Thymol–Menthol Deep Eutectic Solvents and Eutectogels as Pharmaceutical Crystallization Media

Deep eutectic solvents (DES) employing natural products represent a green alternative to conventional crystallization solvents in the pharmaceutical industry. In this work we report the use of the thymol–menthol DES as an effective crystallization solvent for a variety of active pharmaceutical ingredients and pharmaceutical cocrystals, namely aspirin, paracetamol, nicotinamide, benzamide, carbamazepine, mexiletine hydrochloride and ROY. While the involatile nature of thymol–menthol means that evaporative crystallization typically yielded the most thermodynamically stable forms, cooling crystallization yielded surprising metastable forms of the olanzapine precursor ROY depending on the composition of the DES. The 30:70 DES produced the triclinic YN form, the 70:30 composition formed monoclinic ON, while the thermodynamic Y form was obtained from a 50:50 DES mixture. Using l-menthol in the DES instead of racemic menthol resulted in dissolution rate differences in the case of ornidazole and offered the unusual property of chirality in a solvent medium. The DES was successfully used to form salicylic acid–nicotinamide and nevirapine–benzoic acid pharmaceutical cocrystals. It was also gelled by a small molecular bis(urea) gelator allowing supramolecular gel phase DES crystallization.

Green thymol−menthol deep eutectic solvents can be used as effective pharmaceutical crystallization and cocrystallization media both as liquids and as supramolecular eutectogels.