comprehending the formation of eutectics and...

Comprehending the Formation of Eutectics and Cocrystals in Termsof Design and Their Structural InterrelationshipsSuryanarayan Cherukuvada and Tayur N. Guru Row*

Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru 560012, India

*S Supporting Information

ABSTRACT: The phenomenon of cocrystallization, whichencompasses the art of making multicomponent organic solidssuch as cocrystals, solid solutions, eutectics, etc. for novelapplications, has been less studied in terms of reliably andspecifically obtaining a desired cocrystallization product andthe issues that govern their formation. Further, the design,structural, and functional aspects of organic eutectics havebeen relatively unexplored as compared to solid solutions andcocrystals well-established by crystal engineering principles.Recently, eutectics were proposed to be designable materialson par with cocrystals, and herein we have devised a systematicapproach, based on the same crystal engineering principles, tospecifically and desirably make both eutectics and cocrystals for a given system. The propensity for strong homomolecularsynthons over weak heteromolecular synthons and vice versa during supramolecular growth was successfully utilized toselectively obtain eutectics and cocrystals, respectively, in two model systems and in two drug systems. A molecular levelunderstanding of the formation of eutectics and cocrystals and their structural interrelationships which is significant from bothfundamental and application viewpoints is discussed. On the other hand, the obscurity in establishing a low melting combinationas a eutectic or a cocrystal is resolved through phase diagrams.

■ INTRODUCTION

Eutectics are long known multicomponent crystalline solidswhich have varied applications in everyday life.1 They are morepopular as one of the categories of inorganic alloys, the otherbeing solid solutions.1 Both eutectics and solid solutions are alsowell-known in organic systems2 where they can be classified asorganic/molecular alloys. Cherukuvada and Nangia3 recentlyconceptualized the structural interrelationships between eutec-tics and cocrystals. They noted that in a typical cocrystallizationexperiment the formation of multicomponent adducts such assalts, cocrystals, solid solutions, or eutectics depends on thenature of the components and type of interactions that manifestbetween them (Scheme 1).3 However, there are limited studieson the phenomena that specifically lead to a cocrystal or aeutectic as cocrystallization product. They opined that acombination of materials where adhesive (heteromolecular)interactions between components can outweigh cohesive(homo/self) interactions of individual components formcocrystals and those where cohesive interactions are too strongto be outweighed can lead to eutectics. They redefined eutecticsfrom a structural viewpoint as “conglomerates of solidsolutions”3 formed between materials lacking geometrical fitand/or viable heteromolecular interactions (Scheme 1). Theyalso discussed the usage of the term “eutectic” in relation to solidsolutions and cocrystals from a historical perspective andcontextual and rigorous understanding of the issues can beinferred from the article.3 On the other hand, they observed that

the studies on the design elements and understanding of thestructural integrity of eutectics as organic solid materials aremodest in the literature as compared to solid solutions and

Received: May 30, 2014Published: July 2, 2014

Scheme 1. In a Cocrystallization Experiment When AdhesiveInteractions between Materials Dominate over CohesiveInteractions, a New Compound with a Crystal StructureDifferent from That of the Parent Materials Can Form (e.g.,Salt and Cocrystal)a

aCombination of materials having similar size and crystal structuresresults in “continuous solid solutions”, and the ones with mismatchand/or misfit can give rise to a “eutectic”. Culled from Ref 3.

Article

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cocrystals which are well-established by crystal engineeringprinciples.4 Utilizing the same principles, they initiated anempirical approach to design eutectics,3 and we hereinbroadened the empirical factors that dictate their design andformation. In this study, we successfully designed and selectivelyobtained eutectics vis-a-vis cocrystals in two simple modelsystems and also two drug systems.Cherukuvada and Nangia elucidated the intriguing design

element in eutectics and their mutual relationships with solidsolutions and cocrystals through benzoic acid−fluorobenzoicacid/benzamide systems among other examples.3 The isomor-phous nature of hydrogen and fluorine results in continuous solidsolutions of benzoic acid−4-fluorobenzoic acid system,5 thestrong heteromolecular interactions of benzoic acid−pentafluor-obenzoic acid combination resulted in their cocrystal,6 and thelack of such interactions led to a eutectic in case of benzoic acid−benzamide system.7 Thus, for a combination of materials, whenthe attributes of (i) geometric compatibility of functional groupsand/or components and (ii) viable heteromolecular interactionsare positive, the resultant is a cocrystal, and if they are negative itis a eutectic.3 In effect, an “anticrystal engineering” approach,8

wherein materials that can form potential supramolecularsynthons4,9 are intentionally avoided to obtain noncrystallizingionic liquids8a,b and deep eutectic solvents (a class ofeutectics),8c,d forms the basis for empirical design of eutectics.In this article, we exploit the formation of strong and weakheterosynthons,10 judged based on the hydrogen bond donor−acceptor rules,11 to selectively obtain cocrystals and eutectics,respectively. The tendency of the carboxylic acid group to formstrong heteromolecular interactions with pyridine group(carboxylic acid−pyridine heterosynthon with 91% frequency14

of occurrence in the Cambridge Structural Database (CSD),15

Scheme 2), is exploited to selectively make cocrystals. Similarly,the weak carboxamide−pyridine heterosynthon (5% fre-quency),16 which cannot outcompete the carboxamide homo-dimer interactions (35% frequency)17 to form a cocrystal, isexploited to make eutectics. We have chosen succinic acid(contains two carboxylic acid groups), succinamic acid (onecarboxylic acid and one carboxamide group), and succinamide(both carboxamide groups) and combined them respectivelywith pyridine and chloride group containing compounds (Figure1) to understand and screen cocrystal/eutectic formation in aseries. 4,4′-Bipyridine and isonicotinamide (the two mostfrequently used model coformers in cocrystallization studies),12

antitubercular drug isoniazid (of its structural analogy withisonicotinamide), and the antidepressant drug fluoxetine hydro-chloride (of its importance with regard to formation of saltcocrystals)13 were screened. Crystal structures of all the startingcompounds, except succinamic acid, are known in theliterature.15 In this study, we also determined the crystalstructure of succinamic acid which is found to be manifestedby acid−amide heterodimers (Figure 2) and not separate acid/amide homodimers complying with the CSD statistics (Scheme2).

