This paper reports the scale-up of an exothermic reaction step in the process development of the multi-step synthesis of an active pharmaceutical ingredient (API) under investigation. Specifically, we'll present the reaction engineering aspects of the scale-up.

Typical lab synthesis experiments at the 100 to 500 ml scale indicated that the reaction was exothermic. Hence calorimetric work was carried out in a semi-batch mode. The reaction was judged to be of medium intrinsic severity with the standard heat of reaction of - 460 kJ/mol. Further studies were conducted in the reaction calorimeter at different stirring speeds and reagent dosing rates for this two-phase semi-batch reaction. A preliminary kinetics model was developed and used to optimize the peak reaction rate and the accumulated heat at the end of dosing. The model was also used for “what if” type of analysis for HAZOP review.

Extensive heating and cooling studies using water were carried out to determine the heat transfer characteristics of the 100 liter pilot plant reactor. The response of the programmable logic control (PLC) system was conducted in the jacket temperature (Tj) mode and the reactor temperature (Tr) mode using optimized PID parameters.

By combining the lab experiments, reaction calorimetry, kinetics model, and reactor capability, the exothermic reaction step was scaled-up and executed in the 100 liter pilot plant reactor as a part of GMP production.