Recent Advances in Understanding the Mechanism of Cocrystal

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 3 1621–1637

ReViews Recent Advances in Understanding the Mechanism of Cocrystal Formation via Grinding Tomislav Frisˇcˇic´ and William Jones* Department of Chemistry and Pfizer Institute for Pharmaceutical Materials Science, UniVersity of Cambridge, Lensfield Road, Cambridge CB21EW, United Kingdom ReceiVed July 16, 2008

ABSTRACT: A brief and systematic overview of recent advances in understanding the mechanism of mechanochemical cocrystallization at macroscopic (bulk phase transformations) and microscopic levels (molecular recognition) is given. The review particularly addresses neat and liquid-assisted grinding approaches to cocrystal formation.

1. Introduction Recent years have witnessed a tremendous increase in the interest and pace of research related to the synthesis of molecular materials through mechanochemical methods.1 Mechanochemistry2 has been successfully applied to the synthesis of systems based on covalent,3 coordination,4 and supramolecular bonds.5 This review will focus on what currently seems to be the “hottest” area of mechanochemical synthesis at present: the construction of multicomponent crystals (cocrystals)6 by way of grinding.7 Interest in cocrystals brings together supramolecular chemists, materials scientists, and (co)crystal engineers, as cocrystallization has proven to be a versatile approach for the construction of functional solids. Currently, established and proposed applications of cocrystals range from advanced pharmaceutical materials,8 molecular semiconductors,9 and optical materials,10 to media for stereocontrolled synthesis.11 The increase in the number of cocrystal applications and the development of strategies for their design has inspired research in developing efficient and versatile methods of cocrystal synthesis.12 Within this context, cocrystal synthesis by grinding has proven superior to the more traditional method of synthesis from solution. Examples and methodologies of cocrystal formation using grinding have been summarized in reviews by Braga and co-workers.13,14 This review will aim to complement these reviews by focusing on the mechanistic aspects of cocrystal formation by grinding. We believe such an overview is timely, as cocrystallization by grinding is reaching a point where its further advance requires a better understanding of the underlying mechanisms at the macroscopic level (which involve bulk phase transformations) as well as at the microscopic level, involving the formation of individual supramolecular bonds and synthons.15 Whereas the macroscopic aspects of grinding are * To whom correspondence should be addressed. E-mail: [email protected].

becoming clear, the processes that control mechanochemical cocrystal formation at the microscopic level have just begun to be unraveled. Furthermore, it is clear that progress in solidstate supramolecular synthesis today is greatly enhanced by the integration of advanced methods of solid-state analysis: structure solution from X-ray powder diffraction (XRPD) data, solidstate NMR (SS NMR) spectroscopy,16 and terahertz (THz) spectroscopy.17 In this review, we will aim to illustrate this ongoing integration through appropriate examples. 1.1. Cocrystals: Definitions, Design, and Applications. The exact origin of the term cocrystal is unclear, but it is generally recognized that it was introduced into the lexicon of organic solid-state chemistry by Etter and co-workers to describe molecular crystals composed of more than one type of chemical species.18 Recently, several criteria for the rigorous definition of a cocrystal have been proposed, such as the state of aggregation of the cocrystal components or the degree of supramolecular design.19 For the purpose of this review, we adopt the broadest possible definition that all crystalline molecular solids composed of chemically distinct species should be considered as cocrystals.20 Following this definition, similar to the one considered by Dunitz,19 cocrystals (or cocrystals) would encompass hydrates, solvates, as well as solid solutions of molecular compounds. The two most important reasons underlying the rapid success of cocrystallization as a method of constructing advanced materials can be identified as (i) the ability to construct cocrystals following a simple design based on supramolecular synthons,15,21 and (ii) the modularity of the design,22 that allows the exchange of cocrystal components with the intention of improving a particular solid-state property. This has been demonstrated by MacGillivray and co-workers in the development of a “template-switching” strategy to optimize the yield of solid-state [2 + 2] photodimerization reactions in cocrystals.23,24

10.1021/cg800764n CCC: $40.75  2009 American Chemical Society Published on Web 02/04/2009

1622 Crystal Growth & Design, Vol. 9, No. 3, 2009 Scheme 1. Molecular Diagrams of Cocrystal Components p-Benzoquinone, 2,2′- and 4,4′-Biphenol

The synthon-based design of cocrystals is continuously being expanded with halogen-25 or hydrogen-bonding26 functional groups and supramolecular synthons, expanding the diversity of potential cocrystals and cocrystal components. The modularity of cocrystal design22 is exemplified in the definition of a pharmaceutical cocrystal by Zaworotko and coworkers,27 wherein a pharmaceutical cocrystal represents a new solid form of an active pharmaceutical ingredient (API) consisting of the API and a counter-molecule, the pharmaceutical cocrystal former. A similar design has been developed in the area of molecular semiconducting materials by MacGillivray and co-workers, involving a molecular semiconductor building block (SBB) and a semiconductor cocrystal former (SCF).9 An extensively explored application of cocrystals is the control and design of solid-state reactions,11 since the formation of cocrystals provides a unique opportunity to position molecules within a topochemical range. So far, cocrystals have been used to induce and control a range of solid-state reactions, involving nucleophillic substitution reactions,28 [2 + 2] photodimerizations,11,29 diacetylene and triacetylene polymerizations,30 and Diels-Alder reactions.31 1.2. Mechanochemical Cocrystallization and Cocrystallization from Solution. The earliest example of mechanochemical cocrystallization most likely dates from 1893 with the formation of the quinhydrone cocrystal from equimolar amounts of p-benzoquinone and hydroquinone.32 Quinhydrone is also most likely to be the first example of a cocrystal preorganized for a single-crystal-to-single-crystal chemical reaction, since its structure enables a reversible radiation-induced proton transfer through a low-barrier hydrogen bond to form a crystalline semiquinone radical.33 The field of mechanochemical cocrystallization began to develop following efforts of Paul and Curtin34 as well as Etter and co-workers,35 who demonstrated that supramolecular synthesis in the solid state provides a degree of molecular recognition and a diversity of products matching and indeed extending those observed in solution.36 The early reports that the grinding of reactants together can produce cocrystal products not accessible by cocrystallization from solution were provided by Patil et al. for the synthesis of quinhydrones,34 Toda and co-workers in the context of inclusion compounds of 1,4-naphthoquinone,37 and Hollingsworth and coworkers for urea inclusion compounds.38 The application of mechanochemical synthesis for the construction of multicomponent hydrogen-bonded crystals of organometallic compounds has been extensively studied by Braga and co-workers.39 The observed increased efficiency of different grinding methodologies for cocrystal synthesis over solution-based approaches is most likely the result of largely avoiding the effects of solubility and solvent competition that cannot be avoided during solution crystallization. 1.3. Neat and Liquid-Assisted Grinding. It is useful to identify two different techniques for cocrystal synthesis via grinding. Historically, the first method is neat (dry) grinding,40 consisting of mixing the cocrystal components together and grinding them either manually, using a mortar and pestle, or

