Improving physicochemical properties and pharmacological activities of ternary co-amorphous systems

Abstract

The formation of co-amorphous by combining low molecular weight compounds with drugs is a relatively new technology in the pharmaceutical field, which can significantly improve the solubility, dissolution, and stability of poorly water-soluble drugs. However, in our previous studies, the binary co-amorphous system of andrographolide-oxymatrine (AP-OMT) was found to have obvious recrystallization and poor dissolution behavior. Therefore, in this study, we designed three stable ternary co-amorphous systems to improve the physicochemical properties of the binary co-amorphous system of AP-OMT. The ternary co-amorphous systems were prepared with AP, OMT, and trans-cinnamic acid (CA), p-hydroxycinnamic acid (pHCA), or ferulic acid (FA). Intermolecular hydrogen bonds were confirmed by spectroscopy and molecular dynamics simulation. Solubility studies showed that the solubility of the ternary co-amorphous systems of AP-OMT-CA/pHCA/FA was significantly increased compared with that of crystalline AP. Dissolution experiments suggested that the ternary co-amorphous systems of AP-OMT-CA/pHCA/FA exhibited better dissolution behavior without significant recrystallization compared to the binary co-amorphous AP-OMT. The stability study confirmed that the ternary co-amorphous system of AP-OMT-CA/pHCA/FA maintained good physical stability in the long term for 18 months. In addition, pharmacological experiments revealed that the ternary co-amorphous systems of AP-OMT-CA/pHCA/FA have an excellent safety profile and its anti-Alzheimer's disease effects are significantly improved compared to that of the binary co-amorphous systems of AP-OMT. Moreover, this study also found that reducing the pKa value of low molecular weight co-formers would affect the intermolecular interactions and improve the solubility of drugs in the ternary co-amorphous systems. In conclusion, we have successfully prepared ternary co-amorphous systems of AP-OMT-CA/pHCA/FA by amorphization technique, which improves the physicochemical properties of the binary co-amorphous systems of AP-OMT and anti-Alzheimer's disease activity in the Caenorhabditis elegans model. The mechanism for the influence of the pKa value of the co-formers on the physicochemical properties of the ternary co-amorphous system was preliminarily explored, providing theoretical guidance for the development of the ternary co-amorphous system.

Keywords: Andrographolide; Molecular dynamics simulation; Physicochemical properties; Ternary co-amorphous systems; anti-Alzheimer's disease activity.