Comprehending the Formation of Eutectics and Cocrystals in Terms of

Article pubs.acs.org/crystal

Comprehending the Formation of Eutectics and Cocrystals in Terms of Design and Their Structural Interrelationships Suryanarayan 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, which encompasses the art of making multicomponent organic solids such as cocrystals, solid solutions, eutectics, etc. for novel applications, has been less studied in terms of reliably and specifically obtaining a desired cocrystallization product and the issues that govern their formation. Further, the design, structural, and functional aspects of organic eutectics have been relatively unexplored as compared to solid solutions and cocrystals well-established by crystal engineering principles. Recently, eutectics were proposed to be designable materials on par with cocrystals, and herein we have devised a systematic approach, based on the same crystal engineering principles, to specifically and desirably make both eutectics and cocrystals for a given system. The propensity for strong homomolecular synthons over weak heteromolecular synthons and vice versa during supramolecular growth was successfully utilized to selectively obtain eutectics and cocrystals, respectively, in two model systems and in two drug systems. A molecular level understanding of the formation of eutectics and cocrystals and their structural interrelationships which is significant from both fundamental and application viewpoints is discussed. On the other hand, the obscurity in establishing a low melting combination as a eutectic or a cocrystal is resolved through phase diagrams.

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INTRODUCTION Eutectics are long known multicomponent crystalline solids which have varied applications in everyday life.1 They are more popular as one of the categories of inorganic alloys, the other being solid solutions.1 Both eutectics and solid solutions are also well-known in organic systems2 where they can be classified as organic/molecular alloys. Cherukuvada and Nangia3 recently conceptualized the structural interrelationships between eutectics and cocrystals. They noted that in a typical cocrystallization experiment the formation of multicomponent adducts such as salts, cocrystals, solid solutions, or eutectics depends on the nature of the components and type of interactions that manifest between them (Scheme 1).3 However, there are limited studies on the phenomena that specifically lead to a cocrystal or a eutectic as cocrystallization product. They opined that a combination of materials where adhesive (heteromolecular) interactions between components can outweigh cohesive (homo/self) interactions of individual components form cocrystals and those where cohesive interactions are too strong to be outweighed can lead to eutectics. They redefined eutectics from a structural viewpoint as “conglomerates of solid solutions”3 formed between materials lacking geometrical fit and/or viable heteromolecular interactions (Scheme 1). They also discussed the usage of the term “eutectic” in relation to solid solutions and cocrystals from a historical perspective and contextual and rigorous understanding of the issues can be inferred from the article.3 On the other hand, they observed that © 2014 American Chemical Society

Scheme 1. In a Cocrystallization Experiment When Adhesive Interactions between Materials Dominate over Cohesive Interactions, a New Compound with a Crystal Structure Different from That of the Parent Materials Can Form (e.g., Salt and Cocrystal)a

a

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

the studies on the design elements and understanding of the structural integrity of eutectics as organic solid materials are modest in the literature as compared to solid solutions and Received: May 30, 2014 Published: July 2, 2014 4187

dx.doi.org/10.1021/cg500790q | Cryst. Growth Des. 2014, 14, 4187−4198

Crystal Growth & Design

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

Figure 1. Molecular structures and acronyms of the compounds.

of occurrence in the Cambridge Structural Database (CSD),15 Scheme 2), is exploited to selectively make cocrystals. Similarly, the weak carboxamide−pyridine heterosynthon (5% frequency),16 which cannot outcompete the carboxamide homodimer interactions (35% frequency)17 to form a cocrystal, is exploited to make eutectics. We have chosen succinic acid (contains two carboxylic acid groups), succinamic acid (one carboxylic acid and one carboxamide group), and succinamide (both carboxamide groups) and combined them respectively with pyridine and chloride group containing compounds (Figure 1) to understand and screen cocrystal/eutectic formation in a series. 4,4′-Bipyridine and isonicotinamide (the two most frequently used model coformers in cocrystallization studies),12 antitubercular drug isoniazid (of its structural analogy with isonicotinamide), and the antidepressant drug fluoxetine hydrochloride (of its importance with regard to formation of salt cocrystals)13 were screened. Crystal structures of all the starting compounds, except succinamic acid, are known in the literature.15 In this study, we also determined the crystal structure of succinamic acid which is found to be manifested by acid−amide heterodimers (Figure 2) and not separate acid/ amide homodimers complying with the CSD statistics (Scheme 2).