■ METHODSTraditionally, eutectics especially pharmaceutical eutectics are preparedby comelting and solvent-mediated coprecipitation of the component-s.2a,18 Recently, the techniques of compaction19 and grinding20 wereshown to result in eutectic formation. Cocrystals and eutectics of thisstudy were prepared by solid state grinding method (detailed inExperimental Section). Understanding the microstructure of a eutectic

Scheme 2. Few Supramolecular Synthons with Their Frequency of Occurrence in the CSD14−17

Figure 1. Molecular structures and acronyms of the compounds.

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(whose crystal structure is difficult to solve as it is composed of phase-separated solid solutions) is a prerequisite to appreciate eutecticformation, and the issues are discussed in detail by Cherukuvada andNangia.3 Elucidation of the exact eutectic composition and character-izing its complex structural integrity is a laborious task, since the eutecticcomposition is heterogeneous and can be nonstoichiometric unlike acocrystal. The powder X-ray diffraction (PXRD) technique, routinelyemployed for the characterization of cocrystals, is not found to be usefulto diagnose a eutectic.3 This is because the formers are manifested byadhesive interactions that direct distinctive crystal packing, but in thecase of the latter, as the inclusion of a minor component happenssubstitutionally or interstitially in the major component the cohesiveinteractions as well as the lattice structures of parent components remainlargely unaffected (Scheme 1). As a result, no appreciable change can beobserved in the diffraction pattern of a eutectic compared to its parentmaterials, but the eutectic phase integrity can be established firmly bysophisticated powder diffraction techniques3 such as pair distributionfunction (PDF) analysis, small-angle X-ray or neutron scattering(SAXS/SANS), Rietveld fit, etc. However, so far in the literature theseapproaches have not been reported and will form new topics ofinvestigation for organic systems. Currently, thermal techniquesespecially differential scanning calorimetry (DSC), which effectivelyelucidates the melting behavior, works as a bench diagnostic techniquefor a eutectic,3 and we used the same to confirm the formation ofeutectics in this study. We performed DSC measurements to compareand contrast cocrystal- and eutectic-forming systems and did notattempt to determine the exact eutectic composition, which is altogethera separate task. In-depth analysis of all peaks manifesting in the DSCwasnot undertaken because of the complex variety of thermal transitionspossible for a given combination of materials.21 Combinations in 1:1,1:3, and 3:1 molar ratios, prepared by solid state grinding, weresubjected to DSC to ascertain eutectic formation by a low meltingendotherm. The three different compositions exhibited a common lowmelting solidus peak corresponding to the eutectic phase in each of thecompositions, and we, therefore, treat the system as a eutectic in a broadsense. The noneutectic phase of the composition, which can be in excessof the parent components or inhomogeneous weak solid solutions,exhibits a broad to sharp liquidus peak depending on its proportion.2b,3

In all, the formation of cocrystal/eutectic phase is established as follows:(i) solid ground products were diagnosed for distinct PXRD patterns,andmelting points compared to the parent materials−cocrystals showeddistinct PXRD patterns as well as melting points, but eutectics weredifferent only in their melting behavior; (ii) solid ground products werethen subjected to evaporative crystallization (detailed in ExperimentalSection) to obtain single crystals of adductsonly single crystals ofcocrystals were obtained and eutectic-forming compounds separated insolution. The PXRD patterns of the compounds studied in this work areshown in Figures S1−S12, Supporting Information. Phase diagrams are

constructed for one of the low melting systems to differentiate a lowmelting cocrystal from a eutectic and establish their uniqueness.

■ RESULTS AND DISCUSSION

The results of solid form screening experiments for thecombination of compounds in this study are tabulated in Table1 and crystallographic parameters of new cocrystals in Table 2.The melting points of cocrystals and eutectics in the series areproportional to the melting point of coformer as observed byCherukuvada and Nangia.3,20a Succinic acid cocrystals andsuccinamide eutectics showed higher melting points thancorresponding succinamic acid cocrystals and eutectics (Table1).

