Model-based disturbance-conscious design space exploration for drug substance flow synthesis using the Grignard reaction

• Presented a model-based approach for disturbance-conscious design space exploration. • Analyzed the effects of disturbances on reaction performance. • Proposed a novel dimensionless number to streamline the analysis of oscillation impacts. This study presents a model-based disturbance-conscious design space exploration for drug substance flow synthesis using the Grignard reaction. Evaluation models were developed regarding crucial aspects including yield, temperature, productivity, and environmental impact. By employing a previously developed hybrid model, this study identified the design space, i.e., the feasible range of process parameters, in silico. In addition, the process robustness in the presence of pulse disturbances was evaluated to identify disturbances with substantial impact on the process. This evaluation contributes to a strategic deployment of monitoring sensors and the management of the disturbances. Furthermore, the impact of flow rate oscillations on the reaction performance was analyzed. A novel dimensionless number was proposed to enable a streamlined analysis of the oscillations’ impact. The model-based design space and process analysis presented in this study provide valuable insights for optimizing pharmaceutical production, facilitating the manufacture of high-quality products in a more resource-efficient, cost-effective, and sustainable manner.