Process modelling, design and technoeconomic LLE optimisation for comparative evaluation of batch vs. continuous pharmaceutical manufacturing of atropine

Continuous Pharmaceutical Manufacturing (CPM) can revolutionise industrial efficiency via potential operational and economic benefits over currently dominant batch methods. Process modelling and optimisation are valuable towards rapid design space evaluation and elucidation of optimal process design configurations, without expensive and time-consuming experimental campaigns. This paper pursues total cost minimisation via nonlinear optimisation of different separation design options for atropine, a product of great societal importance. The study considers a demonstrated continuous flow synthesis, presents reaction kinetic parameter estimation towards reactor design, and illustrates a comparative analysis of the subsequent batch vs. continuous Liquid-Liquid Extraction (LLE) for product purification, using published partition coefficient data and UNIFAC-modelled ternary liquid-liquid equilibria. Original optimisation results show that toluene is the best continuous LLE solvent, attaining the lowest total costs at both plant capacities considered and the greatest total cost savings with respect to batch LLE design for varying solvent recovery, at acceptable material efficiencies. and physical property estimation and published mass transfer correlations for LLE modelling and an established costing methodology for batch and continuous pharmaceutical processes. Optimisation of a conceptual continuous LLE for the purification of the API synthesis effluent following the continuous flow synthesis (Bédard et al. , 2016) for different LLE solvent choices and design assumptions (plant capacity and solvent recovery) are used to elucidate promising designs for atropine CPM. The LLE solvent-to-feed ratio ( r ) is driven to the lower bound in all design cases while LLE tank volumes vary between different design options due to its effect on LLE efficiency (affecting OpEx components) and CapEx contributions. Toluene emerges as the most economically favourable LLE solvent choice, offering significant total cost savings over batch LLE designs with acceptable material efficiencies for pharmaceutical manufacturing applications. Consideration of impurity limits in the LLE product aqueous stream and LLE solvent selection for harmonisation with subsequent crystallisation processes will provide further insight into optimal process configurations for atropine CPM. This work demonstrates the value of conducting technoeconomic optimisation studies towards the development of continuous processes in pursuit of economically viable end-to-end CPM plants. Industrial implementation and experimental validation of such efforts remain strategic R&D priorities: streamlining the use of lab- and/or pilot plant-scale reaction and separation experiments to guide the CPM process development effort is strongly recommended, especially via first-principles plantwide models which (in contrast to many data-driven ones) are applicable across all plant scales and sizes. Evaluating economic benefits systematically is of critical industrial importance, hence systematic modelling efforts can catalyse an accelerated and widespread adoption of continuous manufacturing.