Structural basis for the transformation pathways of the sodium naproxen anhydrate–hydrate system

Crystal structures are presented for two dihydrate polymorphs (DH-I and DH-II) of the non-steroidal anti-inflammatory drug sodium (S)-naproxen. The structure of DH-I is determined from twinned single crystals obtained by solution crystallization. DH-II is obtained by solid-state routes, and its structure is derived using powder X-ray diffraction, solid-state ¹³C and ²³Na MAS NMR, and molecular modelling. The validity of both structures is supported by dispersion-corrected density functional theory (DFT-D) calculations. The structures of DH-I and DH-II, and in particular their relationships to the monohydrate (MH) and anhydrate (AH) structures, provide a basis to rationalize the observed transformation pathways in the sodium (S)-naproxen anhydrate–hydrate system. All structures contain Na⁺/carboxylate/H₂O sections, alternating with sections containing the naproxen molecules. The structure of DH-I is essentially identical to MH in the naproxen region, containing face-to-face arrangements of the naphthalene rings, whereas the structure of DH-II is comparable to AH in the naproxen region, containing edge-to-face arrangements of the naphthalene rings. This structural similarity permits topotactic transformation between AH and DH-II, and between MH and DH-I, but requires re-organization of the naproxen molecules for transformation between any other pair of structures. The topotactic pathways dominate at room temperature or below, while the non-topotactic pathways become active at higher temperatures. Thermochemical data for the dehydration processes are rationalized in the light of this new structural information.

1. Introduction

The correlation of molecular-level structure with observed physicochemical properties is a fundamental activity in the chemical sciences. Our interest lies principally with pharmaceutical compounds, for which robust physicochemical understanding is paramount (Connelly et al., 2011). According to regulatory guidelines (ICH, 2000; US-FDA, 2007), pharmaceutical companies are encouraged to search for alternative solid forms of active pharmaceutical ingredients (APIs), and to assess the risks associated with solid-state factors such as potential polymorphic transformations. In this context, hydrates have a particular importance because of the ubiquitous nature of water in our environment. Investigation and understanding of hydrates with pharmaceutical relevance, and especially the transformations that occur between different hydration states in anhydrate–hydrate systems, is therefore of significant interest within pharmaceutical materials science (Griesser, 2006; Zhang et al., 2004; Reutzel-Edens et al., 2003; Roy et al., 2008).

In this paper we consider the non-steroidal anti-inflammatory drug (NSAID) sodium (S)-naproxen (chemical structure shown in Scheme 1 with applied labelling scheme). The compound is known to exist as an anhydrate (AH), a monohydrate (MH), two dihydrate polymorphs (DH-I and DH-II) and a tetrahydrate (TH) (Di Martino et al., 2001, 2007; Kim & Rousseau, 2004; Malaj et al., 2009; Raijada et al., 2013). A thorough empirical study of the thermodynamic and kinetic aspects of dehydration in the system has been reported by Malaj et al. (2009). Those authors refer to the various phases as ASN (= AH), MSN (= MH), CSN (= DH-I), DSN (= DH-II) and TSN (= TH). We have also previously studied the transformation pathways for the system using multi-temperature dynamic vapour sorption (DVS) and variable-temperature/humidity powder X-ray diffraction (PXRD), and we have identified routes to isolate bulk samples of the various phases (Raijada et al., 2013).

A summary of the transformation behaviour is shown in Fig. 1. For hydration of AH, different pathways are followed depending on the temperature. At 25°C/55% relative humidity AH transforms to DH-II, while at 50°C/50% relative humidity AH transforms to MH. Hydration of MH proceeds to DH-I, either at 25°C/55% relative humidity or 50°C/80% relative humidity. These results are obtained from variable-temperature/humidity PXRD experiments. Corresponding behaviour is observed on dehydration of the dihydrate phases. Malaj et al. (2009) have reported that DH-I transforms sequentially to MH then to AH, while DH-II transforms immediately to AH under isothermal dehydration conditions in the temperature range 22–37°C. We concur with these results and have also found similar behaviour for dehydration at lower temperature (−5°C) under vacuum (Raijada et al., 2013). Thermogravimetric analysis (TGA) shows that both DH-I and DH-II exhibit a plateau corresponding to MH before proceeding to AH, but MH persists over a larger temperature range for DH-I compared with DH-II (Malaj et al., 2009; Raijada et al., 2013).

Figure 1 Summary of the transformation pathways for the sodium naproxen anhydrate–hydrate system. Hydration is shown with normal text/arrows, dehydration is shown with bold text/arrows.

