Omeprazole enantiomers

Berzas Nevado, J. J., Castaneda Penalvo, G., and Rodriguez Dorado, R. M. (2005). Method development and validation for the separation and determination of omeprazole enantiomers in pharmaceutical preparations by capillary electrophoresis. Anal. Chim. Acta 533, 127-133. 

Figure 3.6 Resolution of the enantiomers of omeprazole using a protein-derived CSP. The chromatogram shows the analysis of esomeprazole API artificially enriched with 0.1% w/w of the R-enantiomer. (Conditions cti-AGP 10 cm X 0.4 cm i.d. mobile phase sodium phosphate [pH 6.0, 60 mM] acetonitrile [85 15, v/v] flow rate 1 mbmin detection UV at 302 nm column temperature ambient sample preparation 0.02mg/ml in sodium phosphate [pH 11.0, 18 mM] methanol [98 2, v/v] injection volume 20 pi.)...

Agents in this class are omeprazole, lansoprazole, pantoprazole and rabeprazole. Esomeprazole is the S-enantiomer of omeprazole. After ingestion of gastric acid resistant formulations they are rapidly and more or less completely absorbed. Bioavailability may be reduced if administered with food or antacids. Elimination is via metabolism in the liver and the renal excretion of inactive metabolites. The elimination half-live is very variable, however, as explained above, not related to the duration of action. 

Esomeprazole (2) is the (5)-enantiomer of racemic omeprazole (1). The former has better pharmacokinetics and pharmacodynamics than the latter and therefore possesses higher efficacy in controlling acid secretion and has a more ideal therapeutic profile. 

Cotton etal. [14] described an asymmetric synthesis of esomeprazole. Esomeprazole, the (S)-enantiomer of omeprazole, was synthesized via asymmetric oxidation of prochiral sulfide 5-methoxy-2-[[(4-methoxy-3,5-dimethyl pyridin-2-yl)methyl]thio]-lH-benzimidazole 1. The asymmetric oxidation was achieved by titanium-mediated oxidation with cumene hydroperoxide in the presence of (S,S)-diethyl tartarate (DET). The enan-tioselectivity was provided by preparing the titanium complex in the presence of sulfide 1 at an elevated temperature and/or during a prolonged preparation time and by performing the oxidation of sulfide 1 in the presence of amine. An enantioselectivity of 94% ee was obtained using this method. 

Balmer et al. [60] separated the two enantiomers of omeprazole on three different stationary phases with immobilized protein, viz, Chiral-AGP with a-1 acid glycoprotein, Ultron ES-OVM with ovomucoid, and BSA-DSC with BSA cross-linked into 3-aminopropyl silica using N-suc-cinimidyl carbonate. The mobile phase (1 ml/min) was phosphate buffer solution with 3—10% 2-propanol as the organic modifier. The enantiomers of omeprazole were separated on Chiralpak AD, an amylose-based chiral stationary phase, with ethanol-hexane (1 4) as mobile phase (1 ml/min). 

Cass et al. [66] used a polysaccharide-based column on multimodal elution for the separation of the enantiomers of omeprazole in human plasma. Amylose tris (3,5-dimethylphenylcarbamate) coated onto APS-Hypersil (5 /im particle size and 120 A pore size) was used under normal, reversed-phase, and polar-organic conditions for the enantioseparation of six racemates of different classes. The chiral stationary phase was not altered when going from one mobile phase to another. All compounds were enantioresolved within the elution modes with excellent selectivity factor. The separation of the enantiomers of omeprazole in human plasma in the polar-organic mode of elution is described. 

Cass et al. [71] described a direct injection HPLC method, with column-switching, for the determination of omeprazole enantiomers in human plasma. A restricted access media of bovine serum albumin octyl column has been used in the first dimension for separation of the analyte from the biological matrix. The omeprazole enantiomers were eluted from the restricted access media column onto an amylose tris (3,5-dimethylphenylcarbamate) chiral column by the use of a columnswitching valve and the enantioseparation was performed using acetonitrile-water (60 40) as eluent. The analytes were detected by their UV absorbance at 302 nm. The validated method was applied to the analysis of the plasma samples obtained from 10 Brazilian volunteers who received a 40-mg oral dose of racemic omeprazole and was able to quantify the enantiomers of omeprazole in the clinical samples analyzed. 

Orlando and Bonato [73] presented a practical and selective HPLC method for the separation and quantification of omeprazole enantiomers in human plasma. Ci8 solid-phase extraction cartridges were used to extract the enantiomers from plasma samples and the chiral separation was carried out on a Chiralpak AD column protected with a CN guard column, using ethanol-hexane (70 30) as the mobile phase, at a flow-rate of 0.5 ml/min. The detection was carried out at 302 nm. The method is linear in the range of 10-1000 ng/ml for each enantiomer, with a quantification limit of 5 ng/ml. Precision and accuracy, demonstrated by within-day and between-day assays, were lower than 10%. 

