Recent developments on co-crystal polymorphs: From formation to prediction

Abstract

Co-crystals offer a promising strategy to create drug constructs for which the pharmacokinetic properties of an active pharmaceutical ingredient can be improved without compromising its pharmacological effectiveness. The integration of APIs and co-formers within a single crystalline phase might open additional roads towards targeted tailoring of drug properties. However, the emergence of elusive polymorphs in multi-component crystals remains a persistent concern, as unexpected polymorphs might influence product quality, formulation performance and therapeutic efficacy. Understanding polymorph formation mechanisms and the structural landscapes of such co-crystalline systems is thus essential to identify, create, and stabilize desired co-crystal polymorphs. Mastering the fine-tuning of macroscopic properties from microscopic principles paves the way for the systematic manipulation of molecular ensembles during the crystallization process, enabling guided nucleation and controlled crystal growth. This review summarizes the mechanisms behind polymorphic formation, stability, transformation pathways, and predictive strategies, including machine learning, which can be exploited to advance the rational design and control of co-crystal polymorphs in pharmaceutical development.