cocrystals which are well-established by crystal engineering principles.4 Utilizing the same principles, they initiated an empirical approach to design eutectics,3 and we herein broadened the empirical factors that dictate their design and formation. In this study, we successfully designed and selectively obtained eutectics vis-à-vis cocrystals in two simple model systems and also two drug systems. Cherukuvada and Nangia elucidated the intriguing design element in eutectics and their mutual relationships with solid solutions and cocrystals through benzoic acid−fluorobenzoic acid/benzamide systems among other examples.3 The isomorphous nature of hydrogen and fluorine results in continuous solid solutions of benzoic acid−4-fluorobenzoic acid system,5 the strong heteromolecular interactions of benzoic acid−pentafluorobenzoic acid combination resulted in their cocrystal,6 and the lack of such interactions led to a eutectic in case of benzoic acid− benzamide system.7 Thus, for a combination of materials, when the attributes of (i) geometric compatibility of functional groups and/or components and (ii) viable heteromolecular interactions are positive, the resultant is a cocrystal, and if they are negative it is a eutectic.3 In effect, an “anticrystal engineering” approach,8 wherein materials that can form potential supramolecular synthons4,9 are intentionally avoided to obtain noncrystallizing ionic liquids8a,b and deep eutectic solvents (a class of eutectics),8c,d forms the basis for empirical design of eutectics. In this article, we exploit the formation of strong and weak heterosynthons,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 form strong heteromolecular interactions with pyridine group (carboxylic acid−pyridine heterosynthon with 91% frequency14

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METHODS

Traditionally, eutectics especially pharmaceutical eutectics are prepared by comelting and solvent-mediated coprecipitation of the components.2a,18 Recently, the techniques of compaction19 and grinding20 were shown to result in eutectic formation. Cocrystals and eutectics of this study were prepared by solid state grinding method (detailed in Experimental Section). Understanding the microstructure of a eutectic 4188



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

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RESULTS AND DISCUSSION The results of solid form screening experiments for the combination of compounds in this study are tabulated in Table 1 and crystallographic parameters of new cocrystals in Table 2. The melting points of cocrystals and eutectics in the series are proportional to the melting point of coformer as observed by Cherukuvada and Nangia.3,20a Succinic acid cocrystals and succinamide eutectics showed higher melting points than corresponding succinamic acid cocrystals and eutectics (Table 1). (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 that the robust acid−pyridine synthon (of 91% frequency)14 should give cocrystals of succinic acid and succinamic acid with bipyridine, and the less occurring amide−pyridine synthon (5%)16 should form eutectic of succinamide with bipyridine. In these lines, we obtained 1:1 succinic acid−bipyridine and 2:1 succinamic acid−bipyridine cocrystals as anticipated (Figure 3). In the former, the 1:1 ratio of acid and pyridyl groups resulted in 1:1 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 the weak amide−pyridine synthon (35% vs 5%),16,17 the resulting cocrystal is, not surprisingly, of 2:1 stoichiometry. The molecules propagate through the acid−pyridine and amide dimer synthon growth units avoiding the amide−pyridine synthon in the cocrystal (Figure 3b). Thus, the dominance of amide homodimer synthon over amide−pyridine heterodimer synthon should avoid heteromolecular interactions for the combination of succinamide and bipyridine (Figure 3c) to result in a eutectic or physical mixture. It should be remembered that the identity of individual components will be lost in a eutectic mixture (as it is composed of solid solutions, Scheme 1) in contrast to a physical mixture which retains their identity.1 DSC showed that the combination is just a physical mixture and not a eutectic (Figure 4). The thermograms 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 thermal transitions characteristic of the individual components. The dehydration of 4,4′-bipyridine (commercial material is in dihydrate form) and polymorphic transformation of succinamide (TGA plots confirm the claimed transitions, Figures S19 and S20 of Supporting Information) apart from their melting events seen in the DSC (Figure 4) confirm the combination to be a simple physical mixture. It seems the less probable amide−pyridine synthon becomes so improbable in the presence of dominant amide dimer synthon that even a minor amount of bipyridine cannot be accommodated in the lattice of succinamide (and vice versa) to form a discontinuous solid solution, and therefore no

