(391c) The Impact Of Mixing Times Scales And Process Parameters On The Optimisation And Scale Up Of Anti-Solvent Addition Crystallizations

Previous work within this research group has highlighted the impact of addition location, addition rate, agitation and scale on the Meta Stable Zone (MSZ). The current research aims to assess the impact of macro, meso and micro mixing times scales on the induction time for the anti-solvent addition crystallization of benzoic acid form an ethanol-water solution. In addition to this the effect of nozzle addition and power law feed profiles on overcoming regions of poor addition (i.e. regions or scales of long mixing time scales) and on optimizing crystallization characteristics such as Metastable Zone Width (MSZW) and chord length distributions (CLDs) have been assessed. Anti-solvent addition crystallizations are mixing sensitive as they rely on the incorporation and blending of two liquids to produce a homogenous system. On scale up the incorporation and efficient blending of the anti-solvent to the bulk solution becomes more difficult, hence they are problematic to scale up. Vessel homogeneity and mixing times scales (macro, meso and micro) are all negatively impacted on scale up, thus leading to fluctuations in product yield / purity and in MSZW and chord length distributions (CLDs) produced. This paper develops a semi-quantitative method for the optimization and scale up of the anti-solvent addition crystallization of benzoic acid from 500 ml to 2L and finally to a 70 L crystallizer. The use of computational fluid dynamics (CFD) for understanding the mechanisms of importance, supersaturation nucleation and growth, is outlined in detail. The combination of this modeling tool with other in-situ tools such as Focused Beam Reflectance Measurement (FBRM), particle dimension characterization, Fourier Transform Infrared spectroscopy (FTIR), for on-line supersaturation and Particle Vision Measurement (PVM), for on-line particle imagery, allow for a more robust and strategic strategy for scale up.

The importance of macro, micro and meso-mixing time scales for successful scale up of anti-solvent crystallizations has been identified. Examining the effect of these times scales on premature nucleation events at the 500ml scale, due to excess supersaturation at the feed point, has been studied. The effect of feed point location and feeding mechanism (i.e. feed tube diameter) on macro and meso-mixing time scales have all been assessed for their impact on inconsistent crystallization characteristics, which include fluctuations in the FBRM statistics and premature nucleation events. Overall the dominant time scale for allowing premature and inconsistent chord length distributions (CLDs) was the meso mixing times scale. The effect of the process parameters, outlined above, on this time scale have been examined, thus allowing for problematic regions of addition (i.e. regions of long meso-mixing time scale) to be noted prior to scale up. This increase in process understanding through CFD minimized the experiments required to efficiently scale from a 500ml crystallizer to a 2L and finally to a pilot scale crystallizer of capacity 70L.