Derisking the Polymorph Landscape: The Complex Polymorphism of Mexiletine Hydrochloride

Andrews, Jessica L.; Nilsson Lill, Sten O.; Freitag-Pohl, Stefanie; Apperley, David C.; Yufit, Dmitry S.; Batsanov, Andrei S.; Mulvee, Matthew T.; Edkins, Katharina; McCabe, James F.; Berry, David J.; Probert, Michael R.; Steed, Jonathan W.

Abstract

This work presents an updated solid form discovery approach to the polymorphism of the anti-arrhythmic drug mexiletine hydrochloride, in which experimental and computational techniques are combined to provide a rigorous characterisation of the solid-form landscape of this compound. The resulting solid forms were characterised by powder and single crystal X-ray diffraction, IR spectroscopy, DSC, 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 is the thermodynamically stable polymorph between 148 °C and 167 °C. The final two forms termed Types A and B comprise two large families of isomorphous channel solvates, including a fourth non-solvated form isostructural to the type A solvates. We report eleven 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 non-solvated forms, at least with Z' = 1, will be discovered under ambient conditions.

Citation

Andrews, J. L., Nilsson Lill, S. O., Freitag-Pohl, S., Apperley, D. C., Yufit, D. S., Batsanov, A. S., …Steed, J. W. (2021). Derisking the Polymorph Landscape: The Complex Polymorphism of Mexiletine Hydrochloride. Crystal Growth and Design, 21(12), 7150-7167. https://doi.org/10.1021/acs.cgd.1c01009

• Journal Article Type: Article
• Acceptance Date: Oct 26, 2021
• Online Publication Date: Oct 29, 2021
• Publication Date: Dec 1, 2021
• Deposit Date: Oct 27, 2021
• Publicly Available Date: Oct 27, 2021
• Journal: Crystal Growth & Design
• Print ISSN: 1528-7483
• Electronic ISSN: 1528-7505
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 21
• Issue: 12
• Pages: 7150-7167
• DOI: https://doi.org/10.1021/acs.cgd.1c01009