Potential Improvement in the Shelf Life of Parenterals Using the Prodrug Approach: Bacampicillin and Talampicillin Hydrolysis Kinetics and Utilization Time

Abstract

The utilization time for a parenteral prodrug solution with a bioavailable fraction of unity was defined as the time during which the total of the prodrug concentration and the drug concentration equals or exceeds 90% of the initial prodrug concentration. This utilization time was calculated as a function of pH, buffer, and temperature using the experimentally determined rate expressions for bacampicillin and talampicillin. The results were compared to the shelf life of ampicillin solutions under identical storage conditions. First-order rate constants were determined for conversion of the prodrugs to ampicillin (k _c), for β-lactam degradation of the prodrugs (k _nc), for the overall loss of prodrugs (k _sum), and for β-lactam degradation of ampicillin (k _h) in aqueous solutions at 25.0 to 60.0°C, µ = 0.5, in the pH range 0.90 to 8.4. Loss of bacampicillin proceeded primarily by degradation at pH levels below 4 but was due predominantly to conversion at pH levels above 5. Loss of talampicillin was due primarily to conversion throughout the entire pH range. While the prodrug utilization times were approximately twice the shelf life of ampicillin in acidic solutions, ampicillin was significantly better in neutral solutions. The results illustrate the potential for increased prodrug storage periods when utilization time is defined on the basis of the bioactivity rather than on the prodrug concentration alone.