Quantitative approach between secondary nucleation and mixing hydrodynamics in solution crystallization system: process development and scale-up

Crystallization via secondary nucleation allows the selective crystallization of a particular crystalline form which can lead to a more consistent crystalline product in terms of particle size distribution (PSD). Scaling up a crystallization process often results in significant changes to crystal size distribution (CSD), purity and morphology, which are key factors of product quality and has implications for downstream operations. The development of robust crystallization processes in which these parameters can be controlled requires a clear mechanistic understanding of nucleation. The convenient method to investigate this behavior is to determine the secondary nucleation threshold (SNT) of a crystallization system, which was found to be very sensitive to process variables such as mixing. Secondary nucleation and its qualitative relationship with agitation rate was a typical criterion used in the past. However, in the present work, a novel approach was established in which particle imaging velocimetry (PIV), a non-intrusive measurement technique, was used to quantify the mixing hydrodynamics with the cooling crystallization kinetics, as a function of fluid turbulent shear stress (TSS). All the crystallization experiments were performed in a solution crystallization of paracetamol in propan-2-ol solvent using a large single seed crystal of paracetamol which was held stationary in the agitating solution. Based on the experimental evidence, crystal nuclei breeding has been proposed as the mechanism of secondary nucleation in which pre-nucleated clusters from the solution nucleated at the interface of the seed crystal. These crystallites were weakly bound to the surface and readily sheared off by the fluid shear, which led to secondary nucleation. At a given scale, with the increased agitation rate, the SNT and product mean particle size were observed to decrease due to increased TSS. The increased TSS enhanced the rate of crystallites detachment from the seed surface, which facilitated the rate of secondary nucleation, and hence a decrease in SNT. From the results, secondary nucleation due to nuclei breeding was found to have a quantitative link with TSS which resulted in SNT to be independent of the scale under the influence of a constant TSS. This, in turn, leads to the production of a consistent PSD, independent of the scale. Moreover, the investigations revealed that using nuclei breeding approach in secondary nucleation, a controlled and uniform (narrow) PSD can be obtained in a given crystallization process through quantitative hydrodynamics. The novel approach established in the present work offers a potential for a more precise model in the process development and scale-up since nucleation is the direct consequence of nuclei breeding in which the fluid shear stress is the driving factor.