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

被引：10

作者：

Oliyai, R ^{[1
]}

Yuan, LC ^{[1
]}

Dahl, TC ^{[1
]}

Swaminathan, S ^{[1
]}

Wang, KY ^{[1
]}

Lee, WA ^{[1
]}

机构：

[1] Gilead Sci Inc, Foster City, CA 94404 USA

来源：

PHARMACEUTICAL RESEARCH | 1998年 / 15卷 / 08期

关键词：

neuraminidase inhibitor; biexponential kinetics; GS-4104; N; N-acyl migration; heteronuclear multiple bond correlation NMR;

D O I：

10.1023/A:1011964529805

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 degrees 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.

引用

页码：1300 / 1304

页数：5

共 8 条

[1] BASE-CATALYZED ACYL MIGRATIONS IN MYOINOSITOL DIBENZOATES [J].