Structural Studies of Sodium Counterion on Naproxen: From Solid State to Stability

Naproxen (NPX) is a widely used nonsteroidal anti‐inflammatory drug (NSAID) with limited aqueous solubility, commonly formulated as its sodium salt (SNPX) to enhance dissolution and absorption. This study systematically examines the influence of the sodium counterion on the structural, supramolecular, and electronic properties of NPX. Comparative analyses are performed using single‐crystal X‐ray diffraction, Hirshfeld surface (HS) mapping, and topological evaluation via the quantum theory of atoms in molecules (QTAIM). Density functional theory (DFT) calculations at the M06‐2X/6‐311++G(d,p) level provided further insights into chemical reactivity through frontier molecular orbitals and molecular electrostatic potential (MEP) maps. Both NPX and SNPX crystallize in the monoclinic space group P2 1 with overall geometric similarity, though significant differences are observed in the carboxyl group. NPX is stabilized by O─H···O hydrogen bonds, while SNPX exhibits four nonequivalent O···Na electrostatic contacts in addition to C─H···π and C─H···O interactions. Electronic descriptors revealed that SNPX and NPX − are more reactive and polarizable than neutral NPX, consistent with enhanced solubility and pharmaceutical performance. These findings highlight the critical role of counterions in modifying supramolecular arrangements and physicochemical properties, reinforcing the importance of solid‐state characterization in the development of Biopharmaceutics Classification System (BCS) Class II drugs.