vishweshwar2006

REVIEW

Pharmaceutical Co-Crystals

PEDDY VISHWESHWAR, JENNIFER A. McMAHON, JOANNA A. BIS, MICHAEL J. ZAWOROTKO

Department of Chemistry, University of South Florida, CHE205, 4202 East Fowler Avenue, Tampa, Florida 33620

Received 12 July 2005; revised 11 September 2005; accepted 21 December 2005

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20578

ABSTRACT: Crystal engineering has evolved in such a manner that it is nowsynonymous with the paradigm of supramolecular synthesis, that is, it invokes self-assembly of existing molecules to generate a wide range of new solid forms without theneed to break or form covalent bonds. This review addresses how crystal engineering hasbeen applied to active pharmaceutical ingredients, APIs, with emphasis upon howpharmaceutical co-crystals, a long known but little explored alternative to the fourtraditionally known forms of API, can be generated in a rational fashion. Case studies onCarbamazepine (CBZ) and Piracetam are presented which illustrate the relative easewith which pharmaceutical co-crystals can be prepared and their diversity in terms ofcomposition and physical properties. 2006 Wiley-Liss, Inc. and the American PharmacistsAssociation J Pharm Sci 95:499516, 2006

Keywords: crystal engineering; hydrogen bond; pharmaceutical co-crystal; poly-morphism; supramolecular synthesis

INTRODUCTION

Crystalline forms of active pharmaceutical ingre-dients, APIs, have traditionally been limitedto salts, polymorphs, and solvates (includinghydrates).1 Given the high intrinsic value of APIsand the importance of structure and compositionin the context of both intellectual propertyand bioavailability, it is perhaps surprisingthat systematic approaches to the developmentof a new broad class of API, pharmaceutical co-crystals, have only been attempted in recentyears.216 Co-crystals represent a long knownclass of compounds, a prototypal example ofwhich is quinhydrone, which was reported atleast as early as 1844 and 1893.17,18 However,how narrowly or broadly one defines the term co-crystal remains a matter of topical debate. For

example, a broad definition is that a co-crystalis a mixed crystal or crystal that contains twodifferent molecules.19 An alternative approachthat arises conceptually from applying theconcepts of supramolecular chemistry and crystalengineering is that a co-crystal is the consequenceof a molecular recognition event between differentmolecular species.20,21 Aakeroy clarified the situa-tion further by suggesting that co-crystals aremade from reactants that are solids at ambienttemperature.22 He also stated that all hydratesand other solvates are excluded which, in princi-ple, eliminates compounds that are typicallyclassified as clathrates or inclusion compounds(where the guest molecule is a solvent or a gasmolecule). That there is such debate concerningthe definition of a co-crystal more than 160 yearsafter they were first reported clarifies a need fordistinguishing between multi-component crystal-line materials that are comprised of two or moresolids versus those composed of one or more solidsand a liquid. The latter have been called solvatesor pseudopolymorphs, an issue that has also

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 3, MARCH 2006 499

Correspondence to: Michael J. Zaworotko (Telephone: 813-974-4129; Fax: 813-974-3203; E-mail: [email protected])

Journal of Pharmaceutical Sciences, Vol. 95, 499516 (2006) 2006 Wiley-Liss, Inc. and the American Pharmacists Association

provoked recent discussion by Seddon, Desiraju,Bernstein, and Nangia.2326 We agree that thetime has come to abandon the term pseudopoly-morph in favor of solvate and recommend thatthe term pharmaceutical co-crystal be applied inthe context of APIs in which all componentsare solids when pure. Pharmaceutical co-crystals,co-crystals that are formed between a molecularor ionic API and a co-crystal former that is a solidunder ambient conditions, represent a clearlydefined subset of multi-component crystals, agroup that also includes salts, solvates, clath-rates, inclusion crystals and hydrates.5 Althoughsuch definitions lessen the level of ambiguity,there would still be an overlap between theseclasses. For example, if a crystalline materialconsists of two or more components that are solidsunder ambient conditions and a liquid componentthen it might be called a co-crystal solvate or, ifappropriate, a co-crystal hydrate. However, amulti-component system made of molecular co-crystal former and an ionic API would simply beclassified as a pharmaceutical co-crystal.9

