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) = kH1 f1(aH+) + kH2 f2(aH+) + ks + kOH(aOH-), where kH1 and kH2 are the catalytic constants (M(-1) h(-1)) for hydrogen ion activity (aH+), kOH is the catalytic constant for hydroxyl ion activity (aOH-), and ks is the first-order rate constant (h(-1)) for spontaneous degradation. The protonated (f1) and unprotonated (f2) fractions were calculated from the dissociation constant, Ka = (8.32x10(-6))e(5295)/RT where T was absolute temperature (T). Accelerated loss due to formate, acetate, phosphate, and borate buffer catalysis was quantitatively described with the catalytic constant, kGA (M(-1) h(-1)) for the acidic component, [GA], and kGB (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, kT = Ae-E/RT, where kT represented kH1, kH2 , kS, kOH, kGA, or kGB. 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) + kGA[GA] + kGB[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 (T90) for approximately 2 days.
Fubara
J O
JO
The Department of Pharmaceutical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston 29425, USA.
Notari
R E
RE
D001120:Arginine / Q000737:chemistry*; D002021:Buffers; D000077723:Cefepime; D002511:Cephalosporins / Q000737:chemistry*; D004347:Drug Interactions; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D008962:Models, Theoretical; D015394:Molecular Structure; D012995:Solubility; D013696:Temperature
D002021:Buffers; D002511:Cephalosporins; D000077723:Cefepime; D001120:Arginine