On the Issues of Resolving a Low Melting Combination As a Definite Eutectic Or an Elusive

SUPPLEMENTARY INFORMATION

On the issues of resolving a low melting combination as a definite eutectic or an elusive cocrystal: A critical evaluation

SURYANARAYAN CHERUKUVADA* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru 560 012, India Email: [email protected]; [email protected]

*For correspondence

Table of Contents: Figure S1: Schematic representation of different solid forms Page S2 Structural integrity of cocrystals, solid solutions and eutectics Pages S2-S3 Table S1: Attributes of cocrystal and eutectic formation Page S3 Preparation and Characterization of Cocrystal and Eutectic Pages S3-S6 Figure S2: Heteromeric units in caffeine cocrystals Page S7 Figure S3: Ornidazole–4-aminobenzoic acid cocrystal and putative Page S7 supramolecular unit for putative ornidazole–4-iodobenzoic acid cocrystal Figure S4: Pyrazinoic acid–isonicotinamide cocrystal and putative Page S8 supramolecular unit for putative pyrazinoic acid–nicotinamide cocrystal Figure S5: Glutarimide–3,5-dihydroxybenzoic acid cocrystal and putative Page S8 supramolecular unit for putative glutarimide–3-hydroxybenzoic acid cocrystal Practicality of Indo-US group's definition on cocrystals Page S9 References S1-S30 Pages S9-S11

S1 Figure S1. Schematic representation of different solid forms. In a cocrystallization experiment, when adhesive (heteromeric) interactions between materials dominate over cohesive (homomeric) interactions, a new adduct with a crystal structure different from that of the parent materials forms (e.g. salt and cocrystal). Combination of materials having similar size/shape/crystal structures results in 'continuous solid solutions' (which resemble one of the parent crystal structures), and the ones with mismatch/misfit/domination of homomeric interactions can give rise to a 'eutectic' (conglomerate/ensemble of solid solutions). Cocrystals and solid solutions are homogenous (single phase) throughout the crystal lattice whereas eutectics are heterogenous (multi-phasic). Extracted from Ref. S1.

Manifestation and structural integrity of cocrystals, solid solutions and eutectics A cocrystal is formed between a combination of substances featuring high geometric (steric fit) and supramolecular (heteromolecular interactions) compatibility such that the components propagate hand-in-hand as continuous heteromolecular units in the crystal lattice in effect making a distinct crystalline entity.S1,S2,S3 A solid solution is manifested between substances having unlimited solubility (i.e. compatibility in terms of size/shape/crystal structures) such that it can form a variable stoichiometry but homogeneous (single phase) crystalline combination (see Figure S1).S1,S3b,S4 The crystal structure of a solid solution, in general, resembles/sustains the crystal structure of one of the parent substances. A eutectic is formed between those having

S2 limited solubility (not-so-supramolecularly compatible in terms of size, shape, heteromolecular interactions etc.) so that each of the substances combined make discontinuous (heterogeneous or multi-phasic) solid solutions within the same crystal lattice upon incorporating minor amounts of other substances of the combination.S1,S3 Since only discontinuous/finite/random heteromeric units manifest among the homomeric units of the components in the crystal lattice, the crystalline environment of a eutectic combination remains as a summation of its individual components taking the form of discontinuous solid solutions (see Figure S1).S1,S3 It was proposed, by this author and Nangia,S1 that a combination of materials where hetero-supramolecular interactions between components can outcompete homo-supramolecular interactions of individual components form cocrystals and those where homo-supramolecular interactions are too strong to be outweighed can lead to eutectics. This concept has been strengthened by Guru Row et al.'s workS3 with further improvements in the understanding of several chemical factors and attributes that dictate cocrystal/eutectic formation as well as their mutual exclusivity (see Table TS1). Given the unpredictability associated and moderate design control on the formation of cocrystals with many failed cocrystallization reports, the studies by Guru Row et al.S3 are remarkable in that they confer enhancement of success rate of cocrystallization, further making it a win-win situation in terms of both cocrystal and eutectic formation. On the other hand, when a combination is not-at-all compatible at supramolecular level, it just remains as a simple mixture illustrated by succinamide–4,4-bipyridine combination.S3a

Table S1. Findings on the attributes of cocrystal/eutectic formation for a combination of materials.S1,S3 S. No. Aspect Attribute Resultant continuous growth cocrystal 1 heteromolecular units finite or discrete eutectic supramolecular affinity or propensity of high cocrystal 2 hydrogen bond donor-acceptor groups low eutectic geometric and steric compatibility of hydrogen high cocrystal 3 bond donor-acceptor groups low eutectic induction strength complementarity of high cocrystal 4 hydrogen bond donor-acceptor groups low eutectic 'W' shape cocrystal 5 temperature vs. composition phase diagramS5,S6 'V' shape eutectic