It is important to note that from a supramole-cular perspective solvates and pharmaceutical co-crystals can be regarded as being closely related toone another since components within the crystalinteract by hydrogen bonding or other directionalnoncovalent interactions. The primary differencebetween solvates and pharmaceutical co-crystalsis simply the physical state of the isolated purecomponents: if one component is a liquid at roomtemperature, a compound is a solvate; if bothcomponents are crystalline solids at room tem-perature, they are pharmaceutical co-crystals.These differences may seem inconsequential butthey can profoundly affect the stability, proces-sing, and physical properties of APIs. The stabilityof solvates (including hydrates) at different tem-peratures and pressures differ from those of theunsolvated forms. These differences can influenceformulation, procession, and stability under var-ious storage conditions of the drug compound, aswell as the pharmaceutical product. Whereassolvates are commonplace because they oftenoccur as a serendipitous result of crystallizationfrom solution. Co-crystals, especially pharmaceu-tical co-crystals, represent a relatively unexploredbut broad ranging class of compounds.

A literature review reveals that co-crystals inwhich both components are solids under ambientconditions are long known as addition com-pounds,27 organic molecular compounds,18,28

mixed binary molecular crystal,29 molecular com-

plexes,30 or solid-state complexes31 or heteromole-cular crystals.32 However, a survey of the 355071crystal structures deposited in the August 2005release of the Cambridge Structural Database(CSD),33 indicates that such co-crystals remainrelatively unexplored. Indeed there are few entriesprior to 1960 and even today there are only ca.Onethousand four hundred eighty seven hydrogenbonded co-crystals versus 35882 hydrates. There-fore, it would be fair to summarize co-crystals asbeing long known but little studied. However,interest in co-crystals is increasing with potentialapplications in nonlinear optics (NLO),34 solvent-free organic synthesis,35,36 host-guest chemis-try,3739 and photographic film formulation.40

Figure 1 reveals the rapid increase in the numberof co-crystals reported from 19902003, a timeperiod which coincided with the emergence of theparadigm of crystal engineering.

The concept of crystal engineering was intro-duced by Pepinsky41 in 1955 and implemented bySchmidt in the context of organic solid-statephotochemical reactions.42 Desiraju subsequentlydefined crystal engineering as the understandingof intermolecular interactions in the context ofcrystal packing and in the utilization of suchunderstanding in the design of new solids withdesired physical and chemical properties.43 Crys-tal engineering has now matured into a paradigmfor the preparation or supramolecular synthesis ofnew compounds. A salient feature of crystalengineered structures is that they are designedfrom first principles using the principles ofsupramolecular chemistry44 and self-assembly.They can therefore consist of a diverse range of

Figure 1. Occurrence of H-bonded co-crystals in theCSD from 19902003.

500 VISHWESHWAR ET AL.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 3, MARCH 2006 DOI 10.1002/jps

chemical components as exemplified by co-ordination polymers (i.e., metals and organicligands),4550 polymers sustained by organome-tallic linkages51 and networks sustained by non-covalent bonds.45,5254 This contribution will focusupon pharmaceutical co-crystals with specialemphasis upon the following: design, methods ofpreparation, and polymorphism in co-crystals.

HOW ARE CO-CRYSTALS DESIGNED?

That pharmaceutical co-crystals are susceptibleto design by crystal engineering distinguishesthem from other crystalline forms of API. Analy-sis of existing crystal structures represents thefirst step in a crystal engineering experiment.This is typically executed via the CSD, whichfacilitates statistical analysis of packing motifsand thereby provides empirical information con-cerning common functional groups and how theyengage in molecular association, that is, how theyform supramolecular synthons.55 The potential ofthe CSD in the context of design was envisaged atleast 22 years ago when Allen and Kennardnoted56 that the systematic analysis of largenumbers of related structures is a powerfulresearch technique, capable of yielding resultsthat could not be obtained by any other method.Two decades later it has become clear that crystalengineering is in many ways synonymous withsupramolecular synthesis and herein we presentcase studies that address how pharmaceutical co-crystals can be prepared from first principles.

