Continuous crystallisation offers a number of benefits over traditional batch processing including reduced variability and consistent quality. This is of particular importance in pharmaceutical manufacturing where ensuring safety, efficacy and quality is essential. The motivation for this work has been to develop a novel meso-scale (internal diameter 10 mm) Continuous Oscillatory Baffled Reactor (COBR) and develop processes that can easily control polymorphic form. Alpha lipoic acid (ALA) is a poorly water soluble compound with challenging physical and chemical properties and is used as a model active pharmaceutical ingredient (API).Chapters 1, 2 and 3 of this thesis details a literature review, overall aims and objectives of the project and the materials and methods used throughout this work, respectively. Chapter 4 focuses on developing a novel crystal engineering approach to produce the metastable form, form II, of ALA. This was achieved using nicotinamide (NIC) as a solution phase additive. NIC is a widely investigated co-crystal former that is also a hydrotrope. Hydrotropic solubilisation of ALA and the impact on polymorphic outcome with respect to hydrotrope concentration has been investigated. The crystal structure of the new metastable form, ALA II, has been determined and the process conditions for achieving this form defined.To gain further insight into the crystallisation of ALA II, the process was scaled up to 1 L in a Stirred Tank Reactor (STR) using Process Analytical Technologies (PAT) (Chapter 5). FBRM enables onset of nucleation and growth of ALA crystals to be studied. The crystallisation of ALA II in the required concentration ranges was shown to be influenced by temperature and cooling rate. Evidence of solution-mediated phase transformation after 12 hours was obtained. The results suggested that continuous crystallisation could offer some opportunities to achieve dynamic control over polymorphic form that would be harder to achieve in batch. This was examined in detail (Chapter 6) which describes the design, development and characterisation of a meso scale COBR.;Residence time distribution (RTD) studies at a variety of mixing conditions were completed and a model predictive temperature control system developed. The novel 10 mm ID platform established can deliver near plug flow operation with accurate temperature control, well suited to control of crystallisation processes.In Chapter 7 the development of a continuous crystallisation process for ALA polymorphs is described. The small scale batch crystallisation conditions investigated in Chapters 4 and 5 were converted into an unseeded cooling CC process. The polymorphic form of ALA was controlled by exploiting the hydrotropic effect of NIC and the ability to rapidly change process conditions in a continuous environment.
|Date of Award||8 Jan 2019|
- University Of Strathclyde
|Sponsors||EPSRC (Engineering and Physical Sciences Research Council)|
|Supervisor||Alastair Florence (Supervisor) & Iain Oswald (Supervisor)|