Rapid deprotection and purification of ceftaroline free base from its phosphoramidate prodrug.

Abstract

Contemporary pharmaceutical design often incorporates functional groups to improve the pharmacokinetic/pharmacodynamic profile of a desired active chemical entity. These compounds are known as prodrugs. While prodrug enhancements may improve a medication's clinical utility, they often limit the ability for in vitro testing of the active drug. Published protocols suggest that commercially available phosphatase enzymes can provide a straightforward and cost-effective way to access the active components of phosphoramidate prodrugs. Here, we demonstrate that commercial phosphatases lack reproducibility in generating the active antibiotic ceftaroline from its prodrug ceftaroline fosamil (Teflaro^®). We propose that previously reported successes with phosphatase-mediated conversion are due to the purification of natural ceftaroline fosamil degradation products or batch-dependent isozyme contaminants present in alkaline phosphatases obtained from biological sources. Here, we demonstrate the chemical/thermodegradation to provide a robust, non-enzymatic source of the ceftaroline free base. This efficient method can be readily adapted to expand the availability of deprotected thermostable commercial pharmaceutical compounds for in vitro testing and research purposes.