De-risking the Polymorph Landscape: The Complex Polymorphism of Mexiletine Hydrochloride

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.