Separation of a racemic pharmaceutical intermediate using closed-loop steady state recycling
Separation of a racemic pharmaceutical intermediate using closed-loop steady state recycling
复制标题
使用闭环稳态回收分离外消旋药物中间体
DOI：
10.1016/s0021-9673(98)00772-9
复制
发表时间：
1998
影响因子：
4.1
通讯作者：
L. Miller
中科院分区：
文献类型：
--
作者：
C. Grill;L. Miller
闭路稳态循环(以前称为周期性内进样闭环循环或CLRPIPI)类似于模拟移动床(SMB)层析。稳态循环(SSR)和SMB都是稳态的双色谱技术，将新鲜样品注入循环色谱线的内部，从流线的两端收集两个馏分或产品流。然而，SMB是一个连续的过程，而SSR是一个重复的、尽管不连续的过程。通过外消旋药物中间体的分离，研究了闭环SSR的潜在机理。我们发现，建立稳定的稳定状态的色谱图是获得高纯度馏分的关键。稳定状态分布的结构，也称为稳定状态库存，由收集的馏分的大小和注入点的位置控制。这些SSR参数具有对应的SMB参数。例如，增加SSR中组分1的大小相当于增加SMB中抽余液的流量；增加SSR中从进样点到组分1的距离相当于增加SMB中III区的大小；等等。最后，将SSR结果与相同外消旋药物中间体的SMB分离结果进行了比较。使用相同的手性固定相(CSP)和流动相，产率(SSR，255克外消旋体/公斤CSP/天；SMB，240克外消旋体/公斤CSP/天)，纯度(SSR，98%e.E.对两种对映体；SMB，98%e.E.两种技术的对映体)和回收率(SSR，两种对映体都为99%；SMB，两种对映体都为99%)相似，但SSR每克外消旋体使用的流动相比SMB多。然而，SSR使用的流动相比批式高效液相色谱少。
Closed-loop steady state recycling (formerly called closed-loop recycling with periodic intra-profile injection or CLRPIPI) is similar to simulated moving bed (SMB) chromatography. Both steady state recycling (SSR) and SMB are steady state, binary chromatographic techniques in which fresh sample is injected into the interior of the circulating chromatographic profile and two fractions or product streams are collected from either end of the profile. However, SMB is a continuous process, whereas SSR is a repetitive, though discontinuous, process. Underlying mechanisms of closed-loop SSR were studied using the separation of a racemic pharmaceutical intermediate. We have found that creation of a stable steady state chromatographic profile is crucial to obtaining high purity fractions. The structure of the steady state profile, also called the steady state inventory, is controlled by the size of the fractions collected and by the location of the injection points. These SSR parameters have corresponding SMB parameters. For example, increasing the size of Fraction 1 in SSR is equivalent to increasing the raffinate flow-rate in SMB; increasing the distance from the injection point to fraction 1 in SSR is equivalent to increasing the size of zone III in SMB; etc. Finally, the SSR results were compared to those of an SMB separation of the same racemic pharmaceutical intermediate. Using the same chiral stationary phase (CSP) and mobile phase, the production rates (SSR, 255 g racemate/kg CSP/day; SMB, 240 g racemate/kg CSP/day), purities (SSR, 98% e.e. for both enantiomers; SMB, 98% e.e. for both enantiomers), and recoveries (SSR, 99% for both enantiomers; SMB, 99% for both enantiomers) for the two techniques were similar, but SSR used more mobile phase per gram of racemate than SMB. SSR, however, used less mobile phase than batch HPLC.