Solids cocrystals

Using the carbamazepine-nicotinamide cocrystal system, a mathematical model has been developed to predict the solubility of cocrystals [41], The model predicted that the solubility of a solid cocrystal is determined by the solubility products of the reactant species and solution complexa-tion constants that could be obtained from the performance of solubility studies. In addition, graphical methods were developed to use the dependence of cocrystal solubility on ligand concentration for evaluation of the stoichiometry of the solution-phase complexes that are the precursor to the crystalline cocrystal itself. It was proposed that the dependence of cocrystal solubility on solubility product and complexation constants would aid in the design of screening protocols, and would provide guidance for systems where crystallization of the cocrystal did not take place. 

Crystal engineering is a scientific area in constant flux, which helps explain why unambiguous definitions have not yet been developed and/or accepted. The term cocrystal is not well defined, and the existing literature contains terms such as molecular complexes, multicomponent solids, cocrystals, molecular adducts, molecular salts, clathrates, and inclusion compounds that frequently describe one and the same family or type of chemical compounds. We will not attempt to add to the ongoing discussion, and we limit our overview to structurally homogeneous crystalline materials containing two or more neutral building blocks that are present in definite stoichiometric amounts and that are made from reactants that are solids at ambient conditions [1] (therefore hydrates and other solvates are excluded from this overview). In addition, we do not discuss... 

Trask AV, Jones W (2005) Crystal Engineering of Organic Cocrystals by the Solid-State Grinding Approach. 254 41-70 Tuntulani T, see Suksai C (2005) 255 163-198... 

Crystal Engineering of Organic Cocrystals by the Solid-State Grinding Approach... 

Keywords Solid-state grinding Cocrystal formation Crystal engineering Pharmaceutical materials Polymorphism... 

Several examples of solid-state formation of cocrystals without charge-transfer interaction were reported by Toda and co-workers in 1987 [20]. Various or-... 

As mentioned above, Caira et al. implicated the stability of an ingoing cocrystallisation component as a factor in the preferential formation of a sulfadimidine cocrystal [36]. A year later,in a detailed structural analysis of three anthracene 16 cocrystals, Pedireddi et al. concluded that the ability of potential constituents to satisfy a network of hydrogen bonds dictated solid-state cocrystal formation [43]. Cocrystallisations of anthracene 16 with 4-chloro-3,5-dini-trobenzoic acid 17,3,5-dinitro-4-methylbenzoic acid 18 and 3,5-dinitrobenzoic... 

Lacking a meta constituent, it is clear that 19 alone cannot satisfy an analogous ring of continuous intermolecular interactions aroimd anthracene. Hence, no cocrystalhsation occurred by sohd-state grinding, and the incorporation of a benzene solvent molecule upon solution evaporation was necessary to permit cocrystalhsation (Fig. 4c). The authors thus attributed the lack of cocrystal formation by solid-state grinding to an inabihty of reactants to satisfy the desired intermolecular interactions, rather than the relative stabihty of reactants. 

One great attraction of preparing cocrystals by solid-state grinding is that, in certain cases, cocrystals unobtainable by other methods may be prepared. The number of reported instances of these cases is small, but may grow as the field of solid-state cocrystal preparation widens. From the standpoint of novel materials design, these cases are of great interest in that they may lead to understanding, prediction and exploitation of this phenomenon. 

An illustrative example was provided by the work of Kuroda and co-workers [50]. They reported that different methods of preparation resulted in distinct cocrystal products in their work with racemic bis-P-napthol (BN) 20 and ben-zoquinone (BQ) 21. Upon solid-state grinding with a mortar and pestle, a 1 1.5 BN BQ cocrystal resulted, termed form I. In contrast, from a solution of ether and hexane, a cocrystal containing 20 and 21 in a 1 1 BN BQ ratio resulted. 

Interestingly, in the same work [23] Etter and Adsmond reported two polymorphs of a 1 1 cocrystal containing 25 and malonic acid 27. Both crystallised from solution, but only one was obtainable from solid-state grinding. Contrary to the examples mentioned above, this instance suggests that solution crystallisation may at times offer more product diversity than grinding. 

At the moment, the aforementioned examples serve as curious exceptions to the general trend that most cocrystals can be produced by both the grinding and solution approaches. However, as research continues in this field, it is hoped that an improved understanding will develop regarding the different mechanisms of these cocrystallisation approaches. With a better understanding in hand, novel solid-state materials for various uses may eventually arise as a consequence. 

Shan et al. first illustrated this solid-state enhancement technique in the context of cocrystals of the compound cyclohexane-l,3cfs,5cfs-tricarboxylic acid (CTA) 28 [55]. CTA readily formed phase-pure cocrystal material with hexamethylenetetramine (HMTA) 29 upon grinding for 20 min (as judged from powder XRD data). 

Solvent-drop grinding was next applied as an eco-friendly modification to a previously described preparation of a crystalline organic inclusion compound. Initial work had demonstrated solution-mediated supramolecular organisation and solid-state topochemically controlled reactivity in a system involving l,2-bis(4-pyridyl)ethylene (bpe) 32 and 1,2,4,5-benzenetetracar-boxylic acid (bta) 33 [57]. A single crystal of a 2 1 bpe bta 32 33 cocrystal was... 

Fig. 9 Crystal packing of bpe bta (32 33) cocrystal material, showing topochemical alignment of bpe molecules prior to UV radiation-induced solid-state dimerisation [57]...

The examples of this section summarise the recent application of the solvent-drop grinding approach to solid-state cocrystal preparation. The approach has been shown in certain instances to provide for either acceleration of CO crystallisation kinetics or selection of a particular polymorph via solid-state grinding. The approach is attractive, as it appears to incorporate some of the beneficial aspects of solvent participation while maintaining an essentially green, eco-friendly process. 

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