Figure 2. Succinamic acid shows contiguous acid−amide heterodimer synthons in the crystal structure. (whose crystal structure is difficult to solve as it is composed of phaseseparated solid solutions) is a prerequisite to appreciate eutectic formation, and the issues are discussed in detail by Cherukuvada and Nangia.3 Elucidation of the exact eutectic composition and characterizing its complex structural integrity is a laborious task, since the eutectic composition is heterogeneous and can be nonstoichiometric unlike a cocrystal. The powder X-ray diffraction (PXRD) technique, routinely employed for the characterization of cocrystals, is not found to be useful to diagnose a eutectic.3 This is because the formers are manifested by adhesive interactions that direct distinctive crystal packing, but in the case of the latter, as the inclusion of a minor component happens substitutionally or interstitially in the major component the cohesive interactions as well as the lattice structures of parent components remain largely unaffected (Scheme 1). As a result, no appreciable change can be observed in the diffraction pattern of a eutectic compared to its parent materials, but the eutectic phase integrity can be established firmly by sophisticated powder diffraction techniques3 such as pair distribution function (PDF) analysis, small-angle X-ray or neutron scattering (SAXS/SANS), Rietveld fit, etc. However, so far in the literature these approaches have not been reported and will form new topics of investigation for organic systems. Currently, thermal techniques especially differential scanning calorimetry (DSC), which effectively elucidates the melting behavior, works as a bench diagnostic technique for a eutectic,3 and we used the same to confirm the formation of eutectics in this study. We performed DSC measurements to compare and contrast cocrystal- and eutectic-forming systems and did not attempt to determine the exact eutectic composition, which is altogether a separate task. In-depth analysis of all peaks manifesting in the DSC was not undertaken because of the complex variety of thermal transitions possible for a given combination of materials.21 Combinations in 1:1, 1:3, and 3:1 molar ratios, prepared by solid state grinding, were subjected to DSC to ascertain eutectic formation by a low melting endotherm. The three different compositions exhibited a common low melting solidus peak corresponding to the eutectic phase in each of the compositions, and we, therefore, treat the system as a eutectic in a broad sense. The noneutectic phase of the composition, which can be in excess of 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, and melting points compared to the parent materials−cocrystals showed distinct PXRD patterns as well as melting points, but eutectics were different only in their melting behavior; (ii) solid ground products were then subjected to evaporative crystallization (detailed in Experimental Section) to obtain single crystals of adductsonly single crystals of cocrystals were obtained and eutectic-forming compounds separated in solution. The PXRD patterns of the compounds studied in this work are shown in Figures S1−S12, Supporting Information. Phase diagrams are

Table 1. Results for the Combination of Compounds in This Study + succinic acid (189 °C) succinamic acid (156 °C) succinamide (265 °C)

4,4′-bipyridine (112 °C)a cocrystalb (231 °C) cocrystal (174 °C) physical mixture (111 and 264 °C)

isonicotinamide (156 °C) cocrystal12a (207 °C) cocrystal (168 °C) eutectic (152 °C)

isoniazid (173 °C) cocrystal20a (143 °C) eutectic (121 °C) eutectic (165 °C)

fluoxetine hydrochloride (156 °C) cocrystal13 (119 °C) eutectic (129 °C) eutectic (153 °C)

a

Melting points (onset temperatures in the DSC) are given in parentheses. bCocrystals can have higher, intermediate or lower melting points compared to their starting materials; DSC plots of cocrystals are shown in Figures S13−S18, Supporting Information. 4189



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Table 2. X-ray Crystallographic Parameters compound empirical formula formula weight crystal system space group Za a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) T (K) Dcalc (g cm−3) μ (mm−1) reflns collected unique reflns observed reflns Δρmin, max (e Å−3) R1 [I > 2σ(I)] wR2 [reflns] goodness-of-fit CCDC no.

