手性分离方法及在中药手性成分研究中的应用

化合物手性是自然界的基本特性之一,组成生命体的重要分子大多含有手性结构。药物有效性和安全性往往与化合物的手性结构密切相关,然而目前对手性小分子化学药物的合成表征、药理学、毒理学等研究相对较多,但对中药等天然药物中所含手性化合物的研究相对较少。手性分离作为手性研究的基础,在手性化合物的研究中具有举足轻重的地位。本文从色谱法和非色谱法的手性拆分方法,以及色谱填料、手性添加剂、手性衍生化等方面系统阐述手性化合物的分离方法,并对近十年报道的中药等天然药物中的手性化合物进行综述,以期为中药中手性化合物的分离、活性评价,以及中药质量标准的提升提供参考。     

配体交换法在手性化合物对映体分离中的应用

许多手性药物对映体在体内的药理活性、代谢动力学过程及毒性方面存在显著差异[1],对其进行分离、分析是一系列体内研究的基础,在手性药物研究中起着重要作用.近几十年来手性化合物的分离分析技术得到了迅速发展,主要为间接法和直接法:间接法是在分离前先与高纯度光学试剂反应形成非对映体,再用非手性柱分离,即柱前衍生化法;直接法是直接用手性色谱柱或在流动相中添加手性试剂来分离手性化合物的方法,即手性固定相法和手性流动相添加法.     

手性药物的色谱分离进展

综述了近年和性药物色谱分离的研究进展。对手性衍生化试剂法、手性流动相添加剂法和手性固定相法的分离机理、检测方法、试剂种类和应用等作了介绍。     

多糖聚合物手性固定相高效液相色谱法拆分二苯甲醇类手性化合物

目的：对6个氯取代的二苯甲醇类手性化合物建立HPLC分析方法。对拆分反应进行监测,并用于拆分产物光学纯度的分析测定。方法：在正相高效液相模式下,采用Chiralcel OD—H和Chiralcel OB-H两种纤维素类手性柱以及Chiralpak AD—H直链淀粉类手性柱,以正己烷-异丙醇或正己烷-异丙醇-三氟乙酸溶剂系统为流动相,流速：0．5ml·min^-1,检测波长：210nm。结果：采用上述方法,基线拆分了合成手性中枢性镇咳药左旋盐酸氯哌啶[（-）cloperastine hydrochloride]的主要原料4-氯二苯甲醇等6个氯取代的二苯甲醇类手性化合物,建立了快速的手性高效液相色谱法。结论：本方法简便准确,可对手性合成反应进行监测和中间体质量控制;同时．对4-氯二苯甲醇和3-氟二苯甲醇的高效液相手性分析方法进行了对比研究。     

多手性中心药物色谱拆分研究进展

多手性中心药物具有多个立体异构体,空间构型的差异导致异构体之间生物活性差异较大,多手性中心药物的手性分离分析仍然是一个巨大的挑战。关于单手性中心化合物手性分离分析的报道很多,而关于多手性中心药物的手性分离却非常少。本文总结了近年来关于多手性中心化合物色谱手性分离研究进展,主要包括HPLC、GC、毛细管电泳、超临界流体色谱及逆流色谱等在多手性药物分离分析中应用。     

手性药物的色谱分离方法

综述了手性药物常用的色谱分离方法，如气相色谱、高效液相色普、高效毛细管电泳色谱及超临界流体色谱等在手性药物扩分研究中的应用及近年来的研究进展。     

手性药物的制备

手性化合物对映异构体进入生命体后会表现出不同的药理学立体选择性，进而产生不同的生物活性、毒性及代谢等，因此对手性药物的深入研究必须将其所有的光学对映体在相同条件下同时对照进行生物学评价试验，以确定是以外消旋体还是以其某一光学活性体作为所要上市的新药。手性药物的制备是手性药物研究及应用的基础和关键，手性技术的发展使得制备大量单一对映体成为可能，     

手性药物的研究策略

近年来,药物手性的临床意义已引起了人们的注意.手性药物的开发已成为国际热点.世界正在开发的1200种新药有三分之一是手性药物.目前,使用的药物中有很大一部分为手性分子,但手性药物有的以外消旋体形式上市,有些以单一对映体上市.天然和半合成的手性药物绝大多数以单个对映体给药;相反,合成的手性药物中仅12%左右是以单个对映体给药[1].在临床应用中由于没有对手性药物各对映体的药效学或药动学行为的差异进行研究,常常将消旋体药物当作单一化合物来处理,由此得出的结论与疗效或不良反应的发生有时不一致,甚至会错误地指导临床用药.     

用液相色谱法分析生物体液中的手性药物

用液相色谱法直接分析生物体液中的手性药物对映体，往往由于谱带增宽和手性固定相被污染等问题而缺乏应有的灵敏度。本文论述了基于非手性聚合衍生化试剂的衍生化方案，对手性药物生物分析的优点，也提出了基于非手性聚合试剂对药物对映体进行直接分析的方法。对外消旋化和态分离等问题，以及在线法的简便，快速，高分辨和高灵敏度等优点进行了评价。     

手性色谱分离2—芳基丙酸类药物对映体

对２－芳基丙酸类药物对映体的手性色谱分离，包括利用手性固定相（ＣＳＰ）或将对映体以手性试剂衍生化生成非对映体的方法，进行了综述。     

Chiral stationary phases for the liquid chromatographic separation of pharmaceuticals

Biological systems exhibit remarkable enantioselectivity which is important in biosynthesis, metabolism, storage and transport processes. It is, therefore, not surprising that the chirality of, for example, pharmaceuticals, pesticides and agrochemicals, has become the focus of extensive research in many laboratories throughout the world. Chiral liquid chromatography is currently very popular for enantiomeric separations since the selectivities afforded by a wide range of commercially available chiral phases enable the separations of many classes of compounds to be routine. This paper discusses the most important types of chiral phases currently in use and reviews their applications to the analysis of compounds of pharmacological interest.     

