Abstract
The PhD project has implemented flow crystallisation / self-assembly methods compatible with Diamond beamlines. Specifically, monitoring of continuous crystallisation processes by a range of synchrotron radiation techniques have been developed in a series of in situ experiments, using bespoke crystallisers optimised for operation on the beamlines at the Diamond Light Source (DLS).The technique of in situ X-ray diffraction (XRD) is applied to the continuous segmented flow crystallisation of highly polymorphic and pharmaceutically relevant model systems: Urea barbituric acid (UBA), carbamazepine (CBZ) and paracetamol (PCM). The cooling crystallisation processes yield crystalline powder and single crystals grown in situ within solution slugs in the flow crystallisation platforms KRAIC-D and KRAIC-S respectively. As a result of the steady-state operation employed in these crystallisers, events that evolve with time, such as polymorphic transitions and crystal growth, can be monitored. The KRAIC-D and KRAIC-S platforms were installed and data captured at the high-resolution powder diffraction beamline I11 and the small molecule single crystal beamline I19 respectively.
Chapter 1 contains a review of the literature of in situ XRD characterisation and flow crystallisation processes, which considers current limitations and opportunities for further investigation. The literature review provides context and builds towards the research project aims and objectives presented at the end of the first chapter. These objectives are targeted at the use of in situ XRD characterisation to provide additional insight to the pathway of crystallisation processes, which is unobtainable from offline analysis. In Chapter 2, the theory behind the analytical techniques used are described. In Chapter 3, the experimental methods implemented in this research project to achieve these research goals are reported.
Chapter 4 applies the synchrotron powder XRD technique at I11 in the study of the cooling crystallisation processes of UBA and CBZ in the KRAIC-D. In addition to unseeded crystallisations, investigation into the introduction of a controlled solid interface in the form of seeds of polymorphic purity introduced at pre-nucleation and post-nucleation stages is investigated. The use of integrated intensity values at various set-points along the length of the KRAIC-D provides an approach to investigate crystal growth. Engineering advances have been made to the KRAIC-D platform, allowing for optimisation to the crystallisation processes under investigation, as well as data capture capabilities. Significant advances to the data analysis of this in situ powder XRD data have been achieved. Chapter 5 applies the synchrotron single crystal XRD technique at I19 in the study of the cooling crystallisation of PCM in the KRAIC-S. Seeding of the metastable PCM form II is investigated. Data processing in CrysAlisPro investigated the degree of crystals rotation with respect to the instrument. Comparison of single crystals grown in situ with single crystals of known crystal size, facilitated crystal sizing predictions of single crystals within the KRAIC-S. An automated data processing strategy using DIALS has also been devised, which allows data processing to be triggered after data acquisition. Chapter 6 explores crystal engineering for materials discovery of the profen family; co-crystallisation is investigated as an approach to improve physicochemical properties of profen targets. In addition to the discovery of new profen co-crystals, the study looks at accessing the multi-component materials via a wide range of crystallisation methods, as well as encompassing structural characterisation and property determination. Chapter 7 investigates in situ XRD monitoring of the slurrying crystallisation process of the IBU-ISO co-crystal discovered by crystallisation in Chapter 6.
In Chapter 8, conclusions from the findings in Chapters 4 to 7 are pulled together and patterns explored. Drawing on these overall findings, some suggestions for future work are also made.
In addition to the academic discovery achieved in this work, this PhD project contributes to the vision of the EPSRC National Centre in Continuous Manufacturing and Advanced Crystallisation (CMAC) and the Diamond Light Source. CMAC is an academic-industrial consortium, aimed at advancing the adoption of continuous manufacturing into the pharmaceutical industry. Diamond Light Source is the UK’s national synchrotron science facility, which allows scientific research advances to be made, which extend beyond the capabilities of standard laboratory facilities. The significant synchrotron component of this project, which has advanced previous data collection and processing capabilities, provides a demonstration and offers additional potential to the beamtime experiments that can be investigated by synchrotron users in the future. Furthermore, the KRAIC-D and KRAIC-S crystallisation platforms developed in this PhD project can be used by Diamond users in the future; the principles of which are currently being translated to a laboratory based X-ray facility.
| Date of Award | 16 Sept 2020 |
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| Original language | English |
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| Supervisor | Chick Wilson (Supervisor), Karen Robertson (Supervisor) & Paul Raithby (Supervisor) |