Sustained release of matrine via salt formation with hesperetin

Abstract

Matrine (MAT) is a natural tetracyclo-quinolizidine alkaloid with various pharmacological activities. Due to its excessive solubility, oral administration of MAT exhibits rapid absorption, short elimination half-life, and low bioavailability. Sustained release forms of MAT may mitigate these effects and achieve improved pharmaceutical properties. In this work, salt formation with hesperetin (HES), a natural flavonoid compound, was explored to reduce the solubility and release rate of MAT. The MAT–HES salt was fully characterized by single crystal and powder X-ray diffraction (XRD), chiral liquid chromatography, Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The solved crystal structure of MAT–HES clearly reveals the intermolecular proton transfer from the –OH group of HES to the tertiary amine group of MAT. In this chiral salt structure, R-HES and S-HES are present as two positionally disordered components at the same crystallographic asymmetric site. For the powder salt sample, no chiral enrichment of HES was detected. Such a result is supported by the theoretical calculations, which show that when the R- or S-isomer is present alone, the energy states of the salt structures are similar. After salt formation, the apparent equilibrium solubility of MAT is markedly reduced in either pH 1.2 or 6.8 medium. The sustained release behaviors of MAT–HES were observed in the in vitro dissolution experiments, indicating its potential to improve the pharmacokinetic properties of the parent MAT. In addition, a hydrate form of MAT was found in this study, which suggests the necessity of examining the moisture stability of the samples. Accelerated experiments demonstrated that MAT–HES has better physical stability against hydration than MAT.