Daniel S Hsieh1, Liang Luo2, Yan Xu2, Joshua D Engstrom2, Qi Gao2. 1. Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey, 08903, USA. daniel.hsieh@bms.com. 2. Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey, 08903, USA.
Abstract
PURPOSE: To understand hydrolysis and alcoholysis of polyvinylpyrrolidone-co-vinylacetate (PVPVA) during formulation and storage, elucidate the reaction mechanism, establish an intrinsic kinetic model, and apply this model coupled with GastroPlus™ modeling to predict the amount of PVPVA degradation in vivo. METHODS: The experimental approach includes the detection of the polymer reaction by solution nuclear magnetic resonance (NMR) and the measurement of reaction product concentration via gas chromatography (GC). The theoretical approach includes the establishment of the intrinsic kinetic model and the application of GastroPlus™ to predict the degree of PVPVA degradation. RESULTS: The kinetic model established is a first order reaction between PVPVA and 2-propanol (IPA) or water under an acidic condition. The application of this kinetic model shows that between 1.7 and 6.8 mg of degradant is formed in the GI tract for a 850 mg dose of PVPVA. CONCLUSIONS: The results from this application provide valuable input for process development and the risk analysis of the degradation of PVPVA.
PURPOSE: To understand hydrolysis and alcoholysis of polyvinylpyrrolidone-co-vinylacetate (PVPVA) during formulation and storage, elucidate the reaction mechanism, establish an intrinsic kinetic model, and apply this model coupled with GastroPlus™ modeling to predict the amount of PVPVA degradation in vivo. METHODS: The experimental approach includes the detection of the polymer reaction by solution nuclear magnetic resonance (NMR) and the measurement of reaction product concentration via gas chromatography (GC). The theoretical approach includes the establishment of the intrinsic kinetic model and the application of GastroPlus™ to predict the degree of PVPVA degradation. RESULTS: The kinetic model established is a first order reaction between PVPVA and 2-propanol (IPA) or water under an acidic condition. The application of this kinetic model shows that between 1.7 and 6.8 mg of degradant is formed in the GI tract for a 850 mg dose of PVPVA. CONCLUSIONS: The results from this application provide valuable input for process development and the risk analysis of the degradation of PVPVA.
Authors: Mohammed Maniruzzaman; Joshua S Boateng; Marion Bonnefille; Attila Aranyos; John C Mitchell; Dennis Douroumis Journal: Eur J Pharm Biopharm Date: 2011-11-13 Impact factor: 5.571
Authors: Daniel S Hsieh; Hongfei Yue; Sarah J Nicholson; Daniel Roberts; Richard Schild; John F Gamble; Mark Lindrud Journal: Pharm Res Date: 2014-12-17 Impact factor: 4.200