SNA C4H7NO3 117.11 monoclinic Pc 2 5.6612(3) 5.1428(3) 9.5438(5) 90 93.246(5) 90 277.42(3) 120(1) 1.4018 0.121 2750 1072 1062 −0.152, 0.183 0.0237 0.0629 1.0678 979160

SA−BP C14H14N2O4 274.28 triclinic P1̅ 4 5.4131(6) 6.0085(5) 9.9526(8) 87.699(7) 84.940(8) 73.561(9) 309.22(5) 120(1) 1.4728 0.110 5894 1226 1039 −0.513, 0.523 0.0656 0.1924 1.1150 979161

2:1 SNA−BP C18H22N4O6 390.40 triclinic P1̅ 6 7.1751(6) 10.167(1) 12.699(1) 82.037(9) 81.412(7) 88.251(8) 907.1(2) 120(1) 1.4292 0.109 17860 3193 2172 −0.524, 0.565 0.0793 0.2669 1.1876 979162

INAM−SNA C10H13N3O4 239.23 orthorhombic P212121 8 5.7188(4) 10.1645(7) 20.459(1) 90 90 90 1189.2(1) 298(1) 1.3360 0.105 7100 2303 1668 −0.193, 0.168 0.0518 0.1454 1.0905 979163

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

Figure 3. (a) Succinic acid and 4,4′-bipyridine molecules connected invariably by the robust acid−pyridine heterosynthon propagate as an infinite tape in the 1:1 SA−BP cocrystal. (b) Succinamic acid and bipyridine molecules form an infinite tape through acid−pyridine and amide homodimer interactions 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 to propagate as a cocrystal or even a eutectic solid solution, and hence the combination remains as a mere physical mixture.

succinic acid forms a 2:1 cocrystal12a involving acid−pyridine and amide dimer interactions (Figure 5a). Combination with succinamic acid and succinamide resulted in a cocrystal and a eutectic, respectively. Isonicotinamide−succinamic acid is a 1:1 cocrystal manifested by acid−pyridine synthon and amide heterodimer propagating in an alternate fashion in the anticipated lines (Figure 5b). Carboxylic acid of succinamic

eutectic formation occurs (Figure 3c). The remote possibility of only available amide−pyridine synthon for bipyridine−succinamide combination endures no growth unit for eutectic solid solution formation, and hence the combination remains as a physical mixture. (2). Isonicotinamide System. Combination of isonicotinamide (containing one pyridine and one carboxamide group) with 4190



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Figure 4. DSC of succinamide−4,4′-bipyridine combination demonstrates it to be a typical physical mixture in which the identity of the components is retained. 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 temperature ca. 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 2:1 INAM−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 synthons were avoided in the cocrystal. (c) For isonicotinamide−succinamide combination, the weak amide−pyridine synthon endures no growth unit to propagate as a cocrystal entity, but the possibility of discrete amide heterodimers leads to a eutectic phase as per Scheme 1

acid preferentially goes to pyridine of isonicotinamide rendering the amide groups of the two molecules to form heterodimeric interactions. Thus, isonicotinamide−succinamic acid cocrystal simultaneously 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 a eutectic phase in the case of isonicotinamide−succinamide combination. In this case, though an amide heterodimer can form between the molecules on one side, the other side sees only the

less occurring amide−pyridine synthon with the result that the system cannot propagate as a cocrystal growth unit (Figure 5c). Therefore, the dominant amide homodimer interactions outweigh the adhesive interactions, but the possibility of finite/ discrete amide heterodimers (indicated by a green check mark in Figure 5c) between the molecules facilitates random incorporation of molecules in each other’s lattice, to a certain extent, to form discontinuous solid solutions eventually leading to a eutectic as per Scheme 1. DSC on three different molar ratios 4191



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Figure 6. DSC of the three different isonicotinamide−succinamide molar mixtures shows a common low melting endotherm pertaining to the eutectic phase 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 2:1 INH−SA cocrystal (CSD Refcode: FADGIC02). (b) For isoniazid−succinamic acid combination, the unknown acid/amide−hydrazide synthon endures 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 phase which could be due to the possibility of such interactions between the molecules at least in random.