Chromatographic separation of enantiomers

In this paper a review is presented on the chromatographic analysis of enantiomers with special attention to high pressure liquid chromatography. Also, some examples of resolution of racemates by thin layer chromatography and gas chromatography are given. The various procedures in the surveyed literature have been divided into three main classes: procedures with formation of diastereomeric compounds prior to the chromatographic separation, procedures in which a chiral mobile phase is used, and procedures with the use of a chiral stationary phase. These methods are subdivided and some examples of their application to drugs and related compounds are presented.     

环糊精及其衍生物在药物分离分析中的应用进展

近年来,环糊精及其衍生物在药物尤其是手性药物分离分析中的应用受到了广泛关注。本文通过查阅有关文献,对CD及其衍生物在高效液相色谱、气相色谱、毛细管电泳色谱、薄层色谱、超,临界流体色谱、高速逆流色谱以及膜分离等方法中的应用作了系统介绍,具有十分重要的参考价值。     

Chiral separation and quantitation of methylphenidate,ethylphenidate, and ritalinic acid in blood using supercritical fluid chromatography

Supercritical fluid chromatography (SFC) is a technique that analyzes compounds that are temperature-labile, have moderately low weight, or are chiral compounds. Methylphenidate (MPH) is a chiral compound with two chiral centers. MPH has two chiral metabolites, ethylphenidate (EPH) and ritalinic acid (RA). MPH is sold as a racemic mixture. The d-enantiomer of threo-MPH is responsible for medicinal effects. Due to the differing effects of the enantiomers, it is important to analyze the enantiomers individually to better understand their effects. This method utilizes SFCand solid-phase extraction (SPE) to separate and analyze the enantiomers of MPH, EPH, and RA in postmortem blood. The objective of this method was to assess a unique approach with SFC for enantiomeric separation of MPH, EPH, and RA. A SPE method was developed and optimized to isolate the analytes in blood and validated as fit-for-purpose following international guidelines. The linear range for MPH and EPH was 0.25–25 and 10–1000 ng/mL for RA in blood. Bias was −8.6% to 0.8%, and precision was within 15.4% for all analytes. Following method validation, this technique was applied to the analysis of 49 authentic samples previously analyzed with an achiral method. Quantitative results for RA were comparable to achiral technique, whereas there was loss of MPH and EPH over time. The l:d enantiomer ratio was calculated, and MPH demonstrated greater abundance of the d-enantiomer. This is the first known method to separate and quantify the enantiomers of all three analytes utilizing SFC and SPE.     

Development of LC chiral methods for neutral pharmaceutical related compounds using reversed phase and normal phase liquid chromatography with different types of polysaccharide stationary phases

The enantioselectivity of a collection of neutral pharmaceutical compounds on six different types of polysaccharide chiral stationary phases (CSPs), Chiralpak AD (and AD-RH), Chiralcel OD (and OD-RH), Chiralpak OJ (and OJ-R), Chiralcel AS (and AS-RH), Sepapak-2 and Sepapak-4 are compared using reversed phase (RPLC) and normal phase liquid chromatography (NPLC). Screening strategies for maximizing the probability of achieving an initial chiral separation hit for neutral compounds using both RPLC and NPLC are described. Further method optimizations are demonstrated by modifying parameters such as organic modifier composition, eluent pH or CSP particle size. Several practical examples of the application of chiral methods for the study of synthetic reaction mixtures are presented. The most critical validation aspects, including limit of detection, specificity, and ruggedness, are also briefly presented.     

手性药物分析方法研究进展

综述了近10年来手性药物分离检测方法的发展,包括高效液相色谱法、气相色谱法、毛细管电泳法,以及超临界流体色谱法等,旨在为该领域的进一步发展提供参考。     

不对称烷基化反应在药物及生物活性化合物 合成中的应用

该文从合成光学活性化合物的3种手性诱导方式——手性源诱导的不对称反应、手性助剂诱导的不对称反应及不对称催化反应来介绍近年来不对称烷基化反应在药物及生物活性化合物合成中的应用。     

ENANTIOSELECTIVE DRUG ANALYSIS: PROBLEMS AND RESOLUTIONS

1. With the increasing appreciation that the enantiomers of a chiral drug can differ pharmacokinetically and/or pharmacodynamically, there is considerable interest in methods for the resolution and quantification of enantiomers. 2. Enantiomers possess identical physical and chemical properties in a symmetrical environment and, therefore, their resolution requires the introduction of an asymmetric or chiral environment allowing diastereomeric interactions. This can be achieved using a number of chromatographic techniques, of which the most developed and widely used is high-performance liquid chromatography (HPLC). 3. Resolution and quantification of enantiomers can be performed using HPLC by either converting the enantiomers to covalent diastereomers prior to chromatography or introducing a chiral environment to the chromatographic system, thereby allowing temporary diastereomeric interactions. 4. Antibodies are chiral molecules which can bind the enantiomers of a chiral drug in a differential manner. This is the basis of enantioselective immunoassay, which is a promising technique for the enantioselective analysis of drugs in biological fluids. 5. Each of the methods available has its limitations, advantages and potential applications in the pharmaceutical industry.     

手性色谱分离2－芳基丙酸类药物对映体

对２－芳基丙酸类药物对映体的手性色谱分离，包括利用手性固定相（ＣＳＰ）或将对映体以手性试剂衍生化生成非对映体的方法，进行了综述。