Abstract / Description of output
Continuous Pharmaceutical Manufacturing (CPM) has the potential to revolutionise the pharmaceutical industry, with many expected benefits in terms of cost, efficiency and quality. Process modeling and optimization are valuable methodologies for comparative technoeconomic evaluations: this paper pursues total upstream CPM cost minimisation via two nonlinear optimization methods. An explicit NRTL solubility estimation method has been used in order to analyse the potential performance of three binary antisolvent mixtures for the crystallization of artemisinin. This Active Pharmaceutical Ingredient (API) is a key antimalarial substance and has been the focus of several CPM studies, including continuous chemistry and separation. Ethanol, acetone and ethyl acetate are the three antisolvents studied. Used as a binary antisolvent with toluene as the solvent, the composition of the binary antisolvent, the quantity of the binary antisolvent with respect to the process solvent, and the temperature the overall mixture is cooled to in the crystallization process are formulated as the three key variables in a nonlinear optimization problem. Two solvers are used, NOMAD and NLOPT-BOBYQA. Results show that they have very similar precision (<1 % difference), but that the latter is up to 66 % faster; NLOPT-BOBYQA was used for the majority of optimization cases. Results show that for the size of the temperature gradient of the crystallization has a much stronger effect on the total cost than the quantity of antisolvent used. Nearly pure antisolvent use (ethyl acetate followed by ethanol) is favoured as yielding the lowest total cost (for a single crystalliser). Considering multiple units, results indicate that higher API recovery, E-factor, and OpEx benefits can be achieved when using two crystallisers, but metrics are inferior with three or more. For sequential crystallisers of varying size, increasing the number of crystallisers also benefits OpEx, E-factor, and API recovery, but CapEx continues to increase, thereby promising technical but no economic benefits.