Understanding, measurement and control of secondary nucleation

Student thesis: Doctoral Thesis


Secondary nucleation is widely present in crystallisation processes, and it is often relied upon to attain desirable critical quality attributes of crystalline products, such as polymorphic form and crystal size distribution. This is particularly the case in continuous crystallisation, where secondary nucleation can be crucial to achieve and maintain steady state operation, and by relying on secondary nuclei, the stochasticity and hence inherent lack of control in primary nucleation is avoided. However, fundamental understanding of secondary nucleation is limited and its quantification and scale up remains elusive. Solubility is the most important physical property in crystallisation as it is needed for the selection of the required supersaturation, the driving force for nucleation and growth. However, obtaining accurate solubility values, especially at higher concentrations and temperatures is not a simple task. A critical evaluation of three experimental techniques for determination of the solubility of glycine in water is presented, aiming to provide more accurate solubilities of ╬▒-glycine at elevated temperatures. A rapid, small-scale workflow was developed utilising agitated vials, combined with in-situ imaging for crystal counting and sizing. The induction time distributions, crystal size distributions and number densities are used to quantify primary and secondary nucleation and crystal growth kinetics of ╬▒glycine across a range of supersaturations in aqueous solutions under isothermal conditions. Both seeded and unseeded crystallisation experiments were conducted and a classification system for the crystallisation behaviour was presented. Using this approach some fundamental insights into relationships between crystal growth, primary and secondary nucleation behaviour have been extracted. A Couette flow cell was developed with in-line imaging enabling the quantification of nucleation and crystal growth kinetics under laminar fluid shear across a range of shear rates and supersaturations. The results indicated that laminar fluid shear alone can induce secondary nucleation at shear rates relevant for both laboratory and industrial scale stirred tanks. This work aims to improve the fundamental understanding and quantification of secondary nucleation and introduce new approaches to assess and quantify nucleation and growth kinetics using small amounts of materials. It is hoped that this will facilitate more efficient development, design, and optimisation of crystallisation processes.
Date of Award10 Oct 2022
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde & EPSRC (Engineering and Physical Sciences Research Council)
SupervisorJan Sefcik (Supervisor) & Mark Haw (Supervisor)

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