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

Lead Research Organisation: University of Leeds
Department Name: Chemical and Process Engineering


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.

Planned Impact



10 25 50
Description A new approach utilising a multi-scale and multi-technique approach to probing the structural progression of nucleation of an organic molecule from solution has been developed as part of the Critical Mass grant. This approach examined data regarding molecular, solution-state, cluster, solid-state and surface structures of an organic material to understand its nucleation and subsequent crystallisation parameters and how the various stages of this process are inter-related.
Molecular dynamics simulations were developed to identify the solvation free energies of single molecules and small clusters and the stability of nano-crystallites in solution in relation to their polymorphic form. These calculations revealed the propensity of water to attack key intermolecular interactions within the alpha PABA structure, hence promoting the crystallisation of the beta form in aqueous solution. Through a joint publication with Pfizer UK, the molecular modelling of crystal morphology and surface chemistry was enhanced to form the basis for the 'Particle Passport' idea. This entails characterising the bulk and surface intermolecular chemistry of a material through computationally efficient calculations, then relating these calculations to physical properties associated with the material. These calculations resulted in the understanding of how the differences in surface interfacial chemistry of two polymorphs of para amino benzoic acid result in the vastly different morphologies and crystal growth mechanisms. Further modelling work with Andreas Klamt and COSMOlogic provided a novel use of the COSMO-RS method to relate the stability of clusters in solution to the polymorphic form crystallised. These calculations resulted in the relation of the stability of small clusters of the alpha and beta polymorphic forms of PABA in a solvent to the polymorphic form crystallised from that solvent, hence enhancing the prediction of the polymorphic purity of a crystallisation process from solution.
The Critical Mass grant was also instrumental in the development of new methodology for the analysis of nucleation mechanisms and associated kinetic parameters. This new poly-thermal analysis method, developed with Dimo Kashchiev builds on previous work in the area of nucleation and allows additional parameters concerning nuclei and crystallite growth to be obtained. The poly-thermal method in combination with isothermal data collection has been shown to be a powerful tool in building an understanding of how a material nucleates from solution and what parameters drive this process. The Critical Mass grant was also responsible for the development of a number of solution-state structural analysis tools. These included a small angle scattering instrument for probing nano-scale structural parameters in solutions and also in-situ flow cells for scattering and diffraction experiments. The flow cells developed were used to analyse the kinetics of a polymorphic interconversion between the beta and alpha polymorphs of PABA. The results revealed that the transformation was a dissolution controlled process and extrapolation of the dissolution and growth rate constants revealed a transformation temperature of 21°C.
Further to this much work was focused on developing techniques and analysis associated with the crystal growth and morphology of organic materials. Through this work several optical microscopy cells were built at Leeds to allow the measurement of in-situ, temperature controlled, crystal growth rates in solution which resulted in the identification of the surface specific crystal growth rate mechanisms of several organic materials. Phase-contrast microscopy was also developed to improve the ability to measure how a crystal is growing in three dimensions. The 2D circular cell has been adapted for use by the University of Manchester and Pfizer UK.
Through the Critical Mass grant a number of collaborations were started between the crystallisation group at Leeds and the research groups at a number of world leading synchrotron sources. This included work at the Brazilian Synchrotron Light Laboratory in Campinas, Brazil, the National Synchrotron Light Source in the USA and BESY in Germany. These collaborations resulted in successful small angle scattering experiments and a resulting publication from the data gathered. This data revealed large disordered aggregations of PABA molecules even in the under saturated state and during cooling experiments into the meta-stable zone carboxylic acid dimer formation was favoured in solution. Further to this a number of scattering and diffraction experiments together with a novel method for characterising the surface chemistry of organic materials using ultra soft near edge X-ray absorption spectroscopy. The spectroscopy experiments allowed the orientation of molecules at different surfaces of organic crystals to be compared to bulk measurements using novel goniometric rotation measurements. In addition, for the first time, single crystals of organic materials were imaged using NEXAFS measurements. These techniques resulted in the identification of changes in the surface and bulk molecular structure of an organic crystal, suggesting that the instability of a surface can result in structural changes. These collaborations build upon a previous track record of successful work with leading synchrotron sources and paves the way for future research projects utilising the techniques used throughout this project.
Exploitation Route Understanding at the fundamental level of the early stages of crystal nucleation, provided by this integrated multi-scale and multi-technique, is important in all aspects of materials' preparation, purification and design not just in terms of the organic systems studied here but also much more widely. Potential application examples include: agrochemicals, energetic materials, fuel systems/flow, nuclear waste storage, pharmaceuticals and speciality fine chemicals.

