Continuous Distillation for Drug Substance Manufacturing

Abstract

Purpose Continuous distillation is widely used in the commodity and petrochemical industry to purify fine chemicals on massive industrial scales; however, this key separation strategy is largely unused within the pharmaceutical industry. This article investigates the development of a pilot-scale continuous distillation system for in-line removal of an excess amine reactant ( i.e. , tert-butylamine) when incorporated within an advanced manufacturing technology (AMT) for continuous drug substance production. Methods Initial design parameters were simulated in ASPEN + to assess potential process solvents, setpoint parameters, and azeotrope formation. Complementary analytical characterization was performed with high performance liquid chromatography (HPLC) and gas chromatography – flame ionization detection (GC-FID). Early continuous distillation prototypes and key engineering design decisions are highlighted. Results The final engineered system is comprised of a + 3-foot distillation column fitted with an Allihn condenser, a 250 mL three-necked round bottom flask, and an automated system for reflux ratio (R D ) control. The column is readily integrated within an advanced manufacturing system to continuously remove amine reagent during continuous manufacturing of albuterol sulfate at a 3.0 mL/min process basis, corresponding to a theoretical throughput of approximately 1,800 doses per hour based on the demonstrated process flowrate, reaction stoichiometry, and operating conditions. Conclusions The application of continuous distillation offers a unique strategy for impurity removal during advanced pharmaceutical manufacturing and can be scaled to meet target throughputs. Here we provide general criteria necessary for successful implementation of similar continuous in-line distillation systems.

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