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 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-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.