Headspace Gas Chromatography–Mass Spectrometry Method for Determination of Class-I Residual Solvents in Several Drug Substances: Method Evaluation by Quality by Design Statistical Tool

Abstract

Background Class-I residual solvents such as 1,1-dichloroethene, 1,1,1-trichloroethane, carbon tetrachloride, benzene, 1,2-dichloroethane are toxic, environmental hazard and carcinogenic to human. Headspace gas chromatography mass spectrometer is the sophisticated instrument for quantification of residual solvents at lower limits. Objective An exact, sensitive, reliable and fast method was developed to determine the 1,1-dichloroethene, 1,1,1-trichloroethane, carbon tetrachloride, benzene and 1,2-dichloroethane present in different drug substances by using a headspace gas chromatography mass spectrometer. Method Helium is used as a carrier gas in this method. N-Methyl-2-pyrrolidone is used as a diluent and the stationary phase is a DB-624 (60 m x 0.25 mm x 1.4 μm film thickness) column with a flow rate of 1.5 mL/min. Results The concentration of limit of detection for 1,1-dichloroethene, 1,1,1-trichloroethane, carbon tetrachloride, benzene and 1,2-dichloroethane were achieved with 0.24 ppm, 5 ppm, 0.12 ppm, 0.06 ppm, 0.15 ppm. Subsequently, the concentrations of limit of quantification for aforementioned impurities were achieved with 0.8 ppm, 15 ppm, 0.4 ppm, 0.2 ppm, 0.5 ppm. The linearity was covered in the range of LOQ to 120% with respect to the specification level. Conclusion The current method's system suitability, precision, linearity, accuracy parameters were performed in accordance to the USP < 1225> and ICH Q2(R2) and results were lies within the acceptance criteria. Highlights No research studies are reported for the determination of class-I residual solvents in lincomycin hydrochloride, dapagliflozin, vonoprazan fumarate, telmisartan drug substances. The proposed study is to develop the common method for quantification of class-I residual solvents for drug substances. QbD concept is utilized in the method performance verification.