Deep eutectic solvents: A strategy for boosting alprazolam solubility and permeability in an intestinal membrane model

چکیده مقاله

This study focuses on alprazolam (Alp), a benzodiazepine with limited water solubility, and investigates its solubility enhancement in the presence of two different deep eutectic solvents (DESs), utilizing choline chloride (ChCl) as the hydrogen bond acceptor and oxalic acid (OX) and glycerol (GLY) as hydrogen bond donors. The influence of Alp solubility on its permeability across the small intestine membrane was subsequently explored using molecular dynamics simulations. The solubility of Alp in these DESs was quantitatively assessed through UV–visible spectroscopy and Fourier-transform infrared (FTIR) spectroscopy, complemented by molecular dynamics (MD) simulations and density functional theory (DFT) analysis to elucidate the underlying molecular mechanisms. The results revealed a remarkable solubility enhancement of over 3100-fold in the ChCl/ OX system compared to pure water. MD simulations demonstrated a homogeneous distribution of Alp molecules within the DES systems, highlighting a considerable reduction in self-aggregation compared to aqueous environments—an essential factor for improving drug permeability across the intestinal membrane. Furthermore, the analysis of mass density profiles and radial distribution functions confirmed that Alp exhibits enhanced permeability, particularly in the ChCl/OX system, where it penetrates deeply into the hydrophobic regions of the membrane. Additionally, the study emphasizes the impact of DESs on the structural characteristics of the intestinal membrane, specifically regarding its thickness, area per lipid, and order parameter. These findings underscore the potential of DESs not only to improve the solubility of poorly soluble drugs significantly but also to enhance their absorption characteristics in biological membranes, paving the way for the development of more effective pharmaceutical formulations.