Abstract
Drug-drug co-amorphous systems are a promising approach to improve the aqueous solubility of poorly water-soluble drugs. This study explores the combination of breviscapine (BRE) and matrine (MAT) form an amorphous salt, aiming to synergistically enhance the solubility and dissolution of BRE. In silico analysis of electrostatic potential and local ionization energy were conducted on BRE-MAT complex to predict the intermolecular interactions, and solvent-free energies were calculated using thermodynamic integration and density functional theory. The co-amorphous mixture, prepared by solvent evaporation, was characterized using various analytical techniques, including polarized microscopy, differential scanning calorimetry, and powder X-ray diffraction, confirming its amorphous nature. Fourier transform infrared spectroscopy and molecular dynamic simulations revealed strong hydrogen bonding, with a proton transfer from the carboxyl group of BRE to the tertiary amine nitrogen of MAT. The resulting co-amorphous salt demonstrated substantial solubility improvement (> 8000-fold in water) and enhanced in vitro dissolution of BRE. The study also confirmed that the co-amorphous salt maintained physical stability at 40 °C and 75% relative humidity over 6 months. These findings provide a viable strategy for developing drug-drug co-amorphous formulations to enhance solubility and stability, with significant potential for pharmaceutical applications.