Pressing solid barbituric acid with KBr to prepare samples for IR spectroscopy leads to the formation of an ionic co-crystal, in which the co-former is a classical ionic salt; co-crystal formation is also obtained with the other alkali bromides (LiBr, NaBr, RbBr and CsBr) and with caesium iodide. The simultaneous presence of alkali and halide ions affects the dissolution properties of barbituric acid in water.

This review is aimed to provide to an “educated but non-expert” readership and an overview of the scientific, commercial, and ethical importance of investigating the crystalline forms (polymorphs, hydrates, and co-crystals) of active pharmaceutical ingredients (API). The existence of multiple crystal forms of an API is relevant not only for the selection of the best solid material to carry through the various stages of drug development, including the choice of dosage and of excipients suitable for drug development and marketing, but also in terms of intellectual property protection and/or extension. This is because the physico-chemical properties, such as solubility, dissolution rate, thermal stability, processability, etc., of the solid API may depend, sometimes dramatically, on the crystal form, with important implications on the drug’s ultimate efficacy. This review will recount how the scientific community and the pharmaceutical industry learned from the catastrophic consequences of the appearance of new, more stable, and unsuspected crystal forms. The relevant aspects of hydrates, the most common pharmaceutical solid solvates, and of co-crystals, the association of two or more solid components in the same crystalline materials, will also be discussed. Examples will be provided of how to tackle multiple crystal forms with screening protocols and theoretical approaches, and ultimately how to turn into discovery and innovation the purposed preparation of new crystalline forms of an API.

In this highlight, the reasons for the widespread interest generated by ionic co-crystals, namely those formed by a neutral molecule and a salt, are addressed. In particular, the class of compounds obtained by co-crystallization of neutral organic molecules and inorganic salts (e.g. alkali and alkaline earth halides, sulfates, phosphates etc.) is discussed with the focus on their applications in diverse areas, such as pharmaceuticals, food and fertilizers, and also in chiral resolution. It is argued that, in terms of structure and intermolecular bonding features, these compounds do not differ from classical coordination compounds (complexes) and that their popularity arises from the effectiveness of the organic–inorganic assembly to enhance thermal stability, improve particle size and morphology and change significantly the solubility and dissolution rate with respect to those of the pure active ingredients.