Antisolvent crystallisation in oscillatory baffled platforms

  • Sebastion Davidson

Student thesis: Doctoral Thesis


Continuous manufacturing finds application in a variety of disciplines. It demonstrates a number of advantages, such as more controllable processes and allows particle attributes to be attained that would otherwise be unattainable. Antisolvent crystallisation is a widely used method of crystallisation in both academia and industry. It is employed to crystallise compounds that are not amenable to other techniques such as cooling crystallisation and can be utilised to produce crystal products with unique properties.;Oscillatory baffled crystallisers (OBCs) are platforms that generate intense mixing by the oscillatory motion of fluid through periodic constrictions, referred to as baffles. The oscillatory motion generates eddy currents through these baffles and induce highly turbulent and efficient mixing. By the superimposition of a net flow, the process can operate at near plug-flow conditions and is the principle of the continuous oscillatory baffled crystalliser (COBC). OBCs have been extensively studied for cooling crystallisations, but their application in antisolvent crystallisation has been limited.;The continuous antisolvent crystallisation of anthranilic acid in a COBC has been investigated for the first time as a function of antisolvent volume fraction and flow conditions, demonstrating the effects of a number of process variables on product outcomes. Metastable form II polymorph of anthranilic acid was consistently produced in a continuous unseeded antisolvent crystallisation from an ethanol and water solvent system.;The incorporation of process analytical technology (PAT) allowed for monitoring of various process conditions in real time, giving insight into the evolution of the antisolvent crystallisation process in continuous flow. Local mixing effects were deemed to be significant in the COBC at the point of contact of solution and antisolvent, such that variable flow rates at fixed antisolvent compositions resulted in different product sizes whilst resulting in the same final solution concentration.;Polymorph control in a moving baffle oscillatory baffled crystalliser (MBOBC) was demonstrated for the anthranilic acid system. By variation of seeding conditions and startup strategy, the continuous production of either stable form I or metastable form II polymorph could be controlled. This demonstrated a novel continuous nucleation platform for an antisolvent crystallisation process that could potentially be coupled with a COBC or other platform for reliable continuous production of a specified polymorph with targeted crystal attributes.;Growth and secondary nucleation kinetic parameters were determined by means of isothermal seeded batch experiments in a batch moving fluid oscillatory baffled crystalliser (MFOBC). Models were developed from these determined parameters, and further refined by the incorporation of a solvent factor that improved the fit of the model predictions to the experimentally measured attributes. The determined parameters were applied to the optimisation of a 30 m DN15 COBC with multiple antisolvent addition points and demonstrates the first such strategy utilising experimentally determined kinetic parameters.;This work has demonstrated novel approaches for the development of antisolvent crystallisation processes in continuous flow in oscillatory baffled crystallisers, detailing a number of control strategies and advancing the knowledge and understanding of such processes for future implementation.
Date of Award20 Mar 2020
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde
SupervisorAlastair Florence (Supervisor) & Joop Ter Horst (Supervisor)

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