Carboxylic acid moieties represent one of themost commonly studied functional groups incrystal engineering43,5759 and they exist in 30 ofthe 100 top-selling prescription drugs in the

USA.60 Carboxylic acids therefore represent anexcellent starting point for crystal engineering ofpharmaceutical co-crystals. Their complementaryhydrogen bond donor and acceptor sites makessupramolecular homosynthon I favorable. How-ever, formation of I is unlikely in competitivesituations. Allen et al.61 determined the probabil-ity of formation of 75 bimolecular hydrogen bondedring synthons in organic crystal structures. Theprobability of formation of I was found to be only33%. This relatively low probability was attributedto competition with other hydrogen-bonded accep-tors (e.g., COO, pyridine N, Amide CO, SO, PO, etc.). A recent CSD study by Steiner62 oncarboxyl donors indicated that carboxylic acidpyridine interactions through OH N hydrogenbonding, II, is more favored than I. Indeed, II is ahighly reliable supramolecular heterosynthon2

that has been widely exploited in crystal engineer-ing.6371 Ab initio calculations support the ideathat the II is energetically favored over I and thatthe acid-amide supramolecular heterosynthonIV7275 is favored over I and III.64,65 Theseobservations are particularly relevant for designof co-crystals since robust supramolecular hetero-synthons represent perhaps the most reliable andrational route to co-crystals. Furthermore, com-plementary supramolecular heterosynthons thatseem to clearly favor formation of co-crystals arenot limited to carboxylic acids. The alcohol-amine7678 and alcohol-pyridine7981 supramole-cular heterosynthons are also well established incrystal engineering.

HOW ARE CO-CRYSTALS PREPARED?

Synthesis of a co-crystal from solution might bethought of as counterintuitive since crystalliza-tion is such an efficient and effective method ofpurification and as such it is used widely in thepharmaceutical industry for isolation of singlecomponent crystals. However, if different mole-cules with complementary functional groupsresult in hydrogen bonds that are energeticallymore favorable than those between like moleculesof either component, then co-crystals are likely tobe thermodynamically (although not necessarilykinetically) favored. Co-crystals involving thesesupramolecular synthons are usually synthesizedby slow evaporation from a solution that containsstoichiometric amounts of the components (co-crystal formers); however, sublimation, growthfrom the melt, slurries, and grinding two solid

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co-crystal formers in a ballmill are also suitablemethodologies. More often than not, the phasethat is obtained is independent of the syntheticmethodology. The recently reported techniqueof solvent-drop grinding, addition of a smallamount of suitable solvent to the ground mixtureto accelerate co-crystallization appears to be aparticularly promising preparation method.15,82

Jones et al.83 reported that grinding of cyclohex-ane-1,3cis,5cis-tricarboxylic acid and 4,40-bipyri-dine does not afford a co-crystal whereas grindingthe two components with few drops of MeOHfacilitates complete conversion within minutes.Solvent drop grinding avoids excessive use ofcrystallization solvent and hence it can be regard-ed as a green process. Solvent-drop grindingcould also prove useful for polymorph control15

and selective polymorph transformation.84

That co-crystals can often be prepared in a facilemanner does not mean that their synthesis andisolation is routine. A detailed understanding ofthe supramolecular chemistry of the functionalgroups present in a given molecule is a prerequi-site for designing a co-crystal since it facilitatesselection of appropriate co-crystal formers. How-ever, when multiple functional groups are presentin a molecule, as is often the case for APIs, the CSDrarely contains enough information to address thehierarchy of the possible supramolecular syn-thons. Furthermore, the role of solvent in nuclea-tion of crystals and co-crystals remains poorlyunderstood, yet solvent can be critical in obtaininga particular co-crystal from solution.

WHY ARE PHARMACEUTICAL CO-CRYSTALSOF RELEVANCE IN THE CONTEXT OF APIs?

