Biexponential decomposition of a neuraminidase inhibitor prodrug (GS-4104) in aqueous solution.
OBJECTIVE
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 products(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 degree C were independent of the initial GS-4104 concentration.


CONCLUSIONS
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.
Gilead Sciences, Foster City, California 94404, USA. reza_oliyai@gilead.com
R
R
Oliyai
L C
LC
Yuan
T C
TC
Dahl
S
S
Swaminathan
K Y
KY
Wang
W A
WA
Lee
D000588:Amines / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006868:Hydrolysis; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D053139:Oseltamivir; D011355:Prodrugs / Q000737:chemistry*; D012996:Solutions; D014867:Water
D000588:Amines; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011355:Prodrugs; D012996:Solutions; D014867:Water; D053139:Oseltamivir; D009439:Neuraminidase