synthons were found in the CSD)15 and the probable compromise of centrosymmetry of hydrazide dimer for isoniazid−succinamic acid combination compared to amide heterodimer of isonicotinamide−succinamic acid cocrystal appear not to confer a growth unit beyond acid−pyridine dimer (Figure 7b) with the result that the combination forms a eutectic. The likelihood of cocrystal for the combination via linking up of isoniazid hydrazide dimers and amide dimers of succinamic acid by acid−pyridine synthon seems to be unfavorable as it needs to disrupt the stronger homomolecular (acid−amide in succinamic acid and amine−pyridine in isoniazid) interactions. The possibility of discrete acid−pyridine heterodimers in the lattice, at least in random, appears to have resulted in the eutectic for the combination. In case of isoniazid− succinamide combination, the unknown amide−hydrazide dimer

(1:1, 1:3, and 3:1) of isonicotinamide−succinamide combination showed a common and invariant low melting endotherm characteristic of a eutectic phase (Figure 6), thus providing unequivocal 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 its structural analogy with isonicotinamide (only difference in hydrazide/amide functionality) and its importance as an antitubercular drug. Combination of isoniazid (containing one pyridine and one hydrazide group) with succinic acid generates a 2:1 cocrystal20a involving acid−pyridine and hydrazide dimer interactions (Figure 7a), similar to isonicotinamide−succinic acid, but isoniazid formed a eutectic with succinamic acid (Figure 8a), unlike isonicotinamide which formed a cocrystal. The misfit in acid/amide−hydrazide cyclic dimer interactions (no such 4192



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

break and form new O−Hacid···Cl− (i.e., replace C−H···Cl−) and N+−H···Oacid charge-assisted hydrogen bonds when they combine with fluoxetine hydrochloride. Thus, the domination of adhesive interactions over cohesive interactions resulted in fluoxetine hydrochloride−carboxylic acid cocrystals including succinic acid cocrystal.13 Combination of fluoxetine hydrochloride with succinamic acid and succinamide resulted in eutectics respectively (Figure 10). This can be due to the presence of additional strong N−H donor on amide group whose requirement of strong acceptor can cause steric hindrance for amide−chloride interactions (Figure 9b) compared to acid− chloride interactions (similar to amide−pyridine vs acid− pyridine synthons) with the result that they cannot replace the homomolecular acid−amide and amide dimer interactions. The discrete O−Hacid/N−Hamide···Cl− and N+−H···Oacid/amide interactions could have led to eutectic phases in these cases. Binary Phase Diagrams. A phase diagram can be used to dissect and comprehend the distinct phases plausible for a given system as a function of temperature, pressure, etc.1 Traditionally, a eutectic is characterized by a phase diagram as a low melting

and the less frequent amide−pyridine synthon (Figure 7c) should result in a physical mixture but led to a eutectic (Figure 8b), which is somewhat intriguing. This example shows that unless the combination is evaluated by its thermal behavior, the plausibility of such interactions and therefore the formation of eutectic cannot be ruled out. (4). Fluoxetine Hydrochloride System. The exploration of eutectic formation for drug salts is significant because the majority of the drugs are marketed in their salt forms.23 Hence, we selected the drug fluoxetine hydrochloride of its importance in forming salt cocrystals13 and investigated the possibility of salt eutectics. Fluoxetine hydrochloride−succinic acid combination is a salt cocrystal13 involving acid−chloride interaction (Figure 9a). The formation of a cocrystal between them was analyzed3 as follows. In fluoxetine hydrochloride, each Cl− ion is bonded to one protonated secondary NH+ group and four CHs on an average.24 Any strong donors such as carboxylic acid groups can displace/replace the weak CHs bonded to Cl− ion of fluoxetine hydrochloride based on the best donor-best acceptor rule.11 As such, the carboxylic acid homodimers (O−Hacid···Oacid bonds) 4193



