Continuous Total Spontaneous Resolution
Continuous Total Spontaneous Resolution
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DOI：
10.1021/acs.cgd.7b00761
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发表时间：
2017-08-01
影响因子：
3.8
通讯作者：
ter Horst, Joop H.
中科院分区：
文献类型：
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作者：
Steendam, Rene R. E.;ter Horst, Joop H.
我们通过连续结晶实现了手性对称性破缺，这使得手性纯晶体的连续工业生产成为可能。为此，开发并测试了一种新型的回收平台，该平台模拟了具有热浓缩进料和冷悬浮液流出的连续冷却结晶过程。在实验开始时，通过用对映体纯的晶种接种透明的过饱和非手性溶液，实现了几乎对映体纯的稳态。用对映体纯形式接种确保通过二次成核连续产生接种形式的片段。在亚稳区极限以下，只要长停留时间与足够高的进料浓度相结合，产物继续由与晶种形式相同的手性的晶体组成。短的停留时间与低进料浓度相结合导致污垢诱导的两种手性形式的形成和产物的对映体过量的减少。总体而言，这些结果证明了在工业环境中连续全自发拆分手性药物产品的可行性。这种连续生产方法提供了许多好处，包括易于操作，一致的产品质量和高度的过程控制。
We achieved chiral symmetry breaking through continuous crystallizations, which enables the continuous industrial production of chirally pure crystals. For this, a novel recycling platform that mimics a continuous cooling crystallization process with a hot concentrated feed and an outflow of cold suspension was developed and tested. A virtually enantiopure steady-state was realized by seeding a clear supersaturated achiral solution with enantiopure seed crystals at the start of the experiment. Seeding with the enantiopure form ensured that fragments of the seeded form were continuously created through secondary nucleation. Below the metastable zone limit, the product continued to consist of crystals of the same handedness as the seeded form provided that long residence times were applied in combination with sufficiently high feed concentrations. Short residence times in combination with low feed concentrations led to fouling-induced formation of both chiral forms and a decrease in the product's enantiomeric excess. Overall these results demonstrate the feasibility of continuous total spontaneous resolution of chiral pharmaceutical products in an industrial setting. This continuous manufacturing approach provides many benefits including ease of operation, consistent product quality, and a high degree of process control.