Chiral separation and analysis of sertraline and its stereoisomers by supercritical fluid chromatography: Thermodynamic evaluation and molecular docking simulation.

In this study, a supercritical fluid chromatography (SFC) method was developed for the chiral resolution of sertraline hydrochloride (1S, 4S) and its three stereoisomers (1R, 4R), (1R, 4S), and (1S, 4R) using an amylose-tris(3,5-dimethylphenylcarbamate) chiral stationary phase (CSP). Among several polysaccharide-based CSPs screened, the Chiralpak AD-H exhibited the superior separation performance. Under optimized chromatographic conditions, using supercritical CO2 as mobile phase A and a methanol-ethanol mixture (1:1, v/v) containing 0.2% diethylamine (DEA) as mobile phase B, baseline separation of the four stereoisomers was achieved within 15 min at 210 nm. Thermodynamic investigations revealed that the resolution process for the two pairs of enantiomers was enthalpy-driven, whereas the separation of the diastereomers (1R, 4R) and (1R, 4S) was governed by entropy. Furthermore, molecular docking simulations were employed to elucidate the chiral recognition mechanism, showing that the calculated binding energies were in excellent agreement with the experimentally observed elution order. The proposed method was validated and successfully applied to the determination of sertraline in active pharmaceutical ingredients (APIs) and commercial tablets, providing a rapid and eco-friendly analytical tool for quality control.