(34a) Modular Manufacturing of Active Pharmaceutical Ingredients (APIs): Novel Approaches for Continuous Heavy Metal Removal from API Syntheses Solutions

Chemical syntheses involving metallic catalysts and reagents are paramount in the pharmaceutical industry. While increasing the efficiency and selectivity of the reaction dramatically, the removal of the often-toxic metal compounds to a level that is harmless for the human body is time, labor, energy, and chemically intensive.

In this contribution, we present the development of modular purification methods for the removal of zinc after a cyclopropanation reaction by means of a Simmons-Smith reaction. The formed cyclopropyl fragment is of significant importance in the pharmaceutical industry as a wide range of active pharmaceutical ingredients (APIs), such as the anti-diabetic drug Saxagliptin, inhere this versatile molecular structure. While the synthesis and the downstream processes are conventionally carried out batch-wise, our project aims to transfer the involved unit operations to continuous mode, including real-time analysis and advanced process control.

The results of the preliminary experiments in batch indicate that a multistage counter-current extraction of the organic product solution with diluted HCl leads to the desired low level of zinc in the product phase. To provide a continuous way of operation at different scales, a multistage setup involving in-house developed 3D-printed continuous stirred tank reactors, continuous membrane separators (Zaiput), and a commercially available extraction column (Sulzer) have been tested.

Moreover, a novel continuous online analysis of the zinc’s concentration will be demonstrated. Additionally, the individual pros and cons of both experimental setups are discussed. This includes experimental results, the use of simple-to-measure quality attributes, and the additional impact given by real-time process control. We conclude this discussion with recommendations when which setup might be beneficial.