Methods for Preparation of Cocrystal and Eutectic and associated issues

S3 Both cocrystals and eutectics are commonly prepared by thermal (e.g. co-melting),S6b,S7,S8 mechanochemical (e.g. co-grinding)S1,S3,S9,S10 and solution (evaporation/precipitation)S7,S11 based methods. However, solution based methods suffer from the risk of precipitation of individual components and thermal methods can have issues with temperature gradients (for mixing of components and consequent crystallization upon cooling) and moreover are not suitable for heat- labile materials. Recently, Fucke et al.S12 showed that solvent-assisted grinding is more reliable for making a cocrystal. But, unseeded caffeine–benzoic acid (CAF–BA) system proved that the above methods, including the supposedly reliable grinding method, does not ensure the formation of a putative/targeted cocrystal.S13 On the other hand, traditionally employed technique of solvent-mediated co-precipitation and recent technique of co-grinding for making eutecticsS1,S3,S7,S9,S11b have a basic flaw. The resultant material from these techniques is used to be characterized as a eutectic when the material exhibits characteristic lower melting point than that of the components i.e. it is not clear whether co-precipitation or co-grinding can really result in eutectic formation, since a eutectic-forming physical mixture too upon heating results in a eutectic.S1,S3,S6a,S8 Nevertheless, the analogy between heating and grinding and formation of eutectics by compaction techniqueS14 supports grinding to be a technique to form eutectics as follows. Grinding is well established to result in the formation of non-covalent adducts (e.g. cocrystal, molecular salt etc.)S2d,S3,S10,S15 and even covalent adductsS16 for a combination of materials. Grinding induces the development of reactant domains by facilitating molecular agitation and mobility finally leading to reorganization of molecules into a new adduct phaseS17 in a manner heating facilitates. To a first approximation, when grinding results in the formation of cocrystals having different interactions and lattice structure as compared to parent materials through full-fledged molecular reorganization, it is not unusual that it can induce eutectic formation,S18 on par with heating, which needs lesser reorganization as compared to cocrystal. Second, Bi et al.S14 have shown that compaction, a similar physical stress technique like grinding, can result in the formation of eutectics. They showed the difference between a eutectic-forming physical mixture and preformed eutectic (obtained by melting and compaction force independently) in terms of onset of eutectic endotherm and peak broadness. Eutectic-forming physical mixture exhibited a broad eutectic endotherm with higher onset contrast to eutectic material obtained by compaction which showed lower onset and sharp peak. Additionally, they have demonstrated an increase in the intimate contact area and thermal conductivity between the eutectic-forming components in the eutectic phase with increase of compaction force.S14 Thus, grinding and compaction assume to be new techniques that can make eutectics as well as

S4 applicable to heat-labile materials. Atomic pair distribution function (PDF) analysis, small-angle X-ray or neutron scattering (SAXS/SANS) measurements etc. are some of the future endeavors to characterize organic eutecticsS1,S3a in general and to assess eutectic formation upon grinding in specific.

Characterization of Cocrystal and Eutectic Unlike a cocrystal, a eutectic is insensitive to conventional X-ray diffraction and spectroscopy techniques.S1,S3 In case of the former, the replacement of homomolecular interactions by heteromolecular ones takes place followed by change in crystal packing (as compared to parent materials) such that it can be characterized by powder X-ray diffraction (PXRD) and spectroscopy. But, in case of a eutectic, the components of the combination accommodate each other in a substitutional or interstitial manner only partially forming an ensemble of discontinuous solid solutions wherein the homomolecular interactions as well as the parent component lattices are largely unaffected. As a result, no appreciable change can be observed in the diffraction or spectroscopic pattern of a eutectic compared to its parent materials and it manifests as the summation of parents.S1,S3 Traditionally, the only indicator of eutectic formation for a combination is the depression of its melting point which is traced by constructing a temperature vs. composition phase diagram.S1,S3,S5,S6,S19 A typical binary phase diagram of a eutectic assumes a ‘V’ shape with the minimum representing the eutectic melting point and maxima for individual melting of parent materials of the binary combination. For a eutectic- forming combination, only one interface i.e. eutectic phase exists between the combination, while a cocrystal-forming combination manifests at least three different interfaces viz. a cocrystal and two eutectic (independent eutectics between cocrystal and individual parent materials) phases.S3a,S6,S20 Hence, the binary phase diagram of a cocrystal-forming system assumes 'W' shape; the two lower minima in ‘W’ represent eutectics between cocrystal and individual parent materials in excess; the middle maximum pertains to cocrystal phase whose melting point can be upper, median or lower compared to parent materials.S3a,S6,S20

Skepticism in establishing a combination as a cocrystal/eutectic-forming one and solution With respect to establishing a combination as a cocrystal- or eutectic-forming one, caffeine– benzoic acidS13 and benzoquinone–diphenylamineS21 systems formed the premise for the referees to question our assertion in two articles of Guru Row's groupS3c,d that eutectic formation for a particular combination refrains it to form cocrystal. It should be noticed that benzoquinone–

