Structural elucidation of a dimeric impurity in the process development of ceftolozane using LC/HRMS and 2D-NMR

Ceftolozane is MSD's 5th generation cephalosporin antibiotic with broad-spectrum gram-negative activity. While refining the synthetic route to the drug substance, a dimeric impurity was observed in the final active pharmaceutical ingredient (API) of ceftolozane. Through impurity enrichment and preparative isolation, the structure of the impurity was subsequently established through LC/HRMS, HRMSMS, H/D exchange and 2D-NMR studies. A kinetic study of the impurity formation was conducted to determine the best conditions to control it in the final chemical process. (C) 2019 Elsevier B.V. All rights reserved.