セチリジン塩酸塩中の発がん性N-ニトロソピペラジンの定量のための高感度LC-MSベース分析アプローチの強化

Nitrosamine impurities, which are categorized as mutagenic and probable human carcinogens, have been widely detected in various drug substances and products. This study investigates the formation of the N-nitrosopiperazine (NNPZ) genotoxic impurity during the manufacturing of cetirizine dihydrochloride (CTZ), originating from piperazine, a key starting material. A sensitive and selective LC-MS method was developed for the accurate quantification of NNPZ in the CTZ drug substance. The allowable intake limit for NNPZ is 26.5ng/day and maximum daily dose 880mg/day as per US FDA. This analytical method was developed and validated in accordance with ICH Q2R2 guidelines. It demonstrated a low detection limit (LOD) of 0.03 ng/mL and a quantitation limit (LOQ) of 0.1 ng/mL. The linearity study yielded a strong regression coefficient of 0.9974. With a high recovery rate of 96.56% to 102.35% for spiked NNPZ, the method's accuracy was well-established. The overall results confirm that this methodology is reliable, precise, and reproducible, and it can therefore be used for the determination of NNPZ-genotoxic impurity in CTZ drug substance samples via LC-MS.