Bergenin-isonicotinamide (1:1) cocrystal with enhanced solubility and investigation of its solubility behavior

Bergenin ( BER ) is a bioactive compound used for the treatment of chronic bronchitis in China. However, its low solubility and permeation limits its oral bioavailability. In this study, a new BER : isonicotinamide ( ISN ) cocrystal (1: 1, molar ratio) was reported for the first time. BER-ISN shows better solubility and intrinsic dissolution rates (IDRs) in aqueous medias such as water, buffer solutions with pH = 1.2, 4.5, and 6.8 in comparison to BER monohydrate. For instance, the solubilities of BER-ISN and BER monohydrate in water were 3.72 ± 0.22 and 1.42 ± 0.006 mg/mL, respectively, showing 2.62 times improvement. IDRs of BER-ISN and BER monohydrate were 29.90 ± 0.04 and 18.64 ± 0.27 mg/min/cm 2 , respectively, which was consistent with the solubility results. To explain the solubility behavior, phase solubility diagrams of BER monohydrate, ISN and BER-ISN in three pure organic solvents (ethanol, isopropanol and ethyl acetate) were performed according to the solubility product ( K sp ) and complexes formation ( K 11 ) theory. The predicted solubilities are consistent with experimental solubilities considering complexation effects. The Hildebrand solubility parameter (HSP) calculations support the results. Thus, BER-ISN cocrystal (1: 1) with improved solubility is a good candidate for further formulation development.