(198m) Model-Based Design Space Assessment for Flow Synthesis of Amination Reaction Via Nucleophilic Aromatic Substitution

Flow chemistry is gaining increasing acceptance in both academia and industry, particularly in the production of fine chemicals and pharmaceuticals due to its advantages over traditional batch chemistry. The use of small flow reactors is one of the significant features of flow chemistry, allowing for efficient mass and heat transfer. With limited time available for process design in the pharmaceutical industry, a modeling and simulation approach can be advantageous, with mechanistic models providing a reliable method for understanding complex systems, process design, evaluation, and optimization. As such, several simulation studies have been conducted regarding flow synthesis of drug substances. These studies include the mechanistic analysis of flow synthesis for lomustine, an anti-cancer drug substance [1] as well as the model-based analysis of flow synthesis of doripenem, an antibiotic drug substance [2].

This work presents the kinetic study and design space assessment for the flow synthesis of an amination reaction via nucleophilic aromatic substitution. Flow experiments were conducted to obtain kinetic data. The developed one-dimensional model fitted the experimental data with high accuracy. Evaluation models were then constructed, including critical quality attributes and their constraints. Simulation and evaluation were carried out to determine the design space within the given variable ranges. Disturbances were also considered to evaluate the process's robustness, and the resulting design space was obtained within the specified ranges of disturbances. The proposed model can be utilized for in-silico exploration of the design space, reducing the need for experimental trials and identifying disturbances that need careful observation, potentially assisting with sensor placement.

[1] S. Diab, M. Raiyat, D. I. Gerogiorgis, “Flow synthesis kinetics for lomustine, an anti-cancer active pharmaceutical ingredient”, React. Chem. Eng., 2021, 6, 1819.

[2] J. Kim, H. Yonekuara, T. Watanabe, S. Watanabe, S. Yoshikawa, H. Nakanishi, S. Badr, H. Sugiyama, “Model-based comparison of batch and flow syntheses of an active pharmaceutical ingredient using heterogeneous hydrogenation”, Comput. Chem. Eng., 2022, 156, 107541.