Continuous flow synthesis of a pharmaceutical intermediate: a computational fluid dynamics approachElectronic supplementary information (ESI) available: (1) Experimental determination of kinetic parameters, (2) molar ratio calculations, (3) CFD transport equations, (4) fluid and material properties, (5) mesh independence study, (6) numerical diffusion analysis, (7) complete CFD yield results, (8) DoE Pareto plots. See DOI: 10.1039/c8re00252e

Continuous flow chemistry has the potential to greatly improve efficiency in the synthesis of active pharmaceutical ingredients (APIs); however, the optimization of these processes can be complicated by a large number of variables affecting reaction success. In this work, a screening design of experiments was used to compare computational fluid dynamics (CFD) simulations with experimental results. CFD simulations and experimental results both identified the reactor residence time and reactor temperature as the most significant factors affecting product yield for this reaction within the studied design space. A point-to-point comparison of the results showed absolute differences in product yield as low as 2.4% yield at low residence times and up to 19.1% yield at high residence times with strong correlation between predicted and experimental percent yields. CFD was found to underestimate the product yields at low residence times and overestimate at higher residence times. The correlation in predicted product yield and the agreement in identifying significant factors in reaction performance reveals the utility of CFD as a valuable tool in the design of continuous flow tube reactors with significantly reduced experimentation. Computational fluid dynamic and experimental approaches have been compared in the prediction of reaction performance in the preparation of a pharmaceutical intermediate.