Interpreting the Disordered Crystal Structure of Sodium Naproxen Tetrahydrate

The crystal structure of the tetrahydrate of the active pharmaceutical ingredient sodium naproxen is examined using single-crystal X-ray diffraction, supported by ¹³C and ²³Na solid-state NMR. The structure has previously been reported to be a heminonahydrate, Na⁺(naproxen^–)·4.5H₂O. The average structure in space group C2 contains layers of naproxen molecules that are ordered, except for two orientations of the carboxyl groups, and Na⁺/H₂O regions that exhibit complex disorder. The atomic positions in the disordered regions are interpreted as Na­(H₂O)₆ octahedra, alternately sharing edges and faces to define 1-D coordination polymers with translational periodicity twice that of the b axis in the average C2 structure. There is also one noncoordinated H₂O molecule per two naproxen molecules, giving an overall formula of {Na₂(H₂O)₇}²⁺(naproxen^–)₂(H₂O). Two resonances seen for the naproxen methyl group in ¹³C CP/MAS SS-NMR are accounted for by the presence of two orientations along the doubled b axis for the carboxyl group. A single resonance in the ²³Na SS-NMR is consistent with local 2₁/m symmetry in the Na⁺/H₂O regions. The single-crystal X-ray diffraction pattern contains diffuse rods in positions consistent with the doubled b axis, indicating a disordered stacking sequence for the Na⁺/H₂O sections.