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mechanically, using a ball mill or a vibratory mill.38 The second technique for cocrystal synthesis via grinding is that of liquidassisted grinding41 (or kneading39). The method was originally termed solvent-drop grinding,42 but this name is no longer preferred, primarily reflecting different ideas concerning the mechanism in the presence of the liquid.43 In a typical liquidassisted grinding procedure, a small (catalytic) amount44 of an additional liquid is added to the grinding mixture.45 The liquidassisted grinding methodology was originally introduced as a means to increase the rate of cocrystal formation in the solid state, although it was soon established that it provided further benefits over neat grinding procedures, including higher yield, higher crystallinity of the product, ability to control polymorph formation, and a significantly larger scope of reactants and products.41,42,46 Both neat and liquid-assisted grinding have been established as highly efficient methods of screening for cocrystals,41,46 salts,47 and polymorphic forms of pharmaceutical compounds.48 Recently, liquid-assisted grinding of pairs of enantiomeric cocrystals has been introduced as a novel technique of cocrystal-cocrystal grinding for the synthesis and dismantling of cocrystals.20,49,50 1.4. Crystal Structure Determination. The crystal structure of the product from a cocrystallization reaction is without doubt the most important piece of information for the supramolecular synthetic chemists. Unfortunately, the particle size obtained from a grinding reaction prohibits structural characterization via the standard technique of single crystal diffraction. In some cases, however, the product that is obtained via grinding can also be obtained by solution growth after testing a sufficient number of crystallization conditions.51 This then allows the preparation of single crystals for structure determination by normal single crystal methods. In those cases where grinding and solution cocrystallization consistently provide different products, it is sometimes possible to seed a supersaturated solution of the cocrystal components with the material obtained by grinding,46 leading to the crystallization of the desired phase. In cases where solution growth and seeding experiments fail, recent advances in powder X-ray methods and data analysis software enable a fairly routine approach to crystal structure solution from powder data.52 This approach can also be aided through methods of crystal structure prediction (CSP),53 as well as other techniques of solid-state characterization, such as solid-state CP-MAS NMR. In particular, 15N solid-state NMR has been used to differentiate between cocrystal or salt formation in acid-base combinations.51,54 The technique has also been employed recently to aid the ambiguous structure determination of a pair of isostructural cocrystals for which X-ray powder data was not sufficiently informative.50 In that context, THz spectroscopy has recently been compared to PXRD and solid-state FT Raman spectroscopy in the ability to differentiate chiral and racemic cocrystals of similar architecture.55

2. Mechanisms of Neat Grinding Cocrystallization Studies of the macroscopic mechanism of neat (dry) grinding suggest that solid-state cocrystallization cannot be described assuming a single mechanism. Instead, several mechanisms appear to operate through which cocrystals can form on grinding, each mechanism involving a different type of intermediate phase. In particular, the recognized mechanisms would include: molecular diffusion, eutectic formation,56 and cocrystallization mediated by an amorphous phase.57 Common to all three distinct mechanisms is that the intermediate bulk phase (a gas, a liquid, or an amorphous solid) should exhibit enhanced mobility and/ or higher energy of reactant molecules with respect to their

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Crystal Growth & Design, Vol. 9, No. 3, 2009 1623

Figure 1. Hydrogen-bonded chains in the cocrystal of p-benzoquinone and (a) 2,2′-biphenol and (b) 4,4′-biphenol.

Figure 2. (a) Molecular diagram of bis-β-naphthol; (b) and (c) finite and infinite assemblies of p-benzoquinone with racemic bis-β-naphthol that are obtained by grinding and from solution, respectively.62

Figure 3. (a) Molecular diagrams of cocrystal components investigated by Rastogi et al.63 Stacking of molecules in the cocrystal of picric acid with (b) naphthalene and (c) anthracene.

starting crystalline forms.58 Although the examples that we give below represent case studies for each mechanism, there is no reason why the formation of a particular cocrystal could not be simultaneously controlled by several or all of these mechanisms. 2.1. Neat Grinding Cocrystallization through Molecular Diffusion. Cocrystallization through molecular diffusion between two solid reactants is likely to occur in cases where one or both reactants exhibit significant vapor pressures in the solid state. Product formation in such systems is expected to occur readily upon contact between reactant solids, even in the

absence of mechanochemical agitation. It has been established by Rastogi and co-workers that surface migration and diffusion through the vapor phase are the principal mechanisms for the formation of picric acid cocrystals with aromatic hydrocarbons.59 These are also the likely mechanisms for the formation of twoand three-component cocrystals by grinding the volatile solid p-benzoquinone with various phenol derivatives.60,61 That cocrystal formation with p-benzoquinone can be mediated by molecular diffusion was demonstrated by Kuroda and co-workers for p-benzoquinone cocrystals with either 2,2′biphenol or 4,4′-biphenol (Scheme 1).62 Mixing in the solid-state crystals of p-benzoquinone with any of the two crystalline biphenol compounds results in the rapid formation of highly colored cocrystal products, with the components held together through charge-transfer and hydrogenbond interactions (Figure 1). The formation of a cocrystal is also observed upon exposing the crystals of 2,2′-biphenol or 4,4′-biphenol to vapors of p-benzoquinone, again demonstrating that cocrystal formation is aided by diffusion through the gas phase.62 The rate of cocrystal formation by mixing in the solid state was reported to be much slower in the case of 4,4′-biphenol, than for the 2,2′-analogue. This difference in reactivity between the two phenols was explained by a more extensive hydrogen bonding network in the crystal structure of 4,4′-biphenol that hindered the surface diffusion of molecules. The cocrystal formation between powdered p-benzoquinone and 2,2′-biphenol was found to proceed for approximately 60 h in a nonagitated mixture of solid reactants. After that, the reaction could be again initiated and brought to completion by brief milling of the reaction mixture, again suggesting that the cocrystal formation is limited by the availability of fresh surfaces for molecular diffusion on the reactant crystals. This interpretation was supported by vapor diffusion experiments, where cocrystal formation was observed

1624 Crystal Growth & Design, Vol. 9, No. 3, 2009

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Scheme 2. The course of a Solid-solid Reaction through Gas-Phase and Surface Diffusion in the Absence (left) and with the Aid (right) of Grindinga

a

The yellow and blue circles represent molecules of reactant solids, whereas green circles represent constituents of the cocrystal product.

