Abstract
The work presented in this thesis encompasses the crystallisation of multi-component crystalline systems, including co-crystals and salts, for solid form control, focusing on a transfer from batch to continuous crystallisation. The work forms part of the EPSRC funded Future Manufacturing Hub in Continuous Manufacturing and Advanced Crystallisation (CMAC).The opening chapters introduce the background to the project, including the broader context in which the project sits, with the move towards developing continuous crystallisation and manufacturing of pharmaceuticals. Accounts of the methodology used are given, including the importance of the solid-state, crystallisation methods, polymorphism and co-crystallisation and salt formation for multi-component molecular materials.
Chapters 4-5 introduce the primary model system under investigation, urea barbituric acid (UBA), and document the work conducted on the system to further understand the polymorphism of the co-crystal system, achieve selective control of production of two of the UBA polymorphs, including the metastable form III (the relative thermodynamic stabilities of forms I and III are established, through competitive slurrying experiments) and the access of a novel polymorphic form. Chapter 5 discusses the use of seeding in batch cooling crystallisation to allow for control over the resultant solid form as well as demonstrating the transfer of UBA crystallisation, to yield metastable form III, from batch to continuous. Two continuous crystallisation platforms, the Continuous Oscillatory Baffled Crystalliser (COBC) and the Kinetically Regulated Automated Input Crystalliser (KRAIC) are described and their use investigated.
Chapter 6 focuses on the crystallisation of two novel multi-component systems using the barbituric acid derivative thiobarbituric acid (TBA) as the target compound. These multi-component systems are shown to be salt systems, with hydrogen transfer occurring from the target molecule, TBA, to the counter-ion. Their crystallisation is shown to be transferable from evaporative to slurrying and cooling crystallisation techniques in batch. Chapter 6 also demonstrates the successful transfer of the crystallisation of these two salt systems from batch to continuous platforms, using both the COBC and KRAIC.
| Date of Award | 4 Dec 2019 |
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| Original language | English |
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| Supervisor | Paul Raithby (Supervisor) & Chick Wilson (Supervisor) |