Isolation and structure elucidation of major alkaline degradant of Ezetimibe

Anuradha, G; Shah, Vishal D.

doi:10.1016/j.jpba.2010.12.033

Cited by 24 publications

(13 citation statements)

References 14 publications

(12 reference statements)

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“…We also confirmed the same through accurate mass and H/D exchange studies in our study on establishment of comprehensive fragmentation scheme of clopidogrel, which was used for unambiguous structural characterization of several novel DPs of the drug [120]. (iii) Incorrect interpretation of raw data: In a report on a cholesterol absorption inhibitor, ezetimibe [264], a totally wrong structure was established for a principle DP (Fig. 15), based on partial mass fragmentation, poor literature search and probably lack of expertise both in basic reaction mechanism and NMR data interpretation.…”

Section: Pitfalls In the Reported Studiessupporting

confidence: 75%

A critical review on the use of modern sophisticated hyphenated tools in the characterization of impurities and degradation products

Singh

Handa

Narayanam

et al. 2012

Journal of Pharmaceutical and Biomedical Analysis

178

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Section: Pitfalls In the Reported Studiessupporting

confidence: 75%

A critical review on the use of modern sophisticated hyphenated tools in the characterization of impurities and degradation products

Singh

Handa

Narayanam

et al. 2012

Journal of Pharmaceutical and Biomedical Analysis

178

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“…This gave improved results, but the limits of detection and quantification, 20 ng mL −1 and 100 ng mL −1 , respectively, were insufficient for our aim. Authors not conducting quantitative analyses, but instead qualitative ones, used 242 nm [24]; however, in this case, the limits were out of significance.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, many other reported HPLC-UV methods, although effective, were not tested or designed to meet that particular, and very important, aim [3,4,7,9,10,24].…”

Section: Discussionmentioning

confidence: 99%

RP-HPLC-UV Determination of ezetimibe in serum: Method development, validation and application to patients chronically receiving the drug

Suchy¹,

Łabuzek²,

Pierzchała³

2013

Acta Chromatographica

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Summary.Ezetimibe is the first in a new class of antihypercholesterolemic drugs. Since it has not long been available on the market, many of its properties may still be revealed. Analytical methods for its determination are scarce, especially regarding serum samples. A simple, fast, and effective high-performance liquid chromatography-ultraviolet (HPLC-UV) method for the determination of ezetimibe concentration in human serum has therefore been developed. Three mobile phases were analysed, and original modifications to the concentration and flow parameters were made. Of five potential internal standards (IS), only nitrendipine was found to be suitable. The analytical wavelength was chosen based on the absorption spectrum of ezetimibe in the mobile phase. Finally, an extraction analysis was performed using two different solvents, and the extrahent volume was optimised. The final method developed was as follows. Single extraction of 1 mL serum sample, spiked with IS, was performed using 10 mL of methyl-t-butyl ether. Separation was obtained at ambient temperature on a Waters C18 Symmetry Shield (4.6 mm × 250 mm, 5 μm) column. The isocratic mobile phase was composed of acetonitrile and 0.1 M ammonium acetate aqueous solution 55:45 (v/v), set at flow rate of 0.75 mL min −1 . Ezetimibe was detected at a wavelength of 232 nm after 5.49 min, and the IS was detected at 8.05 min. The developed method has been validated according to ICH standards. It was found to be specific, precise, accurate and linear over the range 10-800 ng mL −1 with R 2 > 0.998, and detection and quantification limits of 4.60 ng mL −1 and 13.94 ng mL −1 , respectively. The method has been applied to clinical serum samples. The developed technique allowed for successful in vivo assessment of ezetimibe concentrations in samples obtained from hypercholesterolemia patients who are chronically receiving the drug.

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“…The degradant was identified as 5-(4-fluorophenyl)-2-[(4-fluorophenyl amino)-(4-hydroxyphenyl) methyl]-pent-4-enoic acid (Fig. 4) [14]. …”

Section: Methodsmentioning

confidence: 99%

Impurity Profiling: A Case Study of Ezetimibe

Anuradha

Shah²

2011

TOPROCJ

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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, 1 H and 13 C 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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Isolation and structure elucidation of major alkaline degradant of Ezetimibe

Cited by 24 publications

References 14 publications

A critical review on the use of modern sophisticated hyphenated tools in the characterization of impurities and degradation products

A critical review on the use of modern sophisticated hyphenated tools in the characterization of impurities and degradation products

RP-HPLC-UV Determination of ezetimibe in serum: Method development, validation and application to patients chronically receiving the drug

Impurity Profiling: A Case Study of Ezetimibe

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