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.

本研究采用单晶X射线衍射（single-crystal X-ray diffraction）技术，并辅以13C与23Na固态核磁共振（solid-state NMR）表征，对活性药物成分萘普生钠的四水合物晶体结构进行了系统解析。此前已有文献报道该化合物为半九水合物，其化学式为Na+(naproxen–)·4.5H2O。该结构在空间群C2下的平均晶胞结构中，萘普生分子层整体呈有序排列，仅羧基存在两种取向；而Na+/H2O区域则呈现复杂的无序性。无序区域的原子排布可被解析为Na(H2O)6八面体单元，这些八面体通过交替共享棱与面，构建出一维配位聚合物（coordination polymers），其平移周期性为平均C2结构中b轴的两倍。每两分子萘普生对应一分子非配位水分子，因此该化合物的整体化学式为{Na2(H2O)7}2+(naproxen–)2(H2O)。在13C交叉极化/魔角旋转固态核磁共振（CP/MAS SS-NMR）谱中，萘普生的甲基出现两处共振峰，该现象可归因于羧基沿翻倍后的b轴存在两种不同取向。23Na固态核磁共振谱中仅存在单一共振峰，这与Na+/H2O区域的局部21/m对称性相吻合。单晶X射线衍射图谱中出现了与翻倍b轴位置一致的漫散射棒状特征，表明Na+/H2O区域存在无序堆叠序列。