Our aim in this paper is to link the observed hydration/dehydration behaviour to the molecular-level solid-state structures. To date, crystal structures have been published for AH (Kim et al., 2004) and MH (Kim et al., 1990). A structure described as a heminonahydrate, NS·4.5H₂O, has also been reported (Burgess et al., 2012), which is disordered and which we have re-interpreted as TH (Bond et al., 2013). Structural information for the polymorphic dihydrate, however, has so far not been reported. We discuss the structures of the two DH polymorphs in this paper, and show that they provide a clear basis to understand the transformation behaviour of the system. The structures presented here complete the (currently known) structural landscape of the sodium naproxen anhydrate–hydrate system, and illustrate the value of a complete structural picture for robust physicochemical understanding.

2. Experimental

2.1. Materials

Sodium (S)-naproxen anhydrate (AH; USP grade) was obtained from Divi's Laboratories Ltd, India. Methods for preparation of the various bulk phases have been described previously (Raijada et al., 2013). Single crystals of DH-I were obtained by dissolving 500 mg of AH in 79 mol % EtOH (4.62 ml EtOH + 0.38 ml H₂O) at 60°C. The solution was filtered to remove any undissolved residues of AH then allowed to cool to room temperature. The first single crystals to appear were transferred rapidly from the mother liquor to perfluoropolyether oil, then into the N₂ cryostream (at 150 K) on the diffractometer. Several crystals from different batches were examined, with comparable results.

2.2. X-ray diffraction

Single-crystal X-ray diffraction data were collected using a Bruker–Nonius X8-APEXII instrument equipped with graphite-monochromated Mo Kα radiation (λ = 0.7107 Å). Data were collected at 150 K under an N₂ cryostream in an effort to minimize dehydration during the data collection. Structure solution and refinement were carried out using SHELXL (Sheldrick, 2008). Powder X-ray diffraction data were collected using a Panalytical X'Pert Pro instrument equipped with non-monochromated Cu Kα radiation (average λ = 1.5418 Å). Data were collected in either flat-plate reflection or transmission capillary modes. Preliminary data analysis was carried out using HighScorePlus (Panalytical, 2012), and pattern indexing was achieved using DICVOL (Boultif & Louër, 2004). Rietveld refinements were performed with TOPAS Academic, Version 4.1 (Coelho, 2007) using the DASH (David et al., 2006) interface for construction of the initial input files.

2.3. Solid-state ²³Na and ¹³C MAS NMR

Solid-state MAS NMR spectra were recorded on a Bruker Avance 400 spectrometer operating at Larmor frequencies of 100.62, 105.85 and 400.13 MHz for ¹³C, ²³Na and ¹H, respectively, using a double-tuned CP/MAS probe. A ²³Na MAS NMR spectrum was also recorded for AH on a Bruker Avance-II 700 spectrometer operating at 185.15 MHz. Samples were loaded in sealed tubes to avoid dehydration. The measurement temperature was 313 K. Detailed experimental conditions are provided in the supporting information . All data were initially processed using TOPSPIN 2.1 (Bruker, 2008) then transferred to MATLAB (Mathworks, 2000) to set up figures. Numerical simulations and iterative fitting of the experimental ²³Na MAS spectra to extract isotropic chemical shifts and quadrupolar parameters for ²³Na were performed using a modified version of the software described in Larsen et al. (1998), assuming ideal RF-excitation. Additional experimental methods are discussed in Bennett (1995), Brown (1997), Delaglio (1995) and Peersen (1993).

2.4. Computational methods

Energy minimization of the crystal structures was carried out by dispersion-corrected density functional theory (DFT-D) calculations, using the CASTEP module (Clark et al., 2005) within Materials Studio (Accelrys, 2011). The PBE functional was applied (Perdew et al., 1996) with a plane-wave cut-off energy of 520 eV and a dispersion correction according to Grimme (2006). All other parameters were set to the `fine' defaults within Materials Studio. All atomic coordinates and unit-cell parameters were allowed to optimize within the constraints of the crystal system. A validation study has established that this methodology can be expected to reproduce the geometry of correct molecular crystal structures with an average r.m.s. deviation of ca 0.08 Å for the non-H atoms (van de Streek & Neumann, 2010).

3. Results and discussion

3.1. Crystal structures of AH and MH

The structures of AH (Kim et al., 2004) and MH (Kim et al., 1990) are layered, containing Na⁺/carboxylate/(H₂O) sections alternating with sections containing the naproxen molecules (Fig. 2). For consistent discussion of the structures, we refer to the atomic sites as indicated in Scheme 1, and we transform the published unit-cell setting for AH so that the layers lie parallel to the (100) planes (see supporting information for structures in CIF format). In AH (Fig. 2) the carboxylate groups adopt two different coordination modes: Na⁺–(μ-O)–Na⁺ and Na⁺–[O–C–O]–Na⁺. The latter define polymeric ribbons along the crystallographic b axis. The Na⁺/carboxylate sections are locally centrosymmetric. If the naproxen molecules are deleted so that only the Na⁺ ions and carboxyl groups remain, the structure can be described in space group P2₁/c with one crystallographically distinct Na⁺ ion and one carboxylate group. Reduction of the symmetry to P2₁ arises due to the naproxen molecules, which adopt an edge-to-face type arrangement (Fig. 2). The two crystallographically distinct naproxen molecules display slightly different molecular conformations in the propionate side chain. In both molecules, the naphthalene ring plane lies approximately eclipsed with the C11—H11 bond when viewed in projection along the C5—C11 bond (Fig. 3). Projection along the C11—C12 bond shows that the carboxyl group in one molecule is eclipsed with the C11—C13 bond, while it lies approximately perpendicular to the C11—C5 bond in the other molecule (Fig. 4). DFT-D minimization of the published AH crystal structure results in an r.m.s. Cartesian displacement of 0.15 Å for the non-H atoms, which is consistent with expectations for a correct room-temperature structure.

