Quantifying molecular interactions linking disordered and ordered phases to predict crystallisation

量化连接无序相和有序相的分子相互作用以预测结晶

• 批准号: EP/Z00005X/1
• 负责人: Katharina Edkins
• 金额: $ 275.22万
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FZ00005X%2F1
• 关键词: Quantifying; molecular; interactions; linking; disordered

Even though crystallisation is one of the most used unit processes in the chemical and pharmaceutical industries, it is still impossible to predict the crystallisation outcome without conducting an experiment. The current practice of crystallisation screening costs industry between 50K and 120K Euros per compound in time and manpower. Streamlining this approach with the help of computational crystal structure prediction is currently curbed by computing power and the missing link between the predicted structures and the experimental conditions needed to produce them. Current attempts to investigate solution-state aggregation and its influence on the crystallisation outcome show varying success, are isolated, and do not allow for investigation to yield generalised insights.The aim of this project is to elucidate the molecular interactions in pre-crystallisation states and to link these with crystallisation outcomes. Using a combination of spectroscopic and total scattering techniques, I will extract strength and structure of homomeric interactions from the single component phase (melt or glass), solute-solvent interactions from solution, and the impact of binary solvent microheterogeneity and solvent-solvent interface on aggregation insolution. This approach will yield the fundamental understanding to enable the prediction of the crystallisation behaviour of compounds not investigated in this study. In addition, I will translate this fundamental knowledge into scale bars of interaction strength and easy-to-use rules comparable to Lipinski's 'Rule of Five' or the Biopharmaceutical Classification System allowing the application of the fundamental insights of this project in the everyday work of crystallisation scientists. This will lead to a step-change in how the community approaches crystallisation and enable a tailored and controlled approach to replace the current brute-force screening.

尽管结晶是化学和制药行业最常用的单元过程之一，但如果不进行实验，仍然无法预测结晶结果。当前结晶筛选的做法在时间和人力方面每个化合物的行业成本为 5 万至 12 万欧元。目前，借助计算晶体结构预测来简化这种方法受到计算能力以及预测结构与产生结构所需的实验条件之间缺失的联系的限制。目前研究溶液态聚集及其对结晶结果的影响的尝试显示出不同的成功，并且是孤立的，并且不允许研究产生普遍的见解。该项目的目的是阐明预结晶状态和结晶状态下的分子相互作用。将这些与结晶结果联系起来。结合光谱和全散射技术，我将从单组分相（熔体或玻璃）中提取同聚相互作用的强度和结构，从溶液中提取溶质-溶剂相互作用，以及二元溶剂微观不均匀性和溶剂-溶剂界面对聚合解决方案。这种方法将产生基本的理解，从而能够预测本研究中未研究的化合物的结晶行为。此外，我将把这些基础知识转化为相互作用强度的比例尺和易于使用的规则，类似于利平斯基的“五规则”或生物制药分类系统，允许将该项目的基本见解应用到日常工作中结晶科学家。这将导致社区实现结晶的方式发生巨大变化，并实现定制和受控的方法来取代当前的强力筛选。