Stenhoff et al. [117] determined enantiomers of omeprazole in blood plasma by normal-phase liquid chromatography and detection by atmospheric-pressure ionization tandem mass spectrometry. The enantioselec-tive assay of omeprazole is using normal-phase liquid chromatography on a Chiralpak AD column and detection by mass spectrometry. Omeprazole is extracted by a mixture of dichloromethane and hexane and, after evaporation, redissolution and injection, separated into its enantiomers on the chiral stationary phase. Detection is made by a triple quadrupole mass spectrometer, using deuterated analogs and internal standards. The method enables determination in plasma down to 10 nmol/1 and shows excellent consistency suited for pharmacokinetic studies in man. 

Eberle et al. [134] separated the enantiomers of omeprazole and structurally related drugs by capillary zone electrophoresis with bovine serum albumin as chiral selector. The separations were carried out on a fused silica column (60 cm x 50 pm, 50 cm to detector) with a buffer consisting of 100-/zM-bovine serum albumin and 7% 1-propanol in 10 mM potassium phosphate pH 7.4. Electrokinetic injection was at 5-8 kV for 7 s. An applied voltage of 300 V/cm was used. Detection was at 290 nm. Detection limits were 0.04 mg/ml for the analytes studied. 

Bonato and Paias [136] developed two sensitive and simple assay procedures based on HPLC and capillary electrophoresis for the enantio-selective analysis of omeprazole in pharmaceutical formulations. Racemic omeprazole and (S)-omeprazole were extracted from commercially available tablets using methanol-sodium hydroxide 2.5 mol/1 (90 10). Chiral HPLC separation of omeprazole was obtained on a ChiralPak AD column using hexane-ethanol (40 60) as the mobile phase and detection at 302 nm. The resolution of omeprazole enantiomers by capillary electrophoresis was carried out using 3% sulfated /1-cyclodextrin in 20 mmol/1 phosphate buffer, pH 4 and detection at 202 nm. 

Berzas Nevado et al. [138] developed a new capillary zone electrophoresis method for the separation of omeprazole enantiomers. Methyl-/ -cyclodextrin was chosen as the chiral selector, and several parameters, such as cyclodextrin structure and concentration, buffer concentration, pH, and capillary temperature were investigated to optimize separation and run times. Analysis time, shorter than 8 min was found using a background electrolyte solution consisting of 40 mM phosphate buffer adjusted to pH 2.2, 30 mM /1-cyclodextrin and 5 mM sodium disulfide, hydrodynamic injection, and 15 kV separation voltage. Detection limits were evaluated on the basis of baseline noise and were established 0.31 mg/1 for the omeprazole enantiomers. The method was applied to pharmaceutical preparations with recoveries between 84% and 104% of the labeled contents. 

Tyrbing et al. [166] studied the stereoselective disposition of omeprazole and its formed 5-hydroxy metabolite in five poor metabolizers, and five extensive metabolizers of 5-mephenytoin. After a single oral dose of omeprazole (20 mg), the plasma concentrations of the separated enantiomers of the parent drug and the 5-hydroxy metabolite were determined for 10 h after drug intake. In poor metabolizers, the area under the plasma concentration versus time curve [AUC(0-8)] of (+) omeprazole was larger... 

AstraZeneca (formerly Astra) has launched the proton-pump inhibitor esomeprazole (19) (as Nexium) as a treatment for peptic ulcer, gastroesophageal reflux disease, duodenal ulcer, and esophagitis. Esomeprazole is the (S)-enantiomer of omeprazole and was developed as a result of its improved pharmokinetic profile and better potency after oral dosing than (f )-form of omeprazole or the racemate. The dosage is higher than would be expected for a simple chiral switch. The stereogenic center is at sulfur. Detailed accounts of the development of the process have been published.189190... 

Omeprazole (p. 171) can cause maximal inhibition of HC1 secretion. Given orally in gastric juice-resistant capsules, it reaches parietal cells via the blood. In the acidic milieu of the mucosa, an active metabolite is formed and binds covalently to the ATP-driven proton pump (H+/K+-ATPase) that transports H+ in exchange for I<+ into the gastric juice. Lansoprazole, pantoprazole, and rabeprazole produce analogous effects. Omeprazole is a racemate. With respect to dosage, the now available (S)-omeprazole (esomeprazole) represents the more potent enantiomer, but this offers no therapeutic advantage. 

A new capillary zone electrophoresis method has been developed and used for the separation of enantiomers, for example, omeprazole [1476] and nitrobenzofurazans [1385, 1388, 1447],... 

Astra-Zeneca commercialized esomeprazole (the S enantiomer of omeprazole) obtained by asymmetric oxidation of pyrmetazole (Equation 28) in 2000, using a modified version of the Kagan-Modena protocol. Esomeprazole is an anti-ulcer medicine and one of the largest selling drugs worldwide. It is produced under very mild conditions in a multi tonne per year scale. 

Omeprazole Ratio of binding affinities of (unidentified) enantiomers = 1.43 (47)... 

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