Crystal Form Diversity of the Antiepileptic Drug Retigabine

Abstract

Crystal form screening of the antiepileptic drug Retigabine was undertaken to establish the stability order among the known trimorphs and design new cocrystals of the drug. X-ray crystal structures of polymorphs A and B have been determined, and the thermodynamic stability among the trimorphs at ambient conditions was found to be in the order B (least stable) < C < A (most stable) from thermal and phase transformation experiments. Two anhydrous cocrystals, an anhydrous salt and a eutectic of Retigabine were successfully designed and characterized. Interestingly, Retigabine forms a cocrystal with 4-hydroxybenzoic acid only with a water of crystallization (i.e., as a cocrystal hydrate), or else the binary combination manifests as a eutectic. The number of hydroxyl groups and water is implicated in the formation of anhydrous/hydrated cocrystals and eutectic respectively among the combinations explored.