Operating Strategy for Continuous Multistage Mixed Suspension and Mixed Product Removal (MSMPR) Crystallization Processes Depending on Crystallization Kinetic Parameters

Abstract

Continuous multistage MSMPR crystallization processes are useful for the large scale production of particulate systems. However, the design of operating strategies to meet specific objectives and materials has not been entirely investigated. In this work, the effect of important crystallization kinetic parameters on the optimal operating strategy was examined. The important parameters are the kinetic constants of the primary and secondary nucleation rates, the orders of the nucleation and growth rates, and the number of crystallizer stages. The analyses revealed that a drastic cooling strategy in the primary nucleation dominant region and linear cooling in the secondary nucleation dominant region are best for producing large particle sizes. A stage number of around three is effective in both regions.These results can be utilized to roughly determine the operating strategy for a process, if the crystallization kinetic parameters are already roughly known.

API Continuous Cooling and Antisolvent Crystallization for Kinetic Impurity Rejection in cGMP Manufacturing

“…The crystallization modeling used in this application utilized population balance models. Population balance modeling is a common means to model a crystallization process and has been used by others for MSMPR cascades with cooling-driven supersaturation. ,,,,, There have been many studies quantifying crystallization kinetic parameters in MSMPRs. ,,− …”

Process Design and Optimization for the Continuous Manufacturing of Nevirapine, an Active Pharmaceutical Ingredient for HIV Treatment

“…Modeling and optimization methodologies can be used to establish optimal process design configurations. , Advanced theoretical methods have been previously implemented toward optimal pharmaceutical unit design and optimization of pharmaceutical manufacturing processes to elucidate optimal operation, analysis of synthetic pathways, − and life cycle assessments. , Modeling and optimization have also been implemented in the design of separation processes in pharmaceutical manufacturing, such as liquid–liquid extraction (LLE), − crystallization, − and chromatographic methods . Identification of cost-optimal plantwide designs is essential, particularly end-to-end designs encompassing synthesis and purification/separation.…”

Incorporating Solvent-Dependent Kinetics To Design a Multistage, Continuous, Combined Cooling/Antisolvent Crystallization Process

“…First, batch crystallizations tend to undergo separate nucleation and growth events; in an MSMPR crystallizer, growth and nucleation occur simultaneously, competing to reduce supersaturation. 16 Second, batch experiments have limited use for predicting secondary nucleation, which is the dominant nucleation mechanism in an MSMPR crystallizer. 17 Solventdependent kinetic parameters must be regressed from continuous crystallization experiments for a proper antisolvent MSMPR crystallizer design.…”

“…Although procedures exist for regressing solvent-dependent kinetic (SDK) parameters from batch crystallization experiments, these experiments have severe shortcomings. First, batch crystallizations tend to undergo separate nucleation and growth events; in an MSMPR crystallizer, growth and nucleation occur simultaneously, competing to reduce supersaturation . Second, batch experiments have limited use for predicting secondary nucleation, which is the dominant nucleation mechanism in an MSMPR crystallizer .…”