Figure 2 View of the structures of (a) AH and (b) MH along the b axis. Data are taken from Kim et al. (1990, 2004).

Figure 3 Projection of the naproxen molecule approximately along the C5—C11 bond in AH and MH, showing two different orientations for the naphthalene ring. H atoms (except H11) are omitted.

Figure 4 Projection of the two crystallographically independent naproxen molecules in AH approximately along the C11—C12 bond, showing two different orientations for the carboxyl group. H atoms (except H11) are not shown. The conformation in MH is comparable to that of AH (mol. 2).

The MH structure (Fig. 2) contains one-dimensional polymeric ribbons along the crystallographic b axis, formed by Na⁺–[O–C–O]–Na⁺ links, which are closely comparable to those in AH (compare the b dimensions in Table 1). The ribbons are paired through square-shaped Na⁺–(μ-O)₂–Na⁺ units, in which the μ-O linkages are provided by the carboxyl groups. The water molecules project to either side, linking the ribbons along the a axis through O—H⋯O hydrogen bonds. The Na⁺/carboxylate/H₂O sections contain local inversion centres that intersect the crystallographic 2₁ screw axes so that the space group approximates P2₁/m. Again, the inversion symmetry is broken by the naproxen molecules, which in this case adopt a face-to-face type arrangement, with all naphthalene ring planes parallel. The Na⁺ coordination geometry resembles square-based pyramidal, with Na⁺ lying out of the approximate square plane. In contrast to AH, the ring planes of the naproxen molecules lie approximately eclipsed with the C11—C13 bond when viewed in projection along the C10—C11 bond (Fig. 3). The orientation of the carboxyl group is perpendicular to the C11—C5 bond, as shown for AH (mol. 2) in Fig. 4. DFT-D minimization of the published MH crystal structure results in an r.m.s. Cartesian displacement of 0.15 Å for the non-H atoms, which is again consistent with expectations for a correct room-temperature structure.

Table 1
Summary of the crystallographic information for AH, MH, DH-I and DH-II

	AH†	MH	DH-I	DH-II
Source	Kim et al. (2004)	Kim et al. (1990)	This work	This work
Formula	Na^+[C14H13O3]^−	Na^+[C14H13O3]^−·H2O	Na^+[C14H13O3]^−·2H2O	Na^+[C14H13O3]^−·2H2O
Formula weight	252.2	270.3	288.3	288.3
T (K)	298	291	150	298
Crystal system	Monoclinic	Monoclinic	Triclinic	Triclinic
Space group	P21	P21	P1	P1
Z/Z′	4/2	2/1	2/2	4/4
a (Å)	20.823 (6)	21.177 (6)	22.281 (9)	22.750 (6)
b (Å)	5.9346 (16)	5.785 (2)	5.811 (2)	5.747 (3)
c (Å)	9.969 (3)	5.443 (2)	5.435 (2)	10.866 (3)
α (°)	90	90	89.53 (2)	89.61 (4)
β (°)	102.025 (5)	91.41 (3)	85.53 (2)	98.20 (1)
γ (°)	90	90	92.61 (1)	92.11 (6)
V (Å^3)	1204.9 (6)	666.6 (5)	700.8 (5)	1405.2 (8)
Density (g cm^−3)	1.391	1.346	1.366	1.363

†Unit cell transformed compared with Kim et al. (2004).

