*3.1. Crystal Structure of DIC-Na Hydrates*

The crystal structures of DIC-Na 4.75H, 3.5H, and AH were successfully analyzed by SCXRD, and the crystallographic data are shown in Table 1. The phase agreement between the solid powder samples obtained by the method described in Section 2.2 and the analyzed single crystals was confirmed by their PXRD patterns.

**Table 1.** Crystallographic data of diclofenac sodium (DIC-Na) hydrates and anhydrate.


The lattice parameters of DIC-Na 4.75H shown in Table 2 are identical to those reported by Llinàs et al. (Table S1) [34]. The asymmetric unit contained four DIC anions and 19 water molecules (Figure 2). Na<sup>+</sup> ions were surrounded by a large amount of water, and Na<sup>+</sup> was coordinated to either six or five water molecules (6-coordination or 5-coordination, respectively), while DIC anions formed no coordination bonds with Na<sup>+</sup> ions. Five of the 19 water molecules did not coordinate with Na<sup>+</sup> ions and existed as crystalline water molecules in the crystal.

Similarly, the lattice parameters of DIC-Na 3.5H in Table 1 are the same as those reported by Nieto et al. (Table S1) [37]. DIC-Na 3.5H crystallized in the triclinic *P*1 space group, and its asymmetric unit, consisted of two DIC anions, two Na<sup>+</sup> cations, and seven water molecules (Figure 3). All water in the crystal was bound to Na<sup>+</sup> . One Na<sup>+</sup> ion was coordinated to either five water oxygens and a carboxylate oxygen or to four water oxygens and two carboxylate oxygens of DIC, resulting in a 6-coordination configuration in both cases (Figure 4). Although the unit cell of 3.5H was relatively similar to that of 4.75H, its crystallographic symmetry was reduced from monoclinic to triclinic.

**Figure 2.** Asymmetric unit of DIC-Na 4.75H, with fourteen bonded (pink) and five non-bonded (blue) water molecules and 6-coordinated (purple) and 5-coordinated (orange) Na<sup>+</sup> ions.

**Figure 3.** Asymmetric unit of DIC-Na 3.5H (yellow water molecules are not included). One (**left**) DIC is connected to Na<sup>+</sup> ions, but the other (**right**) forms hydrogen bonds with water and does not bond with Na<sup>+</sup> ions.

**Figure 4.** Coordination environment around Na<sup>+</sup> ions in DIC-Na 3.5H. Na2 (purple) is connected to five H2O oxygens and one carboxylate oxygen, whereas Na1 (orange) bonds to four H2O oxygens and two carboxylate oxygens. However, in both cases, Na adopts a six-coordinated configuration.

For the first time, this work elucidated the crystal structure of DIC-Na AH, which crystallizes into an orthorhombic system with the *Pbca* space group, wherein two DIC anions and sodium cations are independent (Figure 5). In contrast to 4.75H and 3.5H, AH does not show an alternating layered structure consisting of a hydrophilic region (Na<sup>+</sup> , water, and carboxylate) and hydrophobic region (the main part of DIC) (Figure 6). However, a one-dimensional hydrophilic Na–O chain structure appears along the b-axis in the AH crystal, where [Na–O]<sup>2</sup> squares and [Na–OCO(carboxylate)] kites are connected alternately to form an infinite rigid chain (Figure 7). In the crystal structure, each Na<sup>+</sup> ion is coordinated to five carboxylate oxygens (three monodentate carboxylates and one bidentate carboxylate) and adopts a 5-coordinated geometry. To visualize the conformational differences in the two independent DIC anions in the asymmetric unit, they are overlaid in Figure 8, which demonstrates great variation at the carboxylate moiety and the second aromatic ring with chlorine atoms.

**Figure 5.** Asymmetric unit of DIC-Na AH.

**Figure 6.** Structural comparison among unit cells of three DIC-Na hydrates.

**Figure 7.** One-dimensional Na–O chain in DIC-Na AH. (**a**) Crystal packing diagrams viewed from the b- (left) and c-axes (right). (**b**) Infinite motif composed of Na–O–Na–O squares and Na–O–C–O kites.

**Figure 8.** Structural overlay between two independent DIC molecules in DIC-Na AH shown in Figure 5.

The consistency between the powdery materials used in subsequent experiments and the single-crystalline phases was confirmed using their PXRD patterns, and the patterns of the experimental samples were verified to be identical to those calculated from the crystal structure via Mercury 4.3.1 (Figure 9) [43].