(1). 4,4′-Bipyridine System. We combined succinic acid,succinamic acid, and succinamide, respectively, with 4,4′-bipyridine (containing two pyridyl groups). The idea is thatthe robust acid−pyridine synthon (of 91% frequency)14 shouldgive cocrystals of succinic acid and succinamic acid withbipyridine, and the less occurring amide−pyridine synthon(5%)16 should form eutectic of succinamide with bipyridine. Inthese lines, we obtained 1:1 succinic acid−bipyridine and 2:1succinamic acid−bipyridine cocrystals as anticipated (Figure 3).In the former, the 1:1 ratio of acid and pyridyl groups resulted in1:1 cocrystal sustained by contiguous acid−pyridine synthon(Figure 3a). In the latter, as the acid/pyridyl group ratio is 1:2,and due to the dominance of amide−amide synthon over theweak amide−pyridine synthon (35% vs 5%),16,17 the resultingcocrystal is, not surprisingly, of 2:1 stoichiometry. The moleculespropagate through the acid−pyridine and amide dimer synthongrowth units avoiding the amide−pyridine synthon in thecocrystal (Figure 3b). Thus, the dominance of amide homodimersynthon over amide−pyridine heterodimer synthon should avoidheteromolecular interactions for the combination of succinamideand bipyridine (Figure 3c) to result in a eutectic or physicalmixture. It should be remembered that the identity of individualcomponents will be lost in a eutectic mixture (as it is composedof solid solutions, Scheme 1) in contrast to a physical mixturewhich retains their identity.1 DSC showed that the combinationis just a physical mixture and not a eutectic (Figure 4). Thethermograms obtained for three different molar combinations(1:1, 1:3, and 3:1) showed no lower melting endotherm, thus,demonstrating no eutectic formation, but exhibited thermaltransitions characteristic of the individual components. Thedehydration of 4,4′-bipyridine (commercial material is indihydrate form) and polymorphic transformation of succinamide(TGA plots confirm the claimed transitions, Figures S19 and S20of Supporting Information) apart from their melting events seenin the DSC (Figure 4) confirm the combination to be a simplephysical mixture. It seems the less probable amide−pyridinesynthon becomes so improbable in the presence of dominantamide dimer synthon that even a minor amount of bipyridinecannot be accommodated in the lattice of succinamide (and viceversa) to form a discontinuous solid solution, and therefore no

Figure 2. Succinamic acid shows contiguous acid−amide heterodimersynthons in the crystal structure.

Table 1. Results for the Combination of Compounds in This Study

+ 4,4′-bipyridine (112 °C)a isonicotinamide (156 °C) isoniazid (173 °C) fluoxetine hydrochloride (156 °C)succinic acid (189 °C) cocrystalb (231 °C) cocrystal12a (207 °C) cocrystal20a (143 °C) cocrystal13 (119 °C)succinamic acid (156 °C) cocrystal (174 °C) cocrystal (168 °C) eutectic (121 °C) eutectic (129 °C)succinamide (265 °C) physical mixture (111 and 264 °C) eutectic (152 °C) eutectic (165 °C) eutectic (153 °C)

aMelting points (onset temperatures in the DSC) are given in parentheses. bCocrystals can have higher, intermediate or lower melting pointscompared to their starting materials; DSC plots of cocrystals are shown in Figures S13−S18, Supporting Information.



eutectic formation occurs (Figure 3c). The remote possibility ofonly available amide−pyridine synthon for bipyridine−succina-mide combination endures no growth unit for eutectic solidsolution formation, and hence the combination remains as aphysical mixture.(2). Isonicotinamide System. Combination of isonicotina-

mide (containing one pyridine and one carboxamide group) with

succinic acid forms a 2:1 cocrystal12a involving acid−pyridine andamide dimer interactions (Figure 5a). Combination withsuccinamic acid and succinamide resulted in a cocrystal and aeutectic, respectively. Isonicotinamide−succinamic acid is a 1:1cocrystal manifested by acid−pyridine synthon and amideheterodimer propagating in an alternate fashion in theanticipated lines (Figure 5b). Carboxylic acid of succinamic

Table 2. X-ray Crystallographic Parameters

compound SNA SA−BP 2:1 SNA−BP INAM−SNAempirical formula C4H7NO3 C14H14N2O4 C18H22N4O6 C10H13N3O4

formula weight 117.11 274.28 390.40 239.23crystal system monoclinic triclinic triclinic orthorhombicspace group Pc P1 P1 P212121Za 2 4 6 8a (Å) 5.6612(3) 5.4131(6) 7.1751(6) 5.7188(4)b (Å) 5.1428(3) 6.0085(5) 10.167(1) 10.1645(7)c (Å) 9.5438(5) 9.9526(8) 12.699(1) 20.459(1)α (deg) 90 87.699(7) 82.037(9) 90β (deg) 93.246(5) 84.940(8) 81.412(7) 90γ (deg) 90 73.561(9) 88.251(8) 90V (Å3) 277.42(3) 309.22(5) 907.1(2) 1189.2(1)T (K) 120(1) 120(1) 120(1) 298(1)Dcalc (g cm

−3) 1.4018 1.4728 1.4292 1.3360μ (mm−1) 0.121 0.110 0.109 0.105reflns collected 2750 5894 17860 7100unique reflns 1072 1226 3193 2303observed reflns 1062 1039 2172 1668Δρmin, max (e Å−3) −0.152, 0.183 −0.513, 0.523 −0.524, 0.565 −0.193, 0.168R1 [I > 2σ(I)] 0.0237 0.0656 0.0793 0.0518wR2 [reflns] 0.0629 0.1924 0.2669 0.1454goodness-of-fit 1.0678 1.1150 1.1876 1.0905CCDC no. 979160 979161 979162 979163

aZ = Z″ (no. of crystallographically nonequivalent molecules of any type in the asymmetric unit)22 × no. of independent general positions of thespace group.

