Synchrotron Radiation X-ray Imaging of Organic Particulate Products and Their Crystallisation

Continuous flow crystallisations have been of particular interest across chemical and pharmaceutical industry sectors because of their potential to overcome many constraints, e.g., in scale-up (or scale-down), choice of crystallisation conditions, innovation cost barriers or batch-to-batch product variations. Moreover, continuous crystallisation of organic compounds from solution is of high industrial interest as it is more flexible and less expensive.
However, a successful use of continuous crystallisation requires a deeper understanding of all crystallisation processes because crystallisation is a very complex dynamic phenomenon. Understanding nucleation is imperative for achieving control over materials and optimising manufacturing processes to result in the desired material. Therefore, it is important to have good insight into the mechanistic details to produce predictive modelling of crystallisation processes.
A programme of X-ray imaging work has been carried out to gain insight into the molecular and mesoscopic processes occurring in the early stages of crystallisation under flow conditions. X-ray Phase-Contrast Imaging (XPCI) reveals the structure dynamics in organic crystallisation processes by providing real-time spatiotemporal resolution of mixing, supersaturation, nucleation and crystal growth zones. This thesis demonstrates how XPCI can be used to study such systems and how it can be applied to investigate other organic particulate products and their crystallisation in industries.
In this thesis, two anti-solvent crystallisation systems were studied, namely glycine and lovastatin. 2D XPCI of glycine system has revealed the size and shape of the concentric mixing flow cone. The results clearly indicate that additional heterogeneous nucleation and growth of crystals take place at the mouth of the inner tube feeding the solution, raising the possibility that seeding and secondary nucleation may take place downstream. In contrast, lovastatin system studies showed microscopic phase behaviour in the metastable zone that reveals a complex interplay between initial mixing, liquid-liquid phase transitions as well as heterogeneous and homogeneous nucleation processes. A new phase has been observed, which interacts strongly with the reactor walls by forming a heterogeneous thin film near the mixing zone, from which crystallisation of the final needle-shaped crystals takes place.
3D XPCI of an organic particulate product provided a visual understanding of the potential cause of bulk powder caking. XPCI indicated that elevated temperature and humidity leads to caking through a transient mobile phase, which forms interparticle bridges that crystallise and form a hard bulk material.
Lastly, additional studies with different X-ray Imaging modalities were successfully employed in this thesis for imaging and providing visual understanding of (i) processes taking place in in situ anti-solvent crystallisation; (ii) processes taking place during filtration and isolation; (iii) extrudates produced by hot melt extrusion.
The novel experimental results reported in this thesis are of significant practical importance for continuous-mode operation in chemical and pharmaceutical manufacturing. The positive outcome of this work confirms that XPCI is a powerful and versatile X-ray imaging technique that can be used to investigate and visualise diverse processes taking place in complex, dynamical systems encountered in studying organic particulates and their crystallisation.