Separation and determination of clopidogrel and its impurities by capillary electrophoresis

Fayed, Ahmed S.; Weshahy, Soheir A.; Shehata, Mohamed; Hassan, Nagiba Y.; Pauwels, Jochen; Hoogmartens, Jos; Schepdael, Ann Van

doi:10.1016/j.jpba.2008.10.031

Cited by 51 publications

(23 citation statements)

References 17 publications

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“…known that clopidogrel may decompose to byproducts via nonenzymatic oxidation (Mohan et al, 2008;Fayed et al, 2009). These byproducts do not seem to have any inhibitory effects on platelet aggregation.…”

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confidence: 99%

Formation, Reactivity, and Antiplatelet Activity of Mixed Disulfide Conjugates of Clopidogrel

et al. 2013

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In this work, we investigated the formation, reactivity, and antiplatelet activity of various mixed disulfide conjugates of clopidogrel. Our results showed that the production of the active metabolite (AM) from 2-oxoclopidogrel by human liver microsomes (HLMs) is greatly affected by the thiol reductants used. Among the 10 thiol compounds tested, glutathione (GSH) is most efficient in producing the AM at a rate of 167 pmoles AM/ min/mg HLM. Interestingly, no AM but only the mixed disulfide conjugates were formed in the presence of 6-chloropyridazine-3-thiol (CPT), 2,5-dimethylfuran-3-thiol, and 3-nitropyridine-2-thiol (NPT). The mass spectrometry (MS) and MS 2 spectra of the conjugates of these thiol compounds confirmed the presence of a mixed disulfide bond linkage between the AM and the thiol reductants. Kinetic studies revealed that the mixed disulfide conjugates were capable of exchanging thiols with GSH to release the AM with second order rate constants ranging from 1.2 to 28 M 21 s 21 . The mixed disulfide conjugates of CPT and NPT showed potent inhibition of platelet aggregation after pretreatment with 1 mM GSH, confirming that the AM is responsible for the antiplatelet activity of clopidogrel. Collectively, our results provide strong support for a cytochrome P450 (P450)-mediated bioactivation mechanism involving the initial formation of a glutathionyl conjugate, followed by thiol-disulfide exchange with another GSH molecule to release the AM. Furthermore, the stable mixed disulfide conjugates identified in this study provide a platform to quantitatively generate the therapeutic AM without the need for P450-mediated bioactivation. This property can be further explored to overcome the interindividual variability in clopidogrel therapy.

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confidence: 99%

Formation, Reactivity, and Antiplatelet Activity of Mixed Disulfide Conjugates of Clopidogrel

et al. 2013

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“…The application of CE in drug impurity analysis has been summarized [79,80]. Table 1 clearly reflects the general trend that CDs are by far the most widely used chiral selectors although some studies utilized other additives such as BSA [81], maltodextrin [82], (+)-18C6H4 [83], ligand exchange [84] or the chiral ionic liquid ethylcholine bis(trifluoromethylsulfonyl) Baclofen α-CD (18 mM) 0.1 M sodium borate, pH 9.9, 1% acetonitrile 2-10 μg/ml, analysis of racemic bulk drug and tablets [103] Benzimidazole derivatives Chloroquine SBE-β-CD (30 mg/ml) 100 mM sodium phosphate, pH 2.5 0.02%, analysis of laboratory sample [108] Clopidogrel Sulfated β-CD (5%) 10 mM triethylamine/phosphoric acid 0.08-0.33 μg/ml, minor enantiomer and related substances [109] Dexamphetamine HDAS-β-CD (10 mg/ml) 0.1 M sodium phosphate buffer, pH 2.5 0.06%, minor enantiomer and charged related substances [91] Dexamphetamine Sulfated β-CD (25 mg/ml), SBE-β-CD (80 mg/ml) 50 mM sodium phosphate buffer, pH 2.5 0.01-0.02%, minor enantiomer and related substances [92] Dexamphetamine Sulfated β-CD (5.5%) 1.5% SDS, 0.5% ethyl acetate, 3.5% 1-butanol, 2.5% 2-propanol and 92% 50 mM sodium phosphate buffer, pH 3.0 0.05-0.2%, minor enantiomer and related substances [93] Econazole HP-γ-CD (40 mM) 50 mM SDS in 20 mM phosphate buffer, pH 8.0…”

