Influence of pH, temperature and buffers on cefepime degradation kinetics and stability predictions in aqueous solutions

First-order rate constants (k) were determined for cefepime degradation at 45, 55, 65, and 75 degrees C, pH 0.5 to 8.6, using an HPLC assay. Each pH-rate profile exhibited an inflection between pH 1 and 2. The pH-rate expression was k((pH)) = k(H1) f(1)(a(H+)) + k(H2) f(2)(a(H+)) + k(S) + k(OH)(a(OH-)), where k(H1) and k(H2) are the catalytic constants (M-1 h(-1)) for hydrogen ion activity (a(H+)), k(OH) is the catalytic constant for hydroxyl ion activity (a(OH-)), and k(S) is the first-order rate constant (h(-1)) for spontaneous degradation. The protonated (f(1)) and unprotonated (f(2)) fractions were calculated from the dissociation constant, K-a = (8.32 x 10(-6))e((5295)/RT) where T was absolute temperature (T). Accelerated loss due to formate, acetate, phosphate, and berate buffer catalysis was quantitatively described with the catalytic constant, k(GA) (M-1 h(-1)) for the acidic component, [GA], and k(GB) (M-1 h(-1)) for the basic component, [GB], of each buffer. The temperature dependency for each rate constant was defined with experimentally determined values for A and E and the Arrhenius expression, k(T) = Ae(-E/RT), where k(T) represented k(H1), k(H2), k(S), k(OH), k(GA), or k(GB). Degradation rate constants were calculated for all experimental pH, temperature, and buffer conditions by combining the contributions from pH and buffer effects to yield, k = k((pH)) + k(GA)[GA] + k(GB)[GB]. The calculated k values had <10% error for 103 of the 106 experimentally determined values. Maximum stability was observed in the pH-independent region, 4 to 6. Degradation rate constants were predicted and experimentally verified for cefepime solutions stored at 30 degrees C, pH 4.6 and 5.6. These solutions maintained 90% of their initial concentration (T-90) for similar to 2 days.