Continuous Distillation for Drug Substance Manufacturing.

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 (RD) 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.