Novel cocrystal inclusion compound of bezafibrate with L-proline: preparation, characterization and in vitro/in vivo evaluation.

OBJECTIVE

To improve the solubility and dissolution of bezafibrate (BEZA) and enhance its bioavailability.

SIGNIFICANCE: BEZA has poor solubility. This study has solved this limitation through a novel cocrystal-inclusion compound strategy.

METHODS

The cocrystal of BEZA and L-proline (L-Pro) (BEZA-L-Pro cocrystal) was prepared using liquid-assisted ball milling method. Additionally, the BEZA-L-Pro/hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion compound was prepared through neat ball milling. The preparation conditions were optimized. The formation of the cocrystal and inclusion compound was confirmed by powder X-ray diffraction, differential scanning calorimetry, Fourier-transform infrared spectroscopy and scanning electron microscopy. The stoichiometry of the inclusion compound was determined by phase solubility tests.

RESULTS

The optimal cocrystal preparation conditions were: BEZA to L-Pro molar ratio of 1: 1, ethanol as solvent, η of 0.8 μL/mg, milling speed of 150 rpm. The optimal inclusion compound preparation conditions were: BEZA-L-Pro to HP-β-CD molar ratio of 1: 1, milling speed of 200 rpm. The saturation solubility test showed that the saturation solubility of cocrystal and inclusion compound was 1.48 times and 3.91 times of BEZA, respectively. The dissolution test showed that the cumulative release rate of cocrystal and inclusion compound in acetate buffer solution (pH 4.5) within 120 min was 2.5 times and 4 times of BEZA, respectively. The in vivo study demonstrated that the bioavailability of cocrystal and inclusion compound was 1.4 times and 2 times of BEZA, respectively.

CONCLUSIONS

The prepared BEZA-L-Pro cocrystal and BEZA-L-Pro/HP-β-CD inclusion compound can significantly improve the solubility and dissolution of BEZA, and enhance its bioavailability.