Isolation, identification and structure elucidation of two novel process-related impurities of retigabine

•Isolation, identification and characterization of process related impurities in retigabine.•Structural conformation of process impurities has been confirmed by MS, 1H, 13C, 2D NMR and IR techniques.•The pathway for the formation of the impurities has been discussed.

Retigabine was the first neuronal potassium channel opener for the treatment of epilepsy. During the manufacture of retigabine, two unknown impurities were present in laboratory batches in the range of 0.05–0.1% based upon HPLC analysis. These unknown impurities were obtained from the enriched reaction mother liquor by column chromatography. The structure of these process-related impurities were elucidated using FT-IR, 1H NMR, 13C NMR, 2D NMR (HSQC, HMBC, NOESY) and MS spectral data. Based on the complete spectral analysis and knowledge of the synthetic route of retigabine, these two new impurities were designated as ethyl 4-fluorobenzyl(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (impurity-II) and diethyl 5-((ethoxycarbonyl)(4-fluorobenzyl)amino)-2-oxo-1H-benzo[d]imidazole-1,3(2H)-dicarboxylate (impurity-III). Impurity identification, structure elucidation and the formation of impurities were also discussed.

Graphical abstractTwo novel process-related impurities (impurity-II and impurity-III) in retigabine bulk drug were isolated, identified, and characterized using HPLC (analytical), MS, 1H, 13C, 2D NMR and IR techniques. Besides, structure elucidation of a known impurity (impurity-I) was also first reported in this paper.Figure optionsDownload full-size imageDownload as PowerPoint slide