Combined optimization of start-up shutdown and grade transition of a multistage continuous crystallization process

Continuous pharmaceutical campaigns may exhibit extremely short operating windows. As a result, the impact of the start-up and shutdown on both costs of production and environmental footprint is extremely important. In this paper, a systematic model-based dynamic optimization strategy was developed to address the combined start-up, shutdown and grade transition of a multistage combined cooling and antisolvent continuous crystallizer. Firstly, the optimal shutdown process was addressed, and several scenarios were considered. Subsequently, a combined start-up and shutdown optimization aimed at the maximization of on-spec production based on the maximization of the steady-state operating window for a fixed total manufacturing schedule. It was shown that 5510.2 g of on-spec products can be obtained during an operating window of 800 minutes, which, compared to the non-optimized scenario, corresponds to a 10% increase in production along with a significant reduction of wastes. In addition, the optimization of grade transition was also considered to improve the dynamic performance and flexibility of the process and helped reduce the transition time from 38.5 minutes to 2.7 minutes.