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Development of Continuous Processes for the Production of Pharmaceutical Substances Using Heterogeneous Catalysis

Heidrun Gruber-Woelfler, Rafael J. P. Eder, Birgit Wilding, Iris Pflueger, Peter Feenstra, Gerburg Schider, Alexander Muhr, Christoph Kutschera, and Johannes G. Khinast. Institute for Process Engineering, Graz University of Technology, Inffeldgasse 21/A, Graz, A-8010, Austria

The pharmaceutical industry is currently attempting a transition towards continuous manufacturing in several areas, driven by the “PAT” and the “Critical-path” initiatives of the FDA (Federal Drug Administration). Currently, many catalysts used in pharmaceutical processing are homogeneous organometallic complexes, colloidal metals and biocatalysts. Tremendous achievements have been made in the implementation of these soluble complexes in industrial applications. However, use of homogeneous catalysts makes the implementation of continuous-flow processes more complex. Furthermore, homogeneous catalysts are usually in the same phase as the starting materials and products. Thus, one drawback is the difficulty to completely remove them from the reaction mixture, as mandated by regulatory bodies (FDA, EMEA = European Medicine Agency), in order to avoid metal carry-over. The immobilization of catalytic active compounds on solid supports is therefore a powerful method for overcoming the drawbacks of homogeneous catalysts, while maintaining their advantages.

In this work we present the development of heterogeneous catalysts and the investigation of their efficiency, long term stability and reusability. In a further step, these catalytic systems were implemented in continuous flow setups, which can be used for the production of pharmaceutical substances, such as

- preparation of amines by hydrosilylation of imines using heterogeneous Group 4 metallocenes

- application of heterogeneous Palladium-catalysts for the syntheses of arylpiperazines

- heterogeneous biocatalysis using enantioselective immobilized enzymes and

- particle formation using microfluidic devices

Preliminary results show that the developed setups lead to improved practicability and flexibility of the processes. Thus, these novel reaction systems constitute promising alternatives to existing batch applications.