Stability study of doripenem antibiotic applying LC-ESI-Q-TOF method and in silico prediction: An analytical investigation focused on degradation products

Abstract

In the present study, the stability of the antibiotic doripenem was evaluated with a focus on identifying the degradation products generated. For this, a method by LC-ESI-Q-TOF was developed and validated. Also, as an auxiliary tool in the identification of degradation products, Zeneth 7 software was used in the prediction of drug degradation in silico. Under stress conditions six degradation products were detected and based on the literature and MS2 analyzes, their structures were proposed. Under hydrolytic conditions, in acid, neutral and alkaline media, the major degradation product was formed through the cleavage of the β -lactam ring. In neutral hydrolysis, the formation of two drug dimers was also observed. Oxidation of the drug using H2O2 (3%) led to the formation of three degradation products, not yet reported in the literature, generated by oxidation of the thioether group and by decarboxylation reaction. The most probable elemental compositions for degradations products were obtained with a high degree of confidence, where the error between the masses observed and calculated was less than 5 ppm. The stability of doripenem after reconstitution was studied in conditions that simulate its clinical use. At room temperature, the drug demonstrated a similar degradation profile when prepared using 0.9% NaCl and 5% glucose for infusion, keeping its content > 90% for at least 8 h, and the LC-ESI-Q-TOF analyzes detected the formation of three degradation products, highlighting two different dimers. Finally, all the data generated helps to understand the degradation behavior of doripenem and its important antibiotic class.