Acid Hydrolytic Degradation Profiling of Ezetimibe: Identification, Isolation, and Structural Elucidation of Its Degradants

Abstract

Ezetimibe (EZE) is a dyslipidemic agent used to treat hyperlipidemia along with statins and diet changes. To ascertain the drug's degradation profile, stress tests were conducted on it in accordance with International Council for Harmonization recommendations. An ultrahigh‐performance liquid chromatography–mass spectrometry method was developed and validated for the identification and quantification of EZE and its degradants. Using preparative high‐performance liquid chromatography, all impurities were isolated, and their structures were characterized thoroughly using advanced spectral techniques. The drug was relatively stable in basic, peroxide, photolytic, and thermal conditions; however, five degradants were observed in acid degradation. Among the five degradants, three degradation products eluted as Peak‐1, Peak‐2, and Peak‐3 which were found to be novel impurities that were not reported previously. However, the remaining two impurities were identified as Peak‐4 and Peak‐5, despite the insufficient information available. The present study has focused on the isolation of these five acid degradation products and the structural confirmation of these degradants by highly efficient spectral techniques. Moreover, the possible degradation mechanism of the azetidinone ring in the presence of acid has been explained, which might be helpful in determining the quality and purity of EZE and similar pharmaceutical compounds.