The overreaching purpose of this study is to evaluate new approaches for determining the optimal operational and column conditions in chromatography laboratories, i.e., how best to select a packing material of proper particle size and how to determine the proper length of the column bed after selecting particle size. As model compounds, we chose two chiral drugs for preparative separation: omeprazole and etiracetam. In each case, two maximum allowed pressure drops were assumed: 80 and 200 bar. The processes were numerically optimized (mechanistic modeling) with a general rate model using a global optimization method. The numerical predictions were experimentally verified at both analytical and pilot scales. The lower allowed pressure drop represents the use of standard equipment, while the higher allowed drop represents more modern equipment. For both compounds, maximum productivity was achieved using short columns packed with small-particle size packing materials. Increasing the allowed backpressure in the separation leads to an increased productivity and reduced solvent consumption. As advanced numerical calculations might not be available in the laboratory, we also investigated a statistically based approach, i.e., the Taguchi method (empirical modeling), for finding the optimal decision variables and compared it with advanced mechanistic modeling. The Taguchi method predicted that shorter columns packed with smaller particles would be preferred over longer columns packed with larger particles. We conclude that the simpler optimization tool, i.e., the Taguchi method, can be used to obtain “good enough” preparative separations, though for accurate processes, optimization, and to determine optimal operational conditions, classical numerical optimization is still necessary.

中文翻译：

---

以奥美拉唑和乙拉西坦的对映体分离为模型优化制备型批量色谱中的柱长和粒径：田口经验优化的可行性

本研究的主要目的是评估确定色谱实验室最佳操作和色谱柱条件的新方法，即如何最好地选择合适粒径的填料以及如何在选择颗粒后确定合适的柱床长度尺寸。作为模型化合物，我们选择了两种手性药物进行制备分离：奥美拉唑和依拉西坦。在每种情况下，假定两个最大允许压降：80 和 200 bar。使用全局优化方法通过通用速率模型对过程进行数值优化（机械建模）。数值预测在分析和中试规模上都得到了实验验证。较低的允许压降代表使用标准设备，而较高的允许压降代表更现代的设备。对于这两种化合物，使用填充有小粒径填料的短色谱柱实现了最大生产率。增加分离中允许的背压可提高生产率并减少溶剂消耗。由于实验室中可能无法进行高级数值计算，因此我们还研究了一种基于统计的方法，即田口方法（经验建模），以寻找最佳决策变量并将其与高级机械建模进行比较。Taguchi 方法预测填充较小颗粒的较短色谱柱将优于填充较大颗粒的较长色谱柱。我们得出的结论是，更简单的优化工具，即田口方法，可用于获得“足够好”的制备分离，但对于准确的过程、优化、