Characterization and Selection of Continuous Plug Flow Reactors in Pharmaceutical Development

The use of plug flow tube reactors (PFR) in the pharmaceutical industry offers many advantages to drug development and scale up of processes. PFRs can enable chemistry that would be difficult to perform batch, increase safety vs. batch reactors, and allow for rapid condition screening to accelerate early phase development. One of the main parameters used to characterize PFRs is the residence time distribution, which can be described by axial dispersion. The extent of dispersion can affect the reaction time as well as influence the impurity profile and must be understood to effectively scale a process. Dispersion in over twenty PFRs was characterized at a variety of Reynolds numbers, length to diameter ratios (L/d), and coil diameters. Reactor volume spanned 0.00175 to 73 L and resulted in vessel dispersion numbers (D/uL) ranging from 5.4 x 10^-6 to 3.85 x 10^-2. For small volume PFRs a lower Reynolds number resulted in a lower D/uL, however at larger volume reactors the trend reversed and a higher Re resulted in a lower D/uL. Reactors with a larger L/d had lower axial dispersion between reactors of constant volume and residence time. Both liquid only and liquid-gas regimes were investigated, and it was found that for a given reactor and constant residence time D/uL was significantly lower with liquid-gas flow.