Discovery and Applications of Novel Solid-State Structures: Water Bridges Salt Forms

该项目旨在提高我们识别和利用晶体水合盐形态的能力，这些晶体水合盐形态是一种独特的固态排列，被称为“水桥”。目前，我们的产品组合中有两种盐形式的活性分子，预计这两种形式的活性分子在片剂配方中不成比例，但显示出出人意料的固态和溶液稳定性。林恩·泰勒教授和辉瑞公司的研究人员最近发表了一篇文章，重点介绍了一项关于两种固态甲磺酸咪康唑(无水和水合物)的案例研究，其中盐-水合物具有同样独特的“水桥”排列。研究表明，水合物形式也具有抗歧化作用。然而，对pH溶解度曲线中的持续溶解度没有进行讨论。这项研究将寻求建立对盐水桥倾向、创造、稳定性和物理性质关系的基本理解。总的来说，目的是发展洞察力，以便在盐类选择过程中根据影响水桥水合物的形成、稳定性和性能的因素有针对性地选择水桥水合物。这将通过三个研究要素的结合来实现：(1)探索有利于分子盐中水桥形成的分子特征，(2)影响分子盐中水桥形成的因素，(3)选定的水桥水合物结构的溶解度、溶解和稳定性。利用固态的一套测量功能(X射线、热、光谱分析)，我们将能够探索晶体结构，并突出对水桥合成至关重要的特征。利用现场监测技术，我们将能够探索固体在各种环境条件下的物理性质。这些实验观察将得到计算努力的支持，以提取系统的能量信息，以及分子间相互作用可能如何影响观察到的性质。

The project is designed to improve our ability to identify and exploit crystalline hydrated salt forms that are in a unique solid-state arrangement known as a "water bridge". Currently, we have two salt forms of active molecules in our portfolio that were expected to disproportionate in tablet formulations but showed unexpected solid-state and solution stability. A recent publication by Prof Lynne Taylor and Pfizer researchers highlighted a case study on two solid-state forms of Miconazole mesylate (anhydrous and hydrate) where the salt-hydrate had this same unique "water bridge" arrangement. The research showed that the hydrate form also had resistance to disproportionation. However, sustained solubility in the pH solubility curve was not discussed. This research will seek to build fundamental understanding of salt "water bridge" propensity, creation, stability, and physical property relationships. Collectively, the aim is to develop insights that can inform the targeted selection of water bridge hydrates during salt selection informed by the factors that influence their formation, stability and performance. This will be achieved through the combination of 3 research elements to (1) explore the molecular features that favour water bridge formation in molecular salts, (2) the factors that affect their formation from solution crystallization and (3) the solubility, dissolution and stability of selected water bridge hydrate structures. Using a suite of measurement capabilities of the solid-state (X-ray, thermal, spectroscopic analysis) we will be able to explore the crystal structures and highlight the features that are crucial for water-bridge synthesis. Using in-situ monitoring techniques we will be able to explore the physical properties of the solid under a variety of environmental conditions. These experimental observations will be underpinned by computational efforts to extract energetic information of the systems and how intermolecular interactions may impact on the observed properties.