The crystalline form of an API profoundly affectsphysical properties such as solubility, stability,dissolution rate, and bioavailability. Pharmaceu-tical co-crystals should be attractive to thepharmaceutical industry because they offer mul-tiple opportunities to modify the chemical and/orphysical properties of an API without making orbreaking covalent bonds. Indeed, the physicalproperties of the pharmaceutical co-crystals thathave been studied in detail indicate differencesfrom those of the pure APIs. The inherent natureof APIs, that is, molecules that contain exteriorhydrogen bonding moieties, means (unfortunatelyto some) that they are predisposed towards theexistence of polymorphs and solvates but it alsomakes them ideally suited for formation of

pharmaceutical co-crystals. The polymorphic ten-dency of APIs varies greatly, but the consensusseems to be that most APIs are at some time oranother going to display polymorphic behavior.However, the extent of polymorphism of APIs isalmost certainly going to be limited to a handful ofcrystal forms. Solvates (including hydrates) canbe more numerous, and in certain cases very largenumbers of solvates can be observed. Indeed,sulfathiazole is inordinately promiscuous interms of solvate formation, with over one hundredsolvates found.85 Salt forms can also be numer-ous, with over 90 acids and 30 bases consideredsuitable for pharmaceutical salt selection.86

Examples of compounds possessing a dozen ormore crystalline salt forms have been pub-lished.87,88 However, it is important to rememberthat salt formation is generally directed at oneacidic or basic functional group. In contrast, co-crystals can simultaneously address multiplefunctional groups in an API, including those thatare not acidic or basic enough to form a salt. Inaddition, the space is not limited to binarycombinations since tertiary68 and quaternary89

co-crystals are realistic possibilities. Co-crystalformers that are suitable for pharmaceutical useremain to be enumerated fully, but there are overa hundred solid materials with generallyregarded as safe (GRAS) status (including foodadditives and other well-accepted substances) andsub-therapeutic amounts of eminently safe drugsubstances, such as aspirin and acetaminophen,are also legitimate co-crystal formers. The spaceof pharmaceutical co-crystals would thereforeappear to be large with thousands of possibilitiesfor any given drug, especially when at least twohydrogen bonding moieties are present in an API.Furthermore, it is unlikely that applications of co-crystals in the context of the pharmaceuticalindustry will be limited to form and formulation.For example, a co-crystal might be used to isolateor purify an API during its processing and the co-crystal former could be discarded prior to for-mulation. In addition, co-crystallization withhomochiral co-crystal formers might be used toseparate enantiomers.

POLYMORPHISM IN SINGLE COMPONENTCRYSTALS VERSUS CO-CRYSTALS

Mitscherlich recognized the phenomenon of poly-morphism as long ago as 1822 and in 1965



McCrone defined polymorphism as a solid crys-talline phase of a given compound resulting fromthe possibility of at least two different arrange-ments of the molecules of that compound in thesolid state.90 McCrones definition is particularlyappropriate in the context of APIs since theymanifest themselves via multiple modes of self-organization or self-assembly. Similar issues faceagrochemicals, explosives, dyes, pigments, fla-vors, and confectionery products.

As revealed by Table 1,91 polymorphism9295

has been observed in ca. Single componentcrystals (1.7%) versus ca. 1.5% of co-crystals.These numbers are likely to be significantlyunderreported. However, there are so few exam-ples of polymorphic co-crystals that it would beappropriate to address such structures individu-ally in order to determine the origin of thepolymorphism. There are 21 hydrogen bondedco-crystals in the CSD that exhibit polymorphismbut there are only 11 for which atomic coordinatesare available for all the forms: (CSD refcodes)AJAJEA, 01; EXUQUJ, 01; HADKUT, 01; JIC-TUK01, 10; MACCID, 01, 02; MUROXA, 01;PDTOMS10, 11; PTZTCQ, 01; QUIDON, 02;TECCAF01, 02; and ZIGPAG, 01. A detailedanalysis96 of the crystal packing in these 11compounds indicates that their polymorphism isnot linked to the supramolecular synthons thatsustain the co-crystal. Rather, it appears to be theresult of subtle conformational or packingchanges. Indeed, to our knowledge there havenot yet been any examples of supramolecularisomerism45 in co-crystals. If these observationshold true over a broader range of compounds itwould suggest that co-crystals represent a desir-

able class of compound from the perspectives ofboth design and phase stability.

