Separation and Characterization of Process-Related Impurities and Forced Degradation Products of G004, a Novel Sulfonylurea Derivative

Abstract

G004, 1-(4-(2-(4-bromobenzenesulphonamino)ethyl)phenylsuphonyl)-3-(trans-4-methylcyclohexyl) urea, is being developed as a potential hypoglycaemic agent. In this study, a stability-indicating HPLC method for G004 and its impurities was investigated. An isocratic HPLC method was developed with an Inertsil C18 column (250 mm × 4.6 mm, 5 µm) and the mobile phase composed of methanol and 25 mM ammonium acetate (65:35, v/v). The flow rate was 1.0 mL min−1 and the column temperature was set at 30 °C. UV detection was carried out at 233 nm. The method was validated with regard to selectivity, linearity, accuracy, precision, and robustness. The analysis of G004 bulk drugs revealed an impurity which had never been reported in G004. The proposed chemical structure of the impurity was confirmed by synthesis and identified as 1-(4-(2-(4-chlorobenzenesulphonamino)ethyl)phenylsuphonyl)-3-(trans-4-methylcyclohexyl) urea. Moreover, a forced degradation study was carried out under acidic, basic, oxidative, photolytic, and thermal conditions. A major degradation product, which was a new compound, was isolated by preparative HPLC and identified as methyl (4-(2-(4-bromobenzenesulphonamino)ethyl)phenylsuphonyl) carbamate. The degradation mechanism of G004 was also proposed.