Crystal structure of the non-steroidal anti-inflammatory drug (NSAID) tolmetin sodium

The asymmetric unit of the title two-dimensional polymer, sodium 2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetate dihydrate, Na+·C15H14NO3 −·2H2O, contains two sodium cations, two organic anions and two water molecules. The title compound exhibits analgesic, anti-inflammatory and antipyretic activities.

The asymmetric unit of the title compound, sodium 2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetate dihydrate, Na + ÁC 15 H 14 NO 3 À Á2H 2 O, contains two sodium cations, two organic anions (A and B) and two water molecules. The coordination geometry around the sodium cations corresponds to a distorted octahedron. Each pair of sodium cations (A-A or B-B) is chelated by two bridging anions coordinated by the O atoms of the deprotonated carboxylic groups, and each sodium atom is coordinated by an O atom of a third anion, which connects pairs of sodium atoms, and a water molecule. As a result, a twodimensional polymer is formed in the crystal. Hirshfeld surface analysis and twodimensional fingerprint plots were used to analyze the intermolecular contacts present in the crystal.

Chemical context
Non-steroidal anti-inflammatory drugs (NSAIDs) are the gold standard for the management of acute or moderate pain associated with inflammatory changes or trauma (Klippel et al., 2010). These drugs can suppress inflammation, lower body temperature, and reduce pain. In terms of the scale and frequency of use of NSAIDs, they rank first in the world. The combination of analgesic, anti-inflammatory and antipyretic effects determines the advantage of NSAIDs over other pain relievers. Tolmetin, which is one of the most widely used NSAIDs, belongs to the class of hetarylacetic acids (Moreland, 2004;McEvoy, 2007). It is commonly used for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and periarticular disorders. Tolmetin sodium (CAS Number 64490-92-2) is the sodium salt form of tolmetin with analgesic, antiinflammatory and antipyretic activities (Cordrey, 1976). In addition, the anticancer activity of Tolmetin has been studied and it was reported that tolmetin has effects on increasing the cytotoxic activity of anti-cancer drugs (Duffy et al., 1998). It inhibits the function of -catenin, so tolmetin can be used to develop new anti-cancer agents (Lu et al., 2005). ISSN 2056-9890 Recently, work has appeared on the use of this well-known active pharmaceutical compound tolmetin sodium for the development of new dosage forms, for example, novel rectal mucoadhesive hydrogels (Ramadan et al., 2018), thermosensitive mucoadhesive liquid suppositories for rectal delivery (Akl et al., 2019) and different topical gel formulations (Auda et al., 2015).
However, to date, the crystal structure of the substance tolmetin sodium has not been studied and described. Knowledge of the spatial structure of the crystal form of the active pharmaceutical compound is very important to ensure the quality and bioavailability of the drug and, according to the latest pharmacopoeia requirements, X-ray diffraction studies are mandatory for pharmaceutical development. In this work, we carried out an X-ray structural analysis of the crystal form of the substance tolmetin sodium and filled the gap in these studies.

Structural commentary
The sodium salt of the C 15 H 14 NO 3 organic anion exists in the crystal as a 1:2 hydrate (Fig. 1). The asymmetric unit contains two sodium cations, two organic anions (A and B) and two water molecules. The coordination geometry around the sodium cations corresponds to a distorted octahedron. Each pair of sodium cations (A-A or B-B) is chelated by two bridging anions coordinated by the O atoms of the deprotonated carboxylic groups, and each sodium atom is coordinated by an O atom of a third anion, which connects pairs of sodium atoms, and a water molecule. As a result, a two-dimensional polymer is formed in the crystal (Fig. 2). The Na-O anion distances are 2.298 (2), 2.416 (2) and 2.441 (2) Å while the Na-O water distances are on average slightly longer, being in the range 2.364 (2)-2.607 (3) Å . It is worth noting that the terminal atom O2B does not interact with a sodium cation.
The analysis of the molecular structure of the anions showed that the terminal C1-O1 and C1-O2 bonds [1.249 (3) and 1.250 (3) Å in anion A, 1.243 (3) and 1.250 (3) Å in anion B] are very similar to each other and are slightly elongated in comparison with the standard value of 1.210 Å of a carbonyl group (Burgi et al., 1994). It is also much shorter than the standard C-O single bond observed for a hydroxyl group (1.362 Å ). We can assume that the negative charge is delocalized on both terminal O atoms for each anion.

Figure 1
The molecular structure of the title compound showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Supramolecular features
In the crystal, O-HÁ Á ÁO hydrogen bonds (Table 1) are formed between H atoms of the water molecules (donors) and O atoms of the anions (acceptors), forming a two-dimensional network parallel to (001).

Hirshfeld surface analysis
Crystal Explorer 17.5 (Turner et al., 2017) was used to analyze the interactions in the crystal: fingerprint plots mapped over d norm (Figs. 3 and 4) were generated. The molecular Hirshfeld surfaces were obtained using a standard (high) surface resolution with the three-dimensional d norm surfaces mapped over a fixed color scale of À0.666 (red) to 1.384 (blue). The areas colored red on the d norm -mapped Hirshfeld surfaces ( Fig. 3) correspond to the contacts which are shorter than van der Waals radii sum of the closest atoms. As can be seen in Fig. 4, short contacts are present at the hydrogen atoms and oxygen lone pair of the water molecules. In addition, the areas of short contacts are located at the oxygen atoms of carbonyl groups (Fig. 3).
All the intermolecular interactions of the title compound are shown in the two-dimensional fingerprint plot presented in Fig. 4. The contribution of the OÁ Á ÁH/HÁ Á ÁO contacts, corresponding to the O-HÁ Á ÁO interaction, is represented by a pair of long sharp spikes (22.1%). This indicates that O-HÁ Á ÁO hydrogen bonds are the strongest interactions in the crystal of the title compound (Fig. 4).

Crystallization
Crystallization by slow evaporation of an aqueous solution of tolmetin sodium was carried out to provide colorless blockshaped single crystals suitable for a X-ray diffraction analysis (Fig. 5).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms were placed in calculated positions (O-H = 0.98 Å , C-H = 0.93-0.96 Å ) and refined as riding with U iso H = 1.2U eq (C) or 1.5U eq (O, C-methyl). Crystals of tolmetin sodium.

Figure 3
The Hirshfeld surface of the title compound mapped over d norm .    (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction: CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: ShelXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009). Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.