Structural Relationships between Hydrates and Anhydrous Crystals: Towards Building an Understanding of Hydration in the Solid State

Abstract

Hydrates can be particularly problematic for the pharmaceutical industry. Water is ubiquitous in our atmosphere and therefore difficult to avoid. As a result, maintaining an anhydrous state can be challenging, when a stable hydrated form exists. Marketing a hydrate also provides difficulties with respect to dehydration, most notably during isolation and drying of multi-kilogram quantities, at high temperature and low humidity. Many have looked to understand why molecules have a propensity to hydrate, and there are a multitude of articles where the solid form landscape of a molecule has been studied in detail. However, when considering hydration and dehydration, an understanding of the factors influencing the kinetic stability of a solid form, when placed into an environment where it is no longer thermodynamically stable, has not received as much attention. This work explores the hydration and dehydration behaviour of fluconazole, a flexible drug compound used in the systemic treatment of fungal infections. Four conformers have been identified within its diverse form landscape; with six anhydrous polymorphic forms and a monohydrate being reported, alongside solvates and co-crystals. Fluconazole offers the opportunity to explore the impact of conformational and packing similarity on hydration and dehydration behaviour. Two conformers are represented in the three experimentally accessible polymorphs, one with a closer similarity to a third conformer, found for the hydrate. The three polymorphs also provide diversity in packing similarity, with one polymorph having a very high level of similarity to the hydrate structure. The hydration kinetics of the three experimentally accessible anhydrous forms were monitored at various relative humidities (54, 75 and 93 %RH), all above the critical water activity, investigating the impact of seeding and mechanical stress on hydration. Adjustment energies, the conformational energy pathway, alongside interaction and intermolecular energies were calculated to elucidate potential barriers impacting hydration behaviour. Experimental (classical thermal methods) and computational simulations (molecular dynamics) have been used in combination to explore the influence of temperature on water diffusion and conformational change, so revealing the dehydration mechanism for fluconazole monohydrate. The Cambridge Structural Data base has been used to perform an evaluation of the influence of molecular and crystal properties on hydrate stoichiometry. Factors such as molecular weight, donor acceptor ratio, Z’, water donor acceptor environment and space group, have been assessed alongside hydrate type and hydrogen bonding environment.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Roger Davey (Supervisor) & Aurora J. Cruz-Cabeza (Supervisor)