Figure 4. (a) Molecular diagram of p-tert-butylcalix-[4]-arene. Wireframe models of molecular arrangement in (b) high-density thermodynamic and (c) porous, low-density kinetic polymorphs of p-tert-butylcalix-[4]-arene.

only on the surface of biphenol reactant crystals that were exposed to p-benzoquinone vapor. Consequently, the role of mechanochemical grinding in solid-state cocrystallization of p-benzoquinone with 2,2′- or 4,4′-biphenol appears to be to enhance the reaction rate by exposing fresh reactant surfaces and mixing the solid reaction mixture.62 In case of racemic bis-β-naphthol (Figure 2a), exposure to p-benzoquinone vapor or solid-state mixing with p-benzoquinone does not provide a cocrystal.62 Nevertheless, grinding of a 2:3 stoichiometric mixture of bis-β-naphthol and p-

benzoquinone provides a cocrystal of that exact stoichiometric composition, composed of finite hydrogen-bonded molecular assemblies (Figure 2b). This would suggest that mechanochemical grinding can play a more important role in cocrystal formation than simply mixing of volatile solid reactants. In particular, grinding was suggested to enable cocrystal formation by overcoming the strong intermolecular forces that hold together the molecules in the crystal of the reactant bis-βnaphthol.62 This is believed to involve forming disordered molecular layers on the surface of reactant crystals through

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Figure 5. (a) External space-filling view of the molecular assembly in the dense-packed thermodynamic polymorph of p-tert-butylcalix-[4]-arene and (b) the cross-section view of the assembly, revealing the ≈40 Å3 pore. For clarity, the molecules surrounding the pore are color-coded and the pore is marked with a yellow circle.

Scheme 3. Molecular Diagrams of Cocrystal Components Caffeine and Acetic Acid

Scheme 4. Reactivity of Caffeine Towards Cocrystallization with Acetic Acid in (a) Grinding and (b) Solution

Figure 6. (a) Molecular diagrams of theophylline and citric acid and (b) wireframe representation of the asymmetric unit of the cocrystal hydrate involving theophylline and citric acid.68

shearingsa mechanism akin to the formation of an amorphous phase, but constrained to the two-dimensional crystal surface. The change from a vapor diffusion-aided mechanism of cocrystal formation in case of 2,2′-biphenol and 4,4′-biphenol to a mechanism that requires mechanochemical activation of reactant surface has been explained by significantly stronger intermolecular forces in the crystals of pure β-naphthol.62 In contrast to solid-state grinding, cocrystallization of the racemic bis-βnaphthol and p-benzoquinone from solution yields a different cocrystal of 1:1 composition, that consists of infinite hydrogenbonded tapes (Figure 2c). The importance of molecular surface diffusion in grinding cocrystallization was first recognized by Rastogi et al. who

monitored the reaction rates of picric acid with different aromatic cocrystal formers (Figure 3).63 Their results suggested a model in which both vapor and surface diffusion aid the formation of the cocrystal. In particular, a significant participation of vapor diffusion was suggested for the cocrystal with naphthalene, while for the heavier aromatic hydrocarbons surface diffusion was a more important cocrystal forming process, consistent with lower vapor pressures of these molecules. The shape and symmetry of molecules were also observed to influence the reaction rate to a lesser extent, with flat and smooth molecules typically reacting faster than the ones that involve bulky substituents. Overall, the experiments of the Rastogi and Kuroda groups suggest a cocrystal forming mechanism that predominantly involves surface diffusion, assisted to varying degrees by diffusion through the gas phase. The role of mechanochemical grinding in such systems is to enhance surface diffusion through mixing the reactants, make fresh reactive surfaces available by removing the product, and activate the reacting surface through introducing strain and defects (Scheme 2). Indeed, the movement of molecules and molecular assemblies over the surface of a crystal, caused by mechano-


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Figure 7. Similar structural motifs between (a) cocrystal hydrate of theophylline and citric acid; (b) citric acid monohydrate, and (c) theophylline monohydrate.68

Scheme 5. An Overview of Solid-State Reactions of Hydrated and Non-Hydrated Forms of Theophylline and Citric Acid68

chemical stress, was studied by Kaupp et al. by nanoscratching and imaging surfaces of molecular crystals using the atomic force microscope (AFM).64 As a result, a three-step mechanism for mechanochemical organic reactions was proposed, that is particularly efficient for gas-solid reactions. Although this mechanism, that consists of phase rebuilding, phase transformation and crystal disintegration steps, was primarily proposed for mechanochemical transformations of molecules, it may very well be significant for the solid-state formation of cocrystals and salts.64 However, the diffusion of molecules is not necessarily restricted to the surface layers of reactant crystals, but can also penetrate into the crystal, if aided by a concerted movement of molecules. This has been demonstrated by Atwood and coworkers who studied the uptake of vapors and gases into nonporous organic solids. In particular, the nonporous thermodynamically stable polymorph of p-tert-butyl-subsituted deriva-

tive of calyx[4]-arene (Figure 4a,b) was found to readily absorb small molecule gases CO2 or N2O under pressure, resulting in the formation of inclusion compounds based on the structure of the porous kinetic polymorph (Figure 4c).65 The reaction is thought to proceed via a mechanism in which the first step is gas inclusion within 40 Å3 voids that exist in the crystal structure of the reactant solid (Figure 5). The large magnitude of molecular movement required for such structural transformations is probably enabled by concerted molecular mobility, similar to that previously observed by Atwood et al. for single-crystal-to-single-crystal inclusion66 of guest molecules within the kinetic (porous) polymorph of p-tert-butylcalix-[4]arene (Figure 4c).67 Although not mechanochemical, this example demonstrates long-range molecular movements that could be relevant in mechanochemical reactions between molecular solids.

