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 singlecrystal X-ray diffraction, IR spectroscopy, differential scanning calorimetry, and 13 C 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 hightemperature 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.

Emerging Landscape of Computational Modeling in Pharmaceutical Development

“…Despite all the challenges facing CSP predictions, modern virtual polymorph screening technologies are accurate enough to provide useful support for pharmaceutical single-component and multicomponent stable form selection. ,,,,,− …”

Professor Roger Davey: Master ofAllCrystal Trades

“…Conformational polymorphs of the Parkinson's drug Entacapone are reported and studied by Nangia et al, 15 while Rietveld et al 19 present an extensive exploration of the phase diagram of the anesthetic drug Butamben. Steed et al 24 studied the complex solid form landscape of mexiletine hydrochloride salts. Modena and Maini et al 11 studied the polymorphism and mechanical behavior of two polymorphs and a solvate of a novel p-type organic semiconductor.…”

“…More than 20 crystallization scientists trained by Roger have gone on to work in the pharmaceutical industry for at least six different companies. This virtual special issue in Celebration of the Career of Roger Davey contains papers that deal with pharmaceutical materials − or arise from the collaboration between academia and the pharmaceutical industry − or come directly from the pharmaceutical industry. , …”

Pseudopolymorphism of a luminescent anthracene‐pentiptycene π‐system: The persistent alkyl‐pentiptycene threading mode

“…[29][30][31][32][33][34] Molecular systems that display both crystal polymorphism and pseudopolymorphism have been reported. [31,[35][36][37][38][39][40] However, it is rarely demonstrated how a polymorphic molecular system could be converted into a pseudopolymorphic counterpart via minor structural modification. Herein, we report one such example with an anthracene-pentiptycene π-conjugated molecular system.…”