Molecules, Clusters and Crystals: A Multi-Scale Approach to Understanding Kinetic Pathways in Crystal Nucleation from Solution

The process of crystal nucleation from solution requires, as its initial stage, separation of solute and solvent molecules and simultaneous formation of molecular clusters in order to create a new, nano scale, phase which can subsequently grow to become a crystal. Elucidating the fundamental physics and chemistry that govern the structure of this nucleation transition state remains one of the truly unresolved 'grand challenges' of the physical sciences. Individual nucleation events are localised in space but rather infrequent on the time-scale of a molecular vibration making both experimental detection and molecular modelling of the process difficult. In addition to this, available experimental techniques provide data averaged over both time and space so that extracting insights into the nucleation process may only be achieved through a combination of experiment and modelling. We propose a novel approach to this problem in which we scrutinise the crystallisation of two related molecular systems in hitherto unprecedented depth, building on established state-of-the-art experimental and computational techniques, but combining these, for the first time, with in situ synchrotron radiation (SR) X-ray scattering and spectroscopy methodologies capable of probing long range and local electronic and geometric structure at molecular resolution. Our hypothesis is that, by utilising appropriate experimental conditions, applying these state of the art time resolved scattering and spectroscopic techniques and building cluster models that are consistent with macroscopic features of the systems studied (crystal morphology, polymorphic form, solution chemistry, crystal growth rates), we can deduce a structural model of a nucleation event from the change in averaged solution structure as a function of increasing solution supersaturation and time. We thus expect incisive structural information for every step of the nucleation process: measured molecular scale properties can be used to confront computational predictions at molecular, supra-molecular and solid-state levels, so that the structural and size parameters for the nucleation pathway are revealed. A step change in our understanding of this area of science is thus expected.

This process of nucleation underpins and directs the creation and resultant forms of crystalline solids and is hence of great importance across a range of disciplines (chemistry, physics, biology, materials science and chemical engineering) and technologies (polymers, pigments, electronics, construction, pharmaceuticals, food/confectionery, petrochemicals, agrochemicals). To give some perspective to this, the worldwide pharmaceutical and specialty chemicals sector prepares 90% of its active materials as crystalline molecular solids and is worth ca. 400 billion pounds p.a. This proposal has been conceived from the perspective that it addresses this basic scientific challenge. The beneficiaries will thus be the academic community and the materials producing commercial sector defined as above in the broadest sense. For academics the impact will be felt in terms of a new experimental focus to study molecular association using in situ SR based spectroscopic probes; a new computational framework for elucidating experimental data; a new holistic framework for thinking and studying problems of crystal nucleation. For the industrial sector, companies are often involved in development, production and formulation activities, so the direct technological impact of this work will be felt by both chemical development and product formulation teams; hence by both scientists and engineers. In multinational companies there often already exist teams of scientists who have special operating remits that directly map onto the scope of this project - so called 'crystallisation scientists'. Technologists working in this area meet a wide range of crystallisation related challenges from the development of processes designed to deliver particular crystal structures (polymorphs), salts or co-crystals to the creation of formulations that require solid forms with optimal activity, stability and processability. The discovery and development of increasingly complex and larger molecular entities poses additional, serious issues of poorly-defined amorphous solids and failure to crystallise that have not often been previously encountered in the industry. These workers will be major beneficiaries in having access to fundamental underpinning science that does not presently exist. As business models in this industry sector change there is likely to be an increasing emphasis on getting the best out of existing molecules, through formulation, as well as applying new science-led capabilities to the rapid and higher quality development of new chemical entities. This will accentuate the added value to companies of enhanced knowledge and understanding in the field of crystallisation. One specific legacy of this project for UK research will be the knowledge transfer in liquid state soft X-ray spectroscopy. These spectroscopies now have very-high-profile impact not only in the Physical Sciences and Engineering but also in the Life Sciences, for example by providing new avenues for studying protein function. This project provides an opportunity for the UK to re-establish itself at the forefront of modern experimental soft matter research with synchrotron radiation. Other beneficiaries will be the students and scientists involved in the project. Many of the scientists now occupying positions as crystallisation experts in UK companies were trained in the Leeds and Manchester Groups and this joint project will extend the people pipeline and provide a new group of PhD graduates with advanced training and skills and hence the potential to make career moves into commercial research. We also note that by embracing the next generation of academics (Hammond, Lai, Schroeder) this project also contributes to the continuity of crystallisation research in the UK.