Section: Pharmaceutical Analysismentioning

confidence: 99%

Chiral electromigration techniques in pharmaceutical and biomedical analysis

Scriba

2011

Bioanal Rev

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Capillary electromigration techniques are often considered ideal methods for enantioseparations due to their high separation selectivity and flexibility. Thus, numerous methods employing a chiral selector as pseudostationary phase in a background electrolyte have been developed and applied for the chiral analysis of drugs in bulk ware, pharmaceutical formulations and biological matrices. Furthermore, electromigration techniques have been combined with spectroscopic methods such as nuclear magnetic resonance in order to understand the complexation of analytes by chiral selectors. The present review focuses on recent developments and applications of chiral electromigration techniques in pharmaceutical and biomedical analysis including examples illustrating analyte-selector complex formation or mechanistic studies which have been published between January 2009 and July 2011. Selector-mediated chiral separations clearly dominate while no applications of capillary electrochromatography to pharmaceutical or biomedical analysis have been reported during this period of time.

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“…Each 1 mL contains 15 mg of Nizatidine along with inactive ingredients methylparaben, propylparaben, glycerin, sodium alginate, purified water, sodium chloride, saccharin sodium, sodium citrate dihydrate, citric acid anhydrous, sucrose, bubble gum flavor, artificial sweetness enhancer, and sodium hydroxide. [1] Literature survey reveals few analytical methods reported for quantification of Nizatidine by LC, [2][3][4][5][6][7] by capillary electrophoresis (CZE), [8] by thin-layer chromatography (TLC), [9] and by titrimetric [10] methods.…”

Section: Introductionmentioning

confidence: 99%

Stability-Indicating Lc Method for the Estimation of Nizatidine Impurities in Nizatidine Oral Solution

Rao

Kumar

Prasad

et al. 2014

Journal of Liquid Chromatography & Related Technologies

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& A novel stability-indicating reversed phase liquid chromatographic (RP-LC) method was developed for the determination of purity of Nizatidine in Nizatidine oral solutions in the presence of its impurities and degradation products. Two unknown impurities were formed in the formulated drug under the stress conditions (40 C=75% RH for 3 months), with relative retention times (RRTs) 0.93 and 2.14. The two degradant impurities were isolated and characterized using liquid chromatography mass spectrometry (LC-MS). Chromatographic method was developed and validated for Nizatidine United States Pharmacopeia (USP) impurities along with the two degradant impurities. Total 13 impurities were well separated and not interfering with placebo peaks in oral solution. The method was developed using C-18 column in gradient elution mode. The eluted compounds were monitored at 254 nm. Nizatidine was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal, and photolytic degradation. The degradation products were well resolved from main peak and its impurities, proving the stability-indicating power of the method. The developed method was validated as per International Conference on Harmonization guidelines with respect to specificity, limit of detection, limit of quantification, precision, linearity, accuracy, robustness, and ruggedness.

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Separation and determination of clopidogrel and its impurities by capillary electrophoresis

Cited by 51 publications

References 17 publications

Formation, Reactivity, and Antiplatelet Activity of Mixed Disulfide Conjugates of Clopidogrel

Formation, Reactivity, and Antiplatelet Activity of Mixed Disulfide Conjugates of Clopidogrel

Chiral electromigration techniques in pharmaceutical and biomedical analysis

Stability-Indicating Lc Method for the Estimation of Nizatidine Impurities in Nizatidine Oral Solution

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