Thesis
Integrated lab-scale continuous manufacturing of pharmaceutical products
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2022
- Thesis identifier
- T16517
- Person Identifier (Local)
- 201351816
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Art relates to something to be done or produced by skill, whilst science must be known, discovered, or invented. Crystallisation is a purification and separation process with a long history, and it can be said often falls somewhere in the middle of the two. Research on crystallisation continues to move our understanding closer to that of science. However, crystallisation on the industrial scale is still partly an art, with experience and intuition commonly important in its successful daily operation. However, this leads to processes that are not repeatable, robust or predictable. Innovation in the pharmaceutical industry has focused for a long time to the research and development of new active compounds; meanwhile, production, dominated by batch-wise technologies, has only recently started to change. As has already been demonstrated in several other industrial sectors, continuous manufacturing (CM) has many advantages over batch processes. The faster, cheaper, and more flexible processes can be developed with a significantly higher level of quality assurance. The stirred tank reactor (STR) is still favoured as a straightforward manufacturing approach for mixing and reaction. The benefits of moving to continuous include; more efficient use of raw materials, minimisation of waste, improved yield, and improved process reliability, which may have otherwise been limited in a batch-type setup. Improved heat/mass transfer, reductions in energy consumption for running processes in addition to reactor downtime for maintenance and cleaning, more efficient use of physical plant space, a significant reduction in process development required for scale-up and better handling of hazardous materials, including dangerous and unstable intermediates. Chapters 1, 2 and 3 of this thesis detail an Introduction, literature review, aims and objectives of the research and the materials and methods used throughout this work, respectively. Chapter 4 focuses on the design, development and characterisation of the novel lab-scale continuous platform for better control over particle attributes. This research has developed a Cascade of Moving Baffle Oscillatory Crystalliser (CMBOC), which has a combination of moving baffles in vessels and continuous operation achieved through connecting sections in series, providing an alternative technology to the cascade of CSTR. Due to uniform oscillation provided over the whole vessel section, with no damping of oscillation caused by entrained bubbles, the CMBOC has the added benefits of uniform mixing, enhanced heat and mass transfer and is exceptionally flexible and so it is well suited for multistage processes. The platform was also characterised for mixing and flow with liquids and slurries, confirming excellent mixing performance for residence times in the range of 20–120 min. Heat transfer characteristics were determined and shown to be well suited to the demands of cooling crystallisation processes. Under this research, the platform was also tested for its suitability to perform continuous cooling crystallisation of alpha lactose monohydrate (ALM) and Paracetamol (PCM) running for more than ten residence times with both substances. Chapter 5 deals with optimising the continuous lactose crystallisation process in the CMBOC by developing a cooling crystallisation population balance equation model using a sequential parameter estimation approach using gPROMS Formulated Products modelling software. A set of experiments were performed in a batch crystalliser to estimate primary and secondary nucleation and crystal growth kinetics. These estimated parameters were utilised in designing a continuous crystallisation process (seeded and unseeded) aiming to dial a particle size. Predictions from the models were validated against the product collected from the continuous trial. Reasonably good agreements were obtained between the experimental measurements and model predictions within the defined model boundaries and uncertainties. Chapter 6 deals with implementing particle engineering methods via spherical agglomeration to control the final product attributes. Spherical agglomeration can simplify downstream processing dramatically and improve the handling of difficult, needle-shaped crystals. As this research progressed, it was identified that there was a gap in the method to produce smaller spherical agglomerates (<500 μm) with tuneable final product properties (dissolution rate, compressibility, flow property, porosity) suitable for direct compression.
- Advisor / supervisor
- Florence, Alastair
- Resource Type
- DOI
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