Abstract
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 product(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°C were independent of the initial GS-4104 concentration.
Conclusions. The degradation profile indicates that development of solution or solid dosage form of GS-4104 with adequate shelf-life stability at room temperature is feasible.
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Oliyai, R., Yuan, LC., Dahl, T.C. et al. Biexponential Decomposition of a Neuraminidase Inhibitor Prodrug (GS-4104) in Aqueous Solution. Pharm Res 15, 1300–1304 (1998). https://doi.org/10.1023/A:1011964529805
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DOI: https://doi.org/10.1023/A:1011964529805