Improving the oral bioavailability of berberine: A crystal engineering approach

Berberine is a poorly bioavailable, naturally occurring therapeutic compound. Despite being marketed as a chloride salt, berberine shows poor solubility, and it has poor permeability owing to its ionic nature. This study focuses on enhancing the oral bioavailability of berberine by improving solubility, drug release profiles and permeability of berberine. To achieve that, the concept of cocrystallization is employed to alter the solid-state/physicochemical properties of berberine. A coformer, i.e., a secondcomponent having uses similar to a drug or whose nature will enhance the physicochemical properties of the drug, will be cocrystallized with the drug. In this study, berberine was cocrystallized with gallic acid, gentisic acid, and pamoic acid. The resultant new crystalline forms were identified as salts through single-crystal X-ray diffraction and the systems were characterized by DSC, TGA and IR spectroscopy. The stability, solubility, dissolution, permeability, oral LD50 and bioavailability studies were performed. Introduction of coformers like gallic acid and gentisic acid in crystal architecture of berberine has enhanced the solubility (1.7-2.0x) and dissolution (1.6-1.8x) of berberine in acidic media, while pamoic acid shows a decreased trend. In the GIT PAMPA studies, gentisic acid and pamoic acid systems supported in enhancing the permeability by1.42 and5.98-folds compared to berberine, whereas gallic acid exhibited a low permeability profile. The berberine-gentisic acid salt enhances the peak plasma concentration by 1.8-fold compared to berberine. Salt formation of berberine via cocrystallization is advantageous in tailoring the solid-state properties with improved solubility, dissolution, permeability, and peak plasma concentration of berberine.