Figure 3. (a) Succinic acid and 4,4′-bipyridine molecules connected invariably by the robust acid−pyridine heterosynthon propagate as an infinite tapein the 1:1 SA−BP cocrystal. (b) Succinamic acid and bipyridine molecules form an infinite tape through acid−pyridine and amide homodimerinteractions in the 2:1 SNA−BP cocrystal. The less occurring amide−pyridine synthon was avoided in the cocrystal. (c) For succinamide−4,4′-bipyridine combination, amide−pyridine synthon is the only available recognition/growth unit and its lower probability endures no growth unit topropagate as a cocrystal or even a eutectic solid solution, and hence the combination remains as a mere physical mixture.



acid preferentially goes to pyridine of isonicotinamide renderingthe amide groups of the two molecules to form heterodimericinteractions. Thus, isonicotinamide−succinamic acid cocrystalsimultaneously shows the dominance/preference of acid−pyridine over acid−amide synthon and avoidance of amide−pyridine synthon. This provides a hint for the formation of aeutectic phase in the case of isonicotinamide−succinamidecombination. In this case, though an amide heterodimer can formbetween the molecules on one side, the other side sees only the

less occurring amide−pyridine synthon with the result that thesystem cannot propagate as a cocrystal growth unit (Figure 5c).Therefore, the dominant amide homodimer interactions out-weigh the adhesive interactions, but the possibility of finite/discrete amide heterodimers (indicated by a green check mark inFigure 5c) between the molecules facilitates random incorpo-ration of molecules in each other’s lattice, to a certain extent, toform discontinuous solid solutions eventually leading to aeutectic as per Scheme 1. DSC on three different molar ratios

Figure 4.DSC of succinamide−4,4′-bipyridine combination demonstrates it to be a typical physical mixture in which the identity of the components isretained. All the three different molar mixtures manifested thermal transitions characteristic of the individual components (4,4′-bipyridine dihydrate:dehydration temperature ca. 70 °C, melting temperature ca. 112 °C; succinamide: polymorphic transition temperature ca. 210 °C, melting temperatureca. 265 °C) and no distinct thermal behavior.

Figure 5. (a) Amide homodimer isonicotinamide molecules connected by succinic acid through acid−pyridine synthon form an infinite tape in the 2:1INAM−SA cocrystal (CSD Refcode: LUNNUD01). (b) Isonicotinamide and succinamic acid molecules form an infinite tape through alternate acid−pyridine and amide heterodimer interactions in the 1:1 INAM−SNA cocrystal. The comparatively weaker acid−amide and amide−pyridine synthonswere avoided in the cocrystal. (c) For isonicotinamide−succinamide combination, the weak amide−pyridine synthon endures no growth unit topropagate as a cocrystal entity, but the possibility of discrete amide heterodimers leads to a eutectic phase as per Scheme 1



(1:1, 1:3, and 3:1) of isonicotinamide−succinamide combinationshowed a common and invariant low melting endothermcharacteristic of a eutectic phase (Figure 6), thus providingunequivocal support to the above conjecture.(3). Isoniazid System. In order to check the validity of the

above case, isoniazid was identified as a probe molecule of itsstructural analogy with isonicotinamide (only difference inhydrazide/amide functionality) and its importance as anantitubercular drug. Combination of isoniazid (containing onepyridine and one hydrazide group) with succinic acid generates a2:1 cocrystal20a involving acid−pyridine and hydrazide dimerinteractions (Figure 7a), similar to isonicotinamide−succinicacid, but isoniazid formed a eutectic with succinamic acid (Figure8a), unlike isonicotinamide which formed a cocrystal. The misfitin acid/amide−hydrazide cyclic dimer interactions (no such

synthons were found in the CSD)15 and the probablecompromise of centrosymmetry of hydrazide dimer forisoniazid−succinamic acid combination compared to amideheterodimer of isonicotinamide−succinamic acid cocrystalappear not to confer a growth unit beyond acid−pyridinedimer (Figure 7b) with the result that the combination forms aeutectic. The likelihood of cocrystal for the combination vialinking up of isoniazid hydrazide dimers and amide dimers ofsuccinamic acid by acid−pyridine synthon seems to beunfavorable as it needs to disrupt the stronger homomolecular(acid−amide in succinamic acid and amine−pyridine inisoniazid) interactions. The possibility of discrete acid−pyridineheterodimers in the lattice, at least in random, appears to haveresulted in the eutectic for the combination. In case of isoniazid−succinamide combination, the unknown amide−hydrazide dimer

Figure 6.DSC of the three different isonicotinamide−succinamide molar mixtures shows a common low melting endotherm pertaining to the eutecticphase in each of the mixtures. The additional peaks manifested beyond pertain to the liquidus phase of the mixture.

Figure 7. (a) Hydrazide homodimer isoniazid molecules connected by succinic acid through acid−pyridine synthon form an infinite tape in the 2:1INH−SA cocrystal (CSD Refcode: FADGIC02). (b) For isoniazid−succinamic acid combination, the unknown acid/amide−hydrazide synthonendures no growth unit to propagate as a cocrystal entity, but the probability of discrete acid−pyridine heterodimers leads to a eutectic phase. (c)Despite the unknown amide−hydrazide and the less occurring amide−pyridine synthons, isoniazid−succinamide combination formed a eutectic phasewhich could be due to the possibility of such interactions between the molecules at least in random.



