Susceptibility of morpholine substituents to photo-oxidative decomposition- Identification of photo-oxidative degradants of linezolid (PNU-100766)

Parenteral formulations of linezolid (PNU-100766), a novel (S)-3-(4'-fluoro phenyl)-5-N-acetamidomethyloxazolidin-2-one antibiotic, were subjected to p hoto-stability testing as required by ICH guidelines. Direct, reversed phas e chromatographic evaluation of the photo-irradiated solutions revealed two chromatographically broad degradants. Following preparative chromatographi c isolation, the structures of both degradants were determined by mass spec trometric, nmr, and vibrational spectroscopic methods. The degradant struct ures formed by decomposition involving photo-oxidation of the morpholine, f ollowed by a carbon-carbon bond scission to a formyloxyethylformamide-conta ining degradant. Facile hydrolytic cleavage of the formate ester in acidic media gave the second chromatographically broad degradant containing a N-2- hydroxyethylformamide group. The formamide substituent underwent further hy drolysis in acidic media to the corresponding secondary amine.