintero, A. Martinez and

D. R. Vega, J. Pharm. Sci., 2010, 99, 4962; (b)E. C. van Tonder, T. S. P. Maleka, W. Liebenberg, M. Song,D. E. Wurster and M. M. de Villiers, Int. J. Pharm., 2004, 269,417; (c) H. D. Clarke, K. K. Arora, L. Wojtas andM. J. Zaworotko, Cryst. Growth Des., 2011, 11, 964; (d)E. W. Pienaar, M. R. Caira and A. P. Lotter, J. Crystallogr.Spectrosc. Res., 1993, 23, 739.

63 (a) M. Suzuki and K. Kohayashi, Cryst. Growth Des., 2011, 11,1814; (b) A. V. Trask, J. van de Streek, W. D. S. Motherwelland W. Jones, Cryst. Growth Des., 2005, 5, 2233.

64 S. Aitipamula, A. B. H. Wong, P. S. Chow and R. B. H. Tan,CrystEngComm, 2013, 15, 5877.

65 D. Britton, M. K. Chantooni Jr. and I. M. Kolthoff, ActaCrystallogr., Sect. C: Cryst. Struct. Commun., 1988, 44, 303.

66 S. Bhattacharya and B. K. Saha, Cryst. Growth Des., 2011,11, 2194.

67 B.-Q. Ma, Y. Zhang and P. Coppens, J. Org. Chem., 2003, 68, 9467.68 J. Bernstein, R. J. Davey and J. O. Henck, Angew. Chem., Int.

Ed., 1999, 38, 3440.69 F. Wöhler and J. Liebig, Ann. Pharm., 1832, 3, 249.70 K. F. Bowes, G. Ferguson, A. J. Lough and C. Glidewell, Acta

Crystallogr., Sect. B: Struct. Sci., 2003, 59, 277.71 N. Schultheiss, M. Roe and S. X. M. Boerrigter,

CrystEngComm, 2011, 13, 611.72 K. Raatikainen and K. Rissanen, CrystEngComm, 2009,

11, 750.

73 Y. Manjare and V. R. Pedireddi, Cryst. Growth Des., 2011,11, 5079.

74 S. Ghosh, A. Mondal, M. S. R. N. Kiran, U. Ramamurty andC. M. Reddy, Cryst. Growth Des., 2013, 13, 4435.

75 U. J. Griesser and A. Burger, Int. J. Pharm., 1995, 120, 83.76 A. V. Trask, W. D. S. Motherwell and W. Jones, Cryst. Growth

Des., 2005, 5, 1013.77 L. R. MacGillivray, J. L. Reid and J. Ripmeester, J. Am. Chem.

Soc., 2000, 122, 7817.78 T. Friščić and L. R. MacGillivray, Chem. Commun., 2009, 773.79 (a) S. Bhattacharya, J. Stojaković, B. K. Saha and

L. R. MacGillivray, Org. Lett., 2013, 15, 744; (b) S. Bhattacharyaand B. K. Saha, Cryst. Growth Des., 2013, 13, 3299.

80 C. Karunatilaka, D.-K. Bučar, L. R. Ditzler, T. Friščić,D. C. Swenson, L. R. MacGillivray and A. V. Tivanski, Angew.Chem., Int. Ed., 2011, 50, 8642.

81 (a) J. Maddox, Nature, 1988, 335, 201; (b) G. R. Desiraju, Nat.Mater., 2002, 1, 77; (c) A. Gavezzotti, Acc. Chem. Res., 1994,27, 309; (d) J. D. Dunitz, Chem. Commun., 2003, 545; (e)F. J. J. Leusen, J. Cryst. Growth, 1992, 166, 900.

82 D. A. Bardwell, C. S. Adjiman, Y. A. Arnautova, E. Bartashevich,S. X. M. Boerrigter, D. E. Braun, A. J. Cruz-Cabeza, G. M. Day,R. G. D. Valle, G. R. Desiraju, B. P. van Eijck, J. C. Facelli,M. B. Ferraro, D. Grillo, M. Habgood, D. W. M. Hofmann,F. Hofmann, K. V. J. Jose, P. G. Karamertzanis, A. V. Kazantsev,J. Kendrick, L. N. Kuleshova, F. J. J. Leusen, A. V. Maleev,A. J. Misquitta, S. Mohamed, R. J. Needs, M. A. Neumann,D. Nikylov, A. M. Orendt, R. Pal, C. C. Pantelides, C. J. Pickard,L. S. Price, S. L. Price, H. A. Scheraga, J. va de Streek,T. S. Thakur, S. Tiwari, E. Venuti and I. K. Zhitkov, ActaCrystallogr., Sect. B: Struct. Sci., 2011, 67, 535.

83 (a) A. J. Florence, C. K. Leech, N. Shankland, K. Shanklandand A. Johnston, CrystEngComm, 2006, 8, 746; (b)A. J. Cruz-Cabeza, G. M. Day, W. D. S. Motherwell andW. Jones, Cryst. Growth Des., 6, 1858; (c) G. W. A. Welch,P. G. Karamertzanis, A. J. Misquitta, A. J. Stone and S. L. Price,J. Chem. Theory Comput., 2008, 4, 522.

84 M. Habgood, M. A. Deij, J. Mazurek, S. L. Price andJ. H. ter Horst, Cryst. Growth Des., 2010, 10, 903.

85 M. Polito, E. D'Oria, L. Maini, P. G. Karamertzanis, F. Grepioni,D. Braga and S. L. Price, CrystEngComm, 2008, 10, 1848.

86 T. S. Thakur and G. R. Desiraju, Cryst. Growth Des., 2008,8, 4031.

87 H. D. Clarke, K. K. Arora, H. Bass, P. Kavuru, T. T. Ong,T. Pujari, L. Wojtas and M. J. Zaworotko, Cryst. Growth Des.,2010, 10, 2152.

88 (a) P. Vishweshwar, J. A. McMahon, M. L. Peterson, M. B. Hickey,T. R. Shattock and M. J. Zaworotko, Chem. Commun., 2005,4601; (b) P. Vishweshwar, J. A. McMahon, J. A. Bis andM. J. Zaworotko, J. Pharm. Sci., 2006, 95, 499; (c) L. S. Reddy,N. J. Babu and A. Nangia, Chem. Commun., 2006, 1369.

89 K. Chadwick, R. Davey, G. Sadiq, W. Cross and R. Pritchard,CrystEngComm, 2009, 11, 412.

90 R. Thakuria, M. D. Eddleston, E. H. H. Chow, G. O. Lloyd,B. J. Aldous, J. F. Krzyzaniak, A. D. Bond and W. Jones,Angew. Chem., Int. Ed., 2013, 52, 10541.


Publ

ished

on

12 F

ebru

ary

2014

. Dow

nloa

ded

by U

nive

rsity

of B

risto

l on

21/0

3/20

14 1

9:10

:17.

View Article Online


Polymorphism in cocrystals

Documents

Transcript of Polymorphism in cocrystals