Multiscale Modeling of a Tubular Reactor for Flow Chemistry and Continuous Manufacturing

Abstract Continuous manufacturing of drug substance with the aid of flow chemistry is mostly performed in the tubular reactors and at low flowrates. The laminar flow in the reactor limits micromixing for advancing the reactions and transport phenomena. Reactor scale-up can be performed based on computational simulations and lab scale experimental studies. The residence time distribution and dispersion of the component will be varied at different scales, which require deep understanding of the multiscale phenomena for design, control, and risk analysis. This study is designed to show how modeling can aid the design and risk assessment of flow chemistry process which are often influenced by the Multiphysics of kinetics, heat transfer, and mass transfer. Previous works used experimental methods to study the dispersion and residence time distribution; developed numerical models without considering the Multiphysics and variable fluid properties (i.e. temperature and composition dependent density); or didn't evaluate the scale-up effect and size dependent distribution for reaction in the laminar flow. This study aims to fill the gap and address these issues by developing the first-principle mechanistic modeling. A Fridel-craft acylation reaction for continuous manufacturing of an intermediate for Ibuprofen synthesis is modeled in this study for different sizes of the reactor. Two models were developed for the process step: a semi-distributed lumped model based on space independent approach, and a Finite Element Method (FEM) model based on space dependent approach with variable discrete volumes in radial and axial dimension. A case of model-based scale-up is also studied. The results demonstrate application of mechanistic modeling in evaluating dispersion and residence time distribution in continuous manufacturing of an API. The coupled reaction and Multiphysics modeling evaluated the scale-up limitations, mixing restrictions, and axial dispersions.