Tebipenem pivoxyl. Derivative spectroscopy study of stability of the first oral carbapenem

Abstract

A simple and selective derivative spectrophotometric method was developed for the quantitative determination of tebipenem and its pivoxyl ester in the presence of degradation products formed during degradation in aqueous solutions (hydrolysis, oxidation, phosphate buffer pH ∼6.0) and in the solid state (photolysis, thermolysis in dry air and at an increased relative air humidity). The method was based on zero-crossing first-derivative spectrophotometry (λ=341nm for tebipenem pivoxyl and λ=320nm for tebipenem), which eliminated the overlapping caused by various degradation products. The selectivity of the method for determination of tebipenem pivoxyl and tepipenem during stability studies was an effect of lack of substituents containing π-bond system chromophores in degradation products. It was also confirmed by comparison of the experimental spectra sample with the theoretical UV spectra and their first derivatives which were obtained by using the density functional theory with the B3LYP hybrid functional and 6-31G(d,p) basis set. The method were linear in the concentration range 16.70–220.0μgmL−1 for tebipenem (λ=320nm; r=0.9989) and 10.70–160.0μgmL−1 for tebipenem pivoxyl (λ=341nm, r=0.9990). The limits of detection and quantitation were 4.72 and 15.60μgmL−1 for tebipenem and 2.54 and 8.40μgmL−1 for tebipenem pivoxyl, respectively. The method had a good intra-day precision (RSD from 0.12% to 0.62%) and inter-day precision (RSD from 0.22% to 2.13%). The recovery of tebipenem and tebipenem pivoxyl ranged from 99.61% to 99.86% and from 99.38% to 99.87%, respectively. First-derivative spectrophotometry was used for a routine analysis of tebipenem and its ester as well as to monitor the conversion of tebipenem pivoxyl to tebipenem and to predict their degradation pathways.