Technoeconomic evaluation and optimization of batch, fed-batch and multistage continuous crystallization processes

Over the last decade, continuous manufacturing techniques have been widely used in pharmaceutical manufacturing industries. However, despite the outstanding performance associated with the steady-state operation, continuous processes face common and important challenges of low efficiency and material waste during the start-up and shutdown. Considering that most pharmaceutical manufacturing is accomplished in a short operation window, an ideal start-up and shut down strategy will have a significant impact on the economic and environmental performance of the continuous pharmaceutical process. In this study, a combined start-up, steady-state, and shutdown optimization of a three-stage mixed suspension mixed product removal (MSMPR) crystallizer was compared against optimized batch and fed-batch crystallizers. The crystallization of aspirin (acetylsalicylic acid, ASA) in ethanol (solvent) and water (antisolvent) was used as a case study. The optimization problems were solved using a hybrid method, which combines a genetic algorithm and a sequential quadratic programming (SQP) method. The multistage continuous crystallizer was designed and optimized to maximize on-spec production over a total operating window of 800 min. It was shown that a max on-spec production of 5858 g can be achieved with the continuous process. A batch and a fed-batch crystallizer were designed and optimized to achieve the same production rate and help establish a reliable basis for rigorous technoeconomic analysis and comparison.