Quantitative Methods for the Trace level Determination of SixPotential Genotoxic impurities in anti-cancer Drug, ImatinibMesylate Using Gas Chromatography With Mass Spectrometry

Abstract

Two novel gas chromatography coupled with mass spectrometry (GC-MS-SIM) methods were developed for quantitation of trace levels of six potential genotoxic impurities (PGI’s) namely 2-(Bromomethyl) benzonitrile (2-BBN), 3-(Bromomethyl) benzonitrile (3-BBN),    4-(Bromomethyl) benzonitrile (4-BBN). 2-(Dibromomethyl) benzonitrile               (2-DBBN). 3-(Dibromomethyl) benzonitrile (3-DBBN) and 4-(Dibromomethyl) benzonitrile (4-DBBN) in Imatinib Mesylate (IMM) drug substance in selective ion monitoring mode. In these two methods, Chromatographic separation of potential genotoxic impurities (PGI’s) were achieved on capillary GC column (Rtx-35, Fused silica capillary column; 30 m length; 0.32mm internal diameter, coated with 35% diphenyl and 65% dimethyl polysiloxane stationary phase of          1.0 µm film thickness) and passing helium as carrier gas with Electron Impact ionization (EI) in Selective Ion Monitoring (SIM) mode by using liquid-liquid extraction sample preparation technique for all six impurities. The mass fragments (m/z) were selected for the quantification of 2-BBN (m/z-116), 3-BBN (m/z-116), 4-BBN (m/z-119),                     2-DBBN (m/z-194), 3-DBBN (m/z-194) and 4-DBBN (m/z-194). The performance of the methods validation was assessed by evaluating the specificity, linearity, sensitivity, precision and accuracy experiments. For 2-BBN, 3-BBN and 4-BBN, the limit of detection (LOD) and the limit of quantitation (LOQ) were 0.12 ppm and 0.38 ppm, respectively. For 2-DBBN, 3-DBBN and   4-DBBN impurities, the limit of detection (LOD) and the limit of quantitation (LOQ) were  0.12 ppm and 0.38 ppm, respectively. The correlation coefficient value of the linearity experiment were in the range of 0.9991–0.9999 for all six impurities. The average recoveries for the accuracy were in the range of 90.6–108.3% for all impurities. The validation results demonstrated the good linearity, precision and accuracy of the method which can be further adopted as an adequate quality control tool for quantitation of six potential genotoxic impurities (PGI’s) at trace levels in Imatinib mesyalte drug substance.