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

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 th...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of pharmaceutical analysis 2015-12, Vol.5 (6), p.356-370
Hauptverfasser: Bellur Atici, Esen, Karlığa, Bekir
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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 chro- matography (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-phenyla- zetidin-2-one which is called desfluoro ezetimibe (lactam-related) impurity, synthesized and char- acterized, 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-I 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.
ISSN:2095-1779
2214-0883
DOI:10.1016/j.jpha.2015.04.002