Thermochemical Analysis of Venlafaxine Hydrochloride Polymorphs 1-5
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- 作者：Saikat Roy ; Srinivasulu Aitipamula ; and Ashwini Nangia
- 刊名：Crystal Growth & Design
- 出版年：2005
- 出版时间：November 2005
- 年：2005
- 卷：5
- 期：6
- 页码：2268 - 2276
- 全文大小：979K
- 年卷期：v.5,no.6(November 2005)
- ISSN：1528-7505
文摘
Five polymorphs of the antidepressant drug venlafaxine hydrochloride (VenHCl) are reported. Forms1 and 2 are crystalline modifications, form 3 is obtained by melting, form 4 is a hydrate/alcoholate, and form 5 is anamorphous, glassy phase from sublimation. These five polymorphs of VenHCl are characterized by differentialscanning calorimetry (DSC), thermogravimetry analysis (TGA), powder X-ray diffraction (XRD), Fourier transforminfrared (FT-IR) spectroscopy, and additionally structures of polymorphs 1 and 2 are confirmed by single-crystalXRD (Pca21 and P21/n). The endotherms for the melting transition of forms 1-4 appear at slightly differenttemperatures 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 @ 2K/min) show that both forms 1 and 2 undergo a phase transition just after the melting event in the temperaturerange 210-220 
C. Form 1 transforms to form 3 (phase from melting) and form 5 (phase from sublimation), whereasform 2 converts completely to form 5 in DSC heat-cool-heat cycles. These transitions are also examined under ahot 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 sublimationto form 5, as characterized by thermogravimetry-infrared (TG-IR) spectroscopy of the evolved vapor. There is nointerconversion between polymorphs 1 and 2 in the ambient-to-melting temperature range. Crystal lattice energyof polymorph 2 is lower than form 1 by 2.0 kcal/mol. However, form 1 is stable to ball mill grinding, whereas form2 partially transforms to hydrate phase 4, suggesting that form 1 is perhaps more suitable in pharmaceuticalformulations. With the identification of at least five different solid-state modifications, VenHCl belongs to the categoryof highly polymorphic drug substances.
C. Form 1 transforms to form 3 (phase from melting) and form 5 (phase from sublimation), whereasform 2 converts completely to form 5 in DSC heat-cool-heat cycles. These transitions are also examined under ahot 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 sublimationto form 5, as characterized by thermogravimetry-infrared (TG-IR) spectroscopy of the evolved vapor. There is nointerconversion between polymorphs 1 and 2 in the ambient-to-melting temperature range. Crystal lattice energyof polymorph 2 is lower than form 1 by 2.0 kcal/mol. However, form 1 is stable to ball mill grinding, whereas form2 partially transforms to hydrate phase 4, suggesting that form 1 is perhaps more suitable in pharmaceuticalformulations. With the identification of at least five different solid-state modifications, VenHCl belongs to the categoryof highly polymorphic drug substances.