Mechanochemistry deals with reactions induced by the input of mechanical energy - for example by impacts within a vibratory ball mill. The technique has a long history with significant contributions from Ostwald, Carey Lea and, notably, Faraday. Mechanochemistry has subsequently seen application in a variety of areas of materials science including mechanical alloying in metallurgy, the synthesis of complex organic molecules and, more recently, the discovery and development of new solid forms of active pharmaceutical ingredients. This paper overviews the broad areas of application of mechanochemistry, some key features which make it a particularly attractive approach to materials synthesis and some mechanistic aspects highlighted within the literature. A significant part, however, will focus on recent applications in the area of pharmaceuticals and its important role in exploring the rich variety of solid forms available for small, drug-like, molecules.
We demonstrate the utility of freeze-drying as a general method for cocrystal synthesis as well as for the preparation of new solid forms of drug-coformer cocrystal systems. Using this approach, several previously reported cocrystal phases containing pharmaceutical compounds were reproduced. In addition, a novel solid solution of caffeine and theophylline and a potential new crystal form of the theophylline:oxalic acid cocrystal were prepared. It is shown that cocrystal formation proceeds via an amorphous phase which is generated as solvent sublimes during the freeze-drying process. The application of freeze drying to cocrystallisation is advantageous as it avoids problems caused by differences in the solubilities of coformers, and is a technique which is widely used to prepare products on an industrial scale, such as in the manufacture of pharmaceutical dosage forms. We demonstrate the utility of freeze-drying as a general method for cocrystal synthesis as well as for the preparation of new solid forms of drug-coformer cocrystal systems. Using this approach, several previously reported cocrystal phases containing pharmaceutical compounds were reproduced. In addition, a novel solid solution of caffeine and theophylline and a potential new crystal form of the theophylline:oxalic acid cocrystal were prepared. It is shown that cocrystal formation proceeds via an amorphous phase which is generated as solvent sublimes during the freeze-drying process. The application of freeze drying to cocrystallisation is advantageous as it avoids problems caused by differences in the solubilities of coformers, and is a technique which is widely used to prepare products on an industrial scale, such as in the manufacture of pharmaceutical dosage forms.3
A polymorph screen on a new 1:1 co-crystal of caffeine, C8H10N4O2, with anthranilic acid, C7H7NO2, has revealed a rich diversity of crystal forms (two polymorphs, two hydrates and seven solvates, including two sets of isostructural solvates). These forms were prepared by liquid-assisted grinding and solution crystallization, and the crystal structures of nine of these forms have been solved using either single-crystal or powder X-ray data. The structures contain O-H...N and N-H...O hydrogen bonds through which caffeine and anthranilic acid molecules assemble to form zigzag-type chains. These chains can interact in an anti-parallel and offset manner to form cage- or channel-type skeletons within which solvent molecules can be located, giving rise to the diversity of forms observed for this co-crystal. In contrast, an equivalent series of liquid-assisted grinding and solution crystallization experiments with the closely related system of theobromine, C7H8N4O2, and anthranilic acid resulted in the formation of only one 1:1 co-crystal form.
Tubular crystals of the pharmaceutical compounds caffeine, carbamazepine, carbamazepine dihydrate, and theophylline monohydrate have been prepared by evaporative crystallization. These novel, rod-shaped, hollow crystals have hexagonal or rectangular cross sections, and pore diameters ranging from 0.1 to 25 μm. Crystallization is believed to occur under conditions where crystal growth was more rapid than diffusion of molecules to the most rapidly growing face of the crystal, leading to formation of a central cavity within the crystal. The two key factors in this mechanism of tubule formation are highly anisotropic crystal growth, where the growth rate of one of the crystal faces is several times greater than that of the others, and high supersaturation levels, giving high crystallization rates and diffusion limited growth. This mechanism of tubular crystal formation is likely to be applicable to a wide range of chemical species, as both of these factors can be achieved for a given compound through selection of appropriate crystallization conditions. On the basis of this mechanism, conditions suitable for the growth of tubular crystals of aspirin were identified systematically through selection of solvent and control of crystallization rate.
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