The methanol sesquisolvate of sodium naproxen

A new solvatomorph of sodium naproxen with methanol as solvent is reported. The asymmetric unit comprises two formula units of sodium naproxen and three methanol molecules.

The asymmetric unit of the methanol solvate of sodium naproxen, systematic name: sodium (2S)-2-(6-methoxynaphthalen-2-yl)propanoate methanol sesquisolvate, Na + ÁC 14 H 13 O 3 À Á1.5CH 3 OH, comprises two formula units of the molecular salt and three methanol molecules. One of the sodium cations exhibits a coordination number of six and is bonded to three carboxylate O atoms and three methanol OH groups whereas the second sodium cation has a coordination number of seven, defined by five carboxylate O atoms and two methanol OH groups. Both coordination polyhedra around the sodium cations are considerably distorted. The two types of cations are bridged into polymeric chains extending parallel to [010]. This arrangement is stabilized by intrachain O-HÁ Á ÁO hydrogen bonds between methanol ligands as donor and carboxylate O atoms as acceptor groups. The hydrophobic 6-methoxynaphthyl moieties flank the hydrophilic sodium oxygen chains into ribbons parallel to [010]. There are no noticeable intermolecular interactions between these ribbons. One of the 6-methoxynaphthyl moieties is disordered over two sets of sites in a 0.723 (3):0.277 (3) ratio.

Chemical context
Naproxen, or (S)-2-(6-methoxynaphthalen-2-yl)propanoic acid, and in particular its better soluble sodium salt are nonsteroidal anti-inflammatory drugs with pain-relieving and antipyretic properties. For a recent project on the crystallization of active pharmaceutical ingredients (APIs; Kovačič et al., 2012), we used sodium naproxen as a model substance. During these investigations, we obtained the methanol sesquisolvate as a solvatomorph of sodium naproxen, [Na(C 14 H 13 O 3 )]Á1.5CH 3 OH. Although a preliminary structure model of this compound has been reported as part of a PhD thesis (Chavez, 2009), it was never published or deposited in the Cambridge Structural Database (Groom et al., 2016). We report here the precise crystal structure determination of [Na(C 14 H 13 O 3 )]Á1.5CH 3 OH, (I), including disorder of one 6-methoxynaphthyl moiety that was not modelled in the preliminary study (Chavez, 2009). ISSN 2056-9890

Structural commentary
The asymmetric unit of (I) is displayed in Fig. 1 and comprises two Na + cations, two naproxate anions (one of which shows disorder of the 6-methoxynaphthyl moiety) and three methanol molecules (Z 0 = 2). Na1 is bound to six oxygen atoms, three of them originating from methanol OH groups and three from monodentate carboxylate groups (O2; O5; O4 i ; for symmetry codes, see: Table 1). The Na1-O bond lengths are not uniformly distributed, revealing a distorted [5 + 1] coordination with five shorter bonds between 2.2355 (14) and 2.4403 (14) Å and one significantly longer bond of 2.856 (2) Å to the OH group of a methanol molecule. In comparison, the coordination sphere of Na2 is enlarged to seven coordination partners, two of them from methanol OH groups, four from two chelating carboxylate groups (O1 i ,O2 i ; O4 i ,O5 i ) and one from a monodentate carboxylate group (O5). The Na2-O distances are somewhat more evenly distributed and range from 2.3418 (13) to 2.5983 (14) Å . Nevertheless, the resulting coordination polyhedron around Na2 is likewise distorted. Details of the Na-O coordination spheres are depicted in Fig. 2. The bond-valence sums (Brown, 2002) of 1.24 and 1.17 valence units for Na1 and Na2, respectively, are higher than expected and point to some strain in the structure.
The two sodium cations are bridged by the O1S and O2S methanol OH groups and by carboxylate atoms O2, O4 and O5 into zigzag chains extending parallel to [010]. The third methanol molecule is terminally bound to Na1. The hydrophobic 6-methoxynaphthyl moieties flank the hydrophilic [Na-O] n chains, leading to the formation of ribbons along the chain direction (Fig. 3). The methoxy groups attached to the naphthyl rings are twisted slightly out of the aromatic plane, with dihedral angles of 6.42 (18) for ring (C1-C10) and methoxy group O3-C14, and 5.2 (3) for ring (C15A-C24A) and methoxy group O6A-C28A.

