新型核/壳型手性固定相评价体系的建立及其在氨基酸衍生物药物对映体分离与质量控制中的应用

手性固定相（CSP）法是手性药物对映体分离中最引人注目的方法，但CSP手性识别机理大多不明确，且CSP评价缺乏量化标准。本课题组长期聚焦CSP研究，近来针对氨基酸研制出具有明显手性识别能力的两种不同构型单一手性聚苯胺内核/二氧化硅外壳复合物。与聚苯胺相比，经二氧化硅包覆后的核/壳复合物手性识别能力增强。在此基础上，拟将复合物外壳衍生化制备系列核/壳CSP，在不同流动相模式中拆分手性药物对映体。根据手性拆分结果，选择4-6个手性药物为“标准物质”，以“标准物质”的选择因子或分离度值为指标，建立CSP量化评价模型，探讨手性识别机理。基于此新型手性识别机理研究模型，建立左旋多巴等4种氨基酸衍生物药物质量控制方法，应用于它们的对映体分离、制备、手性杂质检查以及体内手性转化研究。本项目为新型CSP的制备、量化评价体系建立及机理研究提供借鉴，也为手性药物体内、外手性分离分析研究提供参考。

Chiral drugs and human biological molecules mutual recognition are stereoselectivity, leads to differences in the efficacy and side effects of different enantiomers in the human body. For example, R-thalidomide has sedative, sleep effect, but the S-enantiomer and its metabolites have serious teratogenic effects. Therefore, the separation of enantiomers of chiral drugs has been one of the most important and necessary topics in the pharmaceutical research field. The chiral stationary phase (CSP) method can be used for both analysis and separation,as well as for the preparation and semi-preparation of enantiomers, which is the most striking method for the separation of drug enantiomers, and more than 100 CSPs have been commercialized. However, the chiral recognition mechanism of commercially available chiral columns is mostly unclear and the quantity evaluation system is absent. Our group focused on the study of chiral stationary phase over 20 years. In former experiment, we developed two different configurations of the homochiral polyaniline/silica shell complexes, which have obvious chiral recognition ability for amino acids. Compared with polyaniline, the silica coated core/shell composite got chiral recognition ability enhancement. Base on these results, the program will study a novel category of hybrid core/shell HPLC chiral stationary phase (CSP), which consisting of a unique organic core (homochirality helical polyaniline nanofibers) and functional inorganic shell for enantioseparation. The core of CSP with stereo regularity is homochiral polyaniline nanofibers, which providing a stereo space for chiral recognition. The inorganic shell with functional silica, protecting the core, as well as providing interaction sites of π-π, dipole-dipole, hydrogen-bonding and so on. The enantiosepation ability of different configuration CSP will be evaluated and compared.These new CSPs will be used for the separations of chiral drugs, such as amino acids, β-blocks and other racemates with different mobile phases. Based on the enantioseparation results, 4-6 solutes will be selected as standard substances to build these CSPs assessment model, using selectivity and resolusion as creterion. The chiral recognition mechanism is also investigated. And then the suitable CSPs will be rapidly screened out for the application of enantioseparation and quality control, including quality analysis in vitro and metablism and transfer in vivo of four amino acid derivative drugs, levodopa, levodopa methyl ester, methotrexate and melphalan. The investigation above-mentioned can provide reference for the systematic study of the assessment system and chiral recognition mechanism of other kinds of CSP.