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Investigating approaches to continuous crystallisation using process-analytical technology: establishment of a steady-state cooling crystallisation process

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posted on 28.01.2019, 10:27 by Ikechukwu I. Onyemelukwe
In this work, two approaches to continuous crystallisation are investigated. The first approach is the mesoscale continuous oscillatory flow crystalliser which possesses a smooth periodic constriction design (herein known as the SPC mesoscale crystalliser) and is a tubular device operating at turbulent flow conditions. The second of these approaches is the popular mixed suspension mixed product removal (MSMPR) crystalliser based on stirred tank technology. The investigation of both approaches is aided by integrated process analytical technology (PAT), newly developed characterisation methods, and offline solid-state analytical tools. The SPC mesoscale crystalliser is a type of continuous oscillatory baffled crystalliser (COBC), which unlike the plug flow crystalliser (PFC), decouples mixing from net flow by combining oscillatory flow with steady flow. This enables significantly longer residence times to be achieved in practical lengths of the crystalliser for crystallisation purposes. In the past few years, COBCs have gained increasing attention as promising platforms for developing robust continuous crystallisation processes and transforming already existing commercial batch processes in industry. This small-diameter SPC mesoscale crystalliser, however, has had very little application to crystallisation despite possessing superior capabilities for efficient mixing and solids suspension, and small volume requirements for process development. The MSMPR crystalliser is an idealised crystalliser model that assumes steady-state operation of a well-mixed suspension with no product classification, and uniform supersaturation throughout, leading to constant nucleation and growth rates. The investigation of both approaches in this work involves the characterisation of the mixing and heat transfer performance, and the development of processes for the continuous cooling crystallisation of glycine (GLY) from water in both platforms. A characterisation of the mixing performance of the SPC mesoscale crystalliser is performed using a newly developed RTD measurement technique. The technique known as non-invasive dual backlit imaging involves the use of two high-definition (HD) cameras and light sources to simultaneously and precisely capture the concentration of a tracer in the crystalliser as a function of grayscale intensity. The new technique is benchmarked against the more traditional invasive conductivity measurements to determine the reliability of both techniques. Using the dual backlit imaging technique, the liquid and solid phase axial dispersion performance the SPC mesoscale crystalliser is determined, and the optimum conditions for solid-liquid plug flow are identified for crystallisation. A series of heat transfer experiments are performed to characterise the heat transfer performance of the SPC mesoscale crystalliser and its suitability for tight control of temperature and local supersaturation. Based on these experiments, an empirical correlation is developed to predict the tube-side Nusselt number and enable spatial temperature profile predictions in the SPC mesoscale crystalliser for cooling crystallisation. A seeded continuous cooling crystallisation process is then carried out based on metastable zone width (MSZW) measurements in a batch version of the SPC mesoscale crystalliser. A rapid intermittent vacuum transfer technique is applied to the single- and two-stage configurations of the MSMPR crystalliser to successfully mitigate transfer line blockage issues and obtain uninterrupted steady-state operation. The RTD performance of the MSMPR crystalliser is characterised and benchmarked against the SPC mesoscale crystalliser, confirming the contrasting RTD profiles offered by each platform. Solid suspension performance and determination of critical residence time for heat transfer is also carried out for the MSMPR platform to aid crystallisation process development. Subsequently, using a complete recycle operation, the unseeded cooling crystallisation of GLY from water is investigated systematically to understand the effect of mean residence time, MSMPR operating temperature, and number of MSMPR stages on the GLY product mean size, crystal size distribution (CSD), and yield. The systematic study of GLY-water seeded continuous cooling crystallisation in the SPC mesoscale crystalliser identified an operating strategy for obtaining desired product attributes. Specifically, seeding with small-sized seeds, running at longer mean residence times (by extending the crystalliser length), operating at near plug flow conditions, and implementing a spatial cubic temperature profile will lead to larger product mean sizes, with narrower CSDs, and higher yields. In the MSMPR crystalliser, experimental investigations showcased the higher degree of operational capability offered by cascade operation, whereby a two-stage MSMPR configuration enabled operation at much lower MSMPR temperature than possible in the single-stage MSMPR and provided higher yield. Results particularly highlighted the importance of controlling supersaturation distribution in the MSMPR system by manipulating operating variables such as mean residence time and MSMPR stage temperatures to achieve desired product quality. Overall, the investigations carried out in this body of work demonstrate the potential of the SPC mesoscale crystalliser for application to continuous crystallisation process development of small-volume active pharmaceutical ingredients (APIs). Both platforms are therefore equally feasible for process development and manufacturing.


EPSRC, Centre for Innovative Manufacturing for Continuous Manufacturing and Crystallisation (EP/I033459/1); Doctoral Training Centre in Continuous Manufacturing and Crystallisation (EP/K503289/1).



  • Aeronautical, Automotive, Chemical and Materials Engineering


  • Chemical Engineering


© Ikechukwu Ifeanyi Onyemelukwe

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A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.