PHARMENG · The reaction engineering of Pharmaceuticals: Efficient production of complex drug molecules

Final Activity Report Summary - PHARMENG (The Reaction Engineering of Pharmaceuticals: Efficient Production of Complex Drug Molecules)

Homogeneous catalysts lack the advantages of their heterogeneous analogues, such as easy separation and catalysts' recycling, prevention of metal leaching, improvement of stability etc. The immobilisation of catalytic active compounds on solid supports is therefore a promising method for overcoming the drawbacks of homogeneous systems while maintaining their advantages. As such, the primary goal of this project was the development of covalent immobilised organometallic compounds and heterogeneous biocatalysts. The first selected catalytic system was group4 metallocenes, since these compounds were known to be highly active and selective for the synthesis of pharmaceutical intermediates. In order to optimise the new catalysts and support the synthetic approaches, molecular modelling computations were used. The following significant progresses were achieved: 1. the synthesis of various tethered Ethylenebis(indenyl) (EBI) titanocenes; 2. the covalent immobilisation of the functional metallocenes onto hydrogen-terminated silicon-particles, H-terminated Si(111) wafers and functionalised silica-gel particles; 3. the successful testing of the new homogeneous and heterogeneous metallocenes for the hydrosilylation of imines. Furthermore, we established the heterogenisation of Pd-complexes using methods analogous to those for the metallocenes. The activities of the heterogeneous Pd-catalysts were successfully tested for Buchwald-Hartwig aminations and Suzuki reactions. In addition to the immobilisation of these organometallic catalysts, we developed a versatile two-step method that allowed covalent linking of biomolecules to silicon (Si) surfaces. The first step involved the attachment of an epoxyalkene on a hydrogen (H) terminated Si-surface by ultra violet (UV) mediated hydrosilylation. In the second step, the terminal oxirane of the alkene moiety reacted with the biomolecule leading to a covalent attachment of the enzyme. Using standard photometric assays we could show that the immobilised enzyme was still active and exhibited a notable long-term stability. Regarding simulation of pharmaceutical reactors, the flow in industrial-scale equipment was studied. Such reactors included, for example, fermentation reactors up to a volume of 250 m3. In these systems the high concentration of microorganisms led to a complex flow behaviour of the broth, the so-called non-Newtonian flow behaviour, leading to challenges in reactors' scale-up and operation. We used the Lattice-Boltzmann method to effectively simulate the flow in these reactors. With this method it was for the first time possible to simulate non-Newtonian fluid flow in such equipment in non-preceded high detail. During the last project years a simulation tool was developed to effectively simulate multiphase flow. The method was able to compute flow around deforming boundaries, e.g. bubbles moving in a liquid. More significantly, the code was also able to calculate the distribution of chemical species in the liquid. Furthermore, it was possible to include chemical reactions in the computations. The simulation tool ran on parallel computers and was able to handle non-Newtonian fluid behaviour, including viscoelastic fluids. It was applied to many industry-relevant systems, e.g. catalytic hydrogenation reactions. In addition, research activities included the analysis of processes relevant for the pharmaceutical industry, such as decontamination technologies or novel technologies for the production of drugs. Therefore, we used state of the art techniques, e.g. computational fluid dynamics and computation on parallel computers. The results were useful for the improvement of these processes and provided a sound basis for the scale up of a novel extrusion device. Finally, in terms of particle technology, we used specialised simulation techniques, namely the discrete element method, as well as a sophisticated experimental setup to study mixing, granulation and drying of powders.

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