Effect of Mixing on the Particle Size Distribution of Paracetamol Continuous Cooling Crystallization Products Using a Computational Fluid Dynamics–Population Balance Equation Simulation

Abstract

Continuous crystallization is a widely viewed topic as it has many advantages in industrial production. However, it is very resource intensive and time-consuming to determine operation conditions through trial and error. Computer simulation appears to an effective method in continuous crystallization design. The continuous cooling crystallization of paracetamol in a 5 L crystallizer was modeled to investigate the effect of mixing on the particle size distribution (PSD). A novel coupled computational fluid dynamics−population balance equation (CFD−PBE) simulation was developed in which the PBE was discretized using a high-resolution central scheme and solved simultaneously with CFD equations in ANSYS FLUENT 15.0 utilizing user-defined scalars. The influences of both internal grid and external (spatial) grid on the final PSD were studied, and an appropriate grid was chosen. The spatial distribution of velocity, temperature, slurry density, and nucleation rate were simulated. The continuous cooling crystallization under different stirrer speeds, bath temperatures, and residence times was investigated. It was found that (a) higher stirrer speeds lead to uniform distribution but smaller PSD, and (b) as the average temperature gets higher, or the residence time gets longer, the influence of mixing on final PSD gets smaller.

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

“…This can be associated with an improve supersaturation uniformity in the vessel due to an increase in the turbulence dissipation rate. In a very recent study, it was shown that the mean size of paracetamol crystals was decreased with increasing agitation rates, leading to a uniform PSD . It was reported as the result of increased turbulent dissipation rate which enhanced the supersaturation uniformity in the mixing.…”

“…The increased stirring rate resulted in an increase in the turbulence dissipation rate (TDS), which subsequently resulted in an increase in TSS. The increase in the turbulent dissipation rate in mixing due to the increase in agitation rate has been proposed based on a computational fluid dynamics model . The mechanistic insight of nuclei breeding and its link with fluid shear stress has recently been proven using a laboratory scale experimentation .…”

“…The increase in the turbulent dissipation rate in mixing due to the increase in agitation rate has been proposed based on a computational fluid dynamics model. 34 The mechanistic insight of nuclei breeding and its link with fluid shear stress has recently been proven using a laboratory scale experimentation. 18 From the study, the evidence of nuclei breeding was further examined through SEM, which revealed the presence of nucleated crystallites attached to the surface of the seed.…”

Recent Progress in Continuous Crystallization of Pharmaceutical Products: Precise Preparation and Control

“…This is a helpful tool in establishing the temperature and the concentration fields under different crystallization strategies. There are many reports about PBE–CFD models that focus on optimization of the CSD and the design of the crystallizers. ,− Li et al investigated this complicated crystallization processes in an airlift loop crystallizer by a complete CFD–PBE–PBE solver. The ion consumption rate and CSD results indicated the feasibility of the developed solver.…”

Towards a better understanding of the role of stabilizers in QESD crystallizations

“…As the crystallization of an API or excipient is often part of the final production step, using a crystallization method which can favorably change the micromeritic properties of the product is advantageous. During typical crystallizations, such as cooling, evaporation or antisolvent addition, particle size and morphology can be influenced by, e.g., the super saturation (8), agitation rate (9) or choice of solvent (10).…”