Research progress of molecularly imprinted polymers in separation of chiral drugs by capillary electrochromatography

Abstract

Chiral drugs exert pharmacological effects through strict matching with chiral biological macromolecules and chiral recognition. Each enantiomer has different pharmacological activities, metabolic processes and rates, as well as toxicity pharmacokinetic characteristics owing to the difference in its interactions with the chiral environment. Therefore, method development for the resolution of chiral drugs is of great significance for the synthesis of chiral drugs and for quality control during the production process. Molecularly imprinted polymers (MIPs) are prepared by using a target molecule as the template. MIPs demonstrate highly specific recognition properties toward the target molecule since they have specific spatial molecular structures and functional groups. Hence, MIPs are particularly suitable for the separation and purification of chiral drugs. Capillary electrochromatography (CEC) offers the advantages of high separation efficiency and high selectivity owing to the dual separation mechanisms including capillary electrophoresis and liquid chromatography. By using MIPs as the stationary phases for CEC, the advantages of the two technologies can be combined to achieve efficient separation of chiral drugs. MIPs were first applied to CEC for chiral resolution in 1994, and since then, there have been notable advances in this field. The four main chiral separation modes in CEC involve the use of MIPs as the stationary phases of open tubular, packed, and monolithic columns, and as the pseudostationary phase in the separation medium. This review summarizes the research progress of these four methods and reveals the potential of MIPs in chiral resolution by CEC. The advantages and disadvantages of these methods are commented. MIPs as the stationary phases of packed columns can allow for chiral separation. However, the preparation of packed columns in narrow capillaries is difficult. In addition, frits must be prepared at the ends of the capillaries to seal the MIPs. The frits lead to the formation of bubbles during the CEC analysis, thus resulting in poor repeatability and stability. These problems can be overcome by using MIP-based open tubular columns. Furthermore, conditioning of open tubular columns is easy and less time-consuming. However, open tubular columns have limited capacity. MIP-based monolithic columns have greater capacity than do open tubular columns, and frits are not required in this case. However, in situ preparation of MIPs monolith in narrow capillaries is still challenging. The application of MIPs to chiral CEC can also be realized by using them as pseudostationary phases (additives) in the separation medium, and this allows for ease of operation. Moreover, the amount of MIPs introduced into the capillary can be accurately controlled. Thus, the batch-to-batch reproducibility can be improved, but this has the disadvantage of increased MIP consumption. In order to further expand the potential of MIPs in chiral CEC, the following aspects must be considered. First, improvement of the preparation method. In most reported MIP-based-chiral CEC techniques, the peaks of the imprinted molecules show severe tailing, and this problem must be resolved. Improving the mass transfer rate of the prepared MIPs may be a suitable solution in this regard. Second, development of new functional monomers. A functional monomer is an indispensable component in the preparation of MIPs. New functional monomers can be prepared according to the "three-point interaction" rule. Third, selection of template molecules. A single enantiomer of chiral drugs is used as the template molecule to prepare chiral MIPs. The method is not suitable for the preparation of MIPs of chiral drugs for which a single enantiomer is difficult to obtain. Therefore, appropriate choice of the template molecules for these drugs is imperative. Fourth, discussion of chiral separation mechanism. The mechanism of interaction between the template molecules and MIPs needs to be explored further, in order to obtain theoretical guidance for the design and preparation of chiral MIPs.