质谱法在药物立体异构体区分中的应用及发展

质谱法广泛应用于化学、生命科学、药学等领域，能够提供分子质量信息，有助于未知物结构的解析，具有分辨率高、信息量大、样品用量少、灵敏快速等优点,在测定有机化合物精确分子质量、结构解析、反应机理等方面发挥着重要的作用。手性药物是药学领域的一个研究热点，近年来质谱法逐渐被用于药物手性杂质区分中，而且随着质谱技术的不断发展和改进,其在手性区分和分析中越来越受关注。本工作主要介绍了质谱法在手性药物立体异构体杂质分析中的应用及发展历程，阐述了各类质谱技术用于手性异构体分析的原理和特点，其中详细举例介绍了质谱动力学方法和离子淌度质谱方法在手性杂质分析中的应用。通过对比分析目前已有的各类手性分析方法的优缺点，说明利用质谱法实现手性异构体的区分和定量测定具有明显的优势。质谱法用于药物手性异构体的分离具有快速、不需要复杂的样品前处理和昂贵的手性柱等特点，极大地提高了手性药物分析的效率和准确度。随着质谱分析技术的迅速发展，质谱法将在多手性中心药物的手性杂质分离和生物大分子分析（如多糖、多肽）等领域发挥巨大潜能。

Application and Development of Mass Spectrometry in Drug Stereoisomer Separation

Mass spectrometry (MS) is a kind of analytical method widely used in chemistry, life science, medicine and other fields. This method can provide information on molecular weight and is very helpful to structure analysis of unknown substance. It has advantages of high resolution, informative, less dosage of samples, sensitive, rapid, etc. MS plays an important role in the determination of accurate molecular weight of organic compounds, its structural analysis and the reaction mechanism research. As chiral drugs separation is a hot research topic in the field of medicine, MS has also been gradually applied to the distinction between the chiral impurities in recent years. With the continuous development of MS technology, it has obtained more and more attention in the analysis of chiral drug. This paper mainly reviewed the application and development history of MS in drug stereoisomer analysis of late years. The primary chiral MS methods in the current state come down to four categories, such as host-guest (H-G) method, ion/molecule (equilibrium) reactions, collision-induced dissociation (CID) and ion mobility mass spectrometry (IMS). The collision-induced dissociation (CID) of diastereomeric complex can be subdivided into three types for kinetic method (KM), fixed ligand kinetic method and chiral recognition ratio method (CR). All these MS methods were introduced considering their stereoisomer analysis principle and characteristics in this review. Examples were taken to make detailed instructions of the applications and advantages of the KM and IMS, which are two most popular MS methods said above. It has been widely accepted that mass spectrometry techniques have obvious advantages in separation and quantitative determination of stereoisomers owing to their high speed, accuracy and sensitivity. In conclusion, MS does not need complicated sample preparation and expensive chiral column when used to the optical impurities separation of chiral drugs, which greatly enhances the efficiency and accuracy in analysis of drug stereoisomers. The development of the mass spectrometry techniques would greatly promote the cutting-edge investigation and analysis of chiral impurities separation of drugs with multichiral centers and complicated conformation (such as polysaccharide, peptide) in the future.