Advanced Real-Time Process Analytics for Multistep Synthesis in Continuous Flow*.

In multistep continuous flow chemistry, studying complex reaction mixtures in real time is a significant challenge, but provides an opportunity to enhance reaction understanding and control. We report the integration of four complementary process analytical technology tools (NMR, UV/Vis, IR and UHPLC) in the multistep synthesis of an active pharmaceutical ingredient, mesalazine. This synthetic route exploits flow processing for nitration, high temperature hydrolysis and hydrogenation reactions, as well as three inline separations. Advanced data analysis models were developed (indirect hard modeling, deep learning and partial least squares regression), to quantify the desired products, intermediates and impurities in real time, at multiple points along the synthetic pathway. The capabilities of the system have been demonstrated by operating both steady state and dynamic experiments and represents a significant step forward in data-driven continuous flow synthesis.

Towards a novel continuous HME-Tableting line: Process development and control concept.

The objective of this study was to develop a novel closed-loop controlled continuous tablet manufacturing line, which first uses hot melt extrusion (HME) to produce pellets based on API and a polymer matrix. Such systems can be used to make complex pharmaceutical formulations, e.g., amorphous solid dispersions of poorly soluble APIs. The pellets are then fed to a direct compaction (DC) line blended with an external phase and tableted continuously. Fully-automated processing requires advanced control strategies, e.g., for reacting to raw material variations and process events. While many tools have been proposed for in-line process monitoring and real-time data acquisition, establishing real-time automated feedback control based on in-process control strategies remains a challenge. Control loops were implemented to assess the quality attributes of intermediates and product and to coordinate the mass flow rate between the unit operations. Feedback control for the blend concentration, strand temperature and pellet thickness was accomplished via proportional integral derivative (PID) controllers. The tablet press hopper level was controlled using a model predictive controller. To control the mass flow rates in all unit operations, several concepts were developed, with the tablet press, the extruder or none assigned to be the master unit of the line, and compared via the simulation.