Thesis
A nonlocal thermodynamic framework for mass transfer and phase separation in antisolvent crystallisation
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2026
- Thesis identifier
- T18179
- Person Identifier (Local)
- 202182596
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- A central challenge in pharmaceutical manufacturing is the reliable prediction of when and where crystallisation will occur, as this governs product quality, yield, and process robustness. In antisolvent crystallisation, supersaturation is generated by mixing a solvent–API solution with an antisolvent in which the API has low solubility. Despite its widespread use, antisolvent crystallisation remains difficult to control, often leading to unwanted outcomes such as unexpected crystal forms or liquid–liquid phase separation. This stems from the complex, multiscale nature of the process. At the scales relevant to crystal nucleation, mass transfer is dominated by diffusion, and mixing creates localised composition inhomogeneities that result in regions of high supersaturation. Accurately describing diffusion is therefore critical, as oversimplified models can lead to erroneous conclusions about the onset of supersaturation and nucleation. Traditionally, diffusion has been modelled using Fick’s law, which assumes concentration gradients as the driving force. Yet observations such as uphill diffusion and oiling out demonstrate its limitations in highly non-ideal antisolvent systems. Recent studies have shown that the Maxwell–Stefan framework, which formulates diffusion in terms of chemical potential gradients, provides a more appropriate description. The key challenge now lies in accurately formulating the chemical potential. This work incorporates a nonlocal contribution rooted in the Cahn–Hilliard formulation, which accounts for the free energy cost of composition inhomogeneities and, thus, interfaces. This term enables the modelling of liquid–liquid phase separation and provides a more physically consistent description of diffusion, improving predictions of where and when supersaturation and nucleation are likely to occur. By highlighting the importance of interfacial effects in diffusion, this work provides a powerful framework for understanding supersaturation profiles in antisolvent crystallisation and controlling or avoiding phase separation phenomena such as oiling out. The study systematically examines non-ideality and interfacial contributions in binary and ternary systems, and develops an experimental methodology based on Raman microscopy to obtain composition mixing maps for future model validation.
- Advisor / supervisor
- Cardona, Javier
- Lue, Leo
- Resource Type
- DOI
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