Advances in chiral separation and analysis by capillary electrophoresis-mass spectrometry

Most drugs used to treat diseases are chiral compounds. Drug enantiomers possess similar physical and chemical properties but may feature distinct pharmacological activities. Drug enantiomers may also exhibit different or even opposite functionalities for metabolism, in terms of the metabolic rate and toxicity in the body. Therefore, it is imperative to analyze, separate, and purify the enantiomers of drugs. The separation of chiral compounds is essential for drug research and development. It is also of significance in various fields including biological environments, food, and medicine. Various highly selective and sensitive methods have been developed for the quantitative and qualitative analyses of chiral compounds. A typically employed technique is high performance liquid chromatography-mass spectrometry (HPLC-MS). While HPLC-MS offers high sensitivity and reproducibility, it requires expensive chiral columns and MS-compatible mobile phases for the chromatographic column. Further, the column efficiency and resolution capacity in chiral chromatography packing require improvement. Recent progress has shown that capillary electrophoresis-mass spectrometry (CE-MS) has broad applications in chiral analysis. As a well-established analytical technique, CE-MS combines the highly efficient separation technique of CE with the highly sensitive detection technique of MS. Thus, it offers many essential advantages for analysis. For example, CE-MS has a high separation efficiency and requires very low amounts of samples and reagents. It can also achieve sensitive and selective determination, and the obtained diversified separation modes can be used for different samples. Therefore, CE-MS has proved to be important in analytical chemistry, especially in proteomics and metabolomics. CE can also exhibit excellent performance in chiral separation. Hence, combined with the sensitive detection technique of MS, CE-MS would be ideal for chiral analysis. Chiral CE-MS can provide a wide range of qualitative information on samples simultaneously in a single run, including the migration time, relative molecular mass, and ionic fragments. It addresses the challenges associated with identifying unknown chiral compounds in actual samples (including chiral compounds without UV absorption groups or fluorescence groups). The high-throughput analysis of multiple groups of chiral enantiomers can be achieved while mitigating the matrix effect of biological samples. In the last ten years, high performance chiral analysis strategies based on different CE-MS modes have been developed. These include electrokinetic chromatography-mass spectrometry (EKC-MS), micellar electrokinetic chromatography-mass spectrometry (MEKC-MS), and capillary electrochromatography-mass spectrometry (CEC-MS). CE-MS has been successfully applied in chiral analysis in various fields such as medicine, biology, food, and environmental science. CE-MS is promising in the chiral analysis of drugs, especially for drug development and drug quality control, as well as pharmacokinetics and pharmacodynamics research. Recent studies have focused on the development of MS-friendly and highly selective chiral analytical methods, which will broaden the application of CE-MS. In CEC-MS chiral analysis, more attention has been paid to developing novel capillary chiral stationary phases for monolithic or packed columns. Because of the diversity of chiral selectors for EKC-MS and MEKC-MS, the chiral analysis of drugs using these techniques has attracted intense research interest. Moreover, functional nanoparticles have been employed to increase the surface area of the CEC columns for enhancing the efficiency of chiral analysis. The chiral separation and analysis of miniaturized microchip equipment via CE-MS has also been explored, but remains to be widely used in practical applications. The purpose of this review is to provide insights that would aid in broadening the applications of CE-MS to chiral analysis. In this review, we primarily summarize research progress on the application of CE-MS to chiral analysis, based on the literature published during the years 2011-2021. Chiral selectors (e. g., modified cyclodextrin and polymer surfactants) and their reported applications in CE-MS are presented. The determination results for drug enantiomers using different CE-MS modes are compared. The application of CE-MS in other research fields is also presented, along with the advantages and limitations of different CE-MS methods.