Stability of the antibiotic ceftaroline fosamil with focus on degradation products and decomposition pathways – Integrative analysis by LC-DAD, ESI-QTOF and in silico prediction

Abstract

Stability studies are important tools for pharmacovigilance, enabling the investigation of new compounds made available to the population under different hospital conditions. Indicated for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia, ceftaroline fosamil is a fifth-generation cephalosporin marketed as Zinforo®, a novel antibiotic given the long development time, in the form of powder for infusion. Due to the presence of a phosphate group, ceftaroline fosamil is a prodrug that is converted by hepatic enzymes to active form ceftaroline. The aim of the present study was to investigate the stability of ceftaroline fosamil through forced degradation studies (thermal stress) under exposures to 40°C and 60°C, and clinical use conditions under exposures to 4°C and 25°C, in the forms of powder, reconstituted in purified water, and diluted in 5 % glucose solution and 0.9 % sodium chloride solution (2.4 mg/mL, 5.0 mg/mL, and 8.4 mg/mL), for time periods of 10 min, 30 min, 60 min, 2 h, 24 h, 48 h, and 72 h. The preliminary analysis performed by HPLC-DAD showed that ceftaroline fosamil diluted at 2.4 mg/mL in a 5 % glucose solution was the least stable under clinical use conditions, with a decay of approximately 65 % of ceftaroline fosamil. Through mass spectrometry analysis by ESI-QTOF, the degradation products m/z 303, m/z 337, m/z 442, m/z 483, and m/z 543 and their degradation pathways were proposed. It was possible to partially relate the results of mass spectrometry and in silico experimental model for predicting degradation products.