The effect of acidic and basic additives on the enantioseparation of basic drugs using polysaccharide‐based chiral stationary phases

Abstract

The enantioseparation of nine commercially available basic drugs was achieved on polysaccharide-based chiral stationary phases with the acidic additive ethanesulfonic acid and the basic additive butylamine. Seven different commercially available CSPs were used for the study (AD, AS, OD, OJ, OG, OB, and OC). Mobile phase additives have been proven to be essential in obtaining satisfactory enantio-resolution in terms of both efficiency and selectivity. Significantly improved selectivities were obtained for the basic probe drugs with the acidic additive, ethanesulfonic acid, rather than the basic additive, butylamine. This is best seen with Chiralpak AS CSP. No enantioseparation for the nine drugs was observed when butylamine was used as an additive; however, satisfactory enantioseparation for the nine drugs was achieved using ethanesulfonic acid. Higher column efficiencies were observed with the acidic additive, especially when isopropanol was used as a modifier. Higher sensitivity was also achieved with ethanesulfonic acid because of the significantly lower background at the UV detection wavelength. The acidic additive was demonstrated to be superior to the basic additive for the enantioseparation of basic drugs using seven different polysaccharide-based CSPs. These results are counterintuitive to the common "rule of thumb" in enantioseparation that states acidic additives work best for acidic analytes and basic additives work best for basic analytes. The beneficial effects of acidic additive in enantioseparations observed in this study could significantly improve the applicability of polysaccharide-based CSPs for the enantioseparation of basic analytes.

Chiral Recognition Mechanism: Practical Considerations for Pharmaceutical Analysis of Chiral Compounds

“…Now, a chiral separation can be achieved on many different CSPs based on different chiral recognition mechanisms or in different separation modes on the same CSP. For example, the β-adrenergic blockers, an important class of chiral amino alcohol drugs, were directly resolved on a wide array of CSPs, including phases based on tris(3,5-dimethylphenylcarbamate) cellulose in normalphase (NP) mode [70,142,143] and reversed-phase (RP) mode [70], macrocyclic glycopeptides in polar organic mode (POM) [53][54][55] and SFC [144], proteins in RP [145], β-cyclodextrins in RP [69] and POM [73], chiral crown ethers in POM [134], and Pirkle-type chiral selectors in NP [146].…”

Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery—Building chiral technology toolboxes

“…Similar to identifying parameters for successful enantiomeric separation by HPLC, [231][232][233][234] screening CSPs, alcohol cosolvents, and acidic and basic modifiers are integral components in developing successful chiral separations by SFC. [256][257][258] A note of caution is appropriate as reversal of elution order of enantiomers is neither uncommon nor currently predictive in HPLC and SFC separations. [259][260][261][262] Therefore, spectroscopic characterization of the eluted enantiomers is paramount to successfully correlating configuration with eutomer (biologically active enantiomer) and distomer (biologically inactive enantiomer).…”

High‐Throughput Screening and Method Development Strategies to Separate Chiral Drug Compounds in HPLC, SFC, and CE

“…It has been demonstrated that these compounds are essential for the separation of acidic and basic drugs [54,55]. Trifluoroacetic acid is a frequently used acid.…”

“…Acetic acid and alkylsulfonic acids, such as ethanesulfonic acid, can also be dissolved in the mobile phase. Triethylamine and diethylamine are the common basic additives, while butylamine and dimethylethylamine are possible alternatives [45,55]. The influence of these additives, generally used in concentrations of 0.1% (v/v) in the mobile phase, is versatile.…”