3.2. Solid-state ¹³C and ²³Na NMR

¹³C CP/MAS NMR spectra have been reported previously for AH after exposure to various degrees of humidity (Di Martino et al., 2007) and ²³Na MAS NMR have also been reported for AH and MH (Burgess et al., 2012). Our ²³Na MAS spectra for all phases (Fig. 5) demonstrate that the quadrupolar tensor of the ²³Na site(s) is highly sensitive towards the hydration state. The parameters in Table 2 (obtained by iterative fitting of the experimental spectra; see supporting information ) show that the quadrupolar coupling constant C_Q is 2.3 MHz or greater for AH and both DH forms, while it is close to 1.0 MHz for MH. The presence of two ²³Na sites in AH, as indicated by the crystal structure (Kim et al., 2004), was established by simultaneous iterative fitting of spectra recorded at 9.4 and 16.4 T. A 3Q-MAS spectrum recorded at 9.4 T did not resolve the two sites. The two sites have essentially identical chemical shifts but different quadrupolar parameters, in accordance with previous reports (Burgess et al., 2012). All of the other phases show apparently only one ²³Na site. For DH-II an almost featureless ²³Na MAS lineshape suggests either a disordered structure or a range of mutually exchanging configurations. The contours in the ²³Na 3Q-MAS spectrum (see supporting information ) mainly indicate a distribution in quadrupolar tensor parameters rather than a distribution of chemical shifts.

Table 2
²³Na NMR isotropic chemical shifts (δ_iso), quadrupolar coupling constants (C_Q) and asymmetry parameters (η_Q) for AH, MH, DH-I and DH-II

	δiso (p.p.m.)	CQ (MHz)	ηQ	Relative abundance
AH (site 1)†	2.7	3.17	0.57	0.55
AH (site 2)†	2.7	2.86	0.74	0.45
MH‡	4.1	1.04	0.54	–
DH-I‡	−0.8	2.95	0.25	–
DH-II‡§	−1.7	2.30	0.49	0.5
	0.0	2.50	0.40	0.5
Ibuprofen-DH	0.0	2.80	0.20	–

†Fitted to spectra recorded at 9.4 and 16.4 T.
‡Fitted to spectra recorded at 9.4 T.
§An approximate fit is based on the two listed sites.

Figure 5 Solid-state ^13C CP/MAS (column A) and ^23Na (column B) MAS NMR spectra measured at 313 K. Resonance assignments are shown for AH and MH (labelling according to Scheme 1). The assignments for DH-I and DH-II are clear by analogy. Spectra are also shown for sodium ibuprofen dihydrate (top), which has a similar structure to DH-II in the Na^+/H2O region (see text).

In the ¹³C CP/MAS NMR spectra (Fig. 5), AH exhibits two resolved resonances for each of the sites C5, C6, C11 and C13 (labelling as in Scheme 1), whereas only one resonance is observed for these sites in MH. This reveals the difference between the molecular conformations in the region of the propionate side chain (Figs. 3 and 4) and the edge-on arrangement of the naproxen molecules in AH compared with the parallel arrangement in MH. The ¹³C spectrum of DH-I is similar to MH, indicating that the parallel arrangement of naproxen molecules is also present in DH-I. However, the resonances for the propionate side chain are noticeably broader for DH-I, which may indicate some degree of structural variation in this region. For DH-II, the ¹³C CP/MAS spectrum resembles that of AH, thereby indicating an edge-on arrangement for the naproxen molecules. Again, the lines are slightly broader for DH-II compared with AH, which may indicate some degree of disorder. It should be noted that the NMR spectra in Fig. 5 are measured at 313 K, so they may be influenced by dynamic phenomena.

3.3. Crystal structure of DH-I

Numerous solution-grown crystals of DH-I were examined, and all displayed indications of twinning/disorder (discussed further below). The structure was eventually obtained after data integration using a single component in one crystal, although subsequent structure refinement was problematic. In particular, the data:parameter ratio is low (ca 4), on account of limited observable data and the low symmetry of the structure, and it was necessary to apply restraints to all bond distances and angles in order to maintain a reasonable geometry. The problems with the single-crystal analysis most likely also reflect some degree of dehydration during the transfer of the crystals from the mother liquor to the N₂ cryostream and/or in the course of the data collection. The validity of the established structure is supported by DFT-D minimization, which results in an r.m.s. Cartesian displacement of 0.14 Å for the non-H atoms, comparable to that obtained for minimization of AH and MH. Comparison to the PXRD pattern of the bulk sample by Rietveld refinement also provides a satisfactory fit (see supporting information ).

The structure of DH-I closely resembles that of MH. In particular, the structures have very similar unit cells (Table 1) and they are essentially identical in the regions of the naproxen molecules, consistent with the information deduced from the ¹³C CP/MAS NMR spectra. The naproxen regions exhibit local 2₁ symmetry, and local inversion symmetry also exists within the Na⁺/carboxylate/H₂O sections. The 2₁ symmetry is broken by the Na⁺/carboxylate/H₂O sections and the inversion symmetry is broken by the naproxen molecules, so that the crystallographic symmetry is reduced to P1 with two formula units in the asymmetric unit. Similar examples of pseudosymmetry have been noted in the context of isostructural racemic and enantiomeric crystals (Zhang & Grant, 2005). The molecular conformations of the two crystallographically distinct naproxen molecules are closely comparable, and identical to that in MH. The ring plane of the naproxen molecule lies eclipsed with the C11—C13 bond (Fig. 3), and the carboxyl group is perpendicular to the C5—C11 bond (Fig. 4). As for AH and MH, the DH-I structure contains one-dimensional polymeric ribbons along the b axis, cross-linked by square-shaped Na⁺–(μ-OH₂)₂–Na⁺ units. The linking units are geometrically similar to those in AH, except that the μ-O bridges in DH-I are formed by water molecules (Fig. 6) rather than carboxyl O atoms. The non-bridging H₂O molecules form O—H⋯O hydrogen bonds between ribbons. The Na⁺ coordination geometry is close to regular square-based pyramidal, with Na⁺ in the square plane. Despite the formal crystallographic inequivalence of the two Na⁺ sites, the pseudosymmetry means that their local environments are essentially identical, which can account for the observation of a single site in the ²³Na NMR.

