Exploring the Physical Stability of Three Nimesulide–Indomethacin Co-amorphous Systems from The Perspective of Molecular Aggregates

ABSTRACT Co-amorphization of drugs has been a promising approach to enhance the apparent solubility and dissolution rate of poorly-water soluble drugs. Nimesulide, a BCS Ⅱ drug, was combined with indomethacin to form three co-amorphous systems at molar ratios of 2:1, 1:1 and 1:2 via quench cooling. The aim of this research was mainly to probe the relationship between physical stability (long-term stability and temperature sensitivity) and intermolecular interaction modes among three co-amorphous systems. The calculated glass transition temperature by the Gordon-Taylor equation shows the presence of intermolecular interactions within co-amorphous systems. FTIR spectra further verify that there are hydrogen bonds and π-π stacking in intermolecular interactions. Specific atomic groups involved in the intermolecular hydrogen bonding were investigated using radial distribution function analysis based on molecular dynamic simulation. Gaussian calculation visually gives dominant molecular aggregate composed of multiple hydrogen bonding modes in co-amorphous systems and explains the stability difference of 1:2>1:1>2:1. Finally, powder dissolution profiles were conducted and the 1:2 system has the greatest dissolution advantage with six-fold improvement of dissolution rate compared with pure NMS.