Non-stoichiometric hydrate formation in drug substances

The knowledge of multiple crystalline forms became a central research topic in modern drug development and is a prerequisite for ensuring a high product quality and safety. This is because different solid forms of a chemically defined compound show distinct physical properties (e.g. solubility, density, hardness, melting point, etc.) and thus, the solid form can profoundly influence processing, storage stability and performance of a drug product. Besides polymorphism (same chemical composition) also the formation of solvent adducts (solvates, multi-component systems) is frequently encountered for drug molecules with hydrates (water adducts) being the most relevant since water/moisture is ubiquitous present and unavoidable during processing and storage. Own statistical analyses showed that hydrate formation is observed for a third of all organic (drug) molecules and twice as high for new APIs (active pharmaceutical ingredients). Since we are still not able to predict hydrates and their stability, novel strategies and concepts are in high demand to unravel water adducts. The latter will contribute to the grand challenge of making hydrate formation, their structure and stability more predictable. Water molecules can occupy regular positions in the crystal lattice of other substances. The solvent can either fill structural voids or be an integral part of the structure. Thus, hydrates can be subdivided into two main classes. Stoichiometric hydrates are regarded as molecular compounds. Dehydration always leads to a different structure or the amorphous state. Non-stoichiometric hydrates incorporate a range of water levels as a function of temperature and water vapor pressure. The latter often host water molecules in open structural voids that allow for reversible water uptake/release without significant changes in the crystal structure. The water in non-stoichiometric hydrates is often rather weakly bound and may interact with other components compromising the stability and performance of formulated products. Thus, knowledge of hydrate formation, moisture and temperature dependent stability is crucial for the development of a high quality fine chemical product. The proposed research project aims at a comprehensive molecular understanding of the factors that govern the formation of non-stoichiometric hydrates. This will be achieved by systematically investigating a suitable selection of model compounds, focusing on the interplay of structural aspects and kinetichermodynamic stability, and applying innovative experimental approaches complemented with computational methods (crystal structure prediction, lattice energy minimizations). Applied key analytical techniques are X-ray diffraction studies, spectroscopic techniques, gravimetric moisture sorption/desorption experiments, water activity measurements, thermal analysis and isothermal calorimetry. The unique combination of experiment and theory will allow us to establish a better understanding of the as hitherto poorly understood, but highly relevant, phenomenon of water adducts. The research is both timely and significant and will contribute to avoid manufacturing problems, reduce development time and ultimately ensure the high quality standards of drug products.

Water can have profound and oftentimes adverse effects on drug product manufacturing and performance. Introduced through the drug molecule, excipients or the atmosphere, it can induce phase transitions, dissolve soluble components and increase interactions between the drug and excipients. Because of its wide-ranging impact on physical and chemical properties, water must be accounted for at all stages of drug substance and product manufacturing, as well as throughout the shelf-life of the drug product. When a compound co-crystallises with water, a new crystalline phase, termed hydrate, is formed. Water molecules can occupy regular positions in the crystal lattice of other substances. The solvent can either fill structural voids or be an integral part of the structure. The problematic group of the non-stoichiometric hydrates incorporates a range of water levels as a function of temperature and water vapour pressure, with the water often rather weakly bound, which then may interact with other components compromising the stability and performance of formulated products. The research project aimed at a comprehensive molecular understanding of the factors that govern the formation of non-stoichiometric hydrates. Therefore, a series of 30 organic model (drug) hydrate systems were systematically explored, focusing on the the interplay of structural aspects and kinetichermodynamic stability, and applying innovative experimental approaches complemented with computational methods (crystal structure prediction, energy calculations). Several highlights and tools emerged from this project. It could be demonstrated that intermolecular energy calculations can be used to estimate whether water can be released from a hydrate in a non-stoichiometric way. Furthermore, crystal structure prediction of the water-free forms may indicate (channel) hydrate formation, as the hydrate structures without water can be identified among the high energy and low density structures on the crystal energy landscape. The latter approach is faster than calculating hydrate structures, especially for non-stoichiometric hydrates as more than one search would have to be performed. Finally, this project pioneered in measuring stability differences (enthalpy) between isomorphic dehydrates (water free) and non-stoichiometric hydrates, providing unrivalled thermodynamic stability data. Such information is needed for understanding hydration/dehydration mechanisms and especially for improving computational hydrate modelling algorithms. To conclude, the tested and applied experimental and computational strategies may serve as paradigm for similar efforts in solid-state science and for aiding industrial developments. The approaches are not limited to hydrates but may be adapted for the general class of solvates (organic solvents).