Novel Berberine Ionic Cocrystals with Halogen-Substituted Salicylic Acid Derivatives: From Chloride-Retaining Hydrate to Chloride-Free Anhydrous

Berberine is a natural isoquinoline alkaloid with broad pharmacological activities. In this study, four novel berberine ionic cocrystals (ICCs) with 5-halogen-substituted salicylic acids (X = F, Cl, Br, I) were synthesized and fully characterized ( BBR-5FA, BBR-5CA, BBR-5BA, and BBR-5IA ). Their crystal structures were elucidated by single-crystal and powder X-ray diffraction, while intermolecular interactions were analyzed using FT-IR and Hirshfeld surface analysis. Physicochemical properties were further evaluated through differential scanning calorimetry, thermogravimetric analysis, dissolution testing, and antioxidant assays. BBR-5FA crystallized as a chloride-retaining hydrate, with 5-fluorosalicylic acid in its neutral form. In contrast, the other three ICCs adopted chloride-free anhydrous structures, in which the halogen-substituted salicylic acids existed as one deprotonated and one neutral species. These two types of ICCs exhibited distinct crystal packing, weak interactions, thermal behaviors, dissolution performance, and antioxidant activities. These findings underscore the critical role of halogen substitution in shaping the solid-state architectures and properties of berberine ICCs.