The Relationship of Diastereomer Hydrolysis Kinetics to Shelf-Life Predictions for Cefuroxime Axetil |
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Authors: | Ngoc-Anh T Nguyen |
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Institution: | (1) Pharmaceutical Development, Glaxo Inc., P.O. Box 13960, Research Triangle Park, North Carolina, 27709 |
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Abstract: | Cefuroxime axetil, an ester prodrug of cefuroxime, is comprised of a 50:50 mixture of diastereomers A and B. The first-order hydrolysis kinetics of cefuroxime axetil were investigated as a function of pH, temperature, buffers, and ionic strength. Chromatographically identified hydrolysis products were cefuroxime, 2-cefuroxime axetil, and ,-sulfoxides. Buffer catalysis was observed in acetate and phosphate buffers. No significant kinetic effect was observed for ionic strength in the range µ = 0.1-1.0. The pH–rate profiles for hydrolysis of cefuroxime axetil isomeric mixture were obtained at 45, 35, and 25°C. The equation defining the cefuroxime axetil hydrolysis rate constant as a function of pH was k
obs = k
H(a
H) + k
s + k
OH(K
w/a
H), exhibiting maximal stability in the pH range 3.5 to 5.5. The predicted profile at 5°C was in excellent agreement with experimental data in the pH range 3.6 to 5.5. In the pH range 1 to 9, the maximum difference observed for individual hydrolysis constants of isomers was 27%. Shelf-life estimates based on the hydrolysis rate constants for cefuroxime axetil as an isomeric mixture were shown to be equivalent to those based on individual hydrolysis rate constants for isomers A and B. |
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Keywords: | hydrolysis kinetics cefuroxime axetil shelf life pH– rate profiles isomeric mixture |
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