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Figure 8. (a) Molecular diagrams of cocrystal components diphenylamine and benzophenone; (b) wireframe representation of a single hydrogenbonded assembly in the cocrystal of benzophenone and diphenylamine; and (c) sketch of the binary phase diagram for the mixture of diphenylamine and benzophenone, after Chadwick et al.56 Point A (red) corresponds to the melting point of the submerged eutectic, and the path from A to B (blue) corresponds to the crystallization of the cocrystal from the intermediate eutectic phase.

Figure 9. (a) Molecular diagrams of pharmaceutical cocrystal components saccharine and carbamazepine and (b) wireframe representation of a four-membered molecular assembly in the structure of the pharmaceutical cocrystal of carbamazepine and saccharin.58

2.2. Neat Grinding Cocrystallization Mediated via Liquid PhaseIn mechanochemical cocrystallization mediated by a liquid phase the formation of solid cocrystal product is facilitated by an intermediate liquid phase, that subsequently becomes a part of the cocrystal product and gradually disappears as the reaction approaches completion. The simplest case of a liquid-mediated mechanochemical cocrystal synthesis is clearly when one of the reactants is a liquid under ambient conditions.46,51-53 Alternative examples are those liquid-assisted grinding reactions wherein the liquid phase is originally added with the intention to enhance cocrystal formation but unexpectedly forms a cocrystal hydrate structure.68 In reactions where the liquid templates the formation of a two-component host inclusion framework,41,69 the liquid phase is also depleted from the reaction mixture. However, in this case the depletion of the liquid phase is typically the consequence of loose molecular inclusion within the resulting framework, rather than the formation of strong intermolecular bonds as in a cocrystal hydrate. Consequently, such framework-templating reactions are discussed with other liquid-assisted grinding reactions in Section 3. Mechanochemical cocrystallization can also be mediated by a liquid phase in cases where cocrystal components form an undercooled, metastable eutectic phase that subsequently solidifies to provide the cocrystal.56 2.2.1. Grinding with Liquid Reactants vs Recrystallization from a Solution in Liquid Reactant. There are numerous examples of hydrogen-52,53 or halogen-bonded51,70,71 cocrystal formation which involve at least one component that

is a liquid at ambient conditions. Under these conditions, it is likely that cocrystal formation is facilitated by the presence of a reactant liquid phase that, presumably, enhances molecular diffusion. Cocrystallization by neat grinding a liquid reactant (i.e., no additional liquid) is different to cocrystal formation by recrystallizing a solid cocrystal component the same liquid reactant, and it can provide products that are not accessible from a simple dissolution-recrystallization procedure. This is illustrated in case of solid caffeine and liquid acetic acid as the cocrystal components (Scheme 3).46 Recrystallization of caffeine from a solution in liquid acetic acid results in the formation of a cocrystal composed of caffeine and acetic acid in a respective 1:2 stoichiometric ratio. The structure consists of finite hydrogen-bonded assemblies. The same cocrystal can also be obtained by direct grinding of caffeine and acetic acid in a 1:2 stoichiometric ratio.46 However, the direct grinding methodology also allows reaction of equimolar amounts of caffeine and acetic acid. Under these circumstances, a cocrystal is formed where the stoichiometric ratio of caffeine to acetic acid is 1:1.46 This cocrystal, to date not accessible from a solution in acetic acid, is composed of finite hydrogen-bonded molecular assemblies that structurally resemble the assemblies of the 1:2 cocrystal, although lacking one molecule of acetic acid (Scheme 4).46 2.2.2. Formation of Cocrystal Hydrates. The addition of a liquid to a grinding mixture of two cocrystal components can sometimes enable cocrystallization through the formation of a product that incorporates the molecules of the liquid as a constituent. For that reason, grinding with liquid components is a versatile technique for searching for three-component cocrystals (e.g., cocrystal hydrates,68 inclusion compounds41,69). In some cases, the formation of a three-component cocrystal hydrate can be achieved either by using liquid water as the reactant or by using as reactants one or more crystalline hydrates in the grinding synthesis. For example, neat grinding of anhydrous theophylline and anhydrous citric acid (Figure 6a) with a small amount of water provides a cocrystal hydrate that consists of theophylline, citric acid, and water in equal stoichiometric proportions (Figure 6b).68 The same cocrystal hydrate is also obtained by the neat grinding of theophylline hydrate with anhydrous citric acid, the neat grinding of anhydrous theophylline with citric acid monohydrate, as well as the neat grinding of theophylline monohydrate with citric acid monohydrate. Neat grinding of anhydrous


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Figure 10. An overview of solid-state reactions of hydrated and nonhydrated forms of caffeine and citric acid.68

Figure 11. (a) Molecular diagrams of cocrystal components phenazine and mesaconic acid and (b) fragment of a hydrogen-bonded chain in the cocrystal of phenazine and mesaconic acid.

Figure 12. (a) Chemical diagrams of sulfamidine and cocrystal formers explored by Caira and co-workers78 and (b) fragment of the crystal structure of the sulfamidine cocrystal with anthranilic acid.

theophylline and anhydrous citric acid, by contrast, leads to the formation of an anhydrous cocrystal of 1:1 stoichiometry (Scheme 5). The similarity of the supramolecular motifs within the cocrystal hydrate to those observed in theophylline monohydrate

and citric acid monohydrate crystals (Figure 7) suggests that, in the presence of water, the formation of the cocrystal hydrate is likely to be preferred to the formation of an anhydrous cocrystal.68 Interestingly, a set of similar experiments involving anhydrous β-caffeine and caffeine hydrate instead of theophyl-

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Figure 13. The stepwise formation of linear infinite halogen-bonded chains of the cocrystal of 1,4-thiomorpholine and tetrafluoro-1,4-diiodobenzene, via a finite assembly intermediate.71

Figure 14. The stepwise formation of infinite zigzag halogen-bonded chains of the cocrystal of 1,4-thiomorpholine and tetrafluoro-1,2-diiodobenzene, via a finite assembly intermediate.71

