Crystal structure of a new hydrate form of the NSAID sodium diclofenac

The crystallization of a new hydrated form of sodium diclofenac was achieved, with the anions surrounding an [Na4]4+ cationic cluster formed with water molecules and carboxylic O atoms.


Chemical context
Diclofenac (IUPAC name: 2-[2-(2,6-dichloroanilino)phenyl]acetic acid, C 14 H 11 Cl 2 NO 2 ), sold under the brand names Voltaren and Ecofenac, among others, is a non-steroidal antiinflammatory drug (NSAID), with antipyretic and analgesic properties. It is prescribed for pain management in chronic inflammatory disorders, like arthritis, rheumatoid arthritis, and osteoarthritis (Sallmann, 1986). It is available as sodium diclofenac (SD hereafter) or potassium diclofenac, and generated global retail sales of over USD 440 million in 2018.
Diclofenac acid is a polymorphous compound, for which crystal structures have been reported in space groups C2/c (Moser et al., 1990;Kovala-Demertzi et al., 1993;Muangsin et al., 2004;Niranjana Devi et al., 2019), P2 1 /c (Castellari & Ottani, 1997;Perlovich et al., 2007;King et al., 2011) and Pcan (Jaiboon et al., 2001). This acid can also be co-crystallized with small aromatic compounds (e.g. Bá thori et al., 2011;Zheng et al., 2019). Regarding the carboxylate anion, C 14 H 10 Cl 2 NO 2 The exact water content of the SD salt used by manufacturers as medicine-grade API remains unclear. Vendors generally refer to the CAS-referenced compound CAS-15307-79-6, and describe the raw material as 'slightly hygroscopic'. The aforementioned X-ray structures correspond to the pentahydrate salt, SDÁ5H 2 O (Muangsin et al., 2002) and to a slightly less hydrated phase, SDÁ4.75H 2 O (Llinà s et al., 2007). In the former study, crystals were obtained by slow evaporation of a mixture of chitosan and SD dissolved in ethyl acetate and aqueous acetic acid. The space group is reported as P2 1 /m, with two independent diclofenac anions and partially disordered Na + cations and water molecules. In the latter study, single crystals were obtained by recrystallization from ethanol of commercially available anhydrous SD, affording crystals with cell parameters very close to those of the previous study. However, the structure was refined in space group P2 1 , with four independent diclofenac anions, and 4.75 water molecules per diclofenac. All sites are fully occupied, and the Na positions are different in both structures.
With these results, Llinà s et al. (2007) concluded that in the solid state, the formula of the stable hydrated form of sodium diclofenac should be close to SDÁ5H 2 O. We now report that a less hydrated form with formula SDÁ3.5H 2 O can be crystallized in space group P1, when SD is recrystallized from acetone.

Structural commentary
The asymmetric unit of the triclinic cell contains two diclofenac anions, balanced with two Na + cations. One diclofenac is hydrogen bonded to water molecules, while the other is bridging the Na + cations, with bond lengths Na1-O2 = 2.535 (3) and Na2-O2 = 2.401 (3) Å . The bridge is close to an inversion centre, and then a third Na-O bond is formed, with Na1 i -O2 = 2.542 (3) Å [symmetry code: (i) 2 À x, Ày, 1 À z]. The resulting 3 bridging mode of the diclofenac anion is very uncommon. The triply bridging O-atom mode is well known in metal alkoxides, but very rare for carboxylates (Wu & Mak, 1996), and found almost exclusively in polymeric compounds. This bridging mode was not observed in the previously reported SD hydrates. The asymmetric unit is completed with seven water molecules bonded to the Na + cations at distances ranging from 2.387 (3) to 2.608 (4) Å . One water molecule, O6, bridges the Na + cations, while all others are in terminal positions on their carrier sites. Once the crystallographic inversion centre operates to form the complete structure, the unit-cell content is Na 4 (C 14 H 10 Cl 2 NO 2 ) 4 (H 2 O) 14 (Fig. 1). The compound formula may be reduced to the minimal chemical formula SDÁ3.5H 2 O. There is no evidence of disorder in the molecular structure.
Although numerous Na/O/H 2 O clusters are reported in the literature, the Na-based framework that holds together the four diclofenac ions in the unit cell is only found as a subframework in a few structures with higher complexity, such as dicubanes (Song et al., 2007). The [Na 4 (O carbox ) 2 (H 2 O) 14 ] 4+ cluster, which includes two carboxylate O atoms from the coordinated diclofenac anions, can be described as an incomplete dicubane cluster formed by face-sharing incom-plete cubes. All Na centres are six-coordinate, with distorted octahedral geometry and cis O-Na-O angles in the range 79.41 (10) to 115.21 (10) .
The two independent diclofenac ions display similar conformations, characterized by the dihedral angle formed by the benzene rings, 54.2 (1) and 58.9 (1) . This conformation falls within the expected range of dihedral angles: for 151 structures retrieved from the CSD including the diclofenac anion, the benzene-benzene dihedral angles span the range 54.3 to 89.0 (Groom et al., 2016). This bent conformation results from the rotational barrier imposed by the Cl atoms, and is not influenced by the presence of the core [Na 4 (O carbox ) 2 (H 2 O) 14 ] 4+ cluster. This conformation is also stabilized via intramolecular N-HÁ Á ÁO hydrogen bonds of moderate strength, between the amine and carboxylate groups ( Table 1, entries 1 and 2). The torsion between the aromatic rings is indeed recognized as a factor related to the biological properties of diclofenac (Menassé et al., 1978;Sallmann, 1986).

Figure 2
Part of the crystal structure of SDÁ3. The complete 3D hydrogen-bonding scheme for the whole structure is complex, and obviously very different from supramolecular structures observed in the previously reported SD hydrates (Muangsin et al., 2002;Llinà s et al., 2007). These differences, resulting from the arrangement of water molecules in the crystal, could be relevant regarding the actual bioavailability of SD in vivo (Llinà s et al., 2007). On the other hand, the actual formula of the API used by manufacturers remains unclear, at least with respect to the hydration status. Even some variability of the API formula from one brand to another cannot be excluded. Moreover, we believe that other stable hydrates could be crystallized from commercial SD. Indeed, we did not evaluate the influence of the excipients extracted with SD nor purity of the acetone used for extraction, on the crystallization of the new hydrate.

Synthesis and crystallization
Commercial Volfenac Retard was used (Productos farmacéuticos Collins, Mexico). Each tablet weighs ca 433 mg and includes 100 mg of the API. Main excipients are sucrose, and a small amount of magnesium stearate. One tablet was crushed in a mortar, the resulting fine powder was dispersed in acetone (40 mL) at room temperature, and then filtered over a Bü chner funnel. The yellow solution was left at room temperature for slow evaporation of solvent, affording yellow prismatic single crystals suitable for X-ray diffraction.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 2. Apparently, all studied single crystals were twinned by rotation around reciprocal axis b * . As a consequence, the unit-cell parameters emulate a monoclinic symmetry, with ' ' 90 (