Two Drug-Drug Co-Amorphous Systems of Curcumin and Berberine Chloride/Palmatine Chloride with Synergistic Effects

Background/Objectives: The poor aqueous solubility of curcumin limits its pharmaceutical application. Although amorphization can enhance its solubility, the amorphous form often exhibits insufficient physical stability. Co-amorphization, particularly drug-drug co-amorphous (CAM) formation, offers a promising approach to improve solubility, stability, and therapeutic efficacy. This study aimed to prepare and evaluate two CUR-based CAM systems using isoquinoline alkaloids berberine chloride (BER) and palmatine chloride (PAL) as co-formers to achieve simultaneous stabilization and synergistic bioactivity. Methods: CUR-BER and CUR-PAL CAM systems were prepared via rotary evaporation under vacuum at a 1:1 molar ratio. The solid-state properties were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and solid-state ¹³C NMR spectroscopy. Dissolution, solubility, and stability studies were conducted, while antioxidant and anticancer activities were assessed by DPPH/ABTS⁺ radical-scavenging and MTT assays using HT-29 colorectal cancer cells. Results: PXRD and DSC confirmed the formation of single-phase amorphous systems with higher glass transition temperatures, indicating strong intermolecular interactions between CUR and BER/PAL. 13C ssNMR spectroscopy evidenced hydrogen-bond formation between the enolic hydroxyl moiety of CUR and the methoxy oxygen atoms in BER or PAL molecules. Both CAM systems significantly enhanced the solubility and dissolution rate of CUR, with CUR-PAL CAM showing up to a 15.1-fold solubility improvement. The CAM systems also displayed excellent physical stability and synergistic antioxidant and anticancer effects compared with pure amorphous CUR. Conclusions: Co-amorphization of CUR with isoquinoline alkaloids effectively improved solubility, stability, and pharmacological synergy, representing a promising strategy for the rational design of multifunctional amorphous drug formulations for combinatorial cancer therapy.