ABSTRACT
A simple and facile functional group-specific multilateral derivatization cum extraction method coupled with GC-MS based analytical methodology has been developed for the rapid identification and determination of five potential genotoxic impurities (GTIs), including epichlorohydrin, hydrazine, phenylhydrazine, 3-chloro-1,2-propanediol and 1-(2-chloroethoxy)- 2-methoxybenzene in the carvedilol phosphate (CRV-P) drug active pharmaceutical ingredient (API). A generic synthetic route has been explored to apply the current investigation to the majority of the market available synthetic routes for the carvedilol process. Five significant GTIs were identified, and their toxicity was examined using in-silico model. The pharmacokinetic and pharmacodynamic properties of the impurities were compared with the drug molecule to evince the associated risk of impurities during therapeutic action. Furthermore, a quantitative comparison has been made for each impurity with the drug molecule for their ADMET properties, and the potential nature of the impurities has been thoroughly assessed. The developed method encompasses simple derivatization cum extraction-oriented GC-MS method for the reported GTIs, which was also validated as per current ICH guidelines. The obtained LOD and LOQ for the method were between 0.06 ~ 0.61 µg/g and 0.17 ~ 1.8 µg/g, respectively, and the r2 values (0.994 ~ 0.997) show that the method is very sensitive and linear over a wide range (LOQ to 120 % of the target concentration). The percentage recoveries and relative standard deviation obtained were between 85.3 and 109.5 and 0.1-4.7, respectively, showing fit for purpose. Moreover, method precision, intermediate precision, and robustness of the method have also been successfully demonstrated. Thus, this method could be directly engaged as the quality forecasting tool for the marketed drug samples aimed at the estimation of the reported GTIs at trace level.
