Derisking the Polymorph Landscape: The Complex Polymorphism of Mexiletine Hydrochloride

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.