Figure 15. (a) The stepwise synthesis of the 2:1 cocrystal of nicotinamide and suberic acid, via the intermediate 1:1 cocrystal; (b) relevant hydrogenbonded synthons for each cocrystal, along with approximate enthalpies of formation.80

line and theophylline monohydrate revealed that the addition of water enables the cocrystallization of caffeine with citric acid to form an anhydrous cocrystal, perhaps through the formation of the intermediate caffeine hydrate that is more reactive toward citric acid than anhydrous β-caffeine.68 2.2.3. Eutectic Formation. It is expected that understanding the role of eutectic formation in cocrystal synthesis will become increasingly important in the context of pharmacutical materials, as demonstrated by the recent development of a eutectic-based thermal methodology for cocrystal synthesis by Rodrı´guezHornedo and co-workers.72 Cocrystal formation preceded by the formation of a metastable eutectic liquid phase was investigated by Davey and co-workers in the case of diphenylamine and benzophenone cocrystal (Figure 8a).56 Upon cocrystallization from solution, the two components form a

cocrystal consisting of discrete heteromolecular assemblies held via a single N-H · · · O hydrogen bond (Figure 8b).73 Upon mixing of the two colorless cocrystal constituents in the solid state, the formation of a yellow cocrystal phase is rapidly (within one minute) observed at the interface of the two solids.56 Microscopic observation of the interface between two macroscopic single crystals of diphenylamine and benzophenoáne revealed the melting of the surface that proceeds until most of the material is converted to a liquid at room temperature. Subsequent nucleation of the cocrystal phase results in the solidification of the entire melt to form the solid cocrystal.56 Consequently, the role of grinding in a eutectic-mediated cocrystallization is most likely 2-fold: first, it provides agitation to expose fresh reactant surfaces for eutectic formation and second, it enhances cocrystal formation through inducing cocrystal nucleation in the eutectic phase.


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Figure 16. Three-component phase diagrams for cocrystal component that are (a) congruently and (b) incongruently soluble in a solvent, sketched after to the work of Chiarella et al. 85a The regions of composition corresponding to typical solution-phase and grinding experiments are marked blue and red, respectively.

2.3. Neat Grinding Cocrystallization Mediated by an Amorphous Phase. The formation of an amorphous intermediate is the most likely mechanism of cocrystal formation in the absence of a special mass transfer pathway that would include a liquid or a gas. Conversely, cocrystallization of molecular solids that are not volatile and are held together via strong intermolecular interactions (e.g., hydrogen bonds) is most likely to proceed via an amorphous intermediate. This consideration

is of particular importance in context of pharmaceutical cocrystallization, since a large number of pharmaceutical compounds correspond to the above description. That cocrystal formation via neat grinding is mediated by an amorphous intermediate provides an opportunity to control the outcome of mechanochemical cocrystallization through manipulating the temperature of the grinding process. Such a possibility has been demonstrated by Descamps and co-workers74 for single com-

Reviews Scheme 6. Molecular Diagrams of Cocrystal Components Theobromine and Malonic Acid

ponent systems such as lactose, trehalose, mannitol, and sorbitol. It was concluded that grinding of materials at temperatures below their glass transition point is most likely to result in vitrification to produce an amorphous phase.74 On the other hand, grinding at temperatures that are close to or higher than the glass transition temperature of the ground material is expected to favor the formation of metastable polymorphic forms. In the context of pharmaceutical cocrystals, Rodrı´guezHornedo and co-workers58 have demonstrated that grinding together the cocrystal components carbamazapine and saccharin (Figure 9a) below the expected glass transition temperature of their mixture provides an amorphous phase which, upon standing at room temperature, slowly undergoes a transformation to form the cocrystal (Figure 9b).75 However, grinding of the two reactants at room temperature results in partial amorphization, as well as cocrystal formation. Upon storage at room temperature, the yield of cocrystal in the ground material slowly increases to subsequently provide the pure cocrystal. These results are consistent with a solid-state reaction mechanism wherein mechanochemical agitation enables the cocrystallization of solid carbamazepine and saccharin by producing the amorphous phase as the intermediate of high energy and high molecular mobility. The amorphous phase subsequently transforms into the cocrystal either slowly on storage, or faster through additional grinding. The conversion of amorphous phase is inhibited at low temperatures and is facilitated at temperatures that are close to the glass transition temperature of the amorphous mixture, which can be approximated from the glass transition temperatures of individual cocrystal components.58 Since the formation of carbamazepine-saccharin cocrystal upon neat grinding depends on the glass transition temperature of the amorphous intermediate,75 cocrystallization can be facilitated at lower temperatures by using a plasticizer such as water.58 This is demonstrated by storing the amorphous intermediate at 75% relative humidity or by performing the neat grinding experiment using carbamazepine dihydrate as the reactant. In both cases an enhancement in the rate of cocrystal formation was observed with respect to storage under 0% relative humidity and grinding with anhydrous carbamazepine, respectively.58 In addition to acting as a plasticizer, moisture can generate cocrystals from mixtures of solid cocrystal components under deliquescent conditions, that is, in the presence of a deliquescent substance that in moist atmosphere generates a liquid medium for cocrystallization. In these cases, cocrystal formation occurs through a three-step mechanism that involves moisture uptake, reactant dissolution, followed by cocrystal nucleation and growth.76 At this point it may be noted that a different effect of water of crystallization on the course of solid-state grinding reaction has been observed in case of caffeine and citric acid.68 Neat grinding of anhydrous β-caffeine with either anhydrous citric acid or citric acid monohydrate does not provide a cocrystal product. In contrast, neat grinding together caffeine hydrate with


