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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.

Derisking the Polymorph Landscape: The Complex Polymorphism of Mexiletine Hydrochloride Thumbnail


Jessica L. Andrews

Sten O. Nilsson Lill

David C. Apperley

Matthew T. Mulvee

Katharina Edkins

James F. McCabe

David J. Berry

Michael R. Probert


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.


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.

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
Public URL


Accepted Journal Article (2.6 Mb)

Copyright Statement
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Crystal Growth & Design, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see

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