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.

doi:10.1021/acs.cgd.2c00925

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.

Authors

Jessica L. Andrews

Stuart R. Kennedy

Dr Dmitry Yufit d.s.yufit@durham.ac.uk
Academic Visitor

James F. McCabe

Professor Jonathan Steed jon.steed@durham.ac.uk
Professor

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

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).