Monitoring nucleation at crystalliser walls and formation of prenucleation clusters in solutions

This thesis presents the work carried out to monitor nucleation at crystalliser walls (fouling) through image analysis and the behaviour of solutions prior to nucleation using light scattering techniques. Crystallisation is a process widely used in the pharmaceutical industry, whereby pure solid particles are obtained using supersaturation as the driving force. Fouling occurs when crystals grow on surfaces, where it is difficult to quantify. The consequences of fouling are detrimental to the process and can result in compromising product quality or process shut down. Continuous crystallisation is now increasingly considered as a way to enhance product quality and process efficiency. However, implementing continuous crystallisation in a system prone to fouling becomes problematic and greater understanding is required for either prevention or mitigation. Nucleation is the key process through which crystallisation occurs, whether it be on surfaces or in bulk solution. It is poorly understood, but thought to occur via liquid-like clusters containing the crystallising material and the solvent or solvent mixture. The fouling behaviour of aqueous solutions of L-glutamic acid and glycine was studied in an oscillatory flow crystalliser. Images of the glass surface were analysed to provide information regarding the fouling induction period, which has currently not been studied. Bulk and surface nucleation were decoupled by processing the images in a Fouling Graphical User Interface (GUI) algorithm. No one has attempted to do this before, as bulk nucleation is normally the focus and surface nucleation is observed but ignored. Several variables were investigated including concentration, flow conditions and temperature to test their effect on the fouling outcome. It was discovered that higher concentrations fouled more quickly and to a greater extent and that increasing the oscillatory flow decreased the fouling induction time. This novel non-invasive imaging technique provided a new method for measuring fouling and bulk induction times separately during crystallisation processes. Dynamic light scattering and Brownian microscopy were employed to study the prenucleation behaviour of supersaturated and undersaturated aqueous solutions of glycine and urea. The solutions were exposed to temperature cycling in order to probe the nucleation mechanism and test the reversibility behaviour of the solutions during heating and cooling. It was found that the solutions underwent a reversible transformation above a certain temperature. Larger mesoscale clusters were produced at this point, most likely to aid in maintaining thermodynamic equilibrium in the solution. The larger species were not observed at lower temperatures in the cycle, this was an unexpected result for which the reason is still unclear. Currently in the literature, no studies have been carried out on the reversible effects temperature has on the structure of prenucleation clusters in both undersaturated and supersaturated solutions. Better understanding of clustering phenomena is required to improve our ability to control nucleation during crystallisation processes.This thesis presents the work carried out to monitor nucleation at crystalliser walls (fouling) through image analysis and the behaviour of solutions prior to nucleation using light scattering techniques. Crystallisation is a process widely used in the pharmaceutical industry, whereby pure solid particles are obtained using supersaturation as the driving force. Fouling occurs when crystals grow on surfaces, where it is difficult to quantify. The consequences of fouling are detrimental to the process and can result in compromising product quality or process shut down. Continuous crystallisation is now increasingly considered as a way to enhance product quality and process efficiency. However, implementing continuous crystallisation in a system prone to fouling becomes problematic and greater understanding is required for either prevention or mitigation. Nucleation is the key process through which crystallisation occurs, whether it be on surfaces or in bulk solution. It is poorly understood, but thought to occur via liquid-like clusters containing the crystallising material and the solvent or solvent mixture. The fouling behaviour of aqueous solutions of L-glutamic acid and glycine was studied in an oscillatory flow crystalliser. Images of the glass surface were analysed to provide information regarding the fouling induction period, which has currently not been studied. Bulk and surface nucleation were decoupled by processing the images in a Fouling Graphical User Interface (GUI) algorithm. No one has attempted to do this before, as bulk nucleation is normally the focus and surface nucleation is observed but ignored. Several variables were investigated including concentration, flow conditions and temperature to test their effect on the fouling outcome. It was discovered that higher concentrations fouled more quickly and to a greater extent and that increasing the oscillatory flow decreased the fouling induction time. This novel non-invasive imaging technique provided a new method for measuring fouling and bulk induction times separately during crystallisation processes. Dynamic light scattering and Brownian microscopy were employed to study the prenucleation behaviour of supersaturated and undersaturated aqueous solutions of glycine and urea. The solutions were exposed to temperature cycling in order to probe the nucleation mechanism and test the reversibility behaviour of the solutions during heating and cooling. It was found that the solutions underwent a reversible transformation above a certain temperature. Larger mesoscale clusters were produced at this point, most likely to aid in maintaining thermodynamic equilibrium in the solution. The larger species were not observed at lower temperatures in the cycle, this was an unexpected result for which the reason is still unclear. Currently in the literature, no studies have been carried out on the reversible effects temperature has on the structure of prenucleation clusters in both undersaturated and supersaturated solutions. Better understanding of clustering phenomena is required to improve our ability to control nucleation during crystallisation processes