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Susceptibility of morpholine substituents to photo‐oxidative decomposition‐identification of photo‐oxidative degradants of linezolid (PNU‐100766)
Author(s) -
Martin Gary E.,
Robins Russell H.,
Bowman Phil B.,
Duholke Wayne K.,
Farley Kathleen A.,
Kaluzny Brian D.,
Guido Jane E.,
Sims Sandra M.,
Thamann Thomas J.,
Thompson Brian E.,
Nishimura Toshihide,
Noro Yukimi,
Tahara Tsutoma
Publication year - 1999
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570360140
Subject(s) - chemistry , morpholine , hydrolysis , formamide , formate , chromatography , substituent , amine gas treating , decomposition , organic chemistry , catalysis
Parenteral formulations of linezolid (PNU‐100766), a novel ( S )‐3‐(4′‐fluorophenyl)‐5‐ N ‐acetamidomethyloxazolidin‐2‐one antibiotic, were subjected to photo‐stability testing as required by ICH guidelines. Direct, reversed phase chromatographic evaluation of the photo‐irradiated solutions revealed two chromatographically broad degradants. Following preparative chromatographic isolation, the structures of both degradants were determined by mass spectrometric, nmr, and vibrational spectroscopic methods. The degradant structures formed by decomposition involving photo‐oxidation of the morpholine, followed by a carbon‐carbon bond scission to a formyloxyethylformamide‐containing degradant. Facile hydrolytic cleav age of the formate ester in acidic media gave the second chromatographically broad degradant containing a N ‐2‐hydroxyethylformamide group. The formamide substituent underwent further hydrolysis in acidic media to the corresponding secondary amine.