Functionalized Materials for Continuous API Manufacturing

The goal of this project is to allow the applicant to develop the qualification as a professor in the field of "Pharmaceutical Engineering" with special focus on heterogeneous catalysis, separation and continuous manufacturing of pharmaceutical ingredients. Active pharmaceutical ingredients (APIs) are the active components of drugs, which are mixed with excipients that modify the behavior of the drug. APIs are classified as small molecules (with molecular weights < 1000) and large molecules, such as polypeptides, proteins and other large biological molecules. While small molecules are often made via synthetic or semi-synthetic pathways, large-molecule drugs are exclusively manufactured using genetically modified organisms or mammalian cell lines. The syntheses of small-molecule drugs are usually multistep reactions where often more than 97% of all reactants go to waste and must be deposited or recovered, using expensive separation and rework processes. Therefore, there exists a trend to synthesize APIs via highly selective processes. Thus, selective, active and stable catalysts play an important role in pharmaceutical manufacturing, effectively replacing stoichiometric routes of synthesis. In this context there is an increasing interest using heterogeneous functionalized materials because they have many advantages, such as ease of separation, reusability, etc. After the synthesis the APIs have to be purified. In the case of small-molecule drugs this is often done via crystallization. The purification and recovery of larger molecules, such as biosynthetic products, is carried out by downstream processing, involving several purification and recovery steps. Downstream processing is a significant cost factor and may become a bottleneck for the industrial implementation. In order to develop effective and cost- efficient chromatographic processes, again functionalized materials are needed. Thus, the rational design and tailoring of functional surfaces is a key step for many applications in the pharmaceutical and fine chemical industry. Another aspect of modern pharmaceutical manufacturing is the implementation of continuous processes, which - in contrast to current batch technology - may offer significant benefits. Therefore, the goals of this project are the development, the characterization and the computational analysis of various new functionalized surfaces and materials that can be used for the synthesis and purification of APIs in continuous operation mode. In particular, the applicant will focus on: 1. The synthesis and development of novel chiral titanocenes and Pd-complexes. 2. The covalent immobilization of the catalytic active compounds on a. H-terminated Si-particles b. Functionalized silica-gel and cellulose particles c. H-terminated and cellulose-functionalized wafers 3. The preparation of functionalized silica-based monolithic materials and 4. The implementation of the novel functional materials for continuous manufacturing. All in all, by combination of experimental and computational approaches the outcomes of this project will help to prepare and purify APIs easier, more cost effective, and more environmentally friendly.

The goals of this project were the development, characterization and computational analyses of various new functionalized surfaces and materials for the synthesis and purification of active pharmaceutical ingredients (APIs) in continuous operation mode. The chemical syntheses of APIs are usually multistep reactions in which often more than 97% of all reactants go to waste and must be deposited or recovered, using expensive separation and rework processes. Therefore, there is a trend to synthesize APIs via highly selective catalytic processes. Thus, selective, active and stable catalysts, i.e. molecules that increase the reaction velocity and drive the reaction towards a certain product, play an important role in pharmaceutical manufacturing. In this context there is an increasing interest using heterogeneous (non-soluble in the reaction mixture) catalysts because they have many advantages, such as ease of separation, reusability, etc. In this project different titanium (Ti) and palladium (Pd) complexes were chemically bonded to different solid supports, such as hydrogen-terminated Si-particles and wafers as well as functionalized silica-gel and cellulose particles. The novel heterogeneous catalysts were then successfully used for the synthesis of pharmaceutical model substances. Although the metal of the catalysts is chemically bonded to the solid support it can be dissolved during the reaction. This so-called metal leaching would lead to a contamination of the product and was therefore investigated for the novel catalytic active compounds in detail. The results of the metal leaching studies indicate that the catalysts are sufficiently bonded to the surface and thus they are safe to be used for pharmaceutical processes. Therefore, the next step of this project was to apply the novel catalysts in fixed-bed reactors for the synthesis of APIs in continuous flow mode. This leads to a constant product quality, to a reduction of waste and energy and to an easier automation of the processes. After the synthesis the APIs have to be purified from by-products and non-reacted starting materials. In this project functionalized materials on silica-gel basis (so-called monoliths) were prepared, then implemented in different geometries and used for the continuous purification via electro-chromatography. The interactions of the substances to be purified and the novel materials were also theoretically studied and modelled via Molecular Dynamics (MD) approaches. The results of this investigation helped to find the ideal functionalization for the appropriate API and thus the optimization of the purification processes could be carried out much faster. All in all, by combination of experimental and computational approaches the outcomes of this project helped to prepare and purify APIs easier, more cost effective, and more environmentally friendly.