A Holistic Approach for the Model-based Control of Crystal Size, Shape and Purity in Integrated Batch and Continuous Crystallization-Wet Milling-Classification System

Publication Reference: 
Author Last Name: 
Rojan Parvaresh, Zoltan K. Nagy
Report Type: 
ARR - Annual Report
Research Area: 
Systems Engineering
Publication Year: 
United States

This report summarizes the main achievements during the year 2022 of the project with the aim of developing process systems engineering approaches for improved crystal size and purity control during crystallization processes. The successful crystallization process and system design requires an interdisciplinary effort, which ranges from population balance model (PBM) development of the system concept, through efficient implementation of model equations to soft-sensor development, which is required for the model predictive control (MPC) design as well. This report gives a deeper insight into these interdisciplinary development efforts, which also highlights the achievable improvements enabled by the combination of process modeling, high performance process simulation and optimization.

This year was focused on designing a novel, integrated crystallization system capable of establishing increased control of the properties of crystalline materials. The attainable region of crystal size distribution (CSD) is widened by the application of a recirculation stream and multiple MSMPR units as well as the integration of a downstream wet mill and classification units with recirculation stream(s) for continuous operation. This approach was then applied in finding an attainable region for a commercial active pharmaceutical ingredient (API) to observe real life application of the system. Also, a Quality-by-Control (QbC) guided framework is developed for crystallization processes to meet the CQAs of studied processes. QbC allows for control over techno-economics of the system through productivity and yield in addition to properties such as crystal size and narrow distribution.

The last part of this work focuses on production of Atorvastatin calcium with higher yield and lower cost. To address the limitations that the conventional batch manufacturing possesses, operating end-to-end in a continuous mode to shorten and strengthen product supply chains and add agility and flexibility to manufacturing is proposed. This leads to an integrated cascade of crystallizers that control polymorphism and agglomeration to be the connection between reaction and continuous filtration and drying in carousel (CFC) device.

Achieved Deliverable
1. Development of an integrated continuous crystallization system, wet mill, classifiers with recycle
2. Development of attainable regions for model and commercial compounds
3. Robustness studies via kinetic parameter uncertainties and inlet seed distribution
4. Validation experimental results for continuous crystallization with wet mill, classifier and recycle