Kinetic Study and Model-Based Design Space Determination for a Drug Substance Flow Synthesis Using an Amination Reaction via Nucleophilic Aromatic Substitution

A kinetic study and model-based design space determination for drug substance flow synthesis using an amination reaction are presented. A flow experiment was conducted to synthesize 3-fluoro-4-morpholinobenzonitrile from 3,4-difluorobenzonitrile, morpholine, and diazabicycloundecene. Concentrations, residence time, temperature, and reactor inner diameter were varied to gather the kinetic data. A set of equations was defined to describe the mass and energy balances, and the developed model could reproduce the experimental profiles with high accuracy. By incorporating the Reynolds number into the pre-exponential factor, the developed one-dimensional model could account for performance variations in different inner diameter conditions. The model was then used to identify the design space, considering yield, temperature, productivity, and environment. The study also evaluated the process robustness given pulse disturbances, which could help identify the required sensor monitoring. Finally, a method for facilitating regulatory processes was proposed. The presented model-based approach can aid in producing high-quality pharmaceuticals in an efficient, sustainable, and cost-effective way by utilizing digital power.