and the less frequent amide−pyridine synthon (Figure 7c)should result in a physical mixture but led to a eutectic (Figure8b), which is somewhat intriguing. This example shows thatunless the combination is evaluated by its thermal behavior, theplausibility of such interactions and therefore the formation ofeutectic cannot be ruled out.(4). Fluoxetine Hydrochloride System.The exploration of

eutectic formation for drug salts is significant because themajority of the drugs are marketed in their salt forms.23 Hence,we selected the drug fluoxetine hydrochloride of its importancein forming salt cocrystals13 and investigated the possibility of salteutectics. Fluoxetine hydrochloride−succinic acid combinationis a salt cocrystal13 involving acid−chloride interaction (Figure9a). The formation of a cocrystal between them was analyzed3 asfollows. In fluoxetine hydrochloride, each Cl− ion is bonded toone protonated secondary NH+ group and four CHs on anaverage.24 Any strong donors such as carboxylic acid groups candisplace/replace the weak CHs bonded to Cl− ion of fluoxetinehydrochloride based on the best donor-best acceptor rule.11 Assuch, the carboxylic acid homodimers (O−Hacid···Oacid bonds)

break and form new O−Hacid···Cl− (i.e., replace C−H···Cl−) and

N+−H···Oacid charge-assisted hydrogen bonds when theycombine with fluoxetine hydrochloride. Thus, the dominationof adhesive interactions over cohesive interactions resulted influoxetine hydrochloride−carboxylic acid cocrystals includingsuccinic acid cocrystal.13 Combination of fluoxetine hydro-chloride with succinamic acid and succinamide resulted ineutectics respectively (Figure 10). This can be due to thepresence of additional strongN−Hdonor on amide group whoserequirement of strong acceptor can cause steric hindrance foramide−chloride interactions (Figure 9b) compared to acid−chloride interactions (similar to amide−pyridine vs acid−pyridine synthons) with the result that they cannot replace thehomomolecular acid−amide and amide dimer interactions. Thediscrete O−Hacid/N−Hamide···Cl

− and N+−H···Oacid/amide inter-actions could have led to eutectic phases in these cases.

Binary Phase Diagrams. A phase diagram can be used todissect and comprehend the distinct phases plausible for a givensystem as a function of temperature, pressure, etc.1 Traditionally,a eutectic is characterized by a phase diagram as a low melting

Figure 8. (a) Isoniazid−succinamic acid and (b) isoniazid−succinamide combinations form eutectic phases respectively due to the dominance ofhomomolecular (amide/hydrazide dimer) over heteromolecular (acid/amide−hydrazide and/or amide−pyridine) interactions.



composition of two or more substances.1,2a In a cocrystal screen,when the combination exhibits higher or intermediate meltingpoint compared to the parent materials it can concluded that thecombination makes a cocrystal, but there can be situations wherethe combination exhibits a low melting point but no distinctdiffraction or spectroscopic signatures, which causes a dilemmawhether the combination is a definite eutectic or an unresolvedcocrystal. Furthermore, the formation of cocrystal, thoughcertain, can be elusive however exhaustive the cocrystallizationexperiments may be.25 Thermal analysis by construction of atemperature versus composition phase diagram is known toestablish whether a combination forms a cocrystal or aeutectic.2b,7c,26 A typical binary phase diagram of a eutecticassumes a ‘V’ shape and that of a cocrystal ‘W’ shape,26 but themethod is underutilized because of the complex variety ofthermal transitions21 and difficulties in interpretation of thephases involved. To simplify the issues, for a eutectic-formingcombination only one phase, which is the eutectic phase, exists.26

Hence, one has to look for a single invariant low melting point(solidus) characteristic of the eutectic phase in all the differentcompositions; a small and variable liquidus point manifests forthe near-eutectic or noneutectic compositions pertaining to theparent materials in excess.2b,3 In the case of a cocrystal-formingbinary system (A:B), three different phases, a cocrystal and twoeutectics, one between cocrystal and parent material A and theother between cocrystal and parent material B,26 are possible.Correspondingly, three different melting points of which at leasttwo of low melting nature should be observed. The two lowmelting points relate to the eutectics of cocrystal with parentmaterials and represent the lower left and right intersections of‘W’-type phase diagram of cocrystal. The position of the upperintersection pertaining to melting of the cocrystal phase can beupper, median or lower to the arms, i.e., parent materials.In this study, we selected the lowmelting INH−SA and INH−

SNA systems as representative cases to compare and contrast thethermal behavior of low melting cocrystal and eutectic throughbinary phase diagrams. We analyzed five different molarcompositions, 1:1, 1:2, 2:1, 1:3, and 3:1, by DSC and found

that three compositions can be sufficient to establish theformation of a cocrystal or a eutectic. INH−SA cocrystal systemexhibited two different low melting points (141 °C for 3:1composition and 124 °C for 1:1, 1:2, and 1:3 compositions),apart from the low melting peak of 2:1 cocrystal phase (143 °C),compared to INH (173 °C) and SA (189 °C) (Figure 11).Melting of 3:1 composition relates to the eutectic phase of 2:1cocrystal and 1 mol excess INH. Similarly, the melting of 1:1, 1:2,and 1:3 compositions corresponds to the eutectic phase of 2:1(or 1:0.5) cocrystal and SA molar excess (in 0.5, 1.5, and 2.5ratios respectively). The binary phase diagram of INH−SAcocrystal system is given in Figure 12.In the case of the INH−SNA system, all the five compositions

showed only a single low melting point in the DSC (Figure 13).The melting point is common and invariant for all thecompositions, and no other low melting peaks were manifested(except for broad liquidus peaks), thus establishing INH−SNAto be a eutectic-forming system. Ideally, a composition whichdoes not exhibit liquidus peak is assigned to be a eutecticcomposition1 and, therefore, for INH−SNA system, the 1:3molar composition which did not show discernible liquidus peak(Figure 13) can be ascribed as the eutectic or near-eutecticcomposition. The binary phase diagram of the INH−SNAsystem is given in Figure 14.In all, thermal analysis through a phase diagram can establish

the formation of a eutectic or a cocrystal for a given system. Apartfrom being useful in characterizing a eutectic, the method hastwin advantages in targeted cocrystal screening viz. (1)characterizing an elusive cocrystal when other techniques failto resolve and (2) melt-growth technique to prepare thecocrystal (of course, on the condition that it does not decomposeupon melting).

