BIEXPONENTIAL DECOMPOSITION OF A NEURAMINIDASE INHIBITOR PRODRUG (GS-4104) IN AQUEOUS-SOLUTION

Purpose. To examine the degradation kinetics and identify the degradat ion products of a neuraminidase inhibitor prodrug, GS-4104. Methods. D egradation was studied as a function of pH and temperature using a sta bility-indicating RP-HPLC assay. Degradation products were isolated by RP-HPLC and identified by NMR. Specific rate constants were calculate d based on a scheme defined by product(s) analysis. Results. Three dis tinct 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 isom er II by N, N-acyl migration and ester hydrolysis, respectively. The N , N-acyl migration reaction was characterized using two dimensional he teronuclear multiple bond correlation (HMBC) NMR. The decomposition ki netics of GS-4104 follow a biexponential decay at pH 2-7. The degradat ion kinetics of GS-4104 at pH 4.0, 70 degrees C were independent of th e 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.