(380f) Design and Selection of Continuous Reactors for Pharmaceutical Manufacturing

A variety of continuous reactors have been designed and developed over the past 15 years for drug substance manufacturing at Eli Lilly, enabling chemistries that we chose not to scale up batch. Vertical pipes-in-series PFRs were used for two-phase gas-liquid hydrogenations and oxidations that required long reaction times because of substrate to catalyst ratios greater than 1000. Low axial dispersion and sufficient vapor-liquid mass transfer rates were maintained for reactions with 12 hours mean residence time. A pulsating flow coiled tube PFR was used for a gas-liquid hydroformylation reaction with solids precipitate. Capital cost was lower and safety rating were higher compared to the batch alternatives for each of these high-pressure gas-liquid reaction types. Superheated PFRs were used for reactions involving homogeneous solutions, heated far above the boiling point of the solvent. An imidazole cyclization reaction in superheated methanol had higher yield and purity, an NH4Cl-catalyzed ethoxy ethyl deprotection in superheated THF mitigated the problematic amide bond hydrolysis, and a superheated condensation reaction minimized excess hydrazine reagent compared to the batch alternatives. Amount of hazardous hydrazine reagent present in the reactor at any one time was orders of magnitude less than batch. Disposable coiled tube PFRs were used for highly potent and cytotoxic compounds to lessen the cleaning burden and eliminate the possibility of cross-contamination from the reactor itself. L/d ratios over 20,000 achieved extremely low axial dispersion in the laminar flow regime, even with tubing inside diameter greater than 7 mm. CSTRs, CSTRs-in-series, and intermittent flow CSTRs were used for reactions with long reaction times, positive order kinetics, and multiple reaction phases, either solid/liquid or liquid/liquid. CSTRs were used for several Grignard reagent formations utilizing sequestered Mg solids. Grignard formation examples had higher chiral purity, lower homocoupling byproducts, less product degradation, and better safety compared to batch.