Investigation of reduction process and related impurities in ezetimibe.

During the synthesis of ezetimibe bulk drug, research for the impurities which especially come from the last two steps of synthetic route is of great significance for the quality by design (QbD) concept. The design spaces of last two steps of reduction reaction were established. The critical parameters were discussed under the QbD concept, which have noticeable impact on the impurity profile such as the new process related impurities mentioned in this paper. Three novel reduction process related impurities were prepared by designed synthetic route and co-injected with ezetimibe sample for identification. These novel process related impurities were also detected in different laboratory batches of ezetimibe bulk drug and characterized using MS, (1)H, (13)C, 2D NMR and IR techniques. The synthesis, isolation, identification, structural elucidation and formation of impurities were also discussed in detail.