Design of Continuous Processes for the Synthesis of Pharmaceutical Ingredients

Continuous processing has been considered as highly attractive alternative to batch manufacturing in the pharmaceutical industry for many years, as it offers several advantages, such as reduced capital and operational costs, as well as real-time quality control for increased process reliability, reproducibility and safety. Furthermore, the switch from a synthetic batch-mode to a flow-through concept has other various advantages. Scale-up can be conducted by use of parallel reactors and assembling a line of reactors multistep synthesis can be achieved by minimum or no purification in between two reaction steps. Up to now, batch processing still dominates pharmaceutical manufacturing, however, 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).

The goal of this study is the design of different continuous flow systems for the preparation of pharmaceutical ingredients. In particular, we present the application of homogeneous and heterogeneous organometallic catalysts for the synthesis of chiral amines and substituted biphenyls. In the first step, the kinetics of the catalytic reactions was determined using batch mode experiments. The kinetic data was then used to develop different lab-scale continuous flow systems, including packed bed reactors, monolithic structures and 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.