Continuous organic synthesis - determination of reaction kinetics and structure elucidation of by-products

Have you ever been sick and needed to take a CT or MRI? One of the most crucial components of the way these technologies to work today – is the development of contrast agents which enhances the damaged areas or organs in the body. Today, contrast agents are important for visualizing structures on CT and MRI scans, which makes it possible for doctors to discover everything from broken bones to cancer cells. Contrast agents are complex molecules which are dependent on precise conditions; like controlled temperature and mixing, to be properly formed. Several productions sites produce contrast agents in large tanks with controlled heating and mixing. This process includes start and stop for each step of the production of the molecule – so-called batch mode. The PhD project will be carried out in a collaboration with University of Bergen, UiB, where the candidate will focus on the development of a more continuous method. In a continuous process no start or stop are required for each step in the process of producing the molecule. The method is known to be more precise when it comes to conditions like temperature and mixing. In addition, a continuous production is more energy effective and require less production area. Optimalization of conditions to produce contrast agents would further increase production capacity and reduce the size of the equipment needed. By reaching these conditions we could ensure we meet the growing demand for contrast agents. Over 110 million doses of contrast agents are produced today alone by GE HealthCare, which means that every 4.th second a person is injected with a contrast agent around the world. This demand will continue to increase, which reflects the need for a more continuous production method. By reaching this demand diseases could be discovered earlier, thus leading to better life quality and eventually better treatment options for persons affected by illness.

The alkylation reactions are currently performed in batch mode. By carrying out the reactions in continuous mode, conditions (for example temperature, pH and the nature of base, addition regime of reagents, different solvents and rapid changes in temperature) that are not possible to apply in batch mode. Microwave can also be used when considered beneficial. How the different conditions influence selectivity and reaction rate will be studied. By-product profile at different conditions will be evaluated by HPLC, and if new and unknown by-products in significant amount appear, they will be isolated (for instance by preparative HPLC) and structure elucidated (MS, IR, and NMR). When the chemistry is is better understood, different continuous systems will be employed. In-line instruments such as Raman or similar will be used to monitor the reaction. A model for following the reaction will be built and developed if a suitable technique is identified.