Impurity Profiling: A Case Study of Ezetimibe

ABSTRACT

Impurity profiling includes a description of the identified and unidentified impurities present in new drug substances or drug products. Isolation and elucidation of the structures of degradation products are typically collaborative research involving knowledge of analytical, organic and physical chemistry with spectroscopic information. Stability testing guidelines issued by International Conference on Harmonization (ICH) require the reporting, identification and characterization of degradation products (DPs). The alkaline degradant was detected by high performance liquid chromatography (HPLC) at relative retention time (RRT) of 1.48 with respect to Ezetimibe. This degradant was isolated by preparative HPLC. Purity of the isolated solid was found to be more than 99%. Structure of alkaline degradant was confirmed by LC-MS, 1H and 13C NMR and IR spectroscopy. On the basis of spectral data, the structure of the degradant was confirmed as 5-(4-fluorophenyl)-2-[(4-fluorophenyl amino)-(4-hydroxyphenyl)methyl]-pent-4-enoic acid. An understanding of the parts of the molecule that are susceptible to degradation can help in the design of more stable analogs. Determining the structures of the major degradation products can reveal whether or not a known carcinogen or toxic compound is or might possibly be formed.

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