Process development to prepare sensitive active pharmaceutical ingredients enabled by flow chemistry and modeling

Flow Chemistry is a powerful tool in organic synthesis. It provides great operational advantages such as process intensification, access to new chemical space, efficient mass and heat transfers, straightforward scalability, and increased yields. These distinctive advantages were considered during the process chemistry development of active pharmaceutical ingredients very sensitive to light and oxygen. Within this doctoral thesis, continuous methodologies were employed in a 4-step process to obtain an antibiotic drug urgently needed for the treatment of community-acquired bacterial pneumonia. The process was developed and optimized based on previously described batch procedures found in the literature. Looking at the processes described, it was clear that Flow Chemistry could bring significant advantages, for a product already in the market with a defined batch process. Advantages such as the non-isolation of sensitive intermediates, increase of selectivity and consequently the yield, and reduction of impurities certainly are worth the bureaucratic burden associated with major process changes. Careful selection of the continuous flow equipment and integration of common lab material in handmade setups enabled the preparation process intermediates and final product in a telescoped manner. Downstream unit operations such as distillation and nanofiltration were operated under semi-continuous mode. Mechanistic (Dynochem) and empiric (DoE) modeling were applied for process optimization and design space determination reducing the development time and increasing process knowledge. Implementation of Process Analytical Technology (PAT) allowed greater process understanding and monitoring. Control charts were built to anticipate the impact of equipment malfunctions on the quality of the reaction mixtures. Also, the use of PAT provides a fast-decision-making approach without having to wait for In-Process Control (IPC) analysis such as High-Performance Liquid Chromatography (HPLC). Process intensification enabled by flow chemistry resulted in a reduction of one chemical step, higher global yield, and fewer downstream operations than the process described in the literature