Two Drug–Drug Co-Amorphous Systems of Curcumin and Berberine Hydrochloride/Palmatine Hydrochloride with Improved Physicochemical Properties and Multifunctional Activities

<b>Background/Objectives</b>: The poor aqueous solubility of curcumin (CUR) 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 hydrochloride (BER) and palmatine hydrochloride (PAL) as co-formers to achieve simultaneous stabilization and synergistic bioactivity. <b>Methods</b>: 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), scanning electron microscope (SEM), and ¹³C solid-state nuclear magnetic resonance spectroscopy (ssNMR). 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. <b>Results</b>: 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 superior thermal stability, photolytic stability, and improved short-term humidity resistance, together with enhanced antioxidant and anticancer activities compared with pure amorphous CUR. <b>Conclusions</b>: Co-amorphization of CUR with isoquinoline alkaloids effectively improved solubility, stability, antioxidant and anticancer activities, representing a promising strategy for the rational design of multifunctional amorphous CUR-based drug formulations.