Abstract
Although solvent-based crystallization is widely adopted for separation and purification of crystalline pharmaceutical products, solvent choice and utilisation critically influence product quality, manufacturing cost, and the environmental performance of the pharmaceutical process. Escalating demands to reduce process mass intensity (PMI), together with increasing vulnerabilities in the supply chains, necessitate the development of more efficient and resilient process designs, incorporating solvent and active pharmaceutical ingredient (API) recycling. The conceptual design of crystallization processes offers a viable route to identify flowsheets with substantially reduced solvent consumption. In this paper we present a computer-aided molecular and process design (CAMPD) formulation to explore the benefits of solvent/API recycle for two processes/APIs: (i) a continuous cooling crystallization process for mefenamic acid (MA) employing a binary solvent mixture and (ii) a batch cooling crystallization for paracetamol using a single solvent. At the conceptual design stage, the process is assumed to operate at thermodynamic equilibrium and the SAFT-? Mie group contribution approach is used as a rigorous thermodynamic model. The optimal design for each process is determined based on the trade-off between two key performance indicators (KPIs), crystallization yield and solvent consumption. The resulting bi-objective optimization (BOO) problem is implemented in gPROMS. In addition to the solvent identities the proposed methodology also enables the simultaneous optimization of process temperatures, and the feed composition. The results demonstrate that solvents and API recycling can deliver significant benefits, leading to reduced process mass intensity (PMI) while maximizing the crystallization yield.