PURPOSE: To examine the degradation kinetics and identify the degradation products of a neuraminidase inhibitor prodrug. GS-4104. METHODS: Degradation was studied as a function of pH and temperature using a stability-indicating RP-HPLC assay. Degradation products were isolated by RP-HPLC and identified by NMR. Specific rate constants were calculated based on a scheme defined by products(s) analysis. RESULTS: Three distinct degradation products were observed in the pH region studied (pH 2-8): isomer I, GS-4071, and isomer II. Isomer I resulted from the N, N-migration of the acetyl group. Gs-4071 was formed by the hydrolysis of the ethyl ester. Both GS-4071 and isomer I degraded further to isomer II by N, N-acyl migration and ester hydrolysis, respectively. The N, N-acyl migration reaction was characterized using two dimensional heteronuclear multiple bond correlation (HMBC) NMR. The decomposition kinetics of GS-4104 follow a biexponential decay at pH 2-7. The degradation kinetics of Gs-4104 at pH 4.0, 70 degree C were independent of the initial GS-4104 concentration. CONCLUSIONS: The degradation profile indicates that development of solution or solid dosage from of GS-4104 with adequate shelf-life stability at room temperature is feasible.
PURPOSE: To examine the degradation kinetics and identify the degradation products of a neuraminidase inhibitor prodrug. GS-4104. METHODS: Degradation was studied as a function of pH and temperature using a stability-indicating RP-HPLC assay. Degradation products were isolated by RP-HPLC and identified by NMR. Specific rate constants were calculated based on a scheme defined by products(s) analysis. RESULTS: Three distinct degradation products were observed in the pH region studied (pH 2-8): isomer I, GS-4071, and isomer II. Isomer I resulted from the N, N-migration of the acetyl group. Gs-4071 was formed by the hydrolysis of the ethyl ester. Both GS-4071 and isomer I degraded further to isomer II by N, N-acyl migration and ester hydrolysis, respectively. The N, N-acyl migration reaction was characterized using two dimensional heteronuclear multiple bond correlation (HMBC) NMR. The decomposition kinetics of GS-4104 follow a biexponential decay at pH 2-7. The degradation kinetics of Gs-4104 at pH 4.0, 70 degree C were independent of the initial GS-4104 concentration. CONCLUSIONS: The degradation profile indicates that development of solution or solid dosage from of GS-4104 with adequate shelf-life stability at room temperature is feasible.
Authors: W Li; P A Escarpe; E J Eisenberg; K C Cundy; C Sweet; K J Jakeman; J Merson; W Lew; M Williams; L Zhang; C U Kim; N Bischofberger; M S Chen; D B Mendel Journal: Antimicrob Agents Chemother Date: 1998-03 Impact factor: 5.191
Authors: C U Kim; W Lew; M A Williams; H Liu; L Zhang; S Swaminathan; N Bischofberger; M S Chen; D B Mendel; C Y Tai; W G Laver; R C Stevens Journal: J Am Chem Soc Date: 1997-01-29 Impact factor: 15.419