Molecular Dynamics, Physical Stability and Solubility Advantage from Amorphous Indapamide Drug

Abstract

This study for the first time investigates physicochemical properties of amorphous indapamide drug (IND), which is a known diuretic agent commonly used in the treatment of hypertension. The solid-state properties of the vitrified, cryomilled and ball-milled IND samples were analyzed using X-ray powder diffraction (XRD), mass spectrometry, nuclear magnetic resonance (NMR), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS). These analytical techniques enabled us (i) to confirm the purity of obtained amorphous samples, (ii) to describe the molecular mobility of IND in the liquid and glassy state, (iii) to determine the parameters describing the liquid-glass transition i.e. Tg and dynamic fragility, (iv) to test the chemical stability of amorphous IND in various temperature conditions and finally (v) to confirm the long-term physical stability of the amorphous samples. These studies were supplemented by density functional theory (DFT) calculations and apparent solubility studies of the amorphous IND in 0.1 M HCl, phosphate buffer (pH=6.8), and water (25 and 37 °C).