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

• Published in: Crystal growth & design Vol. 10; no. 5; pp. 2152 - 2167
• Main Authors: Clarke, Heather D, Arora, Kapildev K, Bass, Heather, Kavuru, Padmini, Ong, Tien Teng, Pujari, Twarita, Wojtas, Lukasz, Zaworotko, Michael J
• Format: Journal Article
• Language: English
• Published: Washington,DC American Chemical Society 05.05.2010
• Subjects: Condensed matter: structure, mechanical and thermal properties; Cross-disciplinary physics: materials science; rheology; Crystallographic databases; Exact sciences and technology; Materials science; Methods of crystal growth; physics of crystal growth; Organic compounds; Physics; Structure of solids and liquids; crystallography; Structure of specific crystalline solids; Thermal expansion; thermomechanical effects and density; Thermal properties of condensed matter; Thermal properties of crystalline solids; Crystal growth; Differential scanning calorimetry; Crystal engineering; Infrared spectroscopy; Structure stability; Thermogravimetry; Carboxylic acids; XRD; Thermal stability; Alcohols; X-ray crystallography; Thermal properties; Monocrystals; Hydrogen bonds; Experimental design; Cocrystal; Supramolecular structure; Database; Pharmaceutical care; Structural analysis; Hydrates; Crystal structure; Synthon
• DOI: 10.1021/cg901345u
• ISSN: 1528-7483

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.