Experimental Evaluation of Fluid Shear Stress Impact on Secondary Nucleation in a Solution Crystallization of Paracetamol

Cooling crystallization experiments were performed at 300 and 370 rpm over a range of saturation temperatures for the measurements of the metastable zone width (MSZW) using a large seed of paracetamol crystal in propan-2-ol solution. Particle imaging velocimetry (PIV) was used to quantify the fluid shear stress at each agitation rate employed, which was found to be 0.07 and 0.11 N/m2 respectively. A decrease in MSZW and growth only zone (GNZ) was observed with increasing shear stress, and the secondary nucleation threshold (SNT) was determined with a relative supersaturation ratio (S r) of 1.17 at 0.07 N/m2 and 1.08 at 0.11 N/m2. Focused beam reflectance measurement (FBRM) displayed an increase in particle counts as nucleation progressed, with total counts increased by 25% at a higher fluid shear as more nuclei were being sheared off from the seed surface. Crystal nuclei breeding is proposed as a mechanism of secondary nucleation, where the surface of a seed crystal served as a nucleation site for the pre-existing clusters in the solution as was evident under scanning electron microscopy (SEM). Secondary nucleation and its link with fluid shear stress, a novel approach established in the present work, will offer a more precise model in process development and scale-up.