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

composition of two or more substances.1,2a In a cocrystal screen, when the combination exhibits higher or intermediate melting point compared to the parent materials it can concluded that the combination makes a cocrystal, but there can be situations where the combination exhibits a low melting point but no distinct diffraction or spectroscopic signatures, which causes a dilemma whether the combination is a definite eutectic or an unresolved cocrystal. Furthermore, the formation of cocrystal, though certain, can be elusive however exhaustive the cocrystallization experiments may be.25 Thermal analysis by construction of a temperature versus composition phase diagram is known to establish whether a combination forms a cocrystal or a eutectic.2b,7c,26 A typical binary phase diagram of a eutectic assumes a ‘V’ shape and that of a cocrystal ‘W’ shape,26 but the method is underutilized because of the complex variety of thermal transitions21 and difficulties in interpretation of the phases involved. To simplify the issues, for a eutectic-forming combination 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 different compositions; a small and variable liquidus point manifests for the near-eutectic or noneutectic compositions pertaining to the parent materials in excess.2b,3 In the case of a cocrystal-forming binary system (A:B), three different phases, a cocrystal and two eutectics, one between cocrystal and parent material A and the other between cocrystal and parent material B,26 are possible. Correspondingly, three different melting points of which at least two of low melting nature should be observed. The two low melting points relate to the eutectics of cocrystal with parent materials and represent the lower left and right intersections of ‘W’-type phase diagram of cocrystal. The position of the upper intersection pertaining to melting of the cocrystal phase can be upper, median or lower to the arms, i.e., parent materials. In this study, we selected the low melting INH−SA and INH− SNA systems as representative cases to compare and contrast the thermal behavior of low melting cocrystal and eutectic through binary phase diagrams. We analyzed five different molar compositions, 1:1, 1:2, 2:1, 1:3, and 3:1, by DSC and found

that three compositions can be sufficient to establish the formation of a cocrystal or a eutectic. INH−SA cocrystal system exhibited two different low melting points (141 °C for 3:1 composition 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 2:1 cocrystal 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 2.5 ratios respectively). The binary phase diagram of INH−SA cocrystal 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 the compositions, and no other low melting peaks were manifested (except for broad liquidus peaks), thus establishing INH−SNA to be a eutectic-forming system. Ideally, a composition which does not exhibit liquidus peak is assigned to be a eutectic composition1 and, therefore, for INH−SNA system, the 1:3 molar composition which did not show discernible liquidus peak (Figure 13) can be ascribed as the eutectic or near-eutectic composition. The binary phase diagram of the INH−SNA system 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. Apart from being useful in characterizing a eutectic, the method has twin advantages in targeted cocrystal screening viz. (1) characterizing an elusive cocrystal when other techniques fail to resolve and (2) melt-growth technique to prepare the cocrystal (of course, on the condition that it does not decompose upon melting).

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CONCLUSIONS The study of integral design and organization of eutectics forms a new area of organic solid state chemistry research. In the cocrystallization arena, eutectics are one of the outcomes of the classic battle between “interactions” and “packing” in achieving a 4194



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

Figure 11. DSC of isoniazid−succinic acid system.

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

space for different applications. In this study, we broadened the empirical approach to design and selectively obtained eutectics 4195



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

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

and stability advantages of eutectic drug formulations.3,20a Given the importance of cocrystals and eutectics in modifying the physicochemical properties of materials3,12e,13,20 and also as emerging functional organic materials,27 further studies will broaden the understanding of intermolecular interactions, crystallization process, success and failure of cocrystallization and, thus, augment the efforts toward modulating the structure and function of materials in a desirable way for desired properties. The current challenge is to dissect the organic eutectics into solid solutions and better understand their microstructural organization. At what point a physical mixture nonrandomizes, a weak solid solution transforms into anisotropic/heterogeneous domains of eutectic phase and what kind of factors drive toward eutectic from cocrystal and vice versa need to be understood to a more advanced level.

