Cocrystals have gained much attention, particularly in the pharmaceutical industry, due to their ability to modify physicochemical properties of a given drug molecule without changing their biological efficacy. Therefore, solid form screening - a key step in the early stage of drug development which conventionally includes salts, polymorphs and hydrates/solvates, has also considered cocrystals as possible lead candidates. Compared with molecular cocrystals (MCCs) that contain only neutral components (coformers) in the crystal lattice, ionic cocrystals (ICCs) comprising of at least one ionic coformer that is a salt, have generated widespread interest. ICCs exhibit strong H-bonding or coordination bonding and have more components suggesting greater diversity of physicochemical properties. Although the number of polymorphic cocrystals has increased in recent years, amongst which, polymorphic ICCs take up a very small portion. Cocrystals of biologically active molecules are inherent amenable to be crystal engineered through an understanding of H-bonded supramolecular synthons. The study of supramolecular heterosynthons is particularly valuable to rational design new cocrystals. In this contribution, we targeted phenolic compounds which is estimated to account for 8.7% of approved small-molecule drugs contained in DrugBank database and 10.1% of single-component biologically active compounds archived in the Crystal Structural Database (CSD). Topical issues were addressed from ICC design of phenolic compounds to polymorphism in ICCs and then to their property evaluation. --- An understudied phenol-phenolate supramolecular heterosynthon was established from statistical analysis and energy computation conducted on relevant structures deposited in the CSD and the novel ICCs reported herein. --- ICCs of a polyphenolic bioflavonoid with low solubility were screened based on crystal engineering. New ICCs are sustained by phenol-phenolate heterosynthons and also exhibit polymorphism owing to the conformational flexibility of bioflavonoid. --- Relative stability of ICC polymorphs was evaluated by thermal analysis and competitive slurry; dissolution profiles were studied and ICC polymorphs showed similar modest improvement compared to parent compound. This study has shown to be useful to apply crystal engineering to generate ICCs of phenolic compounds sustained by the phenol-phenolate supramolecular heterosynthon even when polymorphism is possible.

Crystal engineering case study: Ionic cocrystals and their conformational polymorphism with properties modulation

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