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

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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.