Enantioselective Separation and Pharmacokinetics of a Chiral 1,4-Dihydropyrimidine Derivative in Rats: A Combined Chromatography and Docking Approach

Abstract

Chirality in 1,4-Dihydropyrimidines influences their pharmacological properties and synthetic strategies. Enantiomers of chiral drugs often exhibit different pharmacokinetic profiles. Therefore, separating and studying individual enantiomers is crucial to optimize drug efficacy and safety. Enantiomeric separation of ±4-(4-chlorophenyl)-6-methyl-2-oxo-N-(O-toyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (DP-1), which is a 1,4-Dihydropyrimidine derivative is achieved on CHIRALCEL® OD-H column (particle size: 5 μm, inner diameter: 4.6 mm, length:150 mm), following by investigating the kinetic properties of (R) and (S) enantiomers. The separation was achieved with a mobile phase composed of 70% (v/v) isopropyl alcohol and 30% (v/v) n-hexane. For the bioanalytical study, acetonitrile was used to precipitate the rat plasma samples and validated the method according to USFDA guidelines. The validated bioanalytical method was then successfully applied to determine the pharmacokinetic parameters of the drug in biological samples. Molecular modeling techniques, specifically docking simulations, were employed to predict the elution order of DP-1 enantiomers. The docking results revealed moderate binding interactions between the enantiomers and the chiral stationary phase (CSP), which aligns with the theoretical expectation that stronger interactions lead to longer retention times on the column.