Exploring crystal growth and dissolution at the nanoscale: Implications for Industrial-Scale Crystallisation

The aim of this proposal is to utilise the technique of atomic force microscopy (AFM) to explore pharmaceutically active small molecule crystal growth and dissolution at the nanoscale. Crystal growth, from nucleation to extended structure, and dissolution are critical aspects for a number of manufacturing industries including pharmaceutical, agrochemical and electronic. However, not only is there little understanding of reported nanoscale phenomena in crystal growth and dissolution (e.g. the formation of nanoscale triangular pits in paracetamol crystal dissolution), there is little understanding of how excipients influence crystal growth and dissolution at the nanoscale (substrates/supports can also influence crystal growth) and limited understanding of how crystal physicochemical properties influence nanoscale growth/dissolution phenomena.

AFM is a microscopy technique that relies on Newtonian mechanics rather than photonics to image objects across the nanometre to micrometre scale. As AFM relies on force interactions it can also be used to measure picoNewton to nanoNewton forces between objects. Furthermore functionalising the AFM probe with either small or macro- molecules allows forces of interaction between said molecules and materials or other molecules to be determined (chemical force microscopy - CFM). AFM can therefore image nanoscale topographies and obtain nanomechanical properties.

The project will be divided into three key incremental stages: 1) Dissolution studies – the initial stage of this proposal will be to observe in-situ crystal dissolution and explore the changes in nanomechanical properties with crystal dissolution. Correlations will be explored between crystal packing (determined by XRD), nanomechanical properties and nanoscale topographic changes; 2) Growth studies – crystal growth will be observed in-situ (particularly for the occurrence of secondary nucleation – where new crystal growth begins on a growing crystal) and changes in nanomechanical properties will be analysed. Following this objective, excipients will be added to the solution, crystal growth imaged and nanomechanical properties measured in-situ. Correlations will be explored between crystal packing (determined by XRD), excipient chemistry, crystal nanomechanical properties and crystal nanoscale topographic changes; 3) Manufacturing implications – the final stage is to develop models of understanding that correlate crystal nanoscale topography and nanomechanical properties to industrial processes (e.g. if nanoscale property x is seen then the crystal will behave as y). This is envisaged to be the most complicated aspect of the project, particularly the translation of nanomechanical properties to observed industrial aspects, for example, specific nanoscale topographic phenomenon on a crystal face grown under certain conditions (e.g. spiral inclusions, triangular defects etc.) would indicate a faster rate of dissolution.

Techniques to be used: AFM, XRD, crystallisation, chemical reactors