■ CONCLUSIONS

The study of integral design and organization of eutectics forms anew area of organic solid state chemistry research. In thecocrystallization arena, eutectics are one of the outcomes of theclassic battle between “interactions” and “packing” in achieving a

Figure 9. (a) 2:1 Fluoxetine hydrochloride−succinic acid cocrystal sustained by O−H···Cl− interactions (CSD Refcode: RAJFEO). (b) Fluoxetinehydrochloride−succinamic acid and fluoxetine hydrochloride−succinamide combinations formed eutectics respectively which could be due to sterichindrance for contiguous amide−chloride interactions invoked by additional strong N−H donor of succinamic acid/succinamide amide group.



stable supramolecular assembly. Eutectics add to the diversity ofsolid forms and expand the scope of supramolecular solid form

space for different applications. In this study, we broadened theempirical approach to design and selectively obtained eutectics

Figure 10. (a) Fluoxetine HCl−succinamic acid and (b) fluoxetine HCl−succinamide combinations form eutectic phases respectively due to thedominance of homomolecular (acid−amide dimer and amide dimer) over heteromolecular (amide−chloride) interactions.

Figure 11. DSC of isoniazid−succinic acid system.



vis-a-vis cocrystals based on the crystal engineering principles. Itis found that the domination of homomolecular synthons overheteromolecular synthons and vice versa in a supramolecularcompetition directs the formation of eutectic and cocrystalrespectively for a given system. Thus, the strategy can beemployed in a mutually independent manner to specifically anddesirably make eutectics or cocrystals, and therefore it becomes awin-win cocrystallization strategy. It is observed in the systemsstudied that for a two-component system, when the primaryrecognition/growth unit is at least three molecules long (e.g.,acid−pyridine−acid), a cocrystal can form and a eutectic results ifthe unit is just a weak and finite heterodimer (e.g., amide−pyridine). We showed that the obscurity in establishing a lowmelting combination as a cocrystal or a eutectic can be resolvedthrough thermal analysis of as low as three molar compositions,which is significant in terms of saving time, money, and effort intargeted cocrystal or eutectic screens.On the other hand, a correlation between the melting point of

adduct (either cocrystal or eutectic) and coformer in the serieswas observed in line with the earlier studies,3,12e,13,20a which issignificant with respect to tuning the melting property of amaterial. Cherukuvada and Nangia demonstrated the solubility

and stability advantages of eutectic drug formulations.3,20a Giventhe importance of cocrystals and eutectics in modifying thephysicochemical properties of materials3,12e,13,20 and also asemerging functional organic materials,27 further studies willbroaden the understanding of intermolecular interactions,crystallization process, success and failure of cocrystallizationand, thus, augment the efforts toward modulating the structureand function of materials in a desirable way for desiredproperties. The current challenge is to dissect the organiceutectics into solid solutions and better understand theirmicrostructural organization. At what point a physical mixturenonrandomizes, a weak solid solution transforms into aniso-tropic/heterogeneous domains of eutectic phase and what kindof factors drive toward eutectic from cocrystal and vice versaneed to be understood to a more advanced level.

■ EXPERIMENTAL SECTIONMaterials.Commercially available fluoxetine hydrochloride (Yarrow

Chem Products, Mumbai, India) and all other compounds (Alfa Aesar,Bengaluru, India) were used without further purification. Solvents wereof analytical or chromatographic grade and purchased from localsuppliers. Water purified from a Siemens Ultra Clear water purificationsystem was used for experiments.

Figure 12. Binary phase diagram of isoniazid−succinic acid systemexhibits ‘W’-type pattern characteristic of a cocrystal. Solidus points areshown as filled circles and liquidus points as open squares.

Figure 13. DSC of isoniazid−succinamic acid system.

Figure 14. Binary phase diagram of isoniazid−succinamic acid systemexhibits a ‘V’-type pattern characteristic of a eutectic. Solidus points areshown as filled circles and liquidus points as open squares.



Methods. Solid State Grinding. Compounds in molar ratioscombined together in a 200 mg scale were subjected to manual grindingfor 15 min using a mortar-pestle. The groundmaterials were analyzed byPXRD and DSC to ascertain the formation of cocrystal or eutectic. Thereported cocrystals were confirmed by matching the experimentalPXRD patterns with that of the calculated profiles from X-ray crystalstructures.Evaporative Crystallization. Succinamic Acid. A total of 50 mg of

succinamic acid was dissolved in 3 mL of water and left for slowevaporation at room temperature. Colorless plate crystals were obtainedafter a few days upon solvent evaporation.1:1 Succinic Acid−4,4′-Bipyridine Cocrystal. Ground mixture of

succinic acid (12 mg, 0.1 mmol) and bipyridine (16 mg, 0.1 mmol) wasdissolved in 5 mL of methanol and left for slow evaporation at roomtemperature. Colorless plate crystals were obtained after a few days uponsolvent evaporation.2:1 Succinamic Acid−4,4′-Bipyridine Cocrystal. Ground mixture of

succinamic acid (24 mg, 0.2 mmol) and bipyridine (16 mg, 0.1 mmol)was dissolved in 5 mL of isopropanol and left for slow evaporation atroom temperature. Colorless needle crystals were obtained after a fewdays upon solvent evaporation.1:1 Isonicotinamide−Succinamic Acid Cocrystal. Ground mixture

of isonicotinamide (12 mg, 0.1 mmol) and succinamic acid (12 mg, 0.1mmol) was dissolved in 5 mL of ethanol−acetonitrile solvent mixtureand left for slow evaporation at room temperature. Colorless platecrystals were obtained after a few days upon solvent evaporation.X-ray Crystallography. X-ray reflections for SNA (120 K), SA−BP

