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

Abstract

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 2 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.

Experimental Investigation and Modeling of Cocrystal Formation in L-Menthol/Thymol Eutectic System

“…Although this assumption might be applicable to many DES, experimental investigations to prove its validity are lacking. It has been shown that polymorphism can be observed in many eutectic systems. − Corvis et al reported the formation of a 1:1 molar ratio cocrystal in the lidocaine/ l -menthol binary eutectic system. Recently, Hall et al used synchrotron X-ray powder diffraction (XRD) and DSC to prove the formation of several metastable solid phases in different eutectic systems.…”

Metastable crystalline phase formation in deep eutectic systems revealed by simultaneous synchrotron XRD and DSC

“…9 Furthermore, in the phenol : metaxalone VODES system it was shown that the formation of a phenol co-crystal with a ratio of 3 : 1 is a necessary intermediate to the metastable conglomerate form A-R/S. 11 The depression in melting point of a DES compared to the isolated constituents is commonly attributed to charge delocalisation, caused by the formation of a network of hydrogen bonding motifs between the constituent species. 12 However, low-temperature powder X-ray diffraction (pXRD) studies of the choline chloride : urea DES uncovered the formation of a lowmelting co-crystalline phase of the mixture.…”

Carbon Dioxide Solubility in Nonionic Deep Eutectic Solvents Containing Phenolic Alcohols

“…Moreover, DES are easier and less expensive to prepare compared to IL. Therefore, more attention is directed to their use in several process applications, for example, in liquid–liquid chromatography ( Roehrer et al, 2016 ; Bezold and Minceva, 2019 ; Cai and Qiu, 2019 ), extraction of bioactive compounds ( Kalhor and Ghandi, 2019 ; Makoś et al, 2020 ; Perna et al, 2020 ; Rodríguez-Llorente et al, 2020 ; Fernández et al, 2022 ), and crystallization ( Emami and Shayanfar, 2020 ; Hall et al, 2020 ; Hamilton et al, 2020 ; Potticary et al, 2020 ).…”