either anhydrous citric acid or citric acid hydrate readily provides a 1:1 cocrystal of caffeine and citric acid, also known as “caffeine citrate” (Figure 10). That cocrystallization occurs only when water is present in the form of caffeine hydrate, and not in the presence of citric acid hydrate, suggests that cocrystal formation is the result of lower thermodynamic stability of caffeine hydrate with respect to β-caffeine, rather than of the plasticizing effect of water.68 The participation of an amorphous phase intermediate during a neat grinding cocrystallization reaction has also been observed by Nguyen et al.,57 in context of nonpharmaceutical materials, through combined use of X-ray powder diffraction (XRPD) and terahertz timed-domain spectroscopy (THz-TDS). Specifically, the mechanochemical neat grinding reaction between solids phenazine and mesaconic acid, that provides a 1:1 hydrogenbonded cocrystal (Figure 11),77 was followed simultaneously through THz-TDS and XRPD. After 60 min of grinding, XRPD indicated complete conversion of the starting materials to the cocrystal, while THz-TDS data indicated around only 60% yield of the cocrystal. This indicated that approximately 40% of the ground material was present in the form of an amorphous phase that was difficult to detect using either XRPD or THz-TDS. This was further supported by the observation that the yield of the cocrystal, according to THz-TDS measurements, was observed to increase to around 80% upon storing the ground samples at room temperature. In addition, grinding the reaction mixture for longer than 60 min was found to reduce the yield of the cocrystal, as observed by THz-TDS.57 The same effect was observed by neat grinding of pure, solution-grown cocrystals of phenazine and mesaconic acid,77 and is readily explained by amorphization of the cocrystal. In addition to providing a means to detect and quantify amorphous intermediates during neat grinding cocrystallization, THz-TDS also revealed an adverse effect of extensive grinding on mechanochemical cocrystal formation.57 This suggests there may exist an optimum time for a neat grinding reaction, during which the mechanochemical cocrystal buildup is not significantly set back by amorphization of the cocrystal. The mechanistic aspects of neat grinding cocrystallization of the pharmaceutical drug sulfamidine with a variety of carboxylic acids as cocrystal formers were investigated by Caira and coworkers (Figure 12).78 It was established that cocrystallizations with salicylic and anthranilic acids follow a first-order reaction law with respective reaction rate constants of 0.11 min-1 and 0.08 min-1, indicating a random nucleation process. As the authors did not report the formation of a liquid intermediate during neat grinding cocrystallization, it is likely that these reactions also proceed via an intermediate amorphous phase. Neat grinding of sulfamidine with carboxylic acids also revealed a possible effect of the reactant crystal structure on the outcome of mechanochemical cocrystallization. In particular, competition grinding experiments, wherein sulfonamidine was ground with a 1:1 mixture of anthranilic acid and salicylic, benzoic, or acetylsalicylic acid, resulted in exclusive formation of the cocrystal involving anthranilic acid.78 This preference of sulfamidine toward anthranilic acid as a cocrystal former was also evident in solid-state substitution experiments wherein cocrystals of sulfamidine with salicylic, benzoic or acetylsalicylic acid were grond with anthranilic acid. In each case, neat grinding resulted in the displacement of the cocrystal former from the cocrystal and formation of the sulfamidine cocrystal with anthranilic acid. These observations were interpreted as results of differences in crystal structures of investigated cocrystal formers. In particular, salicylic, benzoic and acetyl-


Reviews

Figure 17. Wireframe representation of a fragment of a hydrogen-bonded chain in the cocrystal of theobromine and malonic acid, as established using structure solution from X-ray powder diffraction.52

Figure 18. (a) Molecular diagram of adipic acid and (b) fragment of the crystal structure of the cocrystal of caffeine with adipic acid.41,86

salicylic acids in their respective solids form dimers held by pairs of O-H · · · O bonds organized into R22(8) homodimeric motifs, whereas anthranilic acid in its relevant polymorph I forms hydrogen-bonded chains of zwitterionic molecules. Presumably, the absence of R22(8) dimers in solid anthranilic acid facilitates the migration of molecules from its crystal, resulting in higher reactivity as compared to other carboxylic acids. 2.4. Hierarchy of Supramolecular Interactions in Mechanochemical Cocrystallization. The mechanism of mechanochemical cocrystal formation was so far considered in the macroscopic sense of transformations between bulk reactant, intermediate and product phases. Cincˇic´ et al. have recently addressed the mechanism of neat grinding cocrystallization at the microscopic level, that is, from the standpoint of forming and cleaving individual supramolecular bonds.71 In particular, the formation of halogen-bonded cocrystals of the heteroditopic halogen bond acceptor 1,4-thiomorpholine with linear or bent halogen bond donors was observed to proceed via a stepwise mechanism. In case of the linear 1,4-diiodotetrafluorobenzene donor, the first step of the grinding reaction is the formation of finite three-component assemblies in the solid state, held together by N · · · I halogen bonds.71 The assemblies further react with additional halogen bond donor, if available, to yield cocrystals composed of infinite halogen-bonded chains that are held together via N · · · I and S · · · I interactions (Figure 13).51 Analogous behavior was observed in case of the bent halogen bond 1,2-diiodotetrafluorobenzene, wherein the first step in grinding cocrystallization was the formation of finite fivemembered assemblies held via three N · · · I and a single S · · · I bond. The finite assemblies again cross-link with additional halogen bond donor to form infinite zigzag chains held together by alternating N · · · I and S · · · I halogen bond interactions (Figure 14).71 The stepwise mechanism of cocrystal formation has been interpreted in terms of kinetic and thermodynamic cocrystalli-

zation products, wherein the formation of finite assemblies is the kinetic result driven by the predominant formation of stronger N · · · I halogen bond interactions.71 The formation of the thermodynamic product follows through the formation of enthalpically less favorable halogen bond interactions of the S · · · I type. Consequently, the observed stepwise mechanism is most likely the consequence of the hierarchy79 of strong and weak halogen bonding forces in the solid reaction mixture. Such sequential formation of products may also be common in mechanochemical cocrystallization mediated via an amorphous phase, reminiscent of the Ostwald’s rule of stages80 observed for polymorph crystallization from an amorphous solid.81 The stepwise mechanism is likely to be a general characteristic of cocrystal formation by grinding reactant molecules that have significantly different halogen- or hydrogen-bonding sites. Indeed, Karki et al.82 have reported that the neat grinding formation of a 2:1 cocrystal of nicotinamide and suberic acid proceeds through an intermediate cocrystal having a 1:1 stoichiometry (Figure 15). Considering the approximate enthalpies of hydrogen-bonded supramolecular synthons that could form by combining amide, pyridine and carboxylic acid moieties of nicotinamide and suberic acid provided a tentative explanation of this stepwise process. In particular, the initial formation of the 1:1 cocrystal was explained by the kinetically controlled formation of strongest possible supramolecular synthons: the pyridine-carboxylic acid R22(7) (≈10 kJ mol-1) and amidecarboxylic acid R22(8) (≈15 kJ mol-1) heterosynthons. Subsequent formation of the 1:2 cocrystal by grinding with excess nicotinamide results in the dismantling of the strongest amidecarboxylic acid R22(8) heterosynthons, compensated by the formation of pairs of weaker pyridine-carboxylic acid R22(7) and amide-amide (≈13 kJ mol-1) R22(8) homosynthons.

