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© 2021 American Chemical Society.This work presents an updated solid-form discovery approach to the polymorphism of the antiarrhythmic drug mexiletine hydrochloride, in which experimental and computational techniques are combined to provide a rigorous characterization of the solid-form landscape of this compound. The resulting solid forms were characterized by powder and single-crystal X-ray diffraction, IR spectroscopy, differential scanning calorimetry, and 13C solid-state NMR. This approach reveals five solid-form types of mexiletine hydrochloride. Forms 1, 2, and 3 are mutually enantiotropically related anhydrous polymorphs, with Form 1 the room temperature stable form, Form 2 the high-temperature form, and Form 3 the thermodynamically stable polymorph between 148 and 167 °C. The final two forms termed Types A and B comprise two large families of isomorphous channel solvates, including a fourth nonsolvated form isostructural to the Type A solvates. We report 11 modifications of each solvate, in which a diverse range of solvents are included in the channels, without changing the fundamental structure of the drug framework. These experimental results go hand-in-hand with computational crystal structure prediction (using the AstraZeneca crystal structure prediction approach), which together suggest that it is unlikely further nonsolvated forms, at least with Z′ = 1, will be discovered under ambient conditions.
Author(s): Andrews JL, Nilsson Lill SO, Freitag-Pohl S, Apperley DC, Yufit DS, Batsanov AS, Mulvee MT, Edkins K, McCabe JF, Berry DJ, Probert MR, Steed JW
Publication type: Article
Publication status: Published
Journal: Crystal Growth and Design
Year: 2021
Volume: 21
Issue: 12
Pages: 7150–7167
Online publication date: 29/10/2021
Acceptance date: 02/04/2018
ISSN (print): 1528-7483
ISSN (electronic): 1528-7505
Publisher: American Chemical Society
URL: https://doi.org/10.1021/acs.cgd.1c01009
DOI: 10.1021/acs.cgd.1c01009
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