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Estimation of pitavastatin and ezetimibe using UPLC by a combined approach of analytical quality by design with green analytical technique

Chanduluru Hemanth Kumar, Sugumaran Abimanyu

Acta Chromatographica

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2022

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Vol. 34, no. 3

361--372

EN

The current study explores a design and development of the simple, fast, green and selective novel method of UPLC to quantify pitavastatin and ezetimibe simultaneously. The combined approach of Green Analytical Method with Quality by Design-based risk assessment was done using the Ishikawa fishbone diagram followed by a rotatable central composite design used for the optimization. The optimal chromatographic separation was attained through a mobile phase of 72: 28% v/v ethanol and 0.1% orthophosphoric acid (pH 3.5), with a 0.31 mL min⁻¹ flow rate. The developed UPLC-PDA method was sensitive and specific for pitavastatin and ezetimibe, with linearity ranging from 2 to 30, 10–150 μg mL⁻¹ with an R2 of 0.9999 and 0.9997, respectively. The forced degradation study of stability-indicating assay results shows the degradation in respective stress conditions. The developed UPLC method was validated and found to have sensible results with good linearity, accuracy and precision. Further, the greenness was evaluated using five states of art metrics like NEMI, GAPI, AES, AMGS, and AGREE metrics and found the greenest results. Based on the results we concluded that the developed UPLC method could be efficient for the simultaneous determination of pitavastatin and ezetimibe in bulk and tablet dosage.

2

Simultaneous determination of ezetimibe, atorvastatin and simvastatin using quadrupole LC-MS: Application to combined tablets and plasma after SPE

Elawady Tarek, Ibrahim Fawzia, Khedr Alaa, Belal Fathalla

Acta Chromatographica

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2021

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Vol. 33, no. 3

245--252

EN

A simple and sensitive liquid chromatography-mass spectrometric (LC-MS) method has been developed and validated for the simultaneous determination of ezetimibe (EZE), atorvastatin calcium (ATO), and simvastatin (SMV) in combined dosage forms and human plasma. Successful separation of the studied drugs was achieved on a Zorbax Eclipse Plus C18 column (3.0 × 150 mm, 5 µm) using a mobile phase consisting of acetonitrile and 0.1% formic acid in water (65:35, v/v) at a flow rate of 0.5 mL min-1. Total run time was 9.3 min and diclofenac sodium was used as internal standard (IS). Positive selected ion monitoring (SIM) mode was applied where, the monitored ions were those at m/z values of 392.1, 559.3, 296.0, and 441.4 corresponding to EZE, ATO, IS, and SMV, respectively. The method was fully validated according to the ICH guidelines. The intraday and interday precision showed relative SD values not more than 1.77 and 1.99%; respectively. The limits of detection (LOD) were 0.25, 0.25, and 0.75 ng mL-1 while the limits of quantification (LOQ) were 1.25, 0.75, and 2.5 ng mL-1 for EZE, ATO, and SMV, respectively. The developed method was applied on two types of combined tablets concerning drug assay with mean percent recoveries within acceptable range. The method has been extended to the determination of the studied drugs in human plasma where, a solid phase extraction method was optimized for their extraction with percent recovery not less than 97%.

3

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

Suchy D., Łabuzek K., Pierzchała O., Okopień B.

Acta Chromatographica

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2013

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Vol. 25, no. 3

483--502

EN

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 R2 > 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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Ezetymib, lek obniżający poziom cholesterolu : opracowanie technologii wytwarzania produktu o wysokiej czystości stereochemicznej

Bańkowski K., Sidoryk K., Filip K., Chmielowiec U.

Przemysł Chemiczny

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2012

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T. 91, nr 3

289-294

PL

Usprawniono i zoptymalizowano opartą na patencie europejskim EP 1137634 B1 metodę syntezy ezetymibu. Wyizolowano i/lub zsyntetyzowano chemiczne i stereochemiczne zanieczyszczenia półproduktów oraz związku końcowego i scharakteryzowano je metodami fizykochemicznymi. Opracowano metodę oczyszczania związku (S,R,S,S)-15, dostępnego handlowo, zaawansowanego w syntezie półproduktu, który zazwyczaj zawiera niewłaściwy diastereoizomer prowadzący do otrzymania zanieczyszczonego ezetymibu. Opracowano wydajny i powtarzalny proces technologiczny wytwarzania farmaceutycznie czystego ezetymibu, spełniający wymagania dobrej praktyki wytwarzania (GMP) i Prawa Farmaceutycznego.

EN

Known synthesis of (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3- (4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)- 2-azetidinon (azetimibe) was improved and optimized to decrease the formation of other diastereoisomers and increase the stereochem. purity of the final product up to above 99%.

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Validated TLC method for simultaneous quantitation of atorvastatin, ezetimibe, and fenofibrate in bulk drug and formulations

Nikalje A. G, Choudhari V. P

Acta Chromatographica

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2011

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Vol. 23, no. 2

267--280

EN

This article describes a new, simple, precise and accurate TLC method for simultaneous quantitation of atorvastatin (ATO), ezetimibe (EZE), and fenofibrate (FEN) as the bulk drug and in tablet dosage forms. Chromatographic separation of the drugs was performed on aluminum plates precoated with silica gel 60 F254 as the stationary phase and the solvent system consisting of chloroform-toluene-methanol-acetic acid 6:3:0.5:0.15 (υ/υ/υ/υ). Densitometric evaluation of the separated zones was performed at 263 nm. The drugs were satisfactorily resolved with RF values of 0.16 ± 0.02, 0.22 ± 0.02, and 0.76 ± 0.02 for ATO, EZE, and FEN, respectively. The accuracy and reliability of the method was assessed by evaluation of linearity (75–375 ng per spot for ATO, 99–594 ng per spot for EZE, and 66–330 ng per spot for FEN), precision intra-day and inter-day RSD values were always less than 1.51 for the titled drugs, accuracy (99.72 ± 0.75% for ATO, 101.25 ± 0.91% for EZE, and 101.06 ± 0.60% for FEN), and specificity, in accordance with ICH guidelines.