Chapter 2. The Role of Hydrogen Bonding in Co-crystals

Co-crystals, crystals comprised of two or more different but complementary molecules or ions (co-formers), represent a long known but until recently understudied class of crystalline materials. They have become of interest thanks mainly to their potential utility in drug products, agrochemical products and as molecular materials. An aspect of co-crystals that differentiates them from other types of molecular multi-component crystals, such as solvates and hydrates, is that co-crystals with the desired composition can be designed by employing established principles of molecular recognition and crystal engineering. In addition, their synthesis can be achieved by following any of several straightforward synthetic protocols. Importantly, the inherent modularity of co-crystals means that their physicochemical properties can be tuned by substituting one of the co-formers. Herein we address the role of hydrogen bonds in co-crystal design. A brief account of hydrogen bond classification is presented in the context of relative interaction strength. This is followed by an overview of the development of hydrogen bond based co-crystal design that highlights the following: the early contributions made by Etter; the development of the concept of the hydrogen bonded supramolecular synthons by Desiraju; supramolecular synthon hierarchy studies that address the propensity of a particular supramolecular heterosynthon in a competitive environment. Various aspects of hydrogen bonded co-crystals such as polymorphism, co-crystal hydrates or solvates, inclusion compounds and synthesis of higher order co-crystals are discussed. The chapter concludes with case studies that highlight the utility of hydrogen-bonded co-crystals in terms of their properties and potential utility.