3. Liquid-Assisted Grinding The recent addition to the toolbox of solid-state supramolecular synthesis is liquid-assisted grinding.41-43 In contrast to neat grinding cocrystallization mediated by a liquid phase, where the liquid phase is depleted in course of the cocrystallization reaction, in a liquid-assisted grinding reaction the liquid phase has a catalytic role44 and its amount is generally not expected to diminish during the reaction, except perhaps by accidental evaporation.83 An exception to this are liquid-assisted grinding reactions wherein the molecules of the liquid phase template the formation of a porous framework and, consequently, can remain loosely bound within the structure of the product.41,69 It is presently not clear how the liquid phase contributes to the superior efficiency of liquid-assisted grinding in comparison to both neat grinding and solution-based approaches.20 In some cases the small amount of liquid has been suggested to have a purely physical role, acting as a lubricant for the reaction and providing a medium to facilitate molecular diffusion. In other cases, it appears that the nature of the grinding liquid can have a profound effect on the course of mechanochemical cocrys-

Reviews


Scheme 7. (a) Molecular Diagrams of Cocrystal Components 1,1′-Bis(4-pyridyl)ferrocene and Pimelic Acid and (b) the Formation of a Cocrystal or a Salt Involving Pimelic Acid and 1,1′-Bis(4-pyridyl)ferrocene upon Neat Grinding or Exposure to Solvent Vapor, Respectively

Scheme 8. Molecular Diagram of Glutaric Acid

tallization,84 for example, by templating the formation of a multicomponent inclusion framework.41,69 3.1. Liquid as a Medium for Molecular Diffusion. The suggestion that the outcome of liquid-assisted grinding could be independent of the chemical nature of the grinding liquid is supported by the recent analysis, performed by Chiarella, Davey and Peterson, of three-component phase diagrams involving nicotinamide and cinnamic acid as cocrystal components and either water or methanol as a solvent.85a The analysis of the phase diagrams explains the difficulty in obtaining the cocrystal from solution-phase experiments. Cocrystallization from a solvent where the two components are incongruently soluble (i.e., show markedly different solubilities) is likely to result in the precipitation of individual cocrystal components, whereas cocrystallization from a solvent where the components have similar solubilities is expected to yield a cocrystal (Figure 16). This is illustrated by the vertical dotted line in three-component phase diagrams of Figure 16, that corresponds to the process of solvent evaporation. In case when solubilities of cocrystal components are similar (Figure 16a), the dotted line passes

Figure 19. Wireframe representations of the cocrystal of caffeine (yellow) and glutaric acid (black) polymorphs: (a) A obtained by grinding with cyclohexane and (b) B obtained by grinding with chloroform.84

through the region of the diagram corresponding to an undersaturated solution and crosses the line that indicates the solubility of the cocrystal. This indicates that solvent removal results in the formation of the cocrystal as the solid phase. In case when solubilities of cocrystal components are very different (Figure 16b), the dotted line first crosses the line corresponding to the solubility of the least soluble cocrystal component. In this case, solvent removal results in the precipitation of the least soluble component. Since neat and liquid-assisted grinding reactions typically occur in the region of the phase diagram where the content of the solvent is low, the cocrystal is always expected to be the thermodynamically most stable phase (Figure 16b). The low solvent fraction in LAG also indicates that the relative solubilities of the two components are of little significance in controlling the outcome of liquid-assisted grinding.85b For that reason, the liquid phase can be considered as predominantly a means to enhance molecular diffusion. An example of how liquid-assisted grinding can circumvent the problems related to solubility of cocrystal components is given by the cocrystallization of theobromine with malonic acid (Scheme 6).52 Cocrystal formation between the two components was virtually impossible due to the low solubility and rapid precipitation of theobromine. Nevertheless, liquid-assisted grinding of equimolar amounts of theobromine and malonic acid readily yielded the cocrystal in quantitative yield within 20 min.

Figure 20. (a) Molecular diagram of hydrogen-bonded framework component succinic acid and (b) a space-filling representation of a fragment of the hydrogen-bonded framework of caffeine and succinic acid.41 Guest molecules have been omitted for clarity.


Reviews

Figure 21. (a) The library of molecules investigated as templates in the mechanochemical construction of hydrogen-bonded frameworks involving caffeine and succinic acid; (b) a space-filling model of the alternative hydrogen-bonded framework of caffeine and succinic acid,69 with guest molecules omitted for clarity; and (c) molecular parameters that control the formation of hydrogen-bonded frameworks of caffeine and succinic acid, as established by mechanochemical screening.

Scheme 9. The Mechanochemical Formation of a Three-Component Solid Involving Caffeine, Succinic Acid and Cyclohexane Occurs Only in the Presence of a Second Liquid (Acetonitrile), That Acts As a Catalyst41

The reaction speed, high yield, and the crystallinity of the cocrystal product facilitated the structure determination from X-ray powder diffraction data such that the preparation and structural characterization of the product was possible within 24 h (Figure 17).52 Presumably, the same reasons that explain the greater efficiency of liquid-assisted grinding in comparison to cocrystallization from solution can be employed to rationalize the ability of slurry crystallization to provide cocrystal products that are difficult (but not impossible) to achieve from solution. In particular, Bucˇar et al. have utilized slurry crystallization for the reproducible construction of a cocrystal of caffeine and

adipic acid (Figure 18).86 This elusive cocrystal could not be reproducibly obtained by crystallization from solution. The cocrystal was also readily obtainable by liquid-assisted grinding methods.41 3.2. Liquid Control of the Outcome of Liquid-Assisted Grinding Cocrystallization. That the nature of the liquid phase may have a profound effect on the course of the mechanochemical reaction is illustrated in a recent report by Braga and coworkers on the vapor digestion of a ground mixture of pimelic acid and 1,1′-bis(4-pyridy)ferrocene (Scheme 7a).87 Neat grinding of the two compounds together does not yield a new crystalline material. However, exposure of the neat ground

