Chromatographic resolution, chiroptical characterization and urinary excretion of the enantiomers of sulindac

Summary The chromatographic resolution of the enantiomers of sulindac has been achieved using a Chiralpak AD CSP (10 μm, 250×4.6 mm) with a mobile phase of hexane: ethanol (85∶15 v/v) containing trifluoroacetic acid (0.05% v/v) at a flow rate of 1.0 mL min⁻¹. Under these conditions the enantiomers eluted with separation and resolution factors of 1.43 and 2.46 respectively. Semipreparative isolation of the enantiomers and their characterization by circular dichroism spectroscopy and NMR, in the presence of a chiral shift reagent, indicated that the elution order was (−)-(S)- before (+)-(R)-sulindac. The enantiomeric composition of sulindac in urine following administration of the racemic drug to man was determined by sequential achiral-chiral chromatography. Achiral analysis was carried out using a Spherisorb S5 ODS2 stationary phase (5 μm, 250×4.6 mm) and a mobile phase of aqueous acetic acid (2% v/v; pH 3.5): acetonitrile: THF (50∶48∶2 by volume) at a flow rate of 1.0 mL min⁻¹. The HPLC eluate containing sulindac (retention time 4.9 min) was collected and following workup, the enantiomeric composition of the drug was determined using the CSP. Over the 24 h collection period sulindac was excreted predominantly as theR-enantiomer, but the enantiomeric composition was found to vary markedly with time which is presumably associated with the complex metabolism of the drug.