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

• Published in: Pharmaceutical research Vol. 15; no. 8; pp. 1300 - 1304
• Main Authors: OLIYAI, R, YUAN, L.-C, DAHL, T. C, SWAMINATHAN, S, WANG, K.-Y, LEE, W. A
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.08.1998; Springer Nature B.V
• Subjects: Amines - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Biological and medical sciences; Enzyme Inhibitors - chemistry; Hydrolysis; Kinetics; Magnetic Resonance Spectroscopy; Medical sciences; Neuraminidase - antagonists & inhibitors; Oseltamivir; Pharmacology. Drug treatments; Prodrugs - chemistry; Solutions; Water; Stability; Enzyme; Functional group transfer; Enzyme inhibitor; Acyl; NMR spectrometry; Prodrug; Metabolism; In vitro; Glycosidases; Exo-α-sialidase; Hydrolases; Antiviral; Aqueous solution; O-Glycosidases; Degradation product; Physicochemical properties
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1011964529805

To examine the degradation kinetics and identify the degradation products of a neuraminidase inhibitor prodrug. GS-4104. 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. 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. 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.