The Relationship of Diastereomer Hydrolysis Kinetics to Shelf-life Predictions for Cefuroxime Axetil

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, delta 2-cefuroxime axetil, and alpha, beta-sulfoxides. Buffer catalysis was observed in acetate and phosphate buffers. No significant kinetic effect was observed for ionic strength in the range mu = 0.1-1.0. The pH-rate profiles for hydrolysis of cefuroxime axetil isomeric mixture were obtained at 45, 35, and 25 degrees C. The equation defining the cefuroxime axetil hydrolysis rate constant as a function of pH was kobs = kH (aH) + ks + kOH(KW/aH), exhibiting maximal stability in the pH range 3.5 to 5.5. The predicted profile at 5 degrees 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.