Racemic Conglomerate Formation via Crystallization of Metaxalone from Volatile Deep Eutectic Solvents

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. Powder X-ray diffraction and chiral high-performance liquid chromatography were used to infer that the structure of the crystals obtained was 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 three-dimensional 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 crystallization pathways which do not result in crystals of a suitable size and quality for single-crystal X-ray diffraction.