CASE STUDIES OF PHARMACEUTICALCO-CRYSTALS

Whereas there are early examples of pharmaceu-tical co-crystals in the scientific literature theytend to be more the result of serendipity thandesign, and we are unaware of any examplesthat have been approved for use by the FDA.Perhaps the earliest literature that in the contextof APIs relates to a series of studies conducted inthe 1950s by Higuchi. They studied complexformation between macromolecules and certainpharmaceuticals; for example complexes of poly-vinylpyrrolidone with procaine hydrochloride,caffeine, cortisone, chloramphenicol, benzylphe-nicillin, sulfathiazole, phenobarbital, etc. wereisolated. However, these would not be classified aspharmaceutical co-crystals according the criteriaapplied herein.97100 Perhaps the first applicationof crystal engineering to the generation ofpharmaceutical co-crystals was a series of studiesby Whitesides et al. concerning the use ofsubstituted barbituric acid, including barbitaland melamine derivatives to generate supramo-lecular linear tape, crinkled tape, and rosettemotifs sustained by robust three-point NH Oand NH N hydrogen bonds (Fig. 2).11,101105Ironically the focus of these studies was notso much the physical properties of the resultingco-crystals but rather the supramolecular func-tionality of barbitals106 and their complementar-ity with melamine. Nevertheless, these studies

Table 1. CSD Statistics of Polymorphic Single Component and Co-CrystalCrystal Structures

No. of Entries %

Organic crystal structures 130448 100c

Hydrates 9621 7.3c

Single component molecular organic structures 94900 72.7c

Single component polymorphic structures 1600a 1.7d

Co-crystals 1487b 1.1c

Polymorphic co-crystals 21a 1.5d

The CSD searches were conducted with only organic crystal structures. A CSD search with onlyorganics as a parameter also retrieves structures containing metals like Na, K, Ca etc. Such entrieswere excluded from the statistics quoted above (CSD Conquest 1.7, Aug05 update, 355,071 entries).

aOnly one refcode was counted for each polymorphic compound.bCo-crystals sustained by strong hydrogen bonds.cPercentages with respect to organic crystal structures only.dPercentages with respect to 94,900and 1,487 sub-totals, respectively.



Figure 2. Crystal packing of 1:1 co-crystals of 5,5-diethylbarbituric acid (barbital)with melamine derivatives. (a) Crinkled tape motif formed by barbital and 2-amino-4,6-bis(t-butylamino)-1,3,5-triazine co-crystal. (b) Rosette motif of barbital andN,N0-bis(4-t-butylphenyl)melamine co-crystal.



illustrated very well the potential diversity offorms that can exist for a particular API as morethan 60 co-crystals were structurally character-ized in this series of studies. We have chosen toherein focus upon two case studies that involvetwo APIs that are polymorphic in their pureforms and are therefore more directly relevant toissues that face the pharmaceutical industry.

Pharmaceutical Co-Crystals and Solvates ofCarbamazepine (CBZ), 1

Carbamazepine (CBZ) [5H-dibenz(b,f) azepine-5-carboxamide], 1, is known to exist as four wellcharacterized polymorphs,107114 a dihydrate,115

an acetone solvate,109 and two ammoniumsalts.116 CBZ has been in use for over 30 yearsto treat epilepsy and trigeminal neuralgia eventhough it poses multiple challenges to oral drugdelivery, including a small therapeutic window,autoinduction of metabolism, and dissolution-limited bioavailability.117 From a supramolecularperspective, CBZ is a simple molecule with onlyone hydrogen bonding group, a primary amide.The self-complementary nature of the amidemoiety manifests itself in a predictable mannersince all forms of CBZ exhibit supramolecularhomosynthon III118120 (Fig. 3). CBZ thereforerepresents an excellent candidate for a case studythat addresses how APIs can be converted topharmaceutical co-crystals and whether or notpharmaceutical co-crystal forms offer physical,chemical, or biochemical advantages over existingforms of an API.121,122

