Preparative chiral chromatography and chiroptical characterization of enantiomers of omeprazole and related benzimidazoles

Abstract

To chiroptically characterize the enantiomers of omeprazole and some structurally related benzimidazoles with circular dichroism (CD), preparative chiral liquid chromatography was utilized for the isolation of the pure enantiomers. A limited analytical column screen was performed identifying Kromasil-CHI-TBB and the amylose-based phases Chiralpak AD and AS as possible chiral stationary phases (CSPs) for the preparative scale separation of the enantiomers of the different benzimidazoles. Optimization of the chromatographic conditions with respect to retention, enantioseparation, and resolution was achieved by variation of the mobile phase constituents as well as of temperature. Because of the lability of the compound in slightly acidic media, supercritical fluid chromatography (SFC) could not be applied for a preparative scale separation of the enantiomers. The separation of omeprazole was optimized to give high throughput (2.6 kg racemate/kg CSP/day) and high enantiomeric excess of the obtained isomers. The absolute configurations of the pure enantiomers of rabeprazole, lansoprazole, and pantoprazole were determined from the strong correlation to the CD spectrum of (+)-(R)-omeprazole. For all the compounds, the (+)-enantiomers displayed similar chiroptical features as (+)-(R)-omeprazole and were thus assigned the (R)- configuration. Elution order of the optical isomers was monitored by injecting racemic solutions spiked with one of the isomers and also by an on-line laser polarimeter. Both the type of CSP and also the mobile phase constituents had a strong effect on elution order of the enantiomers.

Comparative study of coated and immobilized polysaccharide-based chiral stationary phases and their applicability in the resolution of enantiomers☆

“…Also, use of ethanol instead of 2-propanol in the mobile phase gave an opposite elution order with the (−)-(S)-Omeprazole eluting first. This is in agreement with the results obtained in our earlier studies [23]. Use of non-conventional organic solvents did not improve the resolution, although mobile phases based on acetone (45% in heptane) and ethylacetate did give reasonable separation and peak shape of the enantiomers, Fig.…”

Two‐dimensional chromatography method applied to the enantiomeric determination of lansoprazole in human plasma by direct sample injection

“…The optical rotation of the separated enantiomers was measured in ethanol as reported elsewhere 10 using a Perkin-Elmer Model 241 polarimeter. The absolute configurations for the PPIs have been reported 11 and were used to correlate to the optical rotation obtained of the isolated enantiomers with the highest enantiomeric purity. Then, it was possible to determine the enantiomeric elution order by injection of (R)-(1) and (S)-(2)-lansoprazole on a chiral column of amylose tris(3,5-dimethoxyphenylcarbamate) coated (20% w/w) onto APS-Nucleosil (7 lm particle size and 500 Å pore size) (150 mm 3 4.6 mm I.D.)…”

Liquid chromatographic resolution of proton pump inhibitors including omeprazole on a ligand exchange chiral stationary phase

“…However, we were not able to see any notable relationship between the pH values and the separation factors (˛) and the resolutions (R S ) for the resolution of omeprazole (2), pantoprazole (3), lansoprazole (4) and rabeprazole (5) on CSP 1. PPIs have been known to be degraded to the corresponding sulfenamide in neutral or acidic environment [25]. However, even under the most acidic mobile phase condition (65% acetonitrile in water + 0.50 mM CuSO 4 + 0.1 mM acetic acid, pH = 3.75), PPIs were found to be stable enough to be resolved on CSP 1 within 120 min.…”