Designer Gelators for the Crystallization of a Salt Active Pharmaceutical Ingredient─Mexiletine Hydrochloride

Andrews, Jessica L.; Kennedy, Stuart R.; Yufit, Dmitry S.; McCabe, James F.; Steed, Jonathan W.

Abstract

We report an approach to obtain drug-mimetic supramolecular gelators, which are capable of stabilizing metastable polymorphs of the pharmaceutical salt mexiletine hydrochloride, a highly polymorphic antiarrhythmic drug. Solution-phase screening led to the discovery of two new solvated solid forms of mexiletine, a type C 1,2,4-trichlorobenzene tetarto-solvate and a type D nitrobenzene solvate. Various metastable forms were crystallized within the gels under conditions which would not have been possible in solution. Despite typically crystallizing concomitantly with form 1, a pure sample of form 3 was crystallized within a gel of ethyl methyl ketone. Various type A channel solvates were crystallized from gels of toluene and ethyl acetate, in which the contents of the channels varied from those of solution-phase forms. Most strikingly, the high-temperature-stable form 2 was crystallized from a gel in 1,2-dibromoethane: the only known route to access this form at room temperature. These results exemplify the powerful stabilizing effect of drug-mimetic supramolecular gels, which can be exploited in pharmaceutical polymorph screens to access highly metastable or difficult-to-nucleate solid forms.

Citation

Andrews, J. L., Kennedy, S. R., Yufit, D. S., McCabe, J. F., & Steed, J. W. (2022). Designer Gelators for the Crystallization of a Salt Active Pharmaceutical Ingredient─Mexiletine Hydrochloride. Crystal Growth and Design, 22(11), 6775-6785. https://doi.org/10.1021/acs.cgd.2c00925

• Journal Article Type: Article
• Online Publication Date: Oct 12, 2022
• Publication Date: Nov 2, 2022
• Deposit Date: Nov 21, 2022
• Publicly Available Date: Nov 21, 2022
• Journal: Crystal Growth and Design
• Print ISSN: 1528-7483
• Electronic ISSN: 1528-7505
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 22
• Issue: 11
• Pages: 6775-6785
• DOI: https://doi.org/10.1021/acs.cgd.2c00925
• Public URL: https://durham-repository.worktribe.com/output/1188527