The primary amide dimer, like the carboxylicacid dimer, is well-documented in the CSD. Of the1231 crystal structures that contain at least oneprimary amide functional group, the dimer isexhibited in 428 structures (35%). In most of thesestructures, the peripheral NH moiety forms ahydrogen bond to an adjacent amide, thereby

generating tapes or sheets, or it hydrogen bondsto a different functional group. However, this is notthe case for CBZ, in which the peripheral H-bonddonors and acceptors are unused, presumably dueto steric constraints imposed by the azepine ring ofCBZ. That the CBZ dimer does not engage itsperipheral H-bonding capabilities represents oneavenue for crystal engineering and CBZ forms anumber of co-crystals and solvates that retain theprimary amide dimer. Figure 4 presents thecrystal structures of five pharmaceutical co-crys-tals of CBZ that maintain the amide dimer, 1ae.In the benzoquinone (1a) and terephthalaldehyde(1b) co-crystals, the ketone and aldehyde, respec-tively, H-bond with the anti NH O hydrogenbond of the CBZ dimers and sustain 1-D hydrogenbonded chains. A similar result occurs in 1c, inwhich the aromatic amines of 4,40-bipyridinemolecules act as H-bond acceptors to the anti-oriented NH of CBZ. Structure 1d is a pharma-ceutical co-crystal of CBZ and nicotinamide thatexists as more complex 1-D hydrogen bondedchain. CBZ dimers H-bond to the syn positions ofthe nicotinamide amide group through an exteriortranslation-related pattern. The anti-oriented H-bonding sites of the nicotinamide amide groupform a catemer motif with adjacent nicotinamidemolecules. In 1e saccharin molecules serve as H-bond donors by forming NH O hydrogen bondswith CBZ carbonyl groups. They also serve as H-bond acceptors: the SO group of the saccharinbonds to the exterior NH moiety of CBZ. CBZ alsoforms several solvates in which homosynthon III isretained. The solvent molecules in 1fh all inter-act with the anti NH of the CBZ dimers to formNH OC/S hydrogen bonds.

Figure 3. The CBZ amide dimer III that exists in allpreviously reported forms of CBZ.



A second strategy for co-crystal formationinvolving CBZ involves breakage of homosynthonIII and formation of a supramolecular heterosyn-thon. This would be expected to occur with a

functional group that is complementary with theamides, that is, a moiety with both an H-bonddonor and an H-bond acceptor. Carboxylic acids fitthis criterion and 71 of the 153 structures in the

Figure 4. The supramolecular interactions that occur in pharmaceutical co-crystals1ae. 1ad can be described a 1-D tapes whereas 1e is a discrete structure.



CSD that contain both a carboxylic acid and aprimary amide are sustained by supramolecularheterosynthon IV. Co-crystal formation betweenCBZ and carboxylic acids occurs, and Figure 5presents three examples of solvates that aresustained by supramolecular heterosynthon IV,1oq. All three solvates exhibit four moleculesupramolecular adducts that are sustained by theunused anti NH of IV. Co-crystallization of CBZwith other carboxylic acids affords pharmaceuticalco-crystals that are sustained by synthon IV.Details of their crystal packing are presentedelsewhere.3,4

Pharmaceutical Co-Crystals of Piracetam, 26

Piracetam, (2-oxo-1-pyrrolidinyl)acetamide, 2, isa nootropic drug that enhances learning and

Figure 5. Illustrations of the four molecule supramolecular complexes formed by CBZ:carboxylic acid solvates 1oq.



