posted on 2021-10-29, 14:33authored byJessica
L. Andrews, Sten O. Nilsson Lill, Stefanie Freitag-Pohl, David C. Apperley, Dmitry S. Yufit, Andrei S. Batsanov, Matthew T. Mulvee, Katharina Edkins, James F. McCabe, David J. Berry, Michael R. Probert, Jonathan W. Steed
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.