Structure−Stability Relationships in Cocrystal Hydrates: Does the Promiscuity of Water Make Crystalline Hydrates the Nemesis of Crystal Engineering?

Abstract

This contribution addresses the role of water molecules in crystal engineering by studying the crystal structures and thermal stabilities of 11 new cocrystal hydrates, all of which were characterized by single crystal X-ray crystallography, powder X-ray diffraction (PXRD), infrared spectroscopy (IR), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The cocrystal hydrates can be grouped into four categories based upon thermal stability: (1) water is lost at <100 °C; (2) water is lost between 100 and 120 °C; (3) water is lost at >120 °C; (4) dehydration occurs concurrently with the melt of the cocrystal. In order to address if there is any correlation between structure and stability, the following factors were considered: type of hydrate (tunnel hydrate or isolated hydrate); number of hydrogen bond donors and acceptors; hydrogen bond distances; packing efficiency. Category 1 hydrates exhibit water molecules in tunnels. However, no structure/stability correlations exist in any of the other categories of hydrate. To complement the cocrystal hydrates reported herein, a Cambridge Structural Database (CSD) analysis was conducted in order to address the supramolecular heterosynthons that water molecules exhibit with two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids, and alcohols. The CSD analysis suggests that, unlike cocrystals, there is great diversity in the supramolecular heterosynthons exhibited by water molecules when they form hydrogen bonds with carboxylic acids or alcohols. It can therefore be concluded that the promiscuity of water molecules in terms of their supramolecular synthons and their unpredictable thermal stability makes them a special challenge in the context of crystal engineering.

Diversity of crystal structures and physicochemical properties of ciprofloxacin and norfloxacin salts with fumaric acid

“…9 The fact that several alternative solid forms coexist at the same temperature and pressure implies proximity in their Gibbs free energies. In the case of hydrates, water molecules make an important contribution to stabilizing the crystal lattice of a solid, 26 filling the excess of the free volume (decreasing entropy) and connecting the constituents of the multi-component crystal via intermolecular interactions (increasing enthalpy). It is evident that any changes in the crystal structure of the solid form inevitably alter its physicochemical properties, including solubility and dissolution rate.…”

Prediction of Hydrate and Solvate Formation Using Statistical Models

“…It was estimated that 33% of organic compounds have the ability to form hydrates, while about 10% of them are able to form solvates with organic solvents. 2 Solvate formation has many implications in the pharmaceutical industry, because it affects the physico-chemical properties of materials, such as their density, melting point and dissolution rate, which in turn can influence their manufacturability and pharmacokinetic properties. 3 The unexpected formation of solvates can thus lead to unpredictable behavior of the drug.…”

Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals

“…There are few studies and limited understanding of the structural factors which affect the stability of hydrated cocrystals. Clarke et al presented a comprehensive study on 11 hydrated cocrystals with a view to understanding the interplay between structure and stability [64]. Generally, the correlation between stability (dehydration temperature) and the three structural properties of hydrogen bond donors and acceptors, nature of water cluster (tunnels or isolated) and packing efficiency (the volume fraction of atoms in crystal structure per volume of unit cell) was insignificant [64].…”

“…Clarke et al presented a comprehensive study on 11 hydrated cocrystals with a view to understanding the interplay between structure and stability [64]. Generally, the correlation between stability (dehydration temperature) and the three structural properties of hydrogen bond donors and acceptors, nature of water cluster (tunnels or isolated) and packing efficiency (the volume fraction of atoms in crystal structure per volume of unit cell) was insignificant [64]. The water cluster pattern affected the dehydration temperature, where the tunnels hydrate tended to lose water near the boiling of water, whereas the dehydration temperature of the isolated hydrates depended on the number of strong hydrogen bonds [64].…”

“…Generally, the correlation between stability (dehydration temperature) and the three structural properties of hydrogen bond donors and acceptors, nature of water cluster (tunnels or isolated) and packing efficiency (the volume fraction of atoms in crystal structure per volume of unit cell) was insignificant [64]. The water cluster pattern affected the dehydration temperature, where the tunnels hydrate tended to lose water near the boiling of water, whereas the dehydration temperature of the isolated hydrates depended on the number of strong hydrogen bonds [64]. Cocrystallisation can also decrease the tendency for hydrate formation, where the co-former can take over the role of the water molecule in the crystal structure.…”