INFLUENCE OF PH, TEMPERATURE, AND BUFFERS ON THE KINETICS OF CEFTAZIDIME DEGRADATION IN AQUEOUS-SOLUTIONS

First-order rate constants (k) were determined for the hydrolysis of ceftazidime in the pH range of 0.5 to 8.5 at 45, 55, and 65 degrees C by a stability-indicating HPLC assay, In the absence of buffer effects, the pH-rate expression was k = k(H1)f(1)(a(H+)) + k(H2)f(2)(a(H+)) + k(H3)f(3)(a(H+)) + k(S)f(3) + k(OH)f(3)(a(OH-)), where k(H) and k(OH) are the catalytic rate constants for the activity of hydrogen (a(H+)) and hydroxyl (a(OH-)) ions, respectively, and k(S) is the rate constant for spontaneous hydrolysis, The fractions of ceftazidime in various stages of dissociation (f(1), f(2), and f(3)) were calculated from kinetically determined apparent K-a values of 2.03 x 10(-2) and 4.85 x 10(-5). Catalytic constants (k(cat)) were calculated for formate, acetate, phosphate, and berate buffers, which accelerated hydrolysis. Each of the rate constants (k(H1), k(H2), k(H3), k(S), k(OH), and k(cat)) were described as a function of temperature with calculated A and E values in the Arrhenius equation, k(T) = Ae(-E/RT). Ceftazidime hydrolysis rate constants (k) were calculated as a function of pH, temperature, and buffer by combining the pH-rate expression with the buffer contributions calculated from k(cat) values and the temperature dependencies. These equations and their parameter values successfully calculated 95 of 104 experimentally determined rate constants with errors of <10%. Maximum stability was observed in the relatively pH-independent region from 4.5 to 6.5. Hydrolysis rate constants at 30 degrees C were predicted and experimentally verified for four ceftazidime solutions, three of which (pH 4.4 acetate buffer and pH 5.5 and 6.5 phosphate buffers) maintained 90% of their initial concentration for similar to 1.5 days.