Process-induced phase transformation of carbamazepine dihydrate to its polymorphic anhydrates

Phase transformation of carbamazepine dihydrate during low pressure and atmospheric dehydration was investigated for a temperature range between 20 °C and 50 °C. The dihydrate was prepared by crystallisation from a mixture of ethanol and water, prior to dehydration studies at vacuum pressure (10− 3 to 102 Torr), 5% to 60% relative humidity (RH) and 5% to 90% solvent partial pressure (P/P0). During vacuum pressure dehydration, the dihydrate collapsed to the amorphous form undergoing quick liberation of water of hydration, before converting to a mixture of a metastable anhydrous C-monoclinic polymorph (major component) and a P-monoclinic polymorph (minor component) (Fig. 1). Humidified dehydration (≥ 30 °C) is shown to result in nucleation to a metastable triclinic polymorph, while organic solvent vapour-mediated phase transformation causes reversion to the most stable P-monoclinic anhydrate. The role of water and organic solvent during the dehydration process is investigated and discussed (in context with/with respect to) the molecular mobility and relaxation period required to initiate the nucleation of the more stable anhydrates. It is concluded that the dehydration mechanism itself as well as the metastability of the polymorphic anhydrate product eventually formed are determined by the accessibility of solvent vapour during the dehydration process.