(120 K), 2:1 SNA−BP (120 K), and INAM−SNA (298 K) cocrystalswere collected on an Oxford Xcalibur Mova E diffractometer equippedwith an EOS CCD detector and a microfocus sealed tube using Mo Kαradiation (λ = 0.7107 Å). Data collection and reduction were performedusing CrysAlisPro (version 1.171.36.32)28 and OLEX2 (version 1.2)29

was used to solve and refine the crystal structures. All non-hydrogenatoms were refined anisotropically. Hydrogen atoms on heteroatomswere located from difference electron density maps and all C−H atomswere fixed geometrically. The final CIF files were validated inPLATON.30

Powder X-ray Diffraction. PXRD were recorded on PANalyticalX’Pert diffractometer using Cu−Kα X-radiation (λ = 1.54056 Å) at 40kV and 30 mA. X’Pert HighScore Plus (version 1.0d)31 was used tocollect and plot the diffraction patterns. Diffraction patterns werecollected over 2θ range of 5−40° using a step size of 0.06° 2θ and timeper step of 1 s.Thermal Analysis. DSC was performed on a Mettler Toledo DSC

822e module and TGA on a Mettler Toledo TGA/SDTA 851e module.The typical sample size is 1−3 mg for DSC and 3−5 mg for TGA. Thetemperature range used in both DSC and TGA is 30−300 °C, and thesamples were heated@ 5 °Cmin−1. Samples were placed in crimped butvented aluminum pans for DSC and open alumina pans for TGA andwere purged by a stream of dry nitrogen flowing at 50 mL min−1.PackingDiagrams.X-Seed32 was used to prepare packing diagrams.

■ ASSOCIATED CONTENT

*S Supporting InformationPXRD patterns of compounds, DSC plots of cocrystals, DSCwith TGA plots of 4,4′-bipyridine dihydrate and succinamide,respectively, and CIF files. This material is available free of chargevia the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATION

Corresponding Author*E-mail: [email protected].

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

S.C. thanks the UGC for Dr. D. S. Kothari PostdoctoralFellowship. T.N.G. thanks the DST for the J. C. Bose Fellowship.We would like to thank Prof. Ashwini Nangia, University ofHyderabad, for his interest and useful discussions in this work.We thank the Institute for providing infrastructure andinstrumentation facilities.

■ REFERENCES(1) Askeland, D. R.; Fulay, P. P. Essentials of Materials Science andEngineering, 2nd ed.; Cengage Learning: Independence, KY, 2009.(2) (a) Moore, M. D.; Wildfong, P. L. D. J. Pharm. Innov. 2009, 4, 36.(b) Lu, E.; Rodríguez-Hornedo, N.; Suryanarayanan, R. CrystEngComm2008, 10, 665. (c) Kitaigorodsky, A. I. Mixed Crystals; Springer-Verlag:New York, 1984. (d) Sekiguchi, K.; Obi, N. Chem. Pharm. Bull. 1961, 9,866; 1964, 12, 134. (e) Goldberg, A. H.; Gibaldi, M.; Kanig, J. L. J.Pharm. Sci. 1965, 54, 1145.(3) Cherukuvada, S.; Nangia, A. Chem. Commun. 2014, 50, 906.(4) (a) Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering: ATextbook; World Scientific: Singapore, 2011. (b) Desiraju, G. R. J. Am.Chem. Soc. 2013, 135, 9952.(5) Yamamoto, N.; Taga, T.; Machida, K. Acta Crystallogr., Sect. B1989, 45, 162.(6) Reddy, L. S.; Bhatt, P. M.; Banerjee, R.; Nangia, A.; Kruger, G. J.Chem.Asian J. 2007, 2, 505.(7) (a) Singh, N. B.; Das, S. S.; Singh, N. P.; Agrawal, T. J. Cryst. Growth2008, 310, 2878. (b) Brittain, H. G. Cryst. Growth Des. 2009, 9, 2942.(c) Seaton, C. C.; Parkin, A. Cryst. Growth Des. 2011, 11, 1502.(8) (a) Dean, P. M.; Turanjanin, J.; Yoshizawa-Fujita, M.; MacFarlane,D. R.; Scott, J. L.Cryst. Growth Des. 2009, 9, 1137. (b) Castner, E.W., Jr.;Wishart, J. F. J. Chem. Phys. 2010, 132, 120901. (c) Abbott, A. P.;Boothby, D.; Capper, G.; Davies, D. L.; Rasheed, R. K. J. Am. Chem. Soc.2004, 126, 9142. (d) de María, P. B.; Maugeri, Z. Curr. Opin. Chem. Biol.2010, 15, 1.(9) Desiraju, G. R. Angew. Chem., Int. Ed. 1995, 34, 2311.(10) Walsh, R. D. B.; Bradner, M. W.; Fleischman, S.; Morales, L. A.;Moulton, B.; Rodríguez-Hornedo, N.; Zaworotko, M. J.Chem. Commun.2003, 186.(11) (a) Etter, M. C. J. Phys. Chem. 1991, 95, 4601. (b) Etter, M. C.Acc.Chem. Res. 1990, 23, 120.(12) (a) Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des.2003, 3, 783. (b) Bhogala, B. R.; Basavoju, S.; Nangia, A. CrystEngComm2005, 7, 551. (c) Nichol, G. S.; Clegg, W. Cryst. Growth Des. 2009, 9,1844. (d) Bathori, N. B.; Lemmerer, A.; Venter, G. A.; Bourne, S. A.;Caira, M. R. Cryst. Growth Des. 2011, 11, 75. (e) Schultheiss, N.;Newman, A. Cryst. Growth Des. 2009, 9, 2950.(13) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.;Stahly, B. C.; Stahly, G. P. J. Am. Chem. Soc. 2004, 126, 13335.(14) Steiner, T. Acta Crystallogr., Sect. B 2001, 57, 103.(15) (a) Cambridge Structural Database, ver. 5.35, ConQuest 1.16,www.ccdc.cam.ac.uk. (b) Allen, F. H.; Motherwell, W. D. S. ActaCrystallogr., Sect. B 2002, 58, 407. (c) Bruno, I. J.; Cole, J. C.; Edgington,P. R.; Kessler, M.; Macrae, C. F.; McCabe, P.; Pearson, J.; Taylor, R.ActaCrystallogr., Sect. B 2002, 58, 389. (d) Allen, F. H.; Motherwell, W. D. S.;Raithby, P. R.; Shields, G. R.; Taylor, R. New J. Chem. 1999, 23, 25.(16) Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369.(17) McMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.;McLaughlin, O. L.; Zaworotko, M. J. Z. Kristallogr. 2005, 220, 340.(18) (a) Stott, P. W.; Williams, A. C.; Barry, B. W. Int. J. Pharm. 2001,219, 161. (b) Stott, P. W.; Williams, A. C.; Barry, B. W. J. Contr. Rel.1998, 50, 297.(19) Bi, M.; Hwang, S.-J.; Morris, K. R. Thermochim. Acta 2003, 404,213.(20) (a) Cherukuvada, S.; Nangia, A. CrystEngComm 2012, 14, 2579.(b) Gorniak, A.; Wojakowska, A.; Karolewicz, B.; Pluta, J. J. Ther. Anal.Calorim. 2011, 104, 1195. (c) Gorniak, A.; Karolewicz, B.; Zurawska-Płaksej, E.; Pluta, J. J. Ther. Anal. Calorim. 2013, 111, 2125.



