Cinchona‐alkaloid‐based zwitterionic chiral stationary phases as potential tools for high‐performance liquid chromatographic enantioseparation of cationic compounds of pharmaceutical relevance

Abstract

Enantiomers of cationic compounds of pharmaceutical relevance, namely tetrahydro-ß-carboline and 1,2,3,4-tetrahydroisoquinoline analogs, were separated by high-performance liquid chromatography. Separations were performed on Cinchona-alkaloid-based zwitterionic ion exchanger type chiral stationary phases applied as cation exchangers using mixtures of methanol and acetonitrile or tetrahydrofuran as bulk solvent components containing triethylammonium acetate or ammonium acetate as organic salt additives. On the zwitterionic ZWIX(+) and ZWIX(−) columns investigated, retention and enantioseparation of the studied basic analytes were influenced by the nature and concentration of the organic components of the mobile phase. The effect of organic salt additives on the retention behavior of the studied analytes can be described by the stoichiometric displacement model related to the counterion concentration. Investigations on the structure-retention relationships were performed applying different mobile phase systems for the two types of cationic analytes. For the thermodynamic characterization, parameters such as changes in standard enthalpy (Δ(ΔH • )), entropy (Δ(ΔS • )), and free energy (Δ(ΔG • )) were calculated on the basis of van't Hoff plots derived from the ln α versus 1/T curves. In most cases, enthalpy-driven enantioseparations were observed, with a consistent dependence of the calculated thermodynamic parameters on the mobile phase composition. Elution sequences of the studied compounds were determined in all cases.

A new chiral stationary phase based on noscapine: Synthesis, enantioseparation, and docking study

“…The composition, characteristics, and role of alkaloids in enantioseparation have been the topic of some recent studies 15,16,58 . Figure 6 illustrates the simulation of interactions such as π‐π Stacking and π‐π T‐shaped (pink), π‐Alkyl (white), π‐Sigma (violet), and hydrogen bonding (green) between the noscapine derivative and enantiomers, which possibly leads to enantiomeric separation.…”

“…The composition, characteristics, and role of alkaloids in enantioseparation have been the topic of some recent studies. 15,16,58 Figure 6 illustrates the simulation of interactions such as π-π Stacking and π-π T-shaped (pink), π-Alkyl (white), π-Sigma (violet), and hydrogen bonding (green) between the noscapine derivative and enantiomers, which possibly leads to enantiomeric separation. As shown in Figure 6, there are dominant aromatic π-π interactions between aromatic rings of both enantiomers and noscapine derivative as well as polar interactions between multiple hydrogen bond acceptors of the noscapine derivative and hydrogen bond donors of enantiomers.…”

“…The synthesis and study of functionalization of CSPs with desired active sites are interesting and also challenging, as is discussed in our reports from a microcolumn to a semipreparative column. 13,14 There has been a progressive effort to develop more efficient and economical chiral stationary phases that introduced alkaloid-based chiral selectors such as cinchona, [15][16][17] brucine, 18 strychnine, 19 codeine, 20 and antibiotic degradation products such as vancomycin. 13,[21][22][23] Although these efforts were effective and resulted in potentially versatile selectors, there is a long way to meet the pharmaceutical companies' demand for the suitable chiral LC column from a commercial and strategic point of view.…”

Update on chiral recognition mechanisms in separation science

“…Nonetheless, with an awareness that the numbers obtained from analytical chromatographic data are not "true" but rather "estimated" values, they may be useful for the explanation of some phenomena observed for a given CSP and experimental conditions such as, for example, the temperature-dependent reversal of the enantiomer elution order observed for ketoprofen, naproxen or ibuprofen on polysaccharide CSPs [44][45][46] or the elution profiles of halogenated 4,4′-bipyridine derivatives [47] or planar chiral ferrocenes bearing iodoethynyl substituents [48]. Thermodynamic data derived from chromatography for the analysis of entropic or enthalpic contributions in the case of enantioseparations has also been applied in the case of other types of selectors, for example, macrocyclic antibiotics [49,50] or ion-exchange type selectors [51][52][53].…”