Figure 1
The asymmetric unit of (I) with displacement ellipsoids drawn at the 30% probability level. The minor disordered part B of one 6-methoxynaphthyl moiety is displayed with open bonds and without labelling of atoms.

Figure 2
Part of the crystal structure of (I) emphasizing the coordination environments of the two Na + cations. Displacement ellipsoids are drawn at the 50% probability level. Symmetry codes refer to Table 1.

Figure 3
The crystal structure of (I) in a projection along [001]. O-HÁ Á ÁO hydrogen bonds within a ribbon are displayed in blue on the right hand side. For clarity, only the major part A of the disordered 6-methoxynaphthyl moiety is shown.
There are no notable intermolecular interactions between adjacent ribbons involving the outer hydrophobic parts. It seems that cohesion of the ribbons is dominated by van der Waals forces only.

Database survey
The crystal structure of naproxen, i.e. the free acid (AE)2-(6methoxy-2-naphthyl)propionic acid, was reported by Ravikumar et al. (1985).  (Bond et al., 2013). The structural motif of ribbons formed between sodium cations and oxygen atoms is likewise found in all anhydrous and hydrous sodium naproxen structures.
Only one methanol solvate of naproxen is deposited in the CSD. However, this is an Na salt of naproxen with an additional free acid molecule, viz. sodium hydrogen bis(naproxate) methanol disolvate, [Na(C 14 H 13 O 3 )(C 14 H 14 O 3 )]Á2CH 3 OH (Perumalla & Sun, 2012). A homologous series of alcohol solvates of sodium naproxen obtained as polycrystalline powders and without structure determinations was reported by Chavez et al. (2010). During these investigations, another methanol solvate of sodium naproxen was reported with only one methanol molecule per formula unit (Chavez, 2009;Burgess et al., 2012).

Synthesis and crystallization
Crystals of sodium naproxen methanol sesquisolvate were grown by slow crystallization in methanol. Polycrystalline anhydrous sodium naproxen was dissolved in methanol to yield a solution 20% in weight of the salt. 0.5 ml of this solution were heated to 338 K and slowly cooled down to room temperature (298 K) over the course of 130 min (cooling rate 0.3 K min À1 ). Colourless parallelepipeds with edge lengths of up to 1 cm were obtained. A suitable fragment was broken from a larger specimen for the X-ray diffraction experiment.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 3. The structure model obtained with SHELXT (Sheldrick, 2015a) was very similar to the preliminary model of Chavez (2009) from 173 K data using Cu K radiation. After placing all atoms with full occupancy in the asymmetric unit, elongated displacement parameters of atoms of one of the 6-methoxynaphthyl moieties and conspicuous electron density peaks in the vicinity of these atoms were found. This model converged with R[F 2 > 2(F 2 )] = 0.08 and wR(F 2 ) = 0.23. Consideration of disorder over two sets of sites for this fragment led to more spherical atoms and much better reliability factors (Table 3). The refined occupancy ratio of the two disordered parts is 0.723 (3):0.277 (3) for major part A: minor part B. The positions of C-bound H atoms were calculated and refined using a riding model, with C-H = 0.93-0.98 Å , and with U iso (H) = 1.2U eq (C) or 1.5U eq (C) for methyl H atoms. H atoms bound to methanol O atoms were clearly discernible from difference maps. They were refined with distance restraints of 0.85AE2 Å and free U iso (H)   Computer programs: APEX3 and SAINT (Bruker, 2017), SHELXT (Sheldrick, 2015a), SHELXL2017 (Sheldrick, 2015b), Mercury (Macrae et al., 2008), ATOMS (Dowty, 2006) and XP in SHELXTL (Sheldrick, 2008), publCIF (Westrip, 2010). Table 2 Hydrogen-bond geometry (Å , ). (19) 172 (3) data set (Table 3), revealing that the usual (S) enantiomer is present.
Reflections (100) and (001) were obstructed by the beam stop and were omitted from the refinement.
Lattice parameters refined from single-crystal room temperature X-ray data are a = 12.8458 (9), b = 8.0235 (6) program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2017 (Sheldrick, 2015b); molecular graphics: Mercury (Macrae et al., 2008), ATOMS (Dowty, 2006) and XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: publCIF (Westrip, 2010).  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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (