Co-crystals of berberine with two natural polyphenols: synthesis, crystal structure and bacteriostasis on aquatic pathogens

Pharmaceutical co-crystals could modulate the physio-chemical properties of active pharmaceutical ingredients (APIs) and co-crystal formations (CCFs) via non-covalent interactions, including hydrogen bonds, π–π stacking and hydrophobic effects, which may generate synergistic pharmacological effects. Aiming to the antibiotic resistance and drug residues in aquaculture resulting from antibiotic overuse, in this study, we chose the key bioactive ingredients from traditional Chinese medicine (TCM), namely berberine (BBR), gallic acid (GA), and resveratrol (RSV), sourced from Coptis chinensis , Galla chinensis , and Polygonum cuspidatum , respectively. Through mixed-solution crystallization, two novel co -crystals of berberine and polyphenols (BBR-GA and BBR-RSV) were synthesized. Structural characterization using single crystal X-ray diffraction, Fourier infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), and Hirshfeld surface analysis verified that both BBR-GA and BBR-RSV are predominantly stabilized by hydrogen bonds and hydrophobic interactions. Thermogravimetric analysis indicated that both BBR-GA and BBR-RSV display thermal stability, with decomposition temperatures higher than 200 °C. In vitro antibacterial tests against three typical aquatic pathogens revealed that both BBR-GA and BBR-RSV retained the broad-spectrum antibacterial activity of their respective API monomers. Specifically, BBR-RSV exhibited significant inhibitory effects against Aeromonas veronii and Citrobacter freundii , with minimum inhibitory concentration (MIC) of 0.125 mg/mL and 0.25 mg/mL, respectively. This study gives the first investigation on the potential application of the co-crystals from the active ingredients of TCM in the antibacterial field of aquaculture. It suggests that the co -crystals of berberine with natural polyphenols hold promise for development as new green veterinary drugs to substitute veterinary antibiotics.