Figure 6 Structure of DH-I. The view along the b axis (a) is along the direction of propagation of the polymeric ribbon. The view along the c axis (b) shows one square-shaped Na^+–(μ-OH2)2–Na^+ unit and the square-pyramidal coordination geometry of Na^+.

3.4. Disorder and twinning in DH-I

Reconstructed precession images for DH-I (supporting information ) appear ordered for 0kl, 1kl etc., indicative of regular two-dimensional layers in the structure parallel to the (100) planes. The disorder is evident in the diffraction pattern as reflections split along a*. The probable origin of this can be viewed as a result of the pseudosymmetry. Combination of the local 2₁ operator that relates the naproxen molecules () with the local inversion operator (1-x,1-y,1-z) within the Na⁺/H₂O sections generates a mirror operator (). This local mirror can be applied to the Na⁺/H₂O section to reverse the orientation of the square-shaped Na⁺–(μ-OH₂)₂–Na⁺ units relative to the b axis (Figs. 7 and 8). If this occurs, the next layer of naproxen molecules is shifted by ½b compared with its expected position in order to maintain identical chemical contacts (Fig. 7). A `fault' of this kind corresponds to twinning of the structure by 180° rotation around the b axis. DFT-D minimizations of the two models represented as red and blue in Fig. 7 converge to identical minima, with the unit-cell orientations related to each other by 180° rotation around b, confirming the symmetry and energetic viability of this twinning mechanism.

Figure 7 Probable twinning mechanism in DH-I. The Na^+/H2O section is mirrored perpendicular to b, with an accompanying shift of ½b for the bottom layer of naproxen molecules. The resulting structure (blue) is identical to the starting structure (red) rotated 180° around b.

Figure 8 Schematic illustration of the alternative orientations for the Na^+–(μ-OH2)2–Na^+ units in a Na^+/H2O section in DH-I. The positions of the water molecules do not change.

Since the metric symmetry of DH-I is very close to monoclinic, the twinning is approximately merohedral (i.e. the Bragg peaks in the twin components are approximately overlapped). However, the γ angle deviates sufficiently from 90° for the twinning to be apparent as split peaks in the diffraction pattern, as described. Attempts at two-component integration of the single-crystal data were not successful, apparently due to the close overlap of the diffraction peaks. Post-analysis of the data integrated as a single component using TWINROTMAT in PLATON (Spek, 2009) was able to identify the twinning, and two-component refinement using the generated HKLF-5 format in SHELXL (Sheldrick, 2008) gave a refined batch scale factor of ca. 10%.

The applied preparation route for DH-II, by direct hydration of solid AH, prohibits the formation of diffraction-quality single crystals, and the DH-II structure was therefore considered using a combined PXRD/modelling approach. The ¹³C CP/MAS NMR spectra (Fig. 5) show that the arrangement of the naproxen molecules in DH-II must be very similar to AH, and the PXRD data for DH-II could be indexed on the basis of a unit cell that closely resembled AH (Table 1) to provide a very good Pawley fit. The bc plane of this unit cell is related to DH-I by doubling of the c axis, which is clearly required in order to accommodate the edge-on arrangement of naproxen molecules seen in AH. The first step to model the DH-II structure was therefore to create a supercell from the DH-I structure by doubling of the c axis (Fig. 9a). The resulting enlarged unit cell could be transformed to the AH-type cell obtained from Pawley fitting by application of the matrix [1 0 −½ / 0 1 0 / 0 0 1]. The result corresponds to a supercell of the DH-I structure described in the AH-type cell setting (Fig. 9a).

Figure 9 Modelling of the DH-II structure. (a) The DH-I unit cell is doubled and transformed (without changing the DH-I structure) into a setting comparable to that for AH. (b) One polymeric ribbon is shifted by ½b (red = before shift; blue = after shift), and the naphthalene rings are rotated to emulate the orientation in AH.

