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Derisking the polymorph landscape: The complex polymorphism of mexiletine hydrochloride

DOI: 10.1021/acs.cgd.1c01009 DOI Help

Authors: Jessica L. Andrews (Durham University) , Sten O. Nilsson Lill (AstraZeneca) , Stefanie Freitag-Pohl (Durham University) , David C. Apperley (Durham University) , Dmitry Yufit (Durham University) , Andrei S. Batsanov (Durham University) , Matthew T. Mulvee (Durham University) , Katharina Edkins (University of Manchester) , James F. Mccabe (AstraZeneca) , David J. Berry (Durham University) , Michael R. Probert (Newcastle University) , Jonathan W. Steed (Durham University)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Crystal Growth & Design , VOL 3

State: Published (Approved)
Published: October 2021
Diamond Proposal Number(s): 11145

Abstract: 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.

Journal Keywords: Alcohols; Crystal structure; Molecules; Solvates; Solvents

Subject Areas: Chemistry, Medicine


Instruments: I19-Small Molecule Single Crystal Diffraction

Added On: 01/11/2021 08:35

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Chemistry

Technical Tags:

Diffraction Single Crystal X-ray Diffraction (SXRD)