A Kinetic Oxymoron: Concentration-Dependent First-Order Rate Constants for Hydrolysis of Ceftazidime

Abstract

□ The influence of pH, temperature, and buffers on the hydrolysis of 10–4 M ceftazidime was previously reported. The pH– rate profiles showed that maximum stability occurred in the pH- independent region from 4.5 to 6.5. In the present study, hydrolysis rates of 0.031, 0.14, 0.25, and 0.35M ceftazidime were measured at 30 and 65°C, pH5.5–6.2. The data were consistent with β-lactam hydrolysis and the rapid release of pyridine. The sum of the time- dependent concentrations of ceftazidime and pyridine provided mass balance. Simultaneous nonlinear regression for ceftazidime loss and pyridine formation provided similar rate constants (K) to those determined from first-order plots of ceftazidime loss. Although the loss of ceftazidime was first-order for each initial concentration, the K values increased as the initial concentrations increased. Plots of K versus initial concentration were linear with intercepts similar to the K values for 10–4 M solutions, thus implying that ceftazidime catalyzed its own degradation. At the pH of these studies ceftazidime exists as a base. The ceftazidime catalytic constant, calculated from the slope of the plot, was similar to that found for the general-base catalyst, HPO42–. Therefore, it is feasible that ceftazidime also behaved as a intermolecular general-base catalyst. However, first-order plots exhibited excellent linearity even though the catalyst (ceftazidime) was consumed. This would require that the catalytic moieties on ceftazidime remained relatively constant throughout its hydrolysis. This hypothesis was shown to be consistent with literature reports which indicate that the general-base catalytic groups can remain relatively constant during cephalosporin hydrolysis.