Cocrystallization and Micronization as Strategies to Optimize the Bioavailability of Naringin and Naringenin Molecules: A Comprehensive Review of In Vivo and In Vitro Pharmaceutical Applications

ABSTRACT Naringin, a flavonoid found in citrus fruits, is rapidly metabolized into naringenin through enzymatic action, originating metabolites with therapeutic potential. However, the low solubility and bioavailability of these compounds limit their application. Micronization is used to increase the particle surface area, enhancing dissolution, absorption, and bioavailability. Co‐crystallization modulates the physicochemical properties of compounds without altering their molecular integrity. Co‐crystals can be obtained through mechanical methods or crystallization, involving the organization of molecules into a stable crystalline network through intermolecular interactions. Co‐crystallization provides advantages over micronization, including encapsulation, functionalization, and modulation of the release profile of bioactive compounds. However, the pharmacotechnical performance of co‐crystals depends on the selection of the co‐former. In co‐crystals containing naringenin as co‐former and marketed drugs as active pharmaceutical ingredient, reduced bioavailability and lower dissolution rates of the target molecule were observed, results that should be interpreted according to the proposed therapeutic and pharmacokinetic objectives. This literature review suggests that the integration of micronization and co‐crystallization represents a promising strategy to enhance the pharmacological properties of naringin and naringenin. The advancement of physicochemical modification techniques could expand the biomedical applications of these flavonoids, favoring the development of therapeutic approaches contributing to better clinical outcomes.