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

• Published in: Journal of pharmaceutical sciences 1998-12, Vol.87 (12), p.1572-1576
• Main Authors: Fubara, Josephine O., Notari, Robert E.
• Format: Article
• Language: English
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Arginine - chemistry; Biological and medical sciences; Buffers; Cefepime; Cephalosporins - chemistry; Drug Interactions; Drug Stability; General pharmacology; Hydrogen-Ion Concentration; Medical sciences; Models, Theoretical; Molecular Structure; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Solubility; Temperature
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1021/js980170y

First-order rate constants (k) were determined for cefepime degradation at 45, 55, 65, and 75 °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 ƒ1(aH+) + kH2 f2(aH+) ), where 1 + kS + kOH(aOH-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 = (8.32 × 10−6 )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,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