Identification and characterization of four process-related impurities in retigabine

HPLC analysis of retigabine, a novel antiepileptic drug revealed four previously unknown impurities. These were identified by liquid chromatography-tandem mass spectrometry using electrospray ionization and quadrupole time-of-flight mass analyzer. Further, the structures of the impurities were confirmed by synthesis followed by characterization by mass spectrometry, nuclear magnetic resonance spectroscopy, infrared spectroscopy, and chromatographic retention time profile analysis. On the basis of these data and knowledge of the synthetic scheme of retigabine, the four impurities were identified as ethyl 2,4-diaminophenylcarbamate (Imp-1), ethyl 2-amino-4-(benzylamino)phenylcarbamate (Imp-2), ethyl 2-acetamido-4-(4-fluorobenzylamino)phenylcarbamate (Imp-3), and ethyl 4-(4-fluorobenzylamino)-2-nitrophenylcarbamate (Imp-4). The possible mechanisms by which these impurities were formed are also discussed.