Selective Extraction of Amines and Acids By Continuous Flow Liquid-Liquid Extraction

虽然人们非常重视发展连续流反应，但对连续分离的关注却少得多。这些通常是化学制造中最昂贵的部分，因为生产率和周期时间被忽略了。本项目的目的是开发自动pH控制系统，用于选择性连续萃取和纯化胺和酸。这还可以通过避免使用缓冲器来减少浪费。该系统可用于反应，如生物转化，如转氨酶，或大多数化学反应。该系统将在预测和自我优化模式下进行测试。预测方法涉及组分pKa和分配系数的测量和建模，从而给出操作提取的pH值。如果精确控制，具有类似pKa的胺可以被选择性地提取。一个例子是从2-甲基苄胺中选择性萃取N-苄基-2-甲基苄胺。或者，可以使用自优化方法来确定提取条件，方法是随着输入变量（例如溶剂、pH、浓度、相比例、温度）的变化而连续测量产率/选择性。在该方法中，不需要pH测量。在反应后在选定的pH下分离出一种产物，然后在进入另一个L-L分离器（Zaiput）之前改变剩余流的pH，以在一个连续过程中除去下一种物质（不需要的副产物废物，或原料再循环）的能力突出了自动控制系统的重要性。第二次分离的pH值将取决于第一次提取，因此使用预定设定点不再可行。串联使用不同的膜（疏水膜、亲水膜、截留分子量膜、吸附膜）将允许顺序分离不同的反应组分。其中一些正在开发的另一个刚刚开始的AZ资助的案例奖，这将给机会，有效地联系这些项目。该项目的预期成果是一种高效、高产的胺和酸连续分离工艺，该工艺应广泛适用于制药开发管道;对决定连续分离系统的基础工艺有更深入的了解;提高生产率并减少浪费的自动优化方法。学生将获得各种技术的经验，包括物理有机，化学和工艺化学与工程，PAT，编码，控制，分析，流动化学，设备和实验设计。计划将这个项目与目前的项目结合起来，以便学生们能够相互通报。AZ的参与对于提供正确的方向、有用的范例和将技术转移到工业中至关重要。

Whilst great emphasis is being put on developing continuous flow reactions, far less attention is paid to continuous separations. These are often the most costly part of a chemical manufacture because productivity and cycle times are ignored. The aims of this project are to develop automated pH-controlled system for the selective continuous extraction and purification of amines and acids. This can also reduce waste by avoiding the use of buffers. The system can be used in reactions such as biotransformations, e.g. transaminases, or most chemical reactions. The system will be tested in predictive and self-optimisation modes. The predictive method involves measurement and modelling of component pKa and partition coefficients giving a a pH at which to operate the extraction. If controlled precisely, amines with similar pKa's can be selectively extracted. An example is the selective extraction of N-benzyl-2-methylbenzylamine from 2-methylbenzylamine. Alternatively, self-optimisation methodology can be used to determine the extraction conditions by measuring the yield/selectivity continuously as the input variables such as solvent, pH, concentration, phase ratio, temperature are changed. In this method no pH measurement is required. The ability to separate out one product after the reaction at a selected pH and then alter the pH of the remaining stream before passing into a further L-L separator (Zaiput), to remove the next species (unwanted side product to waste, or starting material to recycle) all in one continuous process highlights the importance of an automated control system. The pH of the second separation will be dependent on the first extraction so using predetermined set points is no longer feasible. The use of different membranes (hydrophobic, hydrophilic, MWt-cut-off, adsorptive) in series will allow sequential separation of different reaction components. Some of these are being developed in another just started AZ funded CASE award, and this will give the opportunity to usefully link these projects. The outcomes expected of this project are an efficient and productive continuous separation process for amines and acids that ought to be widely applicable to the pharma development pipeline; a deeper understanding of the underlying processes that determine the continuous separation systems; automated optimisation methods that improve productivity and reduce waste. The student will gain experience in a wide variety of techniques including physical-organic, chemistry and process chemistry and engineering, PAT, coding, control, analytical, flow chemistry, equipment and experimental design. It is planned to align this project with the current ones so that the students can inform each other. The involvement of AZ is critical in providing the right direction, useful exemplars and transfer of the technology into industry.