vis-à-vis cocrystals based on the crystal engineering principles. It is found that the domination of homomolecular synthons over heteromolecular synthons and vice versa in a supramolecular competition directs the formation of eutectic and cocrystal respectively for a given system. Thus, the strategy can be employed in a mutually independent manner to specifically and desirably make eutectics or cocrystals, and therefore it becomes a win-win cocrystallization strategy. It is observed in the systems studied that for a two-component system, when the primary recognition/growth unit is at least three molecules long (e.g., acid−pyridine−acid), a cocrystal can form and a eutectic results if the unit is just a weak and finite heterodimer (e.g., amide− pyridine). We showed that the obscurity in establishing a low melting combination as a cocrystal or a eutectic can be resolved through thermal analysis of as low as three molar compositions, which is significant in terms of saving time, money, and effort in targeted cocrystal or eutectic screens. On the other hand, a correlation between the melting point of adduct (either cocrystal or eutectic) and coformer in the series was observed in line with the earlier studies,3,12e,13,20a which is significant with respect to tuning the melting property of a material. Cherukuvada and Nangia demonstrated the solubility

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EXPERIMENTAL SECTION

Materials. Commercially available fluoxetine hydrochloride (Yarrow Chem Products, Mumbai, India) and all other compounds (Alfa Aesar, Bengaluru, India) were used without further purification. Solvents were of analytical or chromatographic grade and purchased from local suppliers. Water purified from a Siemens Ultra Clear water purification system was used for experiments.

Figure 13. DSC of isoniazid−succinamic acid system. 4196


Crystal Growth & Design Methods. Solid State Grinding. Compounds in molar ratios combined together in a 200 mg scale were subjected to manual grinding for 15 min using a mortar-pestle. The ground materials were analyzed by PXRD and DSC to ascertain the formation of cocrystal or eutectic. The reported cocrystals were confirmed by matching the experimental PXRD patterns with that of the calculated profiles from X-ray crystal structures. Evaporative Crystallization. Succinamic Acid. A total of 50 mg of succinamic acid was dissolved in 3 mL of water and left for slow evaporation at room temperature. Colorless plate crystals were obtained after 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) was dissolved in 5 mL of methanol and left for slow evaporation at room temperature. Colorless plate crystals were obtained after a few days upon solvent 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 at room temperature. Colorless needle crystals were obtained after a few days upon solvent evaporation. 1:1 Isonicotinamide−Succinamic Acid Cocrystal. Ground mixture of isonicotinamide (12 mg, 0.1 mmol) and succinamic acid (12 mg, 0.1 mmol) was dissolved in 5 mL of ethanol−acetonitrile solvent mixture and left for slow evaporation at room temperature. Colorless plate crystals 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) cocrystals were collected on an Oxford Xcalibur Mova E diffractometer equipped with an EOS CCD detector and a microfocus sealed tube using Mo Kα radiation (λ = 0.7107 Å). Data collection and reduction were performed using CrysAlisPro (version 1.171.36.32)28 and OLEX2 (version 1.2)29 was used to solve and refine the crystal structures. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms on heteroatoms were located from difference electron density maps and all C−H atoms were fixed geometrically. The final CIF files were validated in PLATON.30 Powder X-ray Diffraction. PXRD were recorded on PANalytical X’Pert diffractometer using Cu−Kα X-radiation (λ = 1.54056 Å) at 40 kV and 30 mA. X’Pert HighScore Plus (version 1.0d)31 was used to collect and plot the diffraction patterns. Diffraction patterns were collected over 2θ range of 5−40° using a step size of 0.06° 2θ and time per 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. The temperature range used in both DSC and TGA is 30−300 °C, and the samples were heated @ 5 °C min−1. Samples were placed in crimped but vented aluminum pans for DSC and open alumina pans for TGA and were purged by a stream of dry nitrogen flowing at 50 mL min−1. Packing Diagrams. X-Seed32 was used to prepare packing diagrams.

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ACKNOWLEDGMENTS

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REFERENCES

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

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ASSOCIATED CONTENT

* Supporting Information S

PXRD patterns of compounds, DSC plots of cocrystals, DSC with TGA plots of 4,4′-bipyridine dihydrate and succinamide, respectively, and CIF files. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 4197



Article

(21) For a combination of materials, a variety of thermal transitions can manifest which can be due to multiple-stoichiometry cocrystals, eutectics, polymorphic phase transitions of parent materials as well as their 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) Bučar, 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. Growth Des. 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.; Schröder, 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 POVRay, Program for Better Quality of Crystallographic Figures; University of Missouri-Columbia: Missouri, USA, 1999.

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Comprehending the Formation of Eutectics and Cocrystals in Terms of

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