memory by stimulating the central nervoussystem.123 It is considered virtually nontoxic asacute toxicity studies on Piracetam have shownno measurable LD50 rate for rats, mice, anddogs.124,125 Four polymorphic forms of 2 havebeen deposited in the CSD.126129 Two forms, atriclinic and a monoclinic modification, crystallizevia III, while the other two are monoclinic forms,crystallizes in a catemeric fashion (Fig. 6). In allfour forms, the ring carbonyl is involved inhydrogen bonding to the anti-NH of the primaryamide. The are no co-crystals of piracetam in theCSD, however one hydrate is reported recently.129

One study suggests that 2 may exhibit sixpolymorphs.130

Gentisic acid, 2,5-dihydroxybenzoic acid is anaspirin metabolite that exhibits NSAID activ-ity.131133 Gentisic acid exhibits two polymorphicforms,134 two co-crystals and a clathrate hydrateare reported.135137 Single crystals of the 1:1 co-crystal of piracetam and gentisic acid, 2a wereobtained via slow evaporation from acetonitrileand Figure 7 reveals that 2a is sustained byheterosynthon IV. The 5-hydroxy group of gentisicacid serves as a hydrogen bond donor to the ring

carbonyl of piracetam, resulting in a 4,4-topologynetwork that is twofold interpenetrated. Pirace-tam also forms a 1:1 co-crystal with p-hydroxy-benzoic acid, 2b. Co-crystal 2b crystallizes fromacetonitrile and its crystal structure also revealsthe presence of IVwhich in turn dimerizes to forma tetrameric motif sustained by anti NH Ohydrogen bonding (Fig. 7). This tetrameric motif isfound in 10 (14%) of the 71 structures in the CSDthat contain acid-amide supramolecular hetero-synthons.138 The ring carbonyl of piracetammolecules and the hydroxy group of p-hydroxy-benzoic acid also form hydrogen bonds which linkeach tetramer to four others at the corners,thereby affording a threefold interpenetratednetwork.2a and 2b were screened for the existence of

polymorphs using solvent-drop grinding, a techni-que that has been shown to be able to generate andcontrol polymorphism.15 Mechanical grindingexperiments were conducted in reaction vesselsby adding gentisic acid or p-hydroxybenzoic acid tosolid piracetam form A. Twenty-three solvents(water, acetone, methanol, ethanol, ethyl acetate,n-hexane, toluene, acetonitrile, tetrahydrofuran,isopropyl acetate, benzyl alcohol, nitromethane,dimethyl amine, 2-butanol, ethyl formate, aceticacid, methyl ethyl ketone, methyl tertiary butylether, chlorobenzene, N-methyl pyrrolidone, 1,2-dichloroethane, dimethylsulfoxide, and dimethoxyethane) was evaluated by adding a differentsolvent to each well. The samples were groundfor 20 min and characterized using powder X-raydiffraction. Co-crystals 2a or 2b were obtainedfrom all conditions as a mixture with one or both ofthe starting materials, that is, 2a and 2b do notexhibit polymorphism based on a series of solvent-mediated grinding experiments. That a wide rangeof pharmaceutical crystals can be crystal engi-neered is suggested by our observations with CBZand piracetam, and is further supported by recentstudies from other groups that have focusedupon Triazole,7 Fluoxetine hydrochloride,9 Tri-methoprim,10 Barbital11,101106, Paracetamol,14

and Caffeine15,16. However, there remain severalimportant issues that will only be resolvedby further experimentation. For example, canpharmaceutical co-crystals lead to formulationswith superior bioavailability when compared toconventional forms of APIs and are they more orless prone to polymorphism? Almarsson et al.139

have investigated the CBZ and saccharin co-crystal (1e) in terms of performance attributes,including scale-up, polymorphism, physical stabi-

Figure 6. Carboxamide dimer (a) and catemer (b)motifs as exhibited in Piracetam polymorphs.



lity, in vitro dissolution, and oral bioavailability,with the goal of comparing the novel compositionwith known polymorphs and solvates of the drug.1e was synthesized in 30 g scale through cooling asaturated alcohol solution and the physical stabi-lity of the co-crystal is superior to that of solvates.

