Thermochemical Analysis of Venlafaxine Hydrochloride Polymorphs 1−5

Abstract

Five polymorphs of the antidepressant drug venlafaxine hydrochloride (VenHCl) are reported. Forms 1 and 2 are crystalline modifications, form 3 is obtained by melting, form 4 is a hydrate/alcoholate, and form 5 is an amorphous, glassy phase from sublimation. These five polymorphs of VenHCl are characterized by differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), powder X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, and additionally structures of polymorphs 1 and 2 are confirmed by single-crystal XRD (Pca21 and P21/n). The endotherms for the melting transition of forms 1−4 appear at slightly different temperatures in different patents. Moreover, DSC thermograms of forms 1 and 2 (recorded at 10 K/min) are single, sharp peaks, and there is no discussion of phase transition other than melting. Our DSC profiles (recorded @ 2 K/min) show that both forms 1 and 2 undergo a phase transition just after the melting event in the temperature range 210−220 °C. Form 1 transforms to form 3 (phase from melting) and form 5 (phase from sublimation), whereas form 2 converts completely to form 5 in DSC heat−cool−heat cycles. These transitions are also examined under a hot stage microscope. Form 5 is not very stable and converts to form 1 (inert conditions) or hydrate form 4 (open air) in laboratory experiments. In the heating cycle of DSC (30−300 °C), both polymorphs 1 and 2 undergo sublimation to form 5, as characterized by thermogravimetry-infrared (TG-IR) spectroscopy of the evolved vapor. There is no interconversion between polymorphs 1 and 2 in the ambient-to-melting temperature range. Crystal lattice energy of polymorph 2 is lower than form 1 by 2.0 kcal/mol. However, form 1 is stable to ball mill grinding, whereas form 2 partially transforms to hydrate phase 4, suggesting that form 1 is perhaps more suitable in pharmaceutical formulations. With the identification of at least five different solid-state modifications, VenHCl belongs to the category of highly polymorphic drug substances.