Thesis
Analysis of nucleation kinetics in pH-shift crystallization using agitated and microfluidic systems
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2024
- Thesis identifier
- T16814
- Person Identifier (Local)
- 201969285
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Crystal nucleation is a key event in the process of crystallization and is important in a number of processes in the pharmaceutical industry. Nucleation kinetics impact the crystal quality attributes of the product of a crystallization process. For example, increased crystal nucleation rate can lead to a smaller particle size distribution or increase the likelihood of presence of impurities or inclusions. A greater understanding of the fundamental principles underlying crystal nucleation allows for the development of better processes and tools for controlling this important element of crystallization. The aim of this work was to study nucleation kinetics in pH-shift crystallization of the amino acid DL-phenylalanine (a model compound) through data generated from isothermal induction time experiments in small scale agitated vials and in a novel microfluidic device. The objectives were to gain a detailed understanding of the model system, to accurately determine solubility and supersaturation, collect nucleation rate data in the model system using an established methodology based on the Crystal16 multiple reactor system, develop a novel microfluidic device for collecting nucleation rate data and finally, to compare the nucleation rate data collected from the established and novel techniques. In order to work in this complex system, a model was developed using MATLAB for predicting the pH and supersaturation from the solution composition and the dissociation constants for each component and applying the Davies extension of Debye-Huckel theory. This model was vital for designing experiments as it was not always possible to directly measure solution pH. Nucleation rates were estimated by fitting induction time data collected isothermally, under relevant conditions, to a cumulative probability distribution. A microfluidic device was developed as a tool for induction time determination in a pHshift crystallization system. The nucleation rates determined with this new technique were compared with data collected through a previously established methodology utilizing the Crystal 16 multiple reactor system. We report that nucleation in the microfluidic system behaves in a similar manner to other non-agitated systems with different regimes of nucleation kinetics: a nonnucleating regime, a slowly nucleating regime and a fast nucleating regime. As such, this type of data is best fitted to a double exponential curve. This behaviour is not yet fully understood, as agitated systems generally show a single nucleation regime, where induction time data can be fitted by a simple exponential curve. Therefore, it is not straightforward to directly compare nucleation rate obtained under agitated and non-agitated conditions. The microfluidic device presented can be used for non-agitated nucleation rate studies, however, further refinement of the design could improve control of crystallization conditions and extend its operational capacity and range.
- Advisor / supervisor
- ter Horst, Joop H.
- Šefčik, Jan
- Zagnoni, Michele
- Resource Type
- DOI
- Date Created
- 2023
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PDF of thesis T16814 | 2024-01-31 | 公开 | 下载 |