The pharmaceutical metaxalone (MTX) was obtained as a conglomerate Form A-R/S, via a newly reported crystallization method exploiting volatile deep eutectic solvents. Homochiral crystals of Form A-S, could previously be obtained only by crystallization from enantiopure MTX, synthesized from enantiopure starting materials, and never from a racemic solution of MTX. Homochiral crystals of Form A-R were obtained here concomitantly for the first time. Powder X-ray diffraction and chiral high performance liquid chromatography were used to infer that the structure of the crystals obtained were a conglomerate relating to the known Form A-S. However, this pathway results in exclusively micron-sized needles, below typical structural solution size, and so 3D electron diffraction, combining low-dose continuous acquisition and a dedicated single-electron detector was used for ab-initio structural solution of Form A-R/S. Crystallization via volatile deep eutectic solvents allowed the structural landscape of metaxalone to be further explored, adding a point to its phase diagram. This example highlights the possibility for symbiotic relationships between structural solution via electron diffraction and crystallisation pathways which do not result in crystals of a suitable size and quality for single-crystal X-ray diffraction.
Hamilton, V. A., Andrusenko, I., Potticary, J. L., Hall, C., Stenner, R. A., Mugnaioli, E., Lanza, A., Gemmi, M., & Hall, S. R. (2020). Racemic Conglomerate Formation via Crystallization of Metaxalone from Volatile Deep Eutectic Solvents. Crystal Growth and Design, 20(7), 4731–4739. https://doi.org/10.1021/acs.cgd.0c00497