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Fast chiral and achiral profiling of compounds with multiple chiral centers by a versatile two-dimensional multicolumn liquid chromatography (LC-mLC) approach.
Journal of Chromatography A ( IF 4.1 ) Pub Date : 2020-02-20 , DOI: 10.1016/j.chroma.2020.460987
Jessica Lin 1 , Charlotte Tsang 1 , Raymond Lieu 1 , Kelly Zhang 1
Affiliation  

It is critical to determine the chiral impurity profile of pharmaceutical compounds. The rising trend of drug candidates bearing multiple chiral centers has aggravated the analytical challenges. The traditional chiral HPLC methods can take gruelingly long time to develop yet may not offer sufficient resolution for all stereoisomers. A fast analytical strategy with a high success rate is in urgent demand for compounds with multiple chiral centers. In this study, we have developed an effective and fast multiple heart-cutting (MHC) multicolumn two-dimensional liquid chromatography (LC-mLC) platform approach. The m in the name of LC-mLC highlights the employment of multiple chiral columns with different chiral selectors and mobile phases in the second dimension (2D) within the same run. A short achiral HPLC method in the first dimension (1D) allows the separation of diastereomers and other achiral impurities, followed by 2D analysis enabling different chiral columns and different mobile phases on each coeluted 1D peak for maximum resolution. This LC-mLC strategy breaks down the complex multiple-chiral-center separation problems into simple individual one-chiral-center separation, which dramatically reduces chiral method development time and sample analysis turnaround. Its versatile nature and fast turnaround approach have made it a highly efficient strategy to enable quick stereoselective synthetic route development. This platform LC-mLC strategy has been successfully demonstrated in separating eight stereoisomers for a pharmaceutical compound with 3 chiral centers, within total method development time of less than 2 hours and a final analysis time of less than 24 min, including column equilibration time. It was also proved highly efficient in separating multiple chiral and achiral components in an in-process sample containing structurally similar starting materials, intermediates, side products and multiple stereoisomers of the product with 3 chiral centers, with minimal method development time.

中文翻译:

通过通用的二维多柱液相色谱(LC-mLC)方法,可以对具有多个手性中心的化合物进行快速手性和非手性分析。

确定药物化合物的手性杂质分布至关重要。具有多个手性中心的候选药物的上升趋势加剧了分析挑战。传统的手性HPLC方法可能需要花费很长时间才能开发,但可能无法为所有立体异构体提供足够的分离度。具有多个手性中心的化合物迫切需要一种具有高成功率的快速分析策略。在这项研究中,我们已经开发出一种有效且快速的多中心切割(MHC)多柱二维液相色谱(LC-mLC)平台方法。LC-mLC名称中的m突出显示了在同一次运行中在第二维(2D)中使用具有不同手性选择剂和流动相的多个手性柱。在第一维(1D)中使用简短的非手性HPLC方法可以分离非对映异构体和其他非手性杂质,然后进行2D分析,从而在每个共洗脱的1D峰上实现不同的手性柱和不同的流动相,从而获得最大的分离度。这种LC-mLC策略将复杂的多手性中心分离问题分解为简单的单手性中心分离,从而大大减少了手性方法开发时间和样品分析周转时间。它的通用性和快速的周转方法使其成为高效的策略,能够快速进行立体选择性合成路线的开发。该平台LC-mLC策略已成功证明可分离具有3个手性中心的药物化合物的8种立体异构体,在不到2小时的总方法开发时间内,并且最终分析时间(包括柱平衡时间)在24分钟以内。事实证明,该方法可高效分离过程中样品中的多个手性和非手性组分,该样品中包含结构相似的起始原料,中间体,副产物和具有3个手性中心的产物的多种立体异构体,且方法开发时间最短。
更新日期:2020-02-20
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