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

目的：利用最新一代的实验技术，确定L-组氨酸的成核和生长行为的结构基础，特别是亚稳区、小面特定的相互作用和表面-溶剂相互作用，并将其与产品性质的变化联系起来。目的：建立A型在水中成核和晶体生长的分子基础，以及在乙醇存在下结晶形成B型。确定溶剂选择如何改变多态结果，了解pH和两性离子效应对多态和形态的影响。研究添加剂使用的机理基础(例如，氨基酸和离子物种)。拟议项目的方法建议：研究的重点将是L-组氨酸在夹套容器反应器中从溶液中冷却和抗溶剂结晶，以及结晶产物的分析。之所以选择L组氨酸，是因为它是一种与工业相关的产物，在构象上比以前研究的系统更复杂，但具有单个官能团，以前的研究已经对其建立了深入的分子水平了解。几十年来，人们已经认识到，我们缺乏对成核和晶体生长过程的分子基础的了解，这是结晶过程预测设计和产品性能定制的根本障碍。目前的设计和控制方法都是基于经典成核理论，该理论没有在分子水平上考虑溶液的分子结构和界面过程的作用。人们普遍认识到，在工艺和产品的预测性设计方面的进展取决于确定正在发生的相关分子转化和开发替代碳纳米管的模型。该项目中应用的一套新的X射线技术首次为实现这一目标建立了一个现实的视角。无论是在学术研究还是工业研究方面，其影响都将是变革性的。L组氨酸是一种必需的氨基酸，用于各种工业环境，如药品、化妆品、肽疗法和合成积木。其微观上的晶体结构是其工业用途的基础，微调结晶参数可以极大地影响最终产品的特性，如其寿命、稳定性以及如何优化其形态。L组氨酸化学结构的一个关键特征是其咪唑侧链，该侧链存在于许多工业产品中，如杀菌剂，同时在血液中氧与血红蛋白的结合中也发挥着关键作用。由于芳环可以在晶体形成和稳定它们的分子间相互作用中发挥关键作用，作为L组氨酸一部分的咪唑官能团的研究将有助于集中研究含咪唑官能团的产品以及任何含咪唑的衍生物的精细结构。除了已建立的用于监测结晶的分析技术(FTIR、拉曼、X射线衍射仪、核磁共振、UV-VIS、DSC、TGA、XCT等)外，最近建立的一套对分子结构敏感的新的X射线技术将被用于确定结晶过程中溶液的动态结构变化，以及所获得的产品的结晶行为的特征界面，包括原位结晶行为和孤立固态晶体的结晶行为。这些方法包括经验势结构修正(EPSR)分析的X射线对分布函数(XPDF)、相衬XCT、X射线拉曼散射(XRS)和近环境压力(NAP)XPS。将使用XPS、NEXAFS和ToF-SIMS进行表面和界面分析。

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.