目的:手性控制在立体异构药物的开发中起着至关重要的作用。由于手性分离的复杂性和缺乏可预测性,柱筛选仍然是启动活性药物成分和合成中间体手性方法开发的金标准。手性反相液相色谱(RPLC)因它在各种基质中的通用性而获得了研究者的青睐,基于此方法进一步探索基于层的手性RPLC筛选策略,用于筛选和分析原料药或中间体。方法:构建和分析手性药物数据库原料药或中间体的手性筛选数据库,共3 401个条目,建立了基于层的手性RPLC筛选策略。结果:用梯度洗脱法筛选了17种多糖基手性固定相和4种流动相。选择10个含有2个流动相的手性固定相,成功地分离了82%的筛网。提出了2个手性RPLC筛选层,第1层(AZ、OD、ID和IG)和第2层(AY、OJ、OZ、IA、IC和IH)以及2个流动相,以使第1层的命中率达到70%,组合集的命中率达到80%。结论:建立了相对简洁高效的多糖手性RPLC筛选策略,且该系统可实自动报告和适用性良好。
Objective: Chiral control plays an important role in development of stereoisomeric drugs. Due to the complexity and lack of predictability of chiral separation, column screening is still the gold standard to start the development of chiral methods for active pharmaceutical ingredients (APIs) and synthetic intermediates. Chiral reversed-phase liquid chromatography(RPLC) has been favored by other methods because of its universality in various matrices. Methods: The chiral drug database and the chiral screening database of APIs or intermediates were constructed and analyzed, with a total of 3 401 entries. A chiral RPLC screening strategy based on layer was established. Results: Seven-teen kinds of polysaccharide chiral stationary phases and 4 kinds of mobile phases were screened by gradient elution. Ten chiral solid phases(CSPs) containing two mobile phases(MPs) were selected and 82% of the screens were successfully separated. Two chiral RPLC screening layers (layer 1: AZ, OD, ID and IG) and (layer 2: AY, OJ, OZ, IA, IC and IH) and two MPs were proposed to make the hit rate of layer 1 reach 70% and the hit rate of combination set reach 80%. Conclusion: A relatively simple and efficient screening strategy of polysaccharide chiral reversed phase liquid chromatography is established, and the system can report automatically and has good applicability.
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