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

目的：使用最新一代的实验技术确定L-组氨酸成核和生长行为的结构基础，特别是亚稳区、特定面相互作用和表面-溶剂相互作用，并将其与产品性质的变化联系起来。目的：建立在乙醇存在下通过结晶从水中生成晶型A和晶型B的成核和晶体生长的分子基础。确定溶剂选择如何改变多晶型结果了解pH值和两性离子效应对多晶型和形态的影响。调查添加剂使用的机械基础（例如，氨基酸和离子种类）。拟议项目的拟议方法：研究将集中在夹套容器反应器中L-组氨酸从溶液中的冷却和抗溶剂结晶，以及结晶产物的分析。选择L-组氨酸是因为它是一种工业相关产品，其构象比先前研究的系统更复杂，但具有先前研究已建立深入分子水平理解的单个官能团。 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理解，这是结晶过程的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是基于经典的成核理论（CNT），它不考虑的分子结构的解决方案和界面过程中的作用在分子水平上。人们普遍认识到，工艺和产品的预测性设计的进展依赖于建立发生的相关分子转化和CNT替代模型的开发。该项目中应用的新的X射线技术套件首次建立了实现这一目标的现实视角。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，如制药，化妆品，肽治疗和合成积木。其在微观水平上的晶体结构对其工业用途至关重要，微调结晶参数可以极大地影响最终产品的特性，例如其寿命，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，它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起着至关重要的作用。由于芳环在晶体形成和稳定它们的分子间相互作用中起着至关重要的作用，因此研究咪唑作为L-组氨酸的一部分的功能性可以使研究集中在含有咪唑官能团的产品以及任何含有咪唑的衍生物的精细结构上。除了已建立的用于监测结晶的分析技术（FTIR、拉曼、XRD、NMR、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射线技术将被应用于确定结晶过程中溶液中的动态结构变化，以及所获得的产物结晶行为中的结晶界面的动态结构变化，包括原位和固态的孤立晶体。这些包括X射线对分布函数（XPDF），其通过经验势结构细化（EPSR）、相衬XCT、X射线拉曼散射（XRS）和近环境压力（NAP）XPS进行分析。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.