Comparison with the AH structure showed that the naproxen molecule positions in one of the polymeric ribbons closely reproduced those in AH, but the second polymeric ribbon should be shifted by ½b in order for the naproxen molecules to adopt positions similar to those in AH (Fig. 9b). Crucially, this shift is permitted by the fact that the water molecules along the coordination polymers are distributed at intervals of approximately ½b, as shown in Fig. 8. Thus, the shift can be applied without changing the positions of the water molecules and without disrupting the hydrogen-bond network. Compelling evidence for the plausibility of the resulting structure is that the Na⁺/carboxylate/H₂O region overlays essentially exactly the comparable region in the dihydrate of the sodium salt of ibuprofen (Ibu-DH; Zhang & Grant, 2005). The 3Q-MAS NMR spectra of DH-II and Ibu-DH also exhibit partially overlapping contours, induced by similar isotropic chemical shifts and EFG tensors (see supporting information ). As a final step to model the DH-II structure, the naphthalene rings of both naproxen molecules in the shifted polymeric ribbon were rotated around the C5—C11 bond to emulate the ring positions in AH. The final model comprises Na⁺/carboxylate/H₂O regions similar to those in Ibu-DH, with naproxen regions similar to those in AH. The broader lines in the ¹³C CP/MAS NMR spectra for DH-II and lack of singularities in the ²³Na MAS NMR lineshapes (Fig. 5) indicate a higher degree of disorder compared with both Ibu-DH and AH.

The DH-II model was subjected to DFT-D minimization in space group P1, initially with the unit-cell parameters constrained to those from the Pawley fit, then with the unit-cell parameters free to optimize. The minimized structure remained practically unchanged compared with the starting model, verifying that it is a viable energetic minimum. Finally, the minimized structure was used as the starting point for Rietveld refinement against the PXRD data, producing the fit illustrated in Fig. 10. The combination of the DFT-D minimization, satisfactory Rietveld fit and close similarity of the ¹³C NMR for DH-II and AH provide strong evidence for the validity of the proposed DH-II structure. The observed `modularity' of the naproxen sections in AH and the Na⁺/carboxylate/H₂O regions in sodium ibuprofen dihydrate provides a further intuitive indication that the structure is correct.

Figure 10 Rietveld refinement for DH-II against laboratory PXRD data (red crosses = measured points, blue line = calculated, black line = difference, blue ticks = Bragg peak positions). The intense low-angle (100) peak at 2θ = 3.94° was partially obscured, so is omitted from the refinement.

The DH-II structure also exhibits extensive pseudosymmetry. The naproxen molecules conform approximately to space group P2₁, as for AH, although DH-II contains both molecular conformations shown in Fig. 3. The Na⁺/carboxylate/H₂O regions alone conform very closely to the space group (as for racemic Ibu-DH; Zhang & Grant, 2005), with a unit-cell volume half that of the DH-II cell (see supporting information ). The line broadening seen in the ¹³C NMR, and the multiple resonances for C11 and C13, can be attributed to the presence of the two alternative molecular conformations (Fig. 3). The resonances for C13 appear to be a superposition of the two resonances seen for AH and the single resonance for MH (or DH-I), as would be expected. The shoulder on the low-field side of the C14 resonance seems to be due to C11. The local environments of all C14 methyl groups are equivalent to those in AH, so variation in the environment of C14 does not account for this shoulder. Instead, the splitting seen for the C11 resonance in AH appears to be increased in DH-II so that the lower-field C11 resonance appears as the low-field shoulder on the C14 resonance.

3.5. Structural basis for the observed hydration/dehydration pathways

The established structures for DH-I and DH-II provide an effective basis to rationalize the observed hydration/dehydration pathways in the sodium naproxen anhydrate–hydrate system. Both the AH↔DH-II and MH↔DH-I transformations can be referred to as topotactic, since they retain comparable crystallographic lattices. The topotactic transformations should have relatively low activation energies compared with the non-topotactic transformations, and they are observed to operate at room temperature or below. Thus, hydration of AH at 25°C proceeds directly to DH-II, and dehydration of DH-II under vacuum at −5°C proceeds directly to AH. Above room temperature, the non-topotactic pathways become viable as their higher activation barriers can be thermally overcome. Thus, AH transforms sequentially to MH then to DH-I at 50°C, while dehydration of DH-II at 40°C produces mainly MH. In this respect, it is notable that DH-II can be stored indefinitely at 25°C/55% relative humidity, where the non-topotactic pathways are not accessible. However, DH-II undergoes transformation to DH-I if it is stored at 50°C/80% relative humidity.

In thermogravimetric analysis (TGA; Fig. 11), both DH-I and DH-II show an intermediate plateau corresponding to MH, but the shapes of the TGA curves are different, and they exhibit a different dependence on the heating rate (Fig. 11). For DH-I, the shape of the curve remains qualitatively similar at heating rates of 1, 5 or 10°C min⁻¹, with the plateau occurring consistently around 93% weight, as expected for MH. For DH-II, the shape of the curve changes as a function of heating rate. As the heating rate is decreased, the plateau becomes less pronounced, and it moves progressively to lower weight %.

