Full Characterization of Linezolid and Its Synthetic Precursors by Solid-State Nuclear Magnetic Resonance Spectroscopy and Mass Spectrometry

ABSTRACT In this work, for the first time we report complementary structural and spectral studies of linezolid and its synthetic precursors (k)-N-{3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl}methanol and (k)-N-{3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2- oxooxazolidin-5-yl}methyl azide employing solid-state nuclear magnetic resonance (SS NMR) spectroscopy and electron ionization mass spectrometry. Each technique provides unique and specific set of information. Through high-resolution SS NMR using 13 C, 15 N, and 19 F as structural probes, we revealed dynamic molecular disorder in the crystal lattice for polymorphs II and III of linezolid, never reported before. Utilizing variable temperature 13 C cross-polarization magic-angle spinning technique, we proved that the disorder has a local character. Only morpholine residue of linezolid is under fast regime exchange at room temperature. This process slows down at a lower temperature and stopped at 213 K. The mass spectrometry revealed that chemical modification at oxazolidinone end of linezolid has a significant influence on fragmentation pathways of studied drug and its synthetic precursors. In particular, the compound that has azide group at the methyl substituent in the position C5 of the oxazolidinone ring is characterized by the most complicated fragmentation pattern, probably caused by thermal decomposition, which was taking place before ionization. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3883–3892, 2015