Recent Advances in the Monitoring, Modeling and Control of Crystallization in Impure Media

Since the vast majority in practical crystallization processes occur in impure media, the effect of impurities or additives on the crystal properties including shape, overall purity as well as on the crystallization mechanisms has attracted growing interest in recent years. Impurities can affect significantly the final properties of the crystals by influencing the nucleation and growth kinetics during the crystallization. While most industrial crystallization processes occur in impure media, and there is significant published literature that demonstrates experimentally the strong effects of impurities or additives on the crystallization behaviour, there is very limited work available that provides systematic modeling and control approaches that directly focus on investigating the simultaneous effect of impurities in the solution on crystal purity as well as size and shape distribution.

In this presentation recent work in the modeling and control of crystallization in impure media will be presented. The combined effect of different crystal growth modifiers on the crystal shape is investigated and applied as control strategy. A novel modeling framework is developed that combines multi-dimensional morphological population balance model (PBM) with a multi-impurity adsorption model (MIAM) to describe the competitive effect of multiple impurities on the crystal purity, shape and size distribution. The large number and highly correlated kinetic parameters, including the effect of impurities on the growth of different crystal faces, are identified using a rigorous experimental design procedure based on in-situ aspect ratio measurements, obtained by using real-time image analysis techniques. The model is used for the design and investigation of different purity and shape control approaches for both batch and continuous crystallization processes. On-line ultra performant liquid chromatography (UPLC) is used for monitoring the crystallization in the presence of multiple components in low (impurities) and high (main APIs) concentrations and to provide real-time concentration measurement of the purity and shape control approaches. A novel competitive purity control (CPC) approach will also be presented which is based on the use of harmless excipient additives to decrease the levels of harmful (e.g. genotoxic) impurities in the crystal lattice based on the competitive adsorption concept and mechanism described in the PBM-MIAM.

Example case studies will be presented that will demonstrate how the combined used of rigorous modeling, state-of-the-art process analytical technologies and novel feedback control approaches can be used to enhance product consistency and to precisely tailor crystalline product properties such as shape and purity.