Achiral-Chiral Two-Dimensional Liquid Chromatography Platform to Support Automated High-Throughput Experimentation in the Field of Drug Development
Achiral-Chiral Two-Dimensional Liquid Chromatography Platform to Support Automated High-Throughput Experimentation in the Field of Drug Development
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DOI：
10.1021/acs.analchem.0c03754
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发表时间：
2020-11-17
影响因子：
7.4
通讯作者：
Zhang, Kelly
中科院分区：
文献类型：
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作者：
Goyon, Alexandre;Masui, Colin;Zhang, Kelly
自动化高通量实验（HTE）是科学家通过同时筛选产率、立体选择性和杂质谱来探索和优化化学转化的强大工具。为了分析HTE样品，高通量分析（HTA）平台必须同时快速、准确、通用和特异。在大数据时代，大量高质量的数据对于机器学习模型的成功至关重要。传统的手性液相色谱-质谱（LC/MS）HTE方法受到化合物共洗脱、可能的离子抑制和在粗反应混合物或复杂样品基质存在下有限的手性柱寿命的阻碍。为了克服这些局限性，一个通用的和快速的非手性-手性心脏切割二维（2D）-LC方法已被开发，以确定在10分钟的运行时间内的化学转化的产率和立体选择性。在常规药物开发环境中成功实施了2D-LC HTA平台，为实际项目提供了支持，迄今为止已分析了96孔板格式中制备的2000多个反应混合物。一维和二维保留时间的相对标准偏差（RSD）低于0.83%，决定系数高于0.99，表明该方法具有良好的性能。所提出的HTA 2D-LC平台通过快速分析HTE样品并进行明确的峰跟踪，并提供了一种在短时间内准确生成大量高质量数据的稳健方法，对药物开发产生了重大影响。
Automated high-throughput experimentation (HTE) is a powerful tool for scientists to explore and optimize chemical transformations by simultaneously screening yield, stereoselectivity, and impurity profiles. To analyze the HTE samples, high-throughput analysis (HTA) platforms must be fast, accurate, generic, and specific at the same time. A large amount of high-quality data is critical for the success of machine learning models in the era of big data. Conventional chiral liquid chromatography-mass spectrometry (LC/MS) HTE methods are hampered by compound co-eluting, possible ion suppression, and limited chiral column lifetime in the presence of crude reaction mixtures or complex sample matrices. To overcome these limitations, a generic and fast achiral-chiral heart-cutting two-dimensional (2D)-LC method has been developed to determine both the yield and stereoselectivity of chemical transformations within a 10 min run time. Successful implementation of the 2D-LC HTA platform in a routine drug development environment was achieved for real-world project support, with the analysis so far of over 2000 reaction mixtures prepared in the 96-well plate format. Excellent performance of the method was demonstrated by relative standard deviation (RSD) lower than 0.83% for the 1D and 2D retention times, and determination coefficients higher than 0.99. The presented HTA 2D-LC platform has had a significant impact on drug development by analyzing the HTE samples rapidly with unambiguous peak tracking and providing a robust approach for accurately generating a large amount of high-quality data in a short time.