Figure 11 Thermogravimetric analysis (TGA) measured for (a) DH-I and (b) DH-II at heating rates 1, 5 and 10°C min^−1.

With the established structural information, we interpret the TGA data as follows:

• (i) For DH-I, topotactic transformation to MH operates initially, while non-topotactic transformation to AH is activated only above a threshold temperature. In the TGA curve at 1°C min⁻¹ the DH-I→MH transformation is essentially complete by 40°C, then the MH → AH transformation begins just below 50°C. Thus, the curve at 1°C min⁻¹ approaches a step function. At higher heating rates, the plateau is less well defined because the non-topotactic MH → AH transformation is activated before the DH-I → MH transformation is complete (i.e. MH that is formed can transform immediately to AH).

• (ii) For DH-II, topotactic transformation to AH operates initially, while the non-topotactic pathway via MH is activated only above a threshold temperature. At 1°C min⁻¹, the DH-II → AH transformation is almost complete before the non-topotactic threshold temperature is reached, so the plateau for MH is small and it appears at a lower weight % because the MH produced from the DH-II that remains at that time comprises only a small fraction of the total sample. At higher heating rates, the non-topotactic pathway is activated while there is still a significant amount of DH-II present, so the plateau for MH appears more pronounced and closer to the expected 93 wt %.

• (iii) Malaj et al. (2009) have previously reported two-step dehydration for DH-I and one-step dehydration for DH-II. They noted that the first step for DH-I has a comparable kinetic profile to the single step for DH-II. We interpret this as the kinetic profile for topotactic dehydration. The second-step dehydration of DH-I was fitted by Malaj et al. to a different empirical rate equation with the implication of a different physical mechanism. We interpret this as the non-topotactic dehydration of MH to AH.

For dehydration of DH-II to AH, it is interesting to consider the sequential DH-II → MH → AH pathway, which involves two non-topotactic steps and operates above room temperature. For the DH-II → MH step, we might speculate on whether the transformation occurs directly, or sequentially via DH-I. Conceptually, this depends on the rate for re­arrangement of the naproxen molecules from edge-on (in DH-II) to parallel (in DH-I), compared with the rate at which the water stoichiometry changes from dihydrate to monohydrate. If the naproxen rearrangement occurs before the water stoichiometry changes, the transformation proceeds via DH-I. If the stoichiometry changes simultaneously with the naproxen rearrangement, the transformation proceeds directly from DH-II to MH. The DFT-D minimized structures of MH and DH-I have essentially identical unit-cell volumes (see supporting information ), which indicates that the packing arrangement is governed by the naproxen molecules and that the Na⁺/H₂O region of either MH or DH-I can be accommodated within the same framework of naproxen molecules. The implication is that the hydrate stoichiometry for a crystalline material having the MH/DH-I structure could be continuously variable between MH and DH. In this case, the distinction between direct DH-II → MH or sequential DH-II → DH-I → MH transformation has little practical meaning, and the process is better represented as DH-II → [DH-I ↔ MH]. There is also a possibility that the water stoichiometry could change from DH to MH before any naproxen rearrangement occurs. This would produce a polymorph of MH having the edge-on naproxen structure (i.e. `MH-II'). We examined this possibility using PXRD and ss-NMR under various in situ dehydration conditions, but we did not find any evidence for such a phase. Likewise, we did not find any evidence for an AH phase having a parallel naproxen arrangement.

4. Conclusions

The structural data provided here for the sodium naproxen anhydrate–hydrate system enable us to rationalize the complex transformation pathways that have previously been observed. The key is to establish the topotactic and non-topotactic nature of the various transformations. For this exercise to be effective, it is clearly important to have structural information for all involved solid phases. For DH-II in particular, the required solid-state preparation route hinders growth of suitable single crystals, and the combined modelling/PXRD/S-NMR approach becomes crucially important. Although the experimental and computational effort required to apply these techniques is significantly greater than that for a contemporary single-crystal X-ray analysis, the rewards for understanding systems of this type are significant.

Supporting information

Computing details

Data collection: APEX2 v2010.1-2 (Bruker, 2010) for DH1; X'Pert Data Collector (Panalytical, 2012) for DH2. Cell refinement: SAINT v.7.68a (Bruker, 2010) for DH1; DICVOL 04 (Boultif & Louer, 2004) for DH2. Data reduction: SAINT for DH1. Program(s) used to solve structure: SHELXTL v.6.12 (Sheldrick, 2008) for DH1; TOPAS Academic (Coelho 2007) for DH2. Program(s) used to refine structure: SHELXTL for DH1; TOPAS Academic (Coelho 2007) for DH2. Molecular graphics: SHELXTL for DH1. Software used to prepare material for publication: SHELXTL for DH1.