Additionally, the development of novel crystallisation characterisation techniques, both in terms of computational modelling and advanced experimental approaches such as using synchrotron radiation, offer significant potential for wider applications. This related to not just crystallisation research but in other studies related to the processing of particulate materials in complex environments.
Sectors Aerospace, Defence and Marine,Agriculture, Food and Drink,Chemicals,Digital/Communication/Information Technologies (including Software),Education,Energy,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Transport

Description The Critical Mass project was focused on obtaining an improved understanding on the fundamental processes underpinning nucleation from the solution phase using a multi-technique and multi-scale approach through research encompassing both theoretical computational modelling and experimental approaches. Thus, its impact in the short term was largely felt within the academic sphere as evidenced through presentations to national conferences (ChemEngDay 2013, British Association of Crystal Growth, Leeds Crystallisation Centre) and international conferences (International School on Crystallisation: Drugs, Foods, Agrochemicals, Minerals & New Materials, 4th European Conference on Crystal Growth, 17th International Conference on Crystal Growth and Morphology, 7th International Conference on Advanced Materials, International Symposium on Pharmaceutical Solid State Research, Asian Crystallisation Technology Symposium, 11th Conference on the Crystal Growth of Organic Materials, BWIC Industrial Workshop on Crystallisation, 5th European Conference on Crystal Growth, Faraday Discussion 159, Crystallisation - A Biological Perspective) and publication in high impact scientific journals. In particular the critical mass project team organised and ran a landmark RSC Faraday Discussion 179, Nucleation: A Transition State to the Directed Assembly of Materials, at Leeds (30/3/15-1/4/15) through which the research developed was articulated and discussed. This meeting was heavily oversubscribed (ca. 150 delegates) and attracted a high number of discussion points. The project formed a key research programme for the EPSRC's Grand Challenge Network in Directed Assembly (EP/H035052/1 and EP/K014382/1, Roberts - Executive Board Member) and its outcomes were disseminated to members through the networks meetings, notably through the project's organisation of two grand challenge workshops. These were: Molecules make Crystals make Products (organised at Pfizer, Sandwich from16-17/2/11) and Crystallisability (organised at Syngenta, Jealott's Hill from 8-9/04/13). The key outputs of the project were articulated to early career researchers through an International Summer School (ca. 200 delegates) Engineering Crystallography: From Molecule to Crystal to Functional Form, organised at Erice, Italy (6-14/6/15). This was followed up by an open invitation end-of-project Town Meeting, Molecules, Clusters and Crystals, held at the Royal Society of Chemistry in London (14/10/15) where all the key outcomes were reviewed. Despite the fundamental nature of the project, it attracted significant industrial interest. The latter reflects the pivotal role that nucleation plays in the initial stages of supersaturation-directed molecular assembly processes associated with particle formation and as its directing role in facilitating solid-state form (polymorph), crystallinity and crystal size. Highly active interactions, in this latter respect, were maintained through the project's advisory board who interacted strongly with the project's researchers and investigators by reviewing reports and publications and through participating in the annual project meetings (Simon Black (AZ), David Bogg (STFC), Stephen Byard (ex Sanofi), Robert Docherty (Pfizer), Neil George (Syngenta), Joop ter Horst (University of Strathclyde), Ken Lewtas (Infineum), Sarah Nicholson (BMS), Martin Sweet (EPSRC), Ake Rasmuson (Limerick), Robert Willacy (GSK) and Grahame Woollam (Novartis). Transfer of the project's outcomes was further facilitated through additional PhD projects supported by industry, most notably Ana Kwokal (Pliva), Thai Thu Hien Nguyen (Pfizer), Diana Camacho Corzo (Infineum) and Xue Tang (Infineum). Several of these students did extended industrial visits at the companies to transfer the project's outcomes through into industrial process R&D work streams. The Leeds PI (Roberts) also served on the Science Advisory Boards for the EPSRC's CMAC Centre, NSF's ERC in Structured Organic Particulate Systems, SFI's Synthesis and Solid-State Pharmaceutical Cluster and Pfizer's Pharmaceutical Sciences Strategy. These provided opportunities for ensuring the Critical Mass project's wider impact both industrially and internationally as well as impacting on policy at the highest levels.
First Year Of Impact 2011
Sector Agriculture, Food and Drink,Chemicals,Digital/Communication/Information Technologies (including Software),Education,Energy,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Transport
Impact Types Societal,Economic,Policy & public services

Title Crystal morphology and interfacial stability of RS-Ibuprofen in relation to its molecular and synthonic structure dataset 
Description Raw data associated with the publication 'Crystal Morphology and Interfacial Stability of RS-Ibuprofen in Relation to Its Molecular and Synthonic Structure'. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Title Data associated with 'Influence of Solvent Composition on the Crystal Morphology and Structure of p-aminobenzoic acid crystallised from mixed ethanol and nitromethane solutions'. 
Description Raw data for the article 'Influence of Solvent Composition on the Crystal Morphology and Structure of p-aminobenzoic acid crystallised from mixed ethanol and nitromethane solutions' 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes