Towards Product Control by Design: Studies of the Nucleation and Crystal Growth of L-Histidine

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Aims:To determine, using the latest generation of experimental techniques, the structural basis for the nucleation and growth behaviour of L-histidine, specifically metastable zone, facet-specific interactions and surface-solvent interactions, and relate this to variations in the product properties. Objectives: Establish the molecular basis for nucleation and crystal growth of Form A from water and Form B by crystallisation in the presence of ethanol. Determine how solvent choice changes the polymorphic outcome Understand the effects of pH and the zwitterionic effect on polymorphism and morphology. Investigate the mechanistic basis for additive use (eg. amino acids and ionic species). Methodology Proposed for the Proposed Project:Studies will focus on the cooling and anti-solvent crystallisation of L-histidine from solution, in jacketed vessel reactors, and analysis of the crystallisation products. L-histidine was chosen because it is an industrially relevant product that is conformationally more complex than previously studies systems, but with individual functional groups for which previous studies have established deep molecular level understanding. It has been recognised for decades that our lack of understanding the molecular basis for nucleation and crystal growth processes is a fundamental obstacle to predictive design of crystallisation processes and tailoring of product properties. Current design and control methods are based on classical nucleation theory (CNT), which does not take account of the molecular structure of solutions and the role of interfacial processes at the molecular level. It is widely recognised that progress towards predictive design of processes and products relies on establishing the relevant molecular transformations taking place and development of alternative models to CNT. The new suite of X-ray techniques applied in this project establishes for a first time a realistic perspective to achieve this. The impact would be transformational, in both academic and industrial research. L-histidine is an essential amino acid used in a variety of industrial settings, such as pharmaceuticals, cosmetics, peptide therapeutics and as synthetic building blocks. Its crystal structure at microscopic level is fundamental to its industrial purpose, and fine-tuning crystallisation parameters can greatly affect characteristics of the final product, such as its longevity, stability, and how its morphology is optimised for purpose. A key feature in L-histidine's chemical structure is its imidazole side-chain, which is present in many industrial products such as fungicides, whilst also playing a crucial role in the binding of oxygen to haemoglobin in the bloodstream. As aromatic rings can play crucial roles in crystal formation and the intermolecular interactions that stabilise them, investigating the imidazole functionality as part of L-histidine can benefit research focussing on the fine structures of products containing imidazole functional groups as well as any imidazole-containing derivatives. In addition to established analytical techniques for monitoring crystallisations (FTIR, Raman, XRD, NMR, UV-vis, DSC, TGA, XCT, etc.) a recently established new suite of X-ray techniques sensitive to molecular structure will be applied to determine the dynamic structure changes in solution during crystallisation, and of the characterise interfaces in the obtained products crystallisation behaviour, both in-situ and for isolated crystals in the solid state. These include X-ray pair distribution functions (XPDFs) alanysed by empirical potential structure refinement (EPSR), phase contrast XCT, X-ray Raman Scattering (XRS), and near-ambient pressure (NAP) XPS. Surface and interface analysis will be performed with XPS, NEXAFS and ToF-SIMS.