Understanding Hydrate Formation in Molecular Compounds

Water plays a critical role within pharmaceutical sciences. This small and simple molecule has the ability to interact with compounds in numerous ways and may therefore affect the performance of a drug product significantly. One of the most interesting, but also most challenging phenomenon in solid state chemistry is the ability of water to occupy regular positions in the crystal lattice of other substances and to form molecular compounds, called hydrates. Our own statistical surveys revealed that such water adducts are very common. About one third of the drug compounds are capable of hydrate formation and more than 40% of all hydrate forming pharmaceuticals are used as water adducts. However, the formation and stability of hydrates is still unpredictable, despite strong efforts in this field. The relevance of the knowledge of the existence of these different solid forms (anhydrates: water/solvent free forms, solvates: solvent containing forms) of a compound arises from the fact that the different forms usually show distinct physical properties, e.g. solubility, density, hardness, melting point, etc., which can profoundly influence the manufacturing properties, storage stability and performance of a product. The phenomenon of multiple solid forms is not only of crucial relevance for pharmaceuticals but a wide range of fine chemicals, including dyes, high energetic materials, plant protection compounds, etc. Accordingly, a deeper understanding about the occurrence and the stability of such water adducts is essential, as contact with water/moisture, and consequently the formation of a hydrate is often unavoidable. The proposed research project aims to develop a comprehensive molecular understanding of the principles and factors governing organic hydrate formation and to establish a novel hydrate (stability) classification system. This will then contribute to the grand challenge of making hydrate formation, hydrate structures and especially their stability more predictable. The full range of experimental data that are needed to develop such a classification based on structural, thermodynamic and kinetic data is hardly available for hydrate forming organic compounds. Therefore the project seeks to elaborate innovative analytical techniques by combining multidisciplinary approaches comprising experimentally derived data about the structural, thermodynamic and kinetic features of hydrate systems. These data will be complemented with computational modelling (void and lattice energy calculations, crystal energy landscapes). A series of organic model hydrate systems (opioid alkaloids, etc.) will be systematically explored to create a data set that comprises different types of hydrates. Only the unique combination of experiment and theory will then allow us to assess a comprehensive picture of these important solvent adducts. In addition, this research will develop innovative screening strategies for catching hydrates and extend the search space for novel physical forms. Furthermore, the highly accurate experimental data emerging from this project will help computational chemists to improve their modelling techniques. The research is both timely and of significant industrial importance, as outcomes will help increase both the quality and meeting the aggressive timescales for the development of specialised chemical products.

Water plays a critical role within pharmaceutical sciences. Introduced through the active ingredient (drug), excipients or the atmosphere, it can induce phase transitions, dissolve soluble components, and increase interactions between the drug and excipients, all of which can adversely affect the physical and chemical stability of the drug substance to the detriment of drug product performance. It must therefore be accounted for at all stages of drug substance and product manufacturing. One of the most interesting, but also most challenging phenomenon in solid state chemistry is the ability of water to occupy regular positions in the crystal lattice of other substances and to form molecular compounds, called hydrates. Statistical surveys revealed that such water adducts are very common. About one third of the drug compounds are capable of hydrate formation and more than 40% of all hydrate forming pharmaceuticals are used as water adducts. To obtain a better understanding of hydrate formation phenomena in organic (drug) compounds a set of 30 (model) hydrate forming substances was carefully chosen with the aim to develop a comprehensive molecular understanding of the principles and factors governing organic hydrate formation and to establish a novel hydrate (stability) classification system. The highly accurate experimental data, which emerged from this project, now help computational chemists to further improve their modelling techniques.The molecular and structural basis for the formation of stoichiometric hydrates (fixed water to compound ratio) has been unravelled for an important class of drug molecules, morphinanes, and experimental and computational methodologies to successful quantify the (thermodynamic) stability of hydrates were established. It could be demonstrated that it is not only possible to calculate hydrate structures but also to predict hydrate formation including its stoichiometry and to estimate thermodynamic stability parameters using lattice energy calculations. Several highlights emerged from this project. For creatine, known for 180 years and one of the most popular dietary supplements, the investigations not only led to the discovery of novel forms that exhibit a higher hydration stability (i.e. lower risk of phase transformation during storing), but the work can also be seen as model study how dehydration has to be seen as an alternative route to novel forms. For 4-aminoquinaldine, an important educt in synthesis, the combined experimental and computational studies can be seen as the first example where the computed results guided the experiments to a novel hydrate phase, which was identified as the most stable phase under conditions relevant for production and storage.To conclude, the applied experimental and computational strategies may serve as paradigm for similar efforts in solid-state science and for aiding industrial developments. The applied concepts are not limited to hydrates but can be adapted for the characterization of solvates (organic solvents) or co-crystals as well.