Biexponential decomposition of a neuraminidase inhibitor prodrug (GS- 4104) in aqueous solution

Article abstract of DOI:10.1023/A:1011964529805

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 [I 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.