Crystal engineering of ionic cocrystals containing phenols

Crystal engineering is “the field of chemistry that studies the design, properties and applications of crystals”. In crystal engineering perspective, crystals are regarded as supermolecules which are constructed by repeating array of molecules directed by molecular recognition. Design and synthesis of new crystalline solids based on the knowledge of their molecular recognition are fundamental features of crystal engineering. It has gained substantial interest because of its widespread applications in diverse scientific disciplines such as cocrystals. Cocrystals have been defined as “solids that are single phase crystalline materials made up of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts”. The term “coformer” has been coined to describe each component that comprises a cocrystal. Pharmaceutical cocrystals are a class of cocrystals in which at least one coformer is a drug molecule or ion and they offer an alternative class of multi-component solid forms to those traditionally used as drug substances in the pharmaceutical industry, e.g. salts, solvates and hydrates. Pharmaceutical cocrystals are of particular interest as they can modulate the physicochemical properties of drug substances that are relevant to drug product performance, especially solubility and stability. That this can occur without covalent modification of the drug molecule or ion means that cocrystal formation does not comprise the efficacy of a biologically active species. Nutraceuticals are “food (or part of a food) that provides medical or health benefits, including the prevention and/or treatment of a disease”. They are also amenable to form cocrystals, which are termed nutraceutical cocrystals. They are of interest as nutraceutical cocrystals might enable clinical use of nutraceuticals which are otherwise impeded by poor physicochemical properties such as low solubility and, in turn, low bioavailability. Cocrystal formation has therefore emerged as a viable strategy towards enhancing properties of bioactive molecules and they are recognised by bodies such as the US Food and Drug Administration and the European Medicines Agency. Cocrystals can be subdivided into two general classes: molecular cocrystals (MCCs) which are comprised of two or more non-volatile neutral coformers, and ionic cocrystals (ICCs) which involve at least one coformer that is a salt. MCCs are typically sustained by hydrogen bonds and halogen bonds. Whereas ICCs are necessarily sustained by charge-assisted hydrogen bonds or, if metal ions are involved, coordination bonds. The key crystal engineering concept that is exploited for design of cocrystals is the supramolecular synthons which are “structural units within super molecules, which can be formed and/or assembled by known or conceivable synthetic operations involving intermolecular interactions”, including supramolecular homosynthons and supramolecular heterosynthons. Many supramolecular synthons, in particular those involving carboxylic acid and pyridine moieties, e.g. pyridine?carboxylic acid, carboxylic acid-amide synthons, etc., have been well defined for rationally designing cocrystal. However, it is not the case for other functional groups commonly found in pharmaceuticals and nutraceuticals, e.g. phenol moiety which is counted to be around 10.1% of single-component biologically active compounds archived in Crystal Structural Database (CSD). This dissertation focuses on crystal engineering of multi-component crystals of polyphenolic compounds, particularly on ICCs.