Kinetics and mechanism of the degradation and epimerization of sodium cefsulodin in aqueous solution.

Abstract

The kinetics of the degradation and epimerization of cefsulodin in various buffer solutions were studied at 25°C and 0.6 ionic strength. The overall degradation was a pseudo-first-order reaction in the pH region studied. The rate law of the degradation could be approximated in terms of specific acid-base and water catalyzed hydrolysis, that is k1 (total degradation rate constant)=kH+×αH++k0+kOH-×αOH-. The apparent activation energies of the degradation reaction were 20.7, 22.3, 23.0 and 27.7 kcal mol-1 at pH values of 2, 4, 6, and 9, respectively. The epimerization of cefsulodin was proved to be catalyzed by hydroxide ion from the epimerization rate constant-pH profile, solvent effects using ethanol, and the apparent activation energies (which were 27.0 and 26.1 kcal mol-1 for the apparent forward and reverse epimerization reactions at pH 9.0, respectively). The mechanism of epimerization of cefsulodin is proposed to involve removal of the α-proton of the benzyl side chain by hydroxide ion to form an anioic intermediate. Interactions of cefsulodin with amines and aminoglycosides were also examined. The reaction was pseudo-second-order and the second-order rate constants for various amines and aminoglycosides were compared. It was found that intramolecular catalysis is the predominant factor for amines. An equation is proposed for the second-order rate constants of aminoglycosides. Peaks of unknown products in the alkaline reaction solutions could be separated under the high performance liquid chromatography conditions of the current study.