Studies on Orally Active Cephalosporin Esters. II. : Chemical Stability of Pivaloyloxymethyl Esters in Phosphate Buffer Solution

The degradation kinetics of pivaloyloxymethyl (POM) esters of cephalosporins in phosphate buffer solution (pH6-8) were investigated. The degradation of the starting Δ3 cephalosporin ester proceeded mainly via isomerization to the Δ2 ester and subsequent hydrolysis to the Δ2 acid. Hydrolysis to the Δ3 acid (the parent acid) was very slow. Analysis of the rate constants indicated that the isomerization rate k12 was approximately equal to the apparent degradation rate of the Δ3 ester kdeg, and slower than the hydrolysis rate of the Δ2 ester k24. The isomerization process to the Δ2 ester was found to be the rate-determining step in the degradation of cephalosporin esters. The substituent at the C-3 position of the cephalosporins affected the degradation kinetics. The degradation was accelerated by increase of pH, buffer concentartion and added protein.