Reviews

mixture to vapors of dichloromethane, chloroform, diethylether, nitromethane, and ethyl lactate provides the cocrystal of 1:1 stoichiometry, whereas exposure to vapors of methanol, ethanol, water or isopropyl alcohol leads to the self-assembly of ground components into a pyridinium salt of 1:2 stoichiometry (Scheme 7b). Cocrystal and salt formation could readily be distinguished through the use of solid-state 14N NMR. Interestingly, kneading of pimelic acid and 1,1′-di(4-pyridyl)ferrocene with either methanol or dichloromethane always produces the cocrystal of 1:1 stoichiometric composition.87 Nevertheless, these results indicate that the properties of the liquid phase could have a profound effect on the course of mechanochemical cocrystallization, even when only microscopic amounts of the liquid are present. How cocrystal formation via liquid-assisted grinding can be controlled by the chemical nature of the liquid phase was demonstrated in cocrystallization of caffeine and glutaric acid (Scheme 8).84 Cocrystallization of the two components from either pure chloroform or pure methanol is difficult, because of significantly different solubilites of the two compounds in each of these solvents. Cocrystal growth from a mixture of chloroform and methanol provides single crystals of two concomitant polymorphs of the 1:1 cocrystal of glutaric acid and caffeine, designed as form A and form B (Figure 19).84 However, liquid-assisted grinding of the two cocrystal components in the presence of a small amount of cyclohexane provides exclusively form A of the cocrystal, whereas grinding with chloroform provides pure form B. In that way, changing the nature of grinding liquid provides an opportunity to circumvent the difficulties of concomitant polymorph formation. 3.3. Templating the Formation of Two-Component Hydrogen-Bonded Frameworks. The ability of the molecules supplied by the liquid phase to act as templates in the mechanochemical formation of a porous hydrogen-bonded framework is demonstrated by grinding of β-caffeine and succinic acid in the presence of dioxane. The grinding reaction leads to the formation of a three-component cocrystal that consists of a bimolecular hydrogen-bonded framework constructed of caffeine and succinic acid (in the 1:1 stoichiometric ratio), along with guest dioxane molecules (Figure 20).41 The guest molecules are disordered within the channels of the host framework, suggesting that the formation of the three-component solid resulted from the ability of dioxane to template the assembly of caffeine and succinic acid rather than on the formation of strong interactions between all three components, as in a cocrystal hydrate.68 Caffeine and succinic acid do not react by neat grinding or by grinding with either methanol (a good solvent for succinic acid) or acetonitrile (a good solvent form caffeine), dismissing the possibility that cocrystal formation is the result of purely solubility effects. The mechanochemical formation of the same framework is templated by a further 17 molecules, most of which are liquids under ambient conditions. In comparison, attempts to obtain the same framework by crystallization from a large volume of the liquid guest (or a concentrated solution of the guest) were successful in only four cases, otherwise providing only precipitates of caffeine or succinic acid. The different outcomes of cocrystallization via grinding and via solution growth were used to illustrate how mechanochemical methods can overcome solubility problems that arise in solution.41 Whereas the framework was readily obtained upon grinding with low-polarity molecules such as tetrahydropyrane, pentamethylene sulfide, and cyclohexene, grinding with cyclohexane


did not lead to cocrystal formation. However, addition of a small amount of acetonitrile or methanol lead to the incorporation of cyclohexane in the two-dimensional framework of caffeine and succinic acid. This mechanochemical formation of a threecomponent cocrystal from a four-component mixture (Scheme 9) demonstrates the use of two liquid phases in a liquid-assisted grinding process. Presumably, the acetonitrile enhances the mixing of reactants and cyclohexane acts as a template to form the framework.41 Interestingly, liquid-assisted grinding also enabled the incorporation of gaseous (e.g. freons) and solid compounds as guests in the framework.69 As an extension of this work, neat grinding of caffeine and succinic acid with chloroform provided an alternative channel inclusion framework,41,69 composed of caffeine and succinic acid in a 4:1 stoichiometric ratio (Figure 21). Neat grinding of anhydrous β-caffeine and succinic acid did not provide a cocrystal. A systematic exploration of 16 carefully selected potential guest molecules, including gases, allowed the identification of molecular structural parameters required for a guest molecule to template the formation of a particular framework (Figure 21a). These included guest size, an ability to form C-H · · · O bonds, as well as the ability to form Cl · · · N or Br · · · N halogen-bonding interactions (Figure 21c).69

4. Conclusion In this brief review we have attempted to provide an overview of cocrystal formation by grinding and highlight the most significant developments in understanding the mechanisms of mechanochemical cocrystallization. In pursuing this goal, we were inclined to attempt and provide what we believe is the first systematical classification of grinding cocrystallization reactions based on the mechanism and reaction intermediates. It is clear that the existing body of mechanistic knowledge on mechanochemical cocrystal formation is still modest, especially in comparison to the rapidly growing number of applications of cocrystals and the rapid development of advanced methods of cocrystal synthesis. In this context, we struggled to remain focused and have given significantly less attention than we might have desired to specific applications of mechanochemical synthesis, such as the use of liquid-assisted grinding to screen for cocrystal formation41 and for systematic analysis of molecular recognition sites.69 Similarly, we were forced to omit the technologically highly attractive cases of cocrystallization involving gaseous components,88 development of strategies to construct three-89 and four-component cocrystals,90 and the recent development of cocrystal-cocrystal grinding as a synthetic method.49,50 We hope that our attempt to provide a systematic overview of grinding cocrystallization mechanisms will be of interest to the growing audience of supramolecular synthetic chemists and will be taken as a point from which further scientific inquiry and dialogue will be generated, directed toward developing an organized, environmentally friendly system of supramolecular, and perhaps covalent, synthesis in the solid state. Acknowledgment. Drs. Pete Marshall and Neil Feeder from Pfizer Global R&D are generously acknowledged for useful discussions. Dr. Scott Childs from SSCI Inc. is also thanked for several informative discussions.

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For that reason, we find it appropriate to encompass all possible mechanisms of mechanochemical cocrystal formation that utilize an additional liquid phase under the common name “liquid-assisted grinding”. In that way, a bias towards a particular mechanism, introduced by the term “solvent-drop grinding”, is avoided. From that perspective, solvent-drop grinding is more appropriate to describe a strategy of liquid-assisted grinding that utilizes the solubility of reactants in the liquid phase to enhance or enable cocrystal formation. (44) Braga, D.; Giaffreda, S. L.; Rubini, K.; Grepioni, F.; Chierotti, M. R.; Gobetto, R. CrystEngComm 2007, 9, 39–45. 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