The Challenge:
Prof. Michael Zaworotko (former SSPC Co-Director and Materials co-theme lead) is leading work on the design, screening and scale-up of cocrystals. Cocrystals of biologically active molecular compounds have potential utility in drug products thanks to their effect upon physicochemical properties such as aqueous solubility.
The fact that control of cocrystallization can be more challenging than crystallization of single-component crystals means that systematic studies that address the methodology of cocrystal screening, production, and purification are a topical subject.
The Solution:
Prof. Zaworotko’s group previously reported a comparison of slow evaporation vs mechanochemistry for a library of 25 molecular cocrystals. Herein, they compare the previously reported mechanochemistry results (solvent-drop grinding (SDG) with eight solvents) with new results obtained from slurrying in five preferred solvents using the same library of 25 cocrystals. Overall, both methods were found to be effective with slurrying and SDG being 94 (21/25 for water under supersaturation conditions) and 78.5% successful, respectively. Importantly, 96% of the cocrystals formed via slurrying were observed to be free of starting materials (coformers) according to powder X-ray diffraction (PXRD), whereas this was the case for only 72% of the cocrystals prepared by SDG.
Slurrying therefore compared favorably with mechanochemistry, which tends to leave small amounts of unreacted coformer(s) as byproducts, and solution crystallization, which often affords crystals of the least soluble coformer because it can be difficult to control the saturation of three or more solids. Perhaps the most interesting and surprising result of this study was that water slurrying proved to be highly effective, even for low-solubility coformers. Indeed, water slurrying was found to be effective for 21 of the 25 cocrystals studied. Co-crystals have emerged as a class of drug substances for both innovative and generic companies but their screening and scale-up is even more challenging than for single-component crystalline solids.
The Impact:
This work was published in June 2021 in Crystal Growth & Design (Molly M. Haskins and Michael J. Zaworotko, Screening and Preparation of Cocrystals: A Comparative Study of Mechanochemistry vs Slurry Methods, Crystal Growth & Design 2021 21 (7), 4141-4150 DOI: 10.1021/acs.cgd.1c00418) and has been one of the ten most read publications in CG&D since it was published. The translational impact of this work is that water slurrying can be scalable, green and viable with high impact for this research to translate into impact, particularly environmental impact.
