Effect of Initial Concentration on Stability of Panipenem in Aqueous Solution

Abstract

Panipenem (PAPM,, Fig. 1), which was discovered and developed in Sankyo Co., Ltd., is a carbapenem antibiotic with a broad antibacterial spectrum and potent bactericidal activity. [1][2][3][4][5] In the previous report, the degradation kinetics of panipenem in aqueous solution at a fixed initial panipenem concentration (5 mg/mlϷ15 mM) was studied with regards to pH, temperature, ionic strength, and buffer catalysis.6) The degradation of panipenem followed first-order kinetics, and the pH dependence of the apparent first-order rate constants was explained using the specific acid-base catalysis theory and considering the dissociation of the carboxyl group.In the study reported here, the effect of panipenem concentration on the degradation of panipenem was investigated. It had been previously reported that the degradation of carbapenem antibiotics, imipenem and meropenem, followed a pseudo-first-order degradation in an aqueous solution, and the initial concentration was considered to affect the degradation of the drugs.7-11) However, the mechanism of how the concentration affected the degradation had not been elucidated.In this report, we investigated the effect of the initial panipanem concentration on the degradation of panipenem, in particular, in an acidic solution. ExperimentalMaterials Panipenem was obtained from lots produced in-house (Sankyo Co., Ltd.) and used without further purification. 2-(N-Morpholino) ethanesulfonic acid (MES, pK a ϭ6.15) and 3-(N-Morpholino) propanesulfonic acid (MOPS, pK a ϭ7.20) were purchased from Dojin Chemicals Co., Ltd. All the other chemicals used were of reagent grade.Kinetic Runs Aqueous buffer solutions were adjusted to the desired pH with concentrated aqueous sodium hydroxide or diluted hydrochloric acid. The buffer species used were, citrate (pH 2.0-4.5), MES (pH 5.0-6.5), MOPS (pH 7.0-8.0), and carbonate (pH 8.5-10.0). Then, panipenem was weighed and added to the buffered solutions. These buffered solutions were placed in test tubes and maintained at the reaction temperatures in a thermostatic water bath (Ϯ0.1°C). The pH values of these buffered solutions were measured with a pH electrode at every sampling time point to confirm to be within desired pH Ϯ0.1. If the pH value deviated, the pH value was re-adjusted by concentrated aqueous sodium hydroxide or diluted hydrochloric acid, and then the kinetic run was continued. The samples in the test tubes were periodically analyzed, and the residual panipenem concentrations were determined by high performance liquid chromatography (HPLC). In citrate and carbonate buffers, the buffer concentration effects on the rate constants were observed, so the rate constants were obtained by extrapolating the buffer concentration to zero. In MES and MOPS buffers, the concentration effects were not observed, so the experiments were conducted at the buffer concentration of 0.2 M or 0.5 M, and these buffers showed the sufficient buffer index during the kinetic runs. As for the ionic strength of the solution, it was shown that the ionic streng...

Kinetics of Degradation of Biapenem

“…). A similar phenomenon was also observed during degradation in solutions for other compounds containing bicyclic 4:5 fused rings: panipenem and clavulanic acid .…”

Effect of Reconstitution Solvents and Containers on Kinetics and Safety of Cephradine Neutralized with L-Arginine

“…A slight increase in pH of the admixtures was also observed as seen with other cephalosporins [13]. Extended degradation lowers the concentration of the solute in the solution, which has been shown in some studies to change the kinetics of degradation reaction [14][15]. But in the present case the comparison of kinetics of the sample at 30°C after being degraded at 50°C for 2 hours with the sample degraded at 30°C (Not treated initially) did not show any difference.…”

Effect of Reconstitution Solvents and Containers on Kinetics and Safety of Cephradine Neutralised with L-Arginine

“…A slight increase in pH of the admixtures was also observed as seen with other cephalosporins (Viaene et al, 2002). Extended degradation lowers the concentration of the solute in the solution which has been shown in some earlier studies to change the kinetics of degradation reaction (Ito et al, 2005;Meakin et al, 1978), but in the present of case, the comparison of kinetics of the sample at 30 °C after being degraded at 50 °C for 2 h with the sample degraded at 30 °C (not treated initially) did not show any difference.…”