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

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.