Synthesis of naringenin-betaine cocrystal by gas antisolvent technique and cell models for in vitro permeation studies

Naringenin (NRG) is a flavanone characterized by potential neuroprotective properties, even if low water solubility and poor oral bioavailability limit the ability of this compound to target the central nervous system. As an attempt to overcome these limitations, it is here described the synthesis and characterization of a cocrystal obtained with NRG and betaine (BTN) using gas antisolvent (GAS) technique. The ability of NRG, its cocrystal and the parent physical mixture to permeate across the intestinal and the blood-brain (BBB) barriers was simulated in vitro by using monolayers obtained by IEC-6 cells and a model established by ECV 304, respectively. It is evidenced that the NRG: BTN cocrystal improves both the solubility and dissolution rate of NRG, potentially allowing to enhance its oral bioavailability. Moreover, the results of viability studies performed on IEC-6 cells suggest that low doses of cocrystal frequently administered are required for absorption to be efficient and safe. The study also suggests a synergistic effect of NRG and BTN for the cocrystal and physical mixture in enhancing NRG permeation through the BBB. These results indicate that the NRG:BTN cocrystal is potentially useful for the brain targeting of NRG, following its oral administration.