Biexponential decomposition of a neuraminidase inhibitor prodrug (GS-4104) in aqueous solution
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. Specif...
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Veröffentlicht in: | Pharmaceutical research 1998-08, Vol.15 (8), p.1300-1304 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0724-8741 1573-904X |
DOI: | 10.1023/A:1011964529805 |