In situ characterisation of batch and continuous crystallisations

Crystallisations are a ubiquitous class of phase-change processes and have an
importance that spans industrial and natural processes. Being able to control and
understand crystallisation processes is vital for the acquisition of desired properties
for high added-value particulate products. X-ray diffraction (XRD) techniques remain
the gold-standard method of determining crystal structure, which is intricately
connected to the resultant crystal properties. Determining structure (and therefore
properties) during the crystallisation process has traditionally been performed by
taking samples of crystals and determining structure ex situ, which is slow and may
induce inaccuracies. In situ application of XRD has, in recent years, shown promise
for accurate, real-time characterisation of crystallisation processes in batch and
continuous-flow devices, although this has largely been carried out using synchrotron
sources. It is only recently that the next-generation of laboratory-based XRD
instruments has facilitated these capabilities previously constrained to the beamline.
This report presents first a detailed literature review, covering crystallisations, the
concepts underpinning continuous-flow operation and synthesis, and the scientific
theory of XRD. Next, a detailed study of the crystallisation of calcium sulfate in a batch
reaction vessel coupled with in situ laboratory-based XRD characterisation is reported
across different operating conditions. This allowed for a probing of the effects of
reactant concentrations, additives, and solvent selection on the crystallisation kinetics
and structural outcomes. Subsequently reported is the use of a millifluidic device,
which is studied as a continuous crystallisation platform. This was coupled with the
XRD instrument to enable steady-state characterisation, representing a first-of-itskind combined crystallisation and characterisation platform. Experiments from the
batch crystallisation study were replicated on this continuous-flow platform, which
showed utility. Finally, a study of the antisolvent crystallisation of a small organic
molecule in the same continuous crystallisation platform is reported, which showed
the flexibility of the platform across crystallisation systems. Overall, the project marks
a significant step towards demonstrating the application and utility of in situ
characterisation of crystallisations with a laboratory X-Ray diffraction instrument, in
both batch-mode and continuous-flow.