First synthesis and characterization of key stereoisomers related to Ezetimibe

Ren, Yun; Duan, Yanjun; Li, Renjun; Deng, Yong; Li, Hai; Wu, Yong

doi:10.1016/j.cclet.2014.03.035

Cited by 9 publications

(3 citation statements)

References 13 publications

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“…It may be used alone or together with statins for the treatment of primary hypercholesterolemia, homozygous sitosterolemia, homozygous familial hypercholesterolemia, and mixed hyperlipidemia. Impurity profiling of ezetimibe has been reported in a number of scientific articles that assist regulatory agencies in ensuring the availability of consistently high quality API in the market . In an attempt to develop generic ezetimibe following the most commonly adopted synthetic route, we observed the formation of a critical process impurity that was not disclosed in any of the prior reports.…”

Section: Introductionmentioning

confidence: 83%

Structural Correction and Process Improvement for Control of a Critical Process Impurity of Ezetimibe

Mannam

Srimurugan

Gaddam

et al. 2019

Org. Process Res. Dev.

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A new process-related impurity of ezetimibe was identified and characterized. The impurity is critical and common to most of the manufacturing routes of ezetimibe. Structural characterization using HMBC indicated the presence of a six-membered ring rather than a nine-membered ring as proposed by the innovator of ezetimibe. Prominently, the existing pharmacopoeial methods for ezetimibe are not capable of detecting this impurity. A control strategy was established by appropriate process control that is capable of purging the impurity to levels comfortably below the regulatory requirement. The formation of the diastereomer impurity during the demonstration of a scale-up batch under the optimized conditions is attributed to epimerization of ezetimibe induced by thermal degradation of the silylating agent.

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Section: Introductionmentioning

confidence: 83%

Structural Correction and Process Improvement for Control of a Critical Process Impurity of Ezetimibe

Mannam

Srimurugan

Gaddam

et al. 2019

Org. Process Res. Dev.

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“…The overall acceptable daily dose level to be considered is 0.1%. A number of reports on the identification, development and characterization of ezetimiberelated impurities and their degradants were published [9][10][11][12][13][14][15] . Four process-related impurities 4- (impurity -STG -01) were identified during the manufacturing of ezetimibe drug substance.…”

Section: Introductionmentioning

confidence: 99%

Untitled

2021

IJPSR

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The gradient HPLC method was developed to detect and quantify four related substances (FIP, FHO-2, STG-01, and desfluoro) in ezetimibe drug material. The efficient separation was carried out on Water X-Select CSH C18 column (4.6 mm × 100 mm, 2.5 μm). The impurities were separated in gradient mode of elution with 0.1% trifluoroacetic acid in water (mobile phase A) and 0.1% trifluoroacetic acid in acetonitrile (mobile phase B) at a flow rate of 1.0 ml /min. The effluents were detected at 254 nm. The method has been validated in compliance with the regulatory standards suggested by the International Conference on Harmonization. The parameters validated included precision, linearity, detection limit, quantification limit, specificity, accuracy, and robustness. The method showed good linearity from 0.03 μg/ml to 1.5 μg/ml for FIP, FHO-2, STG-01, and desfluoro. The developed method was applied to determine the studied impurities in three different batches of ezetimibe drug material. The method proposed in this work could be employed in quality control of ezetimibe bulk drug.

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“…Few analytical methods have been reported in the literature for the determination of ezetimibe including studies on its pharmaceutical dosage forms and degradation studies [18] , [19] , [20] , [21] . In recent years, studies related to identification, synthesis and characterization of process and degradation related impurities, including stereoisomers of ezetimibe, have been reported [22] , [23] , [24] , [25] , [26] , [27] , [28] .…”

Section: Introductionmentioning

confidence: 99%

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

Atici

Karliga

2015

Journal of Pharmaceutical Analysis

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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.

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First synthesis and characterization of key stereoisomers related to Ezetimibe

Cited by 9 publications

References 13 publications

Structural Correction and Process Improvement for Control of a Critical Process Impurity of Ezetimibe

Structural Correction and Process Improvement for Control of a Critical Process Impurity of Ezetimibe

Untitled

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

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