Polymorphic gabapentin: thermal behaviour, reactivity and interconversion of forms in solution and solid-state

Abstract

The various crystal forms of the neuroleptic drug gabapentin have been investigated, and in some cases re-investigated, by a combination of differential scanning calorimetry, hot stage microscopy and variable temperature powder diffraction methods in order to establish the relative stability of both its anhydrous and hydrated forms. A series of steps involving slurrying, heating, de-hydration and reaction with vapours of HCl have been performed. In this latter case, it has been possible to show that the reaction with HCl vapour leads to the same product as that obtained in solution. In slurry experiments in the absence of water, the most stable form, Form II, is invariably obtained, whereas in water, the slurry leads to the conversion of all crystal forms to the hemihydrated Form I. The conditions for the solid-state formation of the gabapentin-lactam de-hydration product have been analysed. Co-crystal formation has also been attempted. In the course of one such experiment, 1 : 1 co-crystals of gabapentin-lactam and benzoic acid were obtained.