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

Abstract

Precise control of a crystallization process requires a clear understanding of nucleation kinetics. Interpreting secondary nucleation threshold (SNT) of a given crystallization process under optimized hydrodynamic conditions can highlight the impact of critical process variables on product particle size distribution (PSD). In this work, a new approach is proposed in industrial crystallization process development in which a quantitative link was developed between batch cooling crystallization and fluid turbulent shear stress (TSS). The experiments involve solution crystallization of paracetamol in isopropanol. A novel method was adopted in which a large single seed crystal of paracetamol was held stationary in an agitating reactor. Using particle imaging velocimetry, a constant TSS was obtained across different scales which resulted in a constant SNT because of crystal nuclei breeding. This led to better control over the crystallization process which eventually resulted in a consistent PSD, independent of the scale. A uniform PSD was observed at each scale which was evident through scanning electron microscopy. The investigation explicates that it is feasible to control PSD across different scales by controlling the SNT through hydrodynamics. This is proposed to be a robust approach in the crystallization process via crystal nuclei breeding, hence, providing a potential opportunity to improve the manufacturing process.

Secondary Nucleation by Interparticle Energies. II. Kinetics

“…Traditionally, secondary nucleation has been largely attributed to microbreakages of seed crystals caused by crystal-impeller collisions, 3 that is, attrition. 1 , 4 , 5 However, recent research has noted that this mechanism cannot describe secondary nucleation completely, 3 , 6 − 13 based on two main reasons. First, secondary nucleation can occur even when the crystal microbreakages are prevented by precluding any crystal-impeller collision.…”

“…First, secondary nucleation can occur even when the crystal microbreakages are prevented by precluding any crystal-impeller collision. 11 − 13 Second, the attrition mechanism cannot explain some crucial experimental observations according to which secondary nucleation can produce nuclei having a polymorphic 14 or chiral 15 − 17 form different from that of the seeds. In contrast with these observations, secondary nuclei generated by the attrition mechanism must exhibit the same polymorphic form and the same handedness in the case of chiral molecules of the seeds because these nuclei are the broken pieces of the seeds.…”

Diffusion-Enhanced Amide Bond Formation on a Solid Support

“…Diffusion is a limiting factor in both solid- and solution-phase reactions. − The term diffusion is used here to describe the combined effect of mass transfer of the reagents, movement of the beads, and the permeation of the reagents into the beads. The heterogeneous nature and the fast kinetics in SPPS transformations suggest that diffusion plays a key role in dictating the yields and rates of reactions. , Although the enhancement of diffusion by overhead stirring is known, the claim that the beads are destroyed when harsh mixing conditions are applied means that fast overhead stirring (above 500 rpm) is not used, and its contribution to reaction efficiency in SPPS is largely overlooked, at least in academic laboratories. − Reactor design affects the shear stress and diffusion, which are vital for bioreactors, crystallization purposes, and reaction efficiency in heterogeneous systems. − Slow stirring creates low shear forces compared to fast stirring but compromises on diffusion . A careful design of the reactor parameters might allow to increase the mixing rate without applying harsh shear forces on the beads.…”

Overview on the hydrodynamic conditions found in industrial systems and its impact in (bio)fouling formation

“…Mixing in industrial facilities is carried out typically in stirred tanks. These devices ensure the ideal mixing conditions needed for several industrial applications, like chemical reactions [135,136], biological process [137,138], dissolution [51,139], emulsification [140,141], homogenization [142,143], crystallization [144,145], heating and cooling processes [146,147]. In fact, stirred tanks are less prone to develop biofouling than the systems described above.…”

“…The desired characteristics of final products are strongly influenced by the operating mixing conditions. For example, the particle size distribution in the crystallization of paracetamol was improved by controlling the nucleation kinetics through hydrodynamics [145]. The droplet sizes of an emulsion depended on hydrodynamic conditions of its production: the droplets size decreased as the Re increased, due to its high breakup [141].…”