Enantioseparation of chiral pharmaceuticals by vancomycin‐bonded stationary phase and analysis of chiral recognition mechanism

Abstract

The drug chirality is attracting increasing attention because of different biological activities, metabolic pathways, and toxicities of chiral enantiomers.The chiral separation has been a great challenge. Optimized high-performance liquid chromatography (HPLC) methods based on vancomycin chiral stationary phase (CSP) were developed for the enantioseparation of propranolol, atenolol, metoprolol, venlafaxine, fluoxetine, and amlodipine. The retention and enantioseparation properties of these analytes were investigated in the variety of mobile phase additives, flow rate, and column temperature. As a result, the optimal chromatographic condition was achieved using methanol as a main mobile phase with triethylamine (TEA) and glacial acetic acid (HOAc) added as modifiers in a volume ratio of 0.01% at a flow rate of 0.3 mL/minute and at a column temperature of 5°C. The thermodynamic parameters (eg, ΔH, ΔΔH, and ΔΔS) from linear van 't Hoff plots revealed that the retention of investigated pharmaceuticals on vancomycin CSP was an exothermic process. The nonlinear behavior of lnk′ against 1/T for propranolol, atenolol, and metoprolol suggested the presence of multiple binding mechanisms for these analytes on CSP with variation of temperature. The simulated interaction processes between vancomycin and pharmaceutical enantiomers using molecular docking technique and binding energy calculations indicated that the calculated magnitudes of steady combination energy (ΔG) coincided with experimental elution order for most of these enantiomers.

An overview of chiral separations of pharmaceutically active substances by HPLC (2018–2020)

“…An interesting study focused on the analysis of baclofen enantiomers in human plasma using vancomycin-based silica stationary phase by nano-liquid chromatography [ 78 ]. Vancomycin-bonded stationary phase was applied for enantioseparation of propranolol, atenolol, metoprolol, venlafaxine, fluoxetine, and amlodipine and the mechanism of chiral recognition was evaluated [ 79 ].

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Simultaneous enantioseparation and simulation studies of atenolol, metoprolol and propranolol on Chiralpak® IG column using supercritical fluid chromatography

“…This tool facilitates prediction of most favored orientation of small molecules to interact with the stationary phase. The binding energies and the bond lengths of different interaction modes can be estimated with reasonable accuracy [ 22 , 23 ]. Further, it can help in understanding the elution behavior of the enantiomers based on binding energies.…”

“…Several analytical techniques have been used for enantiomeric separation of these drugs, namely, thin layer chromatography [ 10 ], surface enhanced Raman scattering [ 11 ], counter current chromatography [ 12 ], electrochromatography [ 13 , 14 ], capillary electrophoresis [ [15] , [16] , [17] , [18] ], high performance liquid chromatography (HPLC) [ 9 , [19] , [20] , [21] , [22] , [23] ], liquid chromatography-tandem mass spectrometry (LC-MS/MS) [ [24] , [25] , [26] , [27] , [28] , [29] ], and supercritical fluid chromatography (SFC) [ [30] , [31] , [32] , [33] ]. Among different chiral stationary phases (CSPs), polysaccharide (cellulose or amylose) based phases are the most widely used with these techniques [ 20 , 21 , 23 , 32 , 33 ].…”

Enantioselective hydrogenation of α‐ketoesters catalyzed by cinchona alkaloid stabilized Rh nanoparticles in ionic liquid

“…Chiral modifiers are sources of enantioselectivity in most heterogeneous enantioselective catalytic reactions. Appropriate introduction of modifiers into nanometal catalytic systems is one of the most effective ways to promote the performance of heterogeneous enantioselective catalytic systems . As shown in Table , different cinchona alkaloids modified Rh NPs have significantly different catalytic reactivity and enantioselectivity.…”

“…Cinchona alkaloid derivatives including 9‐amino(9‐deoxy)epicinchonidine and o ‐acetylcinchonidine were also tested as the chiral modifier, and decreased catalytic activity and enantioselectivity was observed (Table , entries 5‐6). Only cinchonidine gave much higher enantioselectivity compared with the other cinchona alkaloids in the asymmetric reduction should be owing to the high substrate specificity of heterongeneous enantioselective catalysis …”