A drug-drug co-amorphous system for highly improved solubility of breviscapine: an experimental and computational study

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.

Keywords: Brevascapine; Co-amorphous system; Intermolecular interaction; Matrine; Molecular dynamics simulation; Salt formation; Solubility enhancement.

Fig. 1

Chemical structures of SCU (a) and matrine (b).

Fig. 2

Appearance and morphological images of the bulk or recrystallized drugs, and the physical and co-amorphous mixtures of BRE and MAT.

Fig. 3

Solid characterization of raw and treated samples of BRE and MAT: DSC thermograms (a), PXRD patterns (b), and FTIR spectra (c).

Fig. 4

(a) ESP and (b) ALIE maps for the BRE-MAT complex, highlighting the reactive sites.

Fig. 5

Complexation process between BRE and MAT by molecular dynamic simulation and wavefunction analysis: (a) Initial and final states of simulation; (b) bonding distances; (c) Mayer bond order and (d) charge over time.

Fig. 6

Saturated solubility of BRE in different organic solvents. (*P < 0.01, compared to the bulk BRE.)

Fig. 7

Solvation energies from TI and DFT analysis: (a) SCU; (b) SCU anion.

Fig. 8

In vitro drug dissolution profiles of brevascapine in (a) purified water; (b) pH 5.0; (c) pH 6.8; (d) pH 7.4 PBS buffers.

Fig. 9

Physical stability performance of the BRE-MAT co-amorphous system: (a) powder hygroscopicity of various powders; (b) appearance before and after moisture absorption; (c) PXRD patterns under accelerated conditions; (d) BRE dissolution profiles.