Mechanism and Improved Dissolution of Glycyrrhetinic Acid Solid Dispersion by Alkalizers

Abstract

The purpose of this study was to increase the dissolution of glycyrrhetinic acid (GA) by preparing ternary solid dispersion (TSD) systems containing alkalizers, and to explore the modulating mechanism of alkalizers in solid dispersion systems. GA TSDs were prepared by hot melt extrusion (HME) with Kollidon® VA64 as the carrier and L-arginine/meglumine as the alkalizers. The in vitro release of the TSD was investigated with a dissolution test, and the dissociation constant (pKa) was used to describe the ionization degree of the drug in different pH buffers. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FTIR), Raman spectra, X-ray photoelectron spectroscopy (XPS), and a molecular model were used for solid-state characterizations and to study the dissolution mechanism of the TSDs. It was evident that the dissolution of GA significantly increased as a result of the TSD compared to the pure drug and binary solid dispersion. SEM, DSC, and XPRD data showed that GA transformed into an amorphous form in TSD. As illustrated by FTIR, Raman, XPS, and molecular docking, high binding energy ion-pair complexes formed between GA and the alkalizers during the process of HME. These can destroy the H-bond between GA molecules. Further, intermolecular H-bonds formed between the alkalizers and Kollidon® VA64, which can increase the wettability of the drug. Our results will significantly improve the solubility and dissolution of GA. In addition, the lower pKa value of TSD indicates that higher ionization is beneficial to the dissolution of the drug. This study should facilitate further developments of TSDs containing alkalizers to improve the dissolution of weakly acidic drugs and gain a richer understanding of the mechanism of dissolution.