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

Connolly, DJ, Blagden, N, Seton, L ORCID: 0000-0002-1487-2497 and Steed, JW (2025) Thymol–Menthol Deep Eutectic Solvents and Eutectogels as Pharmaceutical Crystallization Media. Crystal Growth and Design, 25 (18). pp. 7834-7844. ISSN 1528-7483

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	3405 Organic Chemistry; 34 Chemical Sciences; 0302 Inorganic Chemistry; 0306 Physical Chemistry (incl. Structural); 0912 Materials Engineering; Inorganic & Nuclear Chemistry; 3402 Inorganic chemistry; 3406 Physical chemistry; 4016 Materials engineering
Subjects:	R Medicine > RS Pharmacy and materia medica
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	American Chemical Society
Date of acceptance:	2 September 2025
Date of first compliant Open Access:	22 September 2026
Date Deposited:	22 Sep 2026 10:34
Last Modified:	22 Sep 2026 10:34
DOI or ID number:	10.1021/acs.cgd.5c01081
URI:	https://researchonline.ljmu.ac.uk/id/eprint/29501

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