Secondary Nucleation from Nuclei Breeding and Its Quantitative Link with Fluid Shear Stress in Mixing: A Potential Approach for Precise Scale-up in Industrial Crystallization

Abstract

The development of robust process scale-up involves a clear understanding of mixing hydrodynamics in crystallization. In the present work, particle imaging velocimetry (PIV) was used to determine the fluid turbulent shear stress (TSS) as a function of scale-up involving cooling crystallization experiments at different agitation rates. At a given scale, with increased agitation rate from 300 to 370 rpm, the secondary nucleation threshold (SNT) and product mean particle size were observed to decrease due to increased TSS. In nuclei breeding, the nucleated crystals at the seed surface are readily sheared off by the increased fluid shear stress. This catalytic process enhanced the rate of secondary nucleation, and hence a decrease in SNT. The SNT and mean particle size increased with scale size due to a decrease in average turbulent dissipation rate which resulted from a decrease in TSS. Secondary nucleation due to nuclei breeding was found to have a quantitative link with TSS. This resulted in a constant SNT under the influence of the same TSS which led to a consistent particle size distribution (PSD), independent of the scale. The presented approach shows that a controlled PSD can be obtained across different crystallization scales by controlling secondary nucleation through hydrodynamics.

Quantitative Link between Secondary Nucleation and Mixing Hydrodynamics in Batch Cooling Crystallization: A New Approach in Process Development

“…The core of the present research involves SN based on crystal nuclei breeding. This mechanism has experimentally been proven in our previous studies; , however, there was a need to further investigate the potential impact of nuclei breeding on the crystallization process in industrial application, which has been addressed in this work. The key objective was to have a better understanding and control over PSD in scale-up through controlled SN.…”

“…In general, the SNT was observed to be highly repeatable across each scale. In a previous work, the mechanism of nuclei breeding and its link with fluid shear stress has been proved in a laboratory-scale experimentation. Similarly, in the present investigation, under the influence of same TSS of 0.67 N/m 2 , the resultant SNT achieved was constant, irrespective of the scale.…”

“…Thus, understanding the fundamentals of nucleation is crucial to the control of crystallization processes . The nucleation kinetics, that is, the metastable zone width (MSZW) and secondary nucleation threshold (SNT) of a crystallization system are sensitive to process variables such as mixing. − Interpreting MSZW and SNT under different mixing conditions at the laboratory scale can be helpful in understanding the process operating window which provides considerable information for the likely performance of the crystallization process on scale-up. The complexity of scale-up is of a major concern in pharmaceutical industry as only small amounts of APIs are usually available in early stages of development .…”

Intense Pulse Light Annealing of Perovskite Photovoltaics Using Gradient Flashes

“…Upon spincoating (T 3 −T 1 ), a transparent film was obtained and, as shown in Figure 1C, numerous infinitesimal crystals arranged into smaller size dendrites were formed and covered the entire surface, which could indicate the formation of a CH 3 NH 3 I• PbI 2 •DMSO•DMF•CH 2 I 2 adduct and, thus, successful formation of a perovskite yellow intermediate. 43 This nucleation can be attributed to antisolvent dripping, which resulted in rapid stochastic intermolecular fluctuations of the atoms to form nuclei and, in turn, crystals, as well as the nuclei shear-off from the developing crystals to develop adjacent crystals and proliferate the nucleation throughout the surface, 44 thus consuming and decreasing the size of dendrite clusters. Subsequent annealing of the developed intermediate phase (>T 3 ) enables grain growth and formation of a perovskite black phase to produce charge carriers upon illumination (Figure 1D).…”

Development of a Novel Supersaturation Monitoring System in Continuous Crystallization of KAl(SO4)2·12H2O

“…In recent years, with the development of sensor technology and simulation technology, various crystallization phenomena have been visualized [1][2][3][4][5]. The factors determining the grain size distribution during crystallization are nucleation and growth.…”