Objective: To synthesis a novel 'Pharmaceutical Cocrystal' of berberine (BBR) with coformer 3-methylcinnamic acid (3MCA) for increasing its solubility and intestinal absorption property.
Significance: BBR-HCl has poor liposolubility, difficulty in penetrating the cell membrane and absorption in the gastrointestinal tract, low bioavailability, and limited clinical application. A new cocrystal is formed by the interaction between 3-MCA and BBR through molecular interaction, which improves the physicochemical properties, intestinal absorption property, and hygroscopicity.
Methods: The solvent evaporation method was used to synthesize BCR-3MCA cocrystal. The physicochemical properties of the crystals were confirmed by different spectral techniques, i.e. by X-ray diffraction (PXRD, SXRD), thermogravimetry and differential thermal analysis (DSC, TGA), and scanning electron microscopy (SEM). Hygroscopicity of the cocrystal was evaluated by dynamic water vapor sorption (DVS). The intestinal absorption property was evaluated by the Ussing chamber system.
Results: BBR and 3MCA can be directly self-assembled into uniform co-crystal by hydrogen bonds and π-π stacking interactions. Compared with BBR-HCl, the solubility of BBR-3MCA cocrystal in polar solvents of water, methanol, ethanol, and isopropanol increased by 13.9, 1.5, 4.7, and 15.8 times, respectively. The apparent absorption and the absorption rate constants were increased by 7.7 and 5.6 times, respectively. Surprisingly, BBR-3MCA co-crystal almost had no hygroscopicity.
Conclusion: The absolute molecular structure of the co-crystal was further confirmed by single crystal X-ray diffraction. The hydrogen bonds drove the formation of X-like one-dimensional unit. Compared to the BBR-HCl, BBR-3MCA cocrystal displayed superior dissolution and solubility performance, improved physical-chemical properties and significantly improved intestinal absorption.
Keywords: 3-methylcinnamic acid; Berberine; co-crystal; single crystal structure; solubility; using chamber system.