Accelerating, characterising and controlling nucleation processes

Unwanted nucleation poses a technological problem in a number of particle processing industries, encompassing fuels, agrochemicals, pharmaceuticals, foods, etc. In this, formulated products can undergo unwanted nucleation events over a vast range of time scales, from seconds to years, however, there is currently an inability to predict when these events might occur and a lack of fundamental understanding of how to prevent these events from taking place, either entirely or by suppressing nucleation outside of storage/operational conditions. Therefore, it is necessary to develop a route to predicting when these events might take place over long time scales and also develop better understanding of how formulation conditions and nucleation inhibition additives can affect the complex processes involved in crystal nucleation from solution environments. These developments are the focus of the research presented within this thesis, which utilises both aqueous and non-aqueous crystallising systems to advance the understanding of how to accelerate, control and characterise nucleation process within solutions with a view to predicting and inhibiting unwanted nucleation events.

An accelerated nucleation method, termed Isothermal by Design (IbD), is developed, which enables the rate of nucleation within solutions to be accelerated by rapidly generating high levels of solution supersaturation. Through this, induction times to nucleation are reduced by 5 orders of magnitude for p-aminobenzoic acid crystallising from mixed ethanol/water solutions and key nucleation kinetic parameters are derived over a wide range of supersaturations. A comparison of IbD with a conventional nucleation kinetic analysis route demonstrates the effectiveness of IbD for generating nucleation kinetic data both at low and high supersaturations and provides insight into the behaviour of nucleation in mixed-solvent systems.

An investigation focussing on the influence of solution chemistry on the nucleation process in mixed-solvent systems builds upon these insights and is presented for the system of eicosane crystallising from mixed toluene/acetone solutions. In this, mixed-solvent solution composition is found to be responsible for concurrent trends in the crystallisability, solution thermodynamics and nucleation mechanism over the full range of compositions studied. Grid-based molecular modelling provides molecular-scale insight into the solution structure, suggestive that the high solubility solvent, toluene, dominates the local solvation environment but, as the proportion of acetone increases, a ‘cage’ structure constituting a secondary solvation shell forms, drawing away solvation power towards eicosane, until a critical acetone composition is reached that overcomes this behaviour.

Two types of nucleation inhibition additives are investigated to provide insight into the ability of tailor-made additives and polymeric based additives to disrupt nucleation within solution environments. A workflow is developed to aid in both the understanding and designing of tailor-made additives for nucleation inhibition through a combination of grid-based molecular modelling and experimental techniques. Knowledge of the key intermolecular interactions (synthons) of the crystallising compound is key and is utilised as a foundation in the determination of three effective tailor-made additives from a screen of seven potentially effective ones, corroborated by experimental results.

The impact of a commercially available polymeric based cold-flow improver additive on the nucleation of eicosane from toluene solutions is presented, introducing a developed characterisation procedure for assessing nucleation kinetics from additive systems undergoing phase separations. Insight is gained into the nucleation mechanism and kinetic effects of different additive concentrations (treat rates) as well as fundamental understanding of the inhibition effect.

Conclusions are drawn from these studies and an assessment as to the success of meeting aims and objectives set out as part of this doctoral research is made, with suggested future work that could continue from the foundations built by this research study described.