Crystal engineering considerations for pharmaceutical co-crystals

Abstract

Drug discovery and development is an indispensable sector of R&D, and it is of immense significance due to its relevance and direct impact on human life. However, the discovery of new drugs is an evolving and onerous process with critically low success rates, and the majority of potential drugs face physicochemical limitations. Among the known drugs, poor solubility is a serious limitation, and about 90% of discovered drugs and 40% of commercial drugs are class II and IV drugs with poor aqueous solubility. Crystal engineering has appeared as a facile, quicker, and green approach to address the physicochemical limitations of drugs, including their poor aqueous solubility, through a non-covalent strategy involving the development of polymorphs, pharmaceutical co-crystals, and organic salts. This perspective includes a discussion on the definition, classification, and nomenclature of binary crystal forms; a basic understanding of the design method of pharmaceutical co-crystals (ΔpK_a rule, coformer screening, and synthon concept); synthetic methods and scale-up processes of co-crystallization; crystal nucleation; phase diagrams; and opportunities and challenges in the area.