http://pubs.acs.org

mailto:[email protected]

www.ccdc.cam.ac.uk

(21) For a combination of materials, a variety of thermal transitions canmanifest which can be due to multiple-stoichiometry cocrystals,eutectics, polymorphic phase transitions of parent materials as well astheir cocrystals, or desolvation of solvates formed during combination.(22) van Eijck, B. P.; Kroon, J. Acta Crystallogr., Sect. B 2000, 56, 535.(23) Saal, C.; Becker, A. Eur. J. Pharm. Sci. 2013, 49, 614.(24) Robertson, D.W.; Jones, N. D.; Swartzendruber, J. K.; Yang, K. S.;Wong, D. T. J. Med. Chem. 1988, 31, 185.(25) Bucar, D.; Day, G. M.; Halasz, I.; Zhang, G. G. Z.; Sander, J. R. G.;Reid, D. G.; MacGillivray, L. R.; Duer, M. J.; Jones, W. Chem. Sci. 2013,4, 4417.(26) (a) Davis, R. E.; Lorimer, K. A.; Wilkowski, M. A.; Rivers, J. H.;Wheeler, K. A.; Bowers, J. ACA Trans. 2004, 39, 41. (b) Stahly, G. P.Cryst. Growth Des. 2009, 9, 4212. (c) Habgood, M.; Deij, M. A.;Mazurek, J.; Price, S. L.; ter Horst, J. H. Cryst. Growth Des. 2010, 10, 903.(d) Yamashita, H.; Hirakura, Y.; Yuda, M.; Teramura, T.; Terada, K.Pharm. Res. 2013, 30, 70. (e) Zhang, S.; Harasimowicz, M. T.; de Villiers,M. M.; Yu, L. J. Am. Chem. Soc. 2013, 135, 18981.(27) (a) Morimoto, M.; Irie, M. J. Am. Chem. Soc. 2010, 132, 14172.(b) Gao, H. Y.; Zhao, X. R.; Wang, H.; Pang, X.; Jin, W. J. Cryst. GrowthDes. 2012, 12, 4377. (c) Dong, M.; Wang, Y.; Zhang, A.; Peng, Y.Chem.Asian J. 2013, 8, 1321. (d) Griffini, G.; Brambilla, L.; Levi, M.;Castiglioni, C.; Zoppo, M. D.; Turri, S. RSC Adv. 2014, 4, 9893.(e) Karaipekli, A.; Sari, A. J. Ind. Eng. Chem. 2010, 16, 767. (f) Huang, X.;Qin, D.; Zhang, X.; Luo, Y.; Huang, S.; Li, D.; Meng, Q. RSC Adv. 2013,3, 6922.(28) CrysAlisPro, ver. 1.171.36.32; Agilent Technologies UK Ltd:Yarnton, England, 2011.(29) Dolomanov, O. V.; Blake, A. J.; Champness, N. R.; Schroder, M. J.Appl. Crystallogr. 2003, 36, 1283.(30) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool;Utrecht University: Utrecht, Netherlands, 2002.(31) X’Pert HighScore Plus, The Complete Powder Analysis Tool;PANalytical B. V., 2003.(32) Barbour, L. J. X-Seed, Graphical Interface to SHELX-97 and POV-Ray, Program for Better Quality of Crystallographic Figures; University ofMissouri-Columbia: Missouri, USA, 1999.



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