In Silico Assessment and Quantitative Estimation of Potential Toxic Impurities From Propafenone (PFN) Through Generic Route and Using UPLC-MS/MS Technique

Abstract

The generic and most probable synthetic route for the preparation of propafenone (PFN) has been evaluated, common toxic impurities have been identified, their in silico toxicity has been assessed, and novel UPLC-MS/MS method was developed for the identification and quantification of five potential toxic impurities (PGIs) in the active pharmaceutical ingredients of PFN, a Class 1C antiarrhythmic agent. Five PGIs were identified for this study, namely 1-2-3-amino impurity, 1-2-2-hydroxy impurity, 1-2-oxiran impurity, propafenone, EP-Impurity-C, and EP-Impurity-E and were validated following the International Conference of Harmonization (ICH) guidelines, this methodology is capable of quantifying five PGIs at 1.6 ppm with a sample concentration of 20 mg/mL. This validated approach presented very low LOD and LOQ limits (0.08–0.2 ppm), excellent linearity (coefficients > 0.9944), and a satisfactory recovery range (88.1%–102.8%). The method was sufficient in terms of sensitivity, linearity, precision, accuracy, selectivity, and robustness, and marketed samples analysis also proved that the method could directly apply for the PFN drug substance of real-time sample testing.