S5 diphenylamine system and several other systems manifest cocrystals past heating of their eutectic melts (in thermal microscopy or differential scanning calorimetry (DSC)), respectively, indicating that eutectic formation is a preceding step for cocrystal formation in those cases.S6b,S8,S21 They typically exhibit at least two endotherms in DSC (initial one for eutectic and latter for cocrystal melting) and 'W'-type phase diagrams characteristic of cocrystal-forming systems. Lu et al.S8 have provided a rationale on the mechanism of cocrystal formation from eutectic melt for such cases. But, pure CAF–BA system did not show any sign of cocrystal formation from its eutectic melt as analyzed by DSC (only a single endotherm is observed) and PXRD (no new or distinct peaks are observed) in this study (see Figure 1 of main article). Further, it manifested 'V'-type pattern of a eutectic-forming system (Figure 1b). The system gave cocrystal only upon seeding with cocrystals of caffeine and various fluorobenzoic acids.S13 Thus, the combination behaved as a eutectic-forming one in pure state and as a cocrystal-forming one when subjected to heteronuclear seeding. There seems to be an inherent nucleation issue, the rate-limiting step of crystallization,S22 for CAF–BA combination such that the formation of cocrystal happens only when the nucleation step is evaded by seeding. Heating or co-melting a combination is known to result in adduct (cocrystal) formationS6b,S8,S21,S23 by facilitating higher energy state/activation of the reactants so that they can reorganize into a new adduct phase. Similarly, as discussed before, grinding method too can facilitate molecular agitation and consequent reorganization to result in a new adduct. This tends to mean that heat/grinding process is able to cross the kinetic barrier for nucleation to result in the growth of a cocrystal but it actually did not happen in the case of CAF–BA. Therefore, a technique which evades or crosses the activation barrier for cocrystal nucleation and sustains the growth of cocrystal nuclei will be helpful to resolve cocrystal/eutectic formation for a particular combination. Heteronuclear seedingS24 followed by slurry crystallization,S25 which resulted in the formation of long elusive CAF–BA cocrystal,S13 has the potential to facilitate cocrystal formation. This is because the technique synergizes the evasion of rate-limiting nucleation step through seed effectS24 and conferment of supersaturation for cocrystal growth through solution-mediated phase transformationS25b in slurry conditions to finally result in cocrystal formation. Therefore, heteronuclear seeding can be affirmed as a validation technique to establish a combination as a cocrystal- or eutectic-forming one.

S6 caffeine–2,3-difluorobenzoic caffeine–benzoic acid caffeine–salicylic acid acid (CAF–23DFBA) (CAF–BA) (CAF–SA) Figure S2. Heteromeric units in caffeine cocrystals. In CAF–23DFBA and CAF–SA cocrystals, tetrameric motif formed by carboxylic acid–imidazole and C–H∙∙∙O=C(CAF) interactions extends into other dimensions through methyl–fluoro/hydroxyl interactions. In CAF–BA cocrystal, the same tetrameric motif is propagated through methyl–carbonyl(COOH) interactions in the absence of additional acceptor groups on benzoic acid. CAF–BA cocrystal is isomorphous and isostructural with CAF–23DFBA cocrystal but not with CAF–SA cocrystal.S13,S26

Supramolecular unit for putative Ornidazole–4-aminobenzoic acid cocrystal ornidazole–4-iodobenzoic acid cocrystal (extracted from Ref. S3b) (adapted from Ref. S3b) Figure S3. Tetrameric unit consisting of acid–imidazole and nitro–amine dimers in 1:1 ornidazole–4-aminobenzoic acid cocrystal lends supports to the feasibility of 1:1 ornidazole–4- iodobenzoic acid cocrystal formation based on the commonality in acid–imidazole interactions and analogy of nitro–amine and nitro–iodo interactions.

S7 Pyrazinoic acid–isonicotinamide cocrystal (adapted Supramolecular unit for putative pyrazinoic acid– from Ref. S3c) nicotinamide cocrystal (extracted from Ref. S3c) Figure S4. In 1:1 pyrazinoic acid–isonicotinamide cocrystal, the para location of amide group renders the anti NH donor to make linear supramolecular units to extend into a sheet structure. For the putative 1:1 pyrazinoic acid–nicotinamide cocrystal to form, the amide group should go out-of-plane so as to overcome steric hindrance and render the anti NH donor to make non- planar supramolecular units of the cocrystal.

Supramolecular unit for putative Glutarimide–3,5-dihydroxybenzoic acid glutarimide–3-hydroxybenzoic acid cocrystal cocrystal (extracted from Ref. S3d) (adapted from Ref. S3d) Figure S5. Tetrameric [(acid–imide)–(hydroxyl–imide)] units in 1:1 glutarimide–3,5- dihydroxybenzoic acid cocrystal support the manifestation of putative 1:1 glutarimide–3- hydroxybenzoic acid cocrystal based on the structural similarity between 35DHBA and 3HBA and commonality of interactions.

Indo-US group's definition of cocrystals and its practicality

S8 According to an Indo-US group, cocrystals are "solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio".S27 This evolved definition in 2012 is so inclusive that it is quite handy in categorizing some of the solid forms of drugs, which are otherwise difficult to classify. For example, dapagliflozin propylene glycol monohydrate,S28 escitalopram oxalic acid oxalateS29 and valproic acid sodium valproate,S30 which are the respective marketed solid forms of the drugs namely dapagliflozin, escitalopram and valproic acid, readily come under the Indo-US group's definition of cocrystals.

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