Identification, synthesis and characterization of process related desfluoro impurity of ezetimibe and HPLC method validations

Abstract

Ezetimibe, which selectively inhibits cholesterol absorption across the intestinal wall and is used as an antihyperlipidemic agent, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of ezetimibe, an impurity was detected in the final product at levels ranging from 0.05% to 0.15% in reverse phase gradient high performance liquid chromatography (HPLC) method and its molecular weight was determined by LC–MS analysis. The impurity was identified as (3R,4S)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)-1-phenylazetidin-2-one which is called desfluoro ezetimibe (lactam-related) impurity, synthesized and characterized, the mechanism of its formation was discussed in detail. After all standardization procedures, it was used as a reference standard during validation of HPLC method and routine analyses. In addition, content of Eze-1 desfluoro impurity in Eze-1 intermediates was specified as 0.10% to keep the formation of desfluoro ezetimibe impurity under control and the related substances HPLC method was validated accordingly.

Bioactivity of Dietary Polyphenols: The Role in LDL-C Lowering

“…There are two recognized sources of cholesterol in the body: biosynthesis and the intestinal absorption of dietary cholesterol [22,23]. Inhibiting cholesterol absorption had been shown to reduce the levels of cholesterol in the liver, thereby promoting the synthesis of LDLR (Section 2.4, below) and a subsequent reduction of plasma LDL-C levels [24].…”

Solriamfetol impurities: Synthesis, characterization, and analytical method (UPLC-UV) validation

“…Consequently, API manufacturers attempt to minimize impurity levels; nevertheless, the formation of impurities cannot be fully avoided. There have been many reports on the identification and characterization of unknown impurities formed in drug development processes [ [11] , [12] , [13] , [14] , [15] ]. If some of these characterized impurities are not readily available, appropriate synthetic procedures should be established to produce quantities sufficient for the development and validation of an analytical method and thus benefit pharmaceutical development teams worldwide.…”

Variation in Supersaturation and Phase Behavior of Ezetimibe Amorphous Solid Dispersions upon Dissolution in Different Biorelevant Media

“…In contrast, in an isotropic system, such as a solution or amorphous solid, there is an equal probability for all molecular orientations resulting in nearly perfect cancellation, and therefore no coherent SHG signal generation. Ezetimibe contains three chiral centers (two are located on the β-lactam ring, while the last one (alcohol) is present on the side chain) 32 and is therefore expected to crystallize into an SHG-active space group, enabling this approach to differentiate between undissolved amorphous material/dissolution media components and crystals.…”