Mitigation of failure modes in continuous synthesis (CS) of drug substance (DS) has the potential to widen the adoption of continuous manufacturing (CM) technologies by the pharmaceutical industry. This work...

In this work, a continuous system to produce multi-hundred-gram quantities of aryl sulfonyl chlorides is described. The scheme employs multiple continuous stirred-tank reactors (CSTRs) and a continuous filtration system and incorporates an automated process control scheme. The experimental process outlined is intended to safely produce the desired sulfonyl chloride at laboratory scale. Suitable reaction conditions were first determined using a batch-chemistry design of experiments (DOE) and several isolation methods. The hazards and incompatibilities of the heated chlorosulfonic acid reaction mixture were addressed by careful equipment selection, process monitoring, and automation. The approximations of the CSTR fill levels and pumping performance were measured by real-time data from gravimetric balances, ultimately leading to the incorporation of feedback controllers. The introduction of process automation demonstrated in this work resulted in significant improvements in process setpoint consistency, reliability, and spacetime yield, as demonstrated in medium- and large-scale continuous manufacturing runs.