**5. Conclusions**

The novel crystalline phase of DIC-Na AH was revealed by SCXRD. The re-determination of the crystal structure and crystallographic investigation of 4.75H showed that the presence of non-coordinated water molecules caused pseudo-symmetry and structural complexity. The multi-step dehydration mechanism of DIC-Na 4.75H was successfully elucidated using simultaneous PXRD-DSC, TG, and DVS, as well as a comparison of the crystal structures. During the first dehydration step, only water molecules that were not coordinated to Na<sup>+</sup> ions were lost, which led to the generation of 3.5H. The second dehydration step into the anhydrous phase (AH) was accompanied by a large structural change. For the first time, this work successfully elucidated the solid-state dehydration transition landscape of DIC-Na, which is a commercially available form of this API, using X-ray crystallographic analysis. These findings help understand the dehydration/hydration mechanism as well as the physicochemical properties of pharmaceutical crystals.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/cryst11040412/s1, Figure S1: DSC diagram of DIC-Na 4.75H, Table S1: Crystal structures of diclofenac sodium (DIC-Na) hydrates published thus far.

**Author Contributions:** Conceptualization, H.O., T.M. and H.U. Structural analysis, H.O. and T.M. Investigation, H.O., T.M. and I.N. Writing—original draft preparation, H.O. and T.M. Writing review and editing, H.O., A.S. and H.U. Visualization, H.O. Supervision, A.S. and H.U. Project administration, H.U. All authors have read and agreed to the published version of the manuscript.

**Funding:** Part of this work was supported by JSPS KAKENHI Grant Number JP18H04504 and 20H04661 (H.U.).

**Data Availability Statement:** CCDC 2065083, 2065085, and 2065086 contains the supplementary crystallographic data for this paper (3.5H, 4.75H, and AH, respectively). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

**Acknowledgments:** The authors are thankful to Etsuo Yonemochi (Hoshi University) for the DVS measurement.

**Conflicts of Interest:** The authors declare no conflict of interest.
