No More Than Three: Technoeconomic Mixed Integer Nonlinear Programming Optimization of Mixed Suspension, Mixed Product Removal Crystallizer Cascades for Melitracen, an Antidepressant API

Mixed Suspension, Mixed Product Removal (MSMPR) crystallizers have been considered in numerous cases as a continuous mode of operation in the production of Active Pharmaceutical Ingredients (APIs). The steady-state continuous MSMPR crystallization of melitracen via cooling has been recently demonstrated in the literature, with crystallization kinetic parameters regressed from experimental data. Mixed Integer Nonlinear Programming (MINLP) has been implemented extensively for the optimization of separation process designs in various manufacturing sectors, but not for systematic design and screening of MSMPR cascade flowsheet configurations. This study performs MINLP optimization to maximize the Net Present Value (NPV) of a MSMPR cascade for continuous melitracen crystallization with solid recycling. Process flowsheets consider varying numbers of crystallizers and recycle stream feed point location. First, the MSMPR model describing API solubility, crystallization kinetics, population balance equations, and process mass balances is described. The MINLP problem and constraints are then described with detailed costing equations. The optimal flowsheet configuration for both considered plant capacities (10 3 and 10 4 kg API yr –1 ) is three crystallizers with recycling fed to the first and last vessels. This study illustrates rapid screening of continuous crystallization cascades via MINLP optimization, toward fully Continuous Pharmaceutical Manufacturing (CPM) plant designs.