**1. Introduction**

In drug development, improving the poor water solubility of many active pharmaceutical ingredients (APIs) is an attractive area of research. In addition to the formulation of low-crystallinity solids such as solid dispersions [1,2] and cyclodextrin inclusion compounds [3], other methods can increase solubility through the formation of a stable multi-component crystalline state such as salt formation [4], co-crystallization [5], and salt co-crystallization [6–8], in which the crystal structure differs from the mother API crystal, providing an opportunity to change the solubility. Among these strategies, salt formation is a common method for enhancing the solubility of some APIs with acidic or basic functional groups (carboxy, conjugated hydroxy, amino, etc.) [9,10]. In particular, sodium salt formation is a well-known technique for increasing the solubility of poorly soluble acidic APIs in drug development, and sodium ions account for approximately 60% of the counter cations of acidic API salts [11].

Sodium API salts often form hydrate crystals in which the water coordination geometry around Na<sup>+</sup> is more flexible than the structure of the transition metal ion hydrate owing to the s-block atomic nature of Na [12]. This "pseudo-coordination bond" property

**Citation:** Oyama, H.; Miyamoto, T.; Sekine, A.; Nugrahani, I.; Uekusa, H. Solid-State Dehydration Mechanism of Diclofenac Sodium Salt Hydrates. *Crystals* **2021**, *11*, 412. https:// doi.org/10.3390/cryst11040412

Academic Editor: Sławomir Grabowski

Received: 25 February 2021 Accepted: 7 April 2021 Published: 12 April 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

of Na+–O(water) interactions contributes the specific hydration–dehydration behaviors of sodium API salts [13–19].

Hydrate crystals often undergo dehydration according to variations in the ambient temperature or humidity and transform into an anhydrous phase with different physicochemical properties [20,21]. Approximately one in three pharmaceutical compounds form hydrate crystals [22], and analyzing the X-ray crystal structure is essential [23] because the physicochemical properties of crystalline materials, such as their solubility [24], hygroscopicity [25,26], and tableting properties [27] depend on their crystal structure [28]. Sometimes, alternations in the crystal structure induced by a dehydration/hydration result in a color change [29,30]. For pharmaceutical hydrates, such property changes may affect their bioavailability and safety as pharmaceutical products. Therefore, the structural investigation of polymorphic transitions and the establishment of dehydration mechanisms of drug hydrates are both important processes in drug development [31].

The nonsteroidal anti-inflammatory drug diclofenac (DIC, 2-[2-((2,6-dichlorophenyl) amino)phenyl]acetic acid; Figure 1) is a widely used analgesic, and owing to its high permeability but low solubility, it is categorized as a Biopharmaceutics Classification System (BCS) Class II [32]. Since DIC has an acidic carboxyl group, it can be formulated as a salt with sodium or potassium to improve its solubility. Diclofenac sodium (DIC-Na) has been reported to form several hydrate crystals (Table S1, the Supplementary Materials). Until now, however, the crystal structure of the anhydrous form of DIC-Na and the structural relationship among this anhydrate and DIC-Na hydrates have not yet been elucidated. The crystal structures of DIC-Na pentahydrate, 4.75-hydrate (4.75H), and tetrahydrate were investigated independently, and the reported lattice parameters were almost identical [33–35], implying either that they are isostructural hydrates or that hydrate water molecules are misplaced. The trihydrate has also been recognized in the literature, but its crystal structure is still unknown, and the number of water molecules it contains is not clear [36]. In addition, a hemi-heptahydrate (3.5H) form was reported very recently [37]. Multi-component crystals of DIC-Na with organic agents such as phenanthroline [38] and L-proline [39] have also been reported. In particular, the DIC solubility achieved by forming the DIC-Na L-proline salt cocrystal was significantly higher than that of DIC-Na [39]. In the DIC-Na L-proline study, a new hydrate form was observed, but the structure was not revealed. Furthermore, in order to complete the overall picture of the DIC-Na hydrate structures, analyzing the crystal structure of the anhydrous form of DIC-Na is essential, which would also establish the complicated hydration–dehydration mechanism of DIC-Na hydrates. The elucidation of such mechanisms is important in the pharmaceutical sciences.

**Figure 1.** Molecular structure of diclofenac (DIC).

In this study, a novel crystalline phase, anhydrate (AH), was revealed by singlecrystal X-ray diffraction (SCXRD) analysis, and the 4.75H and 3.5H crystal structures were re-analyzed for an accurate structural comparison under the same measurement conditions, such as temperature. Simultaneous powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) measurements were used to visualize the multistep dehydration process of DIC-Na 4.75H. Based on the crystal structures, the dehydration mechanism of DIC-Na 4.75H is discussed.
