Separation and identification of related substances in Candesartan cilexetil tablets by UHPLC-Q- TOF-MS

Abstract

Abstract Related substances, such as process-related substances and degradation products, may affect the efficacy of drugs and cause adverse reactions. Therefore, identifying and controlling them is of the importance. A rapid ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) method has been developed for the separation and characterization of related substances in Candesartan cilexetil tablets. Chromatographic separation was achieved by using ZORBAX Eclipse XDB-C18 column (2.1 mm× 100 mm, 1.8 µm), with two mobile phases consisting of acetonitrile/water (57:43, v/v) (including 0.1% formic acid) as solvent A and acetonitrile/water (90:10, v/v) (including 0.1% formic acid) as solvent B in a gradient mode of elution. This method is applied to the separation of related substances in commercial tablets obtained from two companies. Moreover, accelerated stability studies (60℃, 90% RH and 4500lx for ten days) and forced degradation studies (acidic, alkaline, oxidative and photolytic degradation conditions) were conducted as described in ICH Q1. A total of eleven related substances (including one process-related impurity and ten degradation products) were detected. The related substances were characterized through Q-TOF fragmentation studies, and their fragmentation pathways were proposed. Among them, four related substances have not been reported in the literature yet, and one of them (RS7) was further confirmed by reference substance. In addition, plausible mechanisms for the formation of these related substances are discussed.