Cocrystal Engineering-Based Strategies for Enhancing the Permeability of Poorly Permeable APIs

The oral bioavailability and, in turn, therapeutic efficacy of an active pharmaceutical ingredient (API) are significantly affected by poor API solubility and permeability issues. Permeability issues affect approximately one-third of commercialized APIs. Cocrystals are a type of supramolecular compound that are obtained by noncovalent interactions, particularly H-bonds, between APIs and coformers in a definite stoichiometric ratio by the process of cocrystallization. Through the meticulous selection of coformers for a given API, both solubility and permeability issues can be mitigated. Cocrystallization, based on the properties of the selected coformer, can improve the permeability of APIs by enhancing the absorption flux, by increasing the lipophilicity of the molecule (lipophilic coformer), and through the enhancement of the thermodynamic activity. This review emphasizes the concepts of permeability and their enhancement through cocrystallization for improving the oral bioavailability of APIs. The selection of coformers for cocrystallization experiments, followed by their characterization post preparation, is discussed. Various in vitro and ex vivo permeability assessment methods have also been described in detail. Authors have discussed the literature trend and industrial progress related to permeability enhancement using cocrystallization over the past two decades and summarized the outcomes. The impact of solution-mediated phase transformation (SMPT) on the cocrystal permeability, followed by regulatory approval guidelines and a filing procedure, has also been discussed. Finally, the review concludes with a regulatory perspective on the cocrystals.