A comparison of oral bioavailability of 1e withTegretol1 tablets in dogs established that 1e couldserve as a practical alternative to anhydrous CBZin oral formulation. Other observations concern-ing 1e include the following: (i) chemical stabilityappears to be similar to other forms of CBZ, (ii)

Figure 7. Views of the intermolecular hydrogen bonding in 2a (a) and 2b (b). Note thecarboxylic acid-amide supramolecular heterosynthon, IV in both the co-crystals andtetrameric motif in 2b.



physical stability of 1e is greater than that ofsolvates and similar to the marketed forms of CBZ;(iii) 1e exhibits good pK performance; (iv) poly-morphism was not observed in the co-crystal

following over 700 experiments that includedhigh-throughput screening, neat grinding, sol-vent-drop grinding with several solvents, andslurry conversion in different solvents.

In summary, if CBZ and piracetam represent amicrocosm of the issues one faces during formselection of APIs then pharmaceutical co-crystalswould appear to represent a significant opportu-nity for improving the diversity and performanceof API forms.

BUT BEWARE OF FAKEPHARMACEUTICAL CO-CRYSTALS!

Before we conclude, it should be emphasizedthat there can sometimes be ambiguity concer-ning whether or not a compound is a co-crystal,a solvate or a salt. The distinction between a co-crystal and a salt can be especially problematicif X-ray crystallography is the only methodof characterization and the difference betweenthe two extremes is ca. 1 A in a hydrogen atomposition. For example, a recent publication9 citeda number of co-crystals of APIs, however severalare questionable in terms of whether or notthey are salts or co-crystals. For instance, tri-methoprim sulfametrole (CSD refcode: HEK-RUK), even though reported under themisleading title 1:1 Molecular complex of tri-methoprim and sulfametrole was described bythe primary authors as an ionic complex (Fig. 8).140

JATMEW, 3-[2-(N0, N0-dimethylhydrazino)-4-thiazolylmethylthio]-N2-sulfamoylpropionami-dine maleic acid (1:1) was reported as a neutralcomplex.141 However, the structural parameters(CO bond lengths, CNC bond angles) sug-gest the formation of a maleate anion and apropionamidinium cation. The physical state ofthe components must also be taken into consid-eration. For instance, SAGQEW is the crystalstructure of Mebendazole and propionic acid.142

The latter exists as a liquid phase at ambienttemperatures (M.p. 218C). Therefore, SAGQEWshould be classified as a solvate rather than a co-crystal.

We have also experienced that CSD searchesretrieve ionic compounds despite limiting thesearch to neutral components. For example,salts EBIBEW, PIKLEA, QAWNAD, VAPBAP,VENLUV, etc. are all retrieved as neutral com-pounds.143147 One should therefore not rely solelyon the CSD for the identification of co-crystals. Thedatabase findings should be supported by inspec-tion of the structural parameters of co-crystal

Figure 8. Examples of fake pharmaceutical co-crystals found in the literature: (a) HEKRUK, Trimetho-prim sulfametrole, a salt. (b) JATMEW, 3-[2-(N0, N0-dimethylhydrazino)-4-thiazolylmethylthio]-N2-sulfamoylpropionamidine maleic acid. Structural para-meters suggest formation of a salt. (c) SAGQEWapropionic acid solvate of mebendazole.



components, and/or revision of the correspondingpublications.

CONCLUSIONS

Whereas there is a clear need for greater under-standing and control of crystalline forms in thecontext of pharmaceutical development, the con-cepts of supramolecular synthesis, and crystalengineering remain largely underexploited. Thiscontribution highlights the need to think supra-molecularly for structural analysis of APIs. Inparticular, applying the concepts of supramole-cular synthesis and crystal engineering to thedevelopment of pharmaceutical co-crystals repre-sents a paradigm that offers many opportunitiesrelated to drug development and delivery. Itseems inevitable that pharmaceutical co-crystalswill gain a broader foothold in drug formulation.

ACKNOWLEDGMENTS

We are grateful for financial support from Trans-form Pharmaceuticals, 29 Hartwell Avenue, Lex-ington, MA 02421.

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