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

Abstract

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 k_deg, 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.