The enantiomers of chiral drugs have obvious differences in pharmacology, toxicology, pharmacokinetics, metabolism, and other biological activities. The separation of enantiomers is the basis of in-depth study on the physiological and pharmacological effects and clinical applications of different isomers of drugs, so it has been paid more and more attention.
Cyclodextrin (CD) is composed of multiple glucose-pyranose units. Each glucose unit has five chiral centers, providing a good chiral environment for chiral separation. Therefore, CD can be used as chiral mobile phase additive (CMPA) or chiral stationary phase (CSP) for the separation of chiral drugs [1].
Separation Techniques Based on CD
Currently, the commonly used chiral separation techniques include high performance liquid chromatography (HPLC), gas chromatography (GC), mass spectrometry (MS), capillary electrophoresis (CE) and supercritical fluid chromatography (SFC). In the separation of chiral drugs, CD can be used as a chiral agent in combination with different separation techniques to achieve a good separation effect. CD-based HPLC, GC, and MS techniques for chiral drug separation are described below.
In HPLC technique, CD can be used as CMPA or CSA to achieve the separation of chiral drugs. The separation of drug enantiomers can be achieved by detecting the different stability constants of the combinations formed by each enantiomer and CDs (as CMPA), and the difference in the distributions of the combinations in the stationary phase. In addition, CD (as CSA) can directly interact with enantiomers and form unstable complexes with one of the enantiomers. Chiral drugs are separated according to the retention time of the CD complex and different components in the chromatographic column.
- For instance, the racemic thioridazine obtained from Thioril tablets was separated into its enantiomers using the β-CD-bonded chiral chromatography column [2].
At present, CD is used to combine with achiral silane, which acts as a CSP commonly used in GC for the separation of chiral drugs. And C-6 silyl-substituted CD has developed rapidly.
- For instance, Takahisa synthesized Octakis(2,3-di-O-methoxymethyl-6-O-tert-butyldimethylsilyl)-gamma-cyclodextrin (2,3-MOM-6-TBDMS-γ-CD) and used it as a stationary phase for capillary gas chromatographic separation of enantiomers. This new CD derivative is suitable for separating a variety of volatile compounds containing different functional groups in chiral drugs, such as secondary alcohols, lactones, aromatics, and methyl or sulfur compounds [3].
CD, as a commonly used chiral selector in MS chiral recognition, can also separate chiral drugs by MS technique. CD can undergo stereoselective reactions or non-covalent interactions with enantiomers to form diastereomeric complexes. Due to the different ionization efficiencies and fragmentation behaviors of the complex ions and enantiomers, they also exhibit different chirality in MS, which is conducive to the separation of different components in chiral drugs by MS technology.
- For instance, Yu Zhan found that heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-β-CD) can be used as a chiral recognition reagent in electrospray ionisation mass spectrometry (ESI-MS). DM-β-CD has a strong chiral recognition ability for menthol enantiomers, which facilitates enantiomers separation [4].
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References
- Fang. Z; et al. Application of cyclodextrin and its derivatives in chiral separation and analysis. Journal of Pharmaceutical Practice and Service. 2010, 28(2): 94-96.
- Bhushan, R.; Gupta, D. HPLC resolution of thioridazine enantiomers from pharmaceutical dosage form using cyclodextrin-based chiral stationary phase. Chromatogr B. 2006, 837(122): 133.
- Takahisa, E.; Engel, K. H. 2,3-Di-O-methoxymethyl-6-O-tert-butyldimethylsilyl-γ-cyclodextrin: a new class of cyclodextrin derivatives for gas chromatographic separation of enantiomers. Chromatogr A. 2005, 1063(122) : 181.
- Zhan, Y.; et al. Investigation of Chiral Recognition of Heptakis-(2, 6-di-O-methyl)-β-cyclodextrin to Menthol Enantiomers by Electrospray Mass Spectrometry. Chinese Journal of Analytical Chemistry. 2006, 5: 671-674.
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