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

Over the last decade, continuous manufacturing techniques have been widely used in the pharmaceutical manufacturing industry. 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 5510 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 techno-economic analysis and comparison.