Process modelling, simulation and technoeconomic optimisation for continuous pharmaceutical manufacturing of (S)-warfarin

Continuous pharmaceutical manufacturing (CPM) has the potential to attain several technical and operational economic benefits compared to the currently prevalent batch production paradigm. Despite the variety of demonstrated continuous flow syntheses of active pharmaceutical ingredients (APIs), the limited number of cost-effective continuous separations is a bottleneck to end-to-end CPM. Establishing promising APIs for integrated CPM is paramount. (S)-Warfarin is an anticoagulant API whose continuous flow synthesis features a single reaction with high enantiomeric selectivity followed by liquid-liquid extraction (LLE). This work describes the steady-state process modelling and technoeconomic optimisation for the upstream CPM of (S)-warfarin, implementing reactor design and LLE solvent comparison for purification. Ethyl acetate, isopropyl acetate, isobutyl acetate, 1-heptanol, 1-octanol and heptane are candidate LLE solvents. Reported reaction conversions and computed LLE efficiencies allow mass balance calculation and total cost estimation to establish promising LLE solvents. The nonlinear optimisation problem is formulated for total cost minimisation. Liquid-liquid phase equilibria, API phase compositions and solubilities for LLE design are implemented via surrogate polynomials based on extensive UNIFAC modelling; API recovery rates are calculated via detailed mass transfer correlations. The methodology used here screens optimum process configurations to achieve a technoeconomically optimal design for a continuous (S)-warfarin manufacturing plant.