Designer gelators for the crystallization of a salt active pharmaceutical ingredient - mexiletine hydrochloride

DOI: 10.1021/acs.cgd.2c00925

Authors: Jessica L. Andrews (Durham University) , Stuart R. Kennedy (Durham University) , Dmitry S. Yufit (Durham University) , James F. Mccabe (AstraZeneca) , Jonathan W. Steed (Durham University)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Crystal Growth & Design , VOL 14

State: Published (Approved)
Published: October 2022
Diamond Proposal Number(s): 22240

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.

Journal Keywords: Crystallization; Diffraction; Gels; Solvates; Solvents

Subject Areas: Chemistry, Medicine


Instruments: I19-Small Molecule Single Crystal Diffraction

Added On: 13/10/2022 14:31

Documents:
acs.cgd.2c00925.pdf

Discipline Tags:

Chemistry Organic Chemistry

Technical Tags:

Diffraction Single Crystal X-ray Diffraction (SXRD)