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Title: Control of nucleation in continuous crystallisation processes
Author: Schacht, Ulrich
ISNI:       0000 0004 5347 4576
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2014
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Crystallisation is an important separation and purification technology in the pharmaceutical and fine chemical industry. Crystallisation processes are designed to generate and control supersaturation, nucleate desired polymorphs as well as crystal shapes and growing product crystals to the required particle size distribution and purity. Traditionally crystallisation is carried out in batch mode, due to the necessary process flexibility, although continuous processing can offer advantages of reproducible product quality, more sustainability as well as lesser waste and lower carbon footprint. This work describes a route towards the development of continuous crystallisation processes for small organic molecules. Supersaturation is the ultimate requirement for nucleation and in processes where mixing of two or more solutions is required to generate supersaturation, this step can affect nucleation. This thesis shows that higher mixing intensities yield higher solid recoveries over time and a smaller particle size. However, this phenomenon only applies to low and medium mixing flow rates, whereas results for high mixing flow rates are at the same level as for the medium ones. Furthermore, this effect was only observed in Valine - water:isopropanol (1:1) and at high supersaturations in Glycine - water:isopropanol (1:1) systems. In L-Glutamic acid - water:isopropanol (1:1) or L-Asparagine - water:isopropanol (1:1) systems this effect was not observed at all. Even the reactive precipitation of L-Glutamic acid (H-Glu) from Na-Glutamate and H2SO4 did not show any effects of mixing intensity on solid recovery over time. The mixing insensitive reactive precipitation of H-Glu was used to study the effect of post-mixing flow treatment on solid recovery over time and final polymorphic population. Micromixed samples were exposed to different batch flow units with hydrodynamics of a quiescent crystalliser (QC), stirred tank crystalliser (STC), magnetically stirred crystalliser (MSC), peristaltic pump recirculation loop (PPL) and an oscillatory baffled crystalliser (OBC). Harsh hydrodynamic conditions or mechanical impact like in the STC, MSC or OBC yield the metastable prismatic Alpha H-Glu polymorph and significantly increase solid recovery over time. Milder hydrodynamics like in a QC or PPL yield the stable platelet/needle like Beta H-Glu polymorph, where the PPL shows enhanced solid recovery over the QC. Despite XRPD analysis indicating pure Beta phase, the QC samples also contain about 0.1 % of the Alpha form, which growth kinetics suggest that they must have formed very shortly after mixing. Connecting the continuous mixing setup with a Beta enhancing flow-through PPL unit and a sample collection vessel made a fully continuous Beta H-Glu crystalliser. However, this system never reached steady-state operation, fouling and blockage was a major challenge and an unexpected change in the polymorph population from the stable Beta to the metastable Alpha was observed. This system did not perform satisfactorily and therefore experiments were discontinued. For the mixing insensitive antisolvent crystallisation of H-Glu, a novel rapid continuous antisolvent crystallisation setup was developed to produce crystal suspension of the Beta polymorph with a small size and narrow particle size distribution. The system jetinjects aqueous H-Glu solution into the bulk of isopropanol antisolvent and its performance was characterised with respect to different antisolvent mass fraction, bulk supersaturation, polymorphic population, steady-state operation, solid recovery over time, crystal size, particle size distribution and scale-up capabilities. Results show that increasing the antisolvent mass fraction reduces the final crystal size and particle size distribution, crystal product is of pure Beta form with a high yield, the system rapidly achieves very high supersaturation and reaches steady-state operations after about 20-30 min. Higher total flow rates and scale-up of the system did not show any effect on particle and system properties. The produced crystal slurry exhibits ideal properties of a Beta H-Glu seeding suspension for further crystal growth. Continuously seeded continuous crystal growth cooling crystallisation experiments were carried out in a tubular continuous oscillatory baffled crystalliser (COBC). H-Glu solution of two different concentrations was pumped through the system and Beta H-Glu seeding suspension of two different seed loadings were injected into the saturated solution. Mass balance calculations, supersaturation data, seed loading & solution concentration, crystal morphology information, crystal growth rates and mean residence time in each temperature section along the rig were used to predict solution concentration, desupersaturation behaviour and the temperature profile of the process. Online Focused Beam Reflectance Measurement (FBRM) analysis and offline laser diffraction particle sizing measurements recorded crystal growth in the system. Offline solid recovery analysis over time at various points along the rig successfully confirmed the predicted solution concentrations and desupersaturation profile of the COBC. However, micrographs and Scanning Electron Microscopy (SEM) analysis indicated that final product crystals are agglomerated. The effect of seed loading & solution concentration on the final agglomerated particle size distribution and solid recovery over time was investigated. Higher solution concentration led to larger product crystals, whereas different seed loadings did not show a clear trend. Steady-state crystallisation was demonstrated based on particle size distribution as well as supersaturation data after each crystalliser residence time and was achieved within 20 min after the system was conditioned with crystal slurry. Fouling and secondary Alpha nucleation was not a problem as long as the supersaturation did not exceed a level of 3.7 in the bulk solution.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available