Figures

(DH1)

Crystal data

C14H13O3^−·Na^+·2(H2O)	Z = 2
Mr = 288.27	F(000) = 304
Triclinic, P1	Dx = 1.366 Mg m^−3
Hall symbol: P 1	Mo Kα radiation, λ = 0.71073 Å
a = 22.281 (9) Å	Cell parameters from 970 reflections
b = 5.811 (2) Å	θ = 2.8–20.6°
c = 5.435 (2) Å	µ = 0.13 mm^−1
α = 89.53 (2)°	T = 150 K
β = 85.53 (1)°	Lath, colourless
γ = 92.61 (1)°	0.20 × 0.10 × 0.04 mm
V = 700.8 (5) Å^3

Data collection

Bruker Nonius X8APEX-II CCD diffractometer	1462 independent reflections
Radiation source: fine-focus sealed tube	1209 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.035
ω and φ scans	θmax = 22.0°, θmin = 3.6°
Absorption correction: multi-scan SADABS (Sheldrick, 2008)	h = −23→23
Tmin = 0.679, Tmax = 0.995	k = −6→6
1462 measured reflections	l = −5→5

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.078	H-atom parameters constrained
wR(F^2) = 0.204	w = 1/[σ^2(Fo^2) + (0.0808P)^2 + 2.7357P] where P = (Fo^2 + 2Fc^2)/3
S = 1.12	(Δ/σ)max = 0.001
1462 reflections	Δρmax = 0.32 e Å^−3
362 parameters	Δρmin = −0.29 e Å^−3
243 restraints	Absolute structure: In the absence of significant anomalous scattering effects, Friedel pairs have been merged as equivalent data
Primary atom site location: structure-invariant direct methods

Special details

Experimental. The diffraction pattern is indicative of multiple twinning. This data set was obtained by integrating a single component. Post-analysis of the data using TWINROTMAT identified non-merohedral twinning by 2-fold rotation around the b axis. ============================================================================== This CIF is based on an HKLF-5 refinement against data generated by TWINROTMAT ============================================================================== All non-H atoms are refined anisotropically, but all ADPs are restrained to approximate isotropic behaviour (ISOR in SHELXL).

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
Na1	0.4339 (3)	0.3634 (10)	0.6135 (10)	0.0454 (16)
Na2	0.5658 (3)	0.6342 (9)	0.3842 (9)	0.0404 (16)
O1W	0.4606 (5)	0.1477 (19)	0.2681 (19)	0.045 (3)
H1W	0.4970	0.1947	0.2339	0.068*
H2W	0.4444	0.1087	0.1372	0.068*
O2W	0.5375 (5)	0.8694 (19)	0.738 (2)	0.050 (3)
H3W	0.5017	0.9125	0.7660	0.075*
H4W	0.5583	0.8886	0.8611	0.075*
O3W	0.5377 (5)	0.357 (2)	0.690 (2)	0.057 (3)
H5W	0.5525	0.3456	0.8292	0.086*
H6W	0.5375	0.2110	0.7046	0.086*
O4W	0.4611 (5)	0.6711 (17)	0.311 (2)	0.045 (3)
H7W	0.4429	0.6620	0.1792	0.067*
H8W	0.4613	0.8171	0.2977	0.067*
O1	0.4010 (5)	0.647 (2)	0.8746 (19)	0.051 (3)
O2	0.4089 (5)	1.032 (2)	0.842 (2)	0.056 (3)
O3	0.0483 (5)	0.850 (2)	1.745 (2)	0.067 (4)
C1	0.1379 (7)	0.992 (3)	1.505 (3)	0.051 (4)
H1	0.1397	1.1259	1.6028	0.061*
C2	0.1822 (7)	0.960 (3)	1.303 (3)	0.039 (4)
C3	0.2305 (7)	1.117 (3)	1.246 (3)	0.043 (4)
H3	0.2339	1.2520	1.3415	0.052*
C4	0.2725 (7)	1.082 (3)	1.059 (3)	0.051 (4)
H4	0.3029	1.1994	1.0193	0.062*
C5	0.2726 (7)	0.876 (3)	0.920 (3)	0.036 (4)
C6	0.2237 (7)	0.720 (3)	0.976 (3)	0.040 (4)
H6	0.2202	0.5868	0.8772	0.048*
C7	0.1802 (6)	0.751 (3)	1.166 (3)	0.032 (4)
C8	0.1306 (8)	0.587 (4)	1.227 (3)	0.067 (6)
H8	0.1267	0.4473	1.1381	0.081*
C9	0.0883 (7)	0.639 (3)	1.420 (3)	0.046 (4)
H9	0.0546	0.5347	1.4583	0.055*
C10	0.0938 (7)	0.828 (3)	1.552 (3)	0.050 (4)
C11	0.3209 (6)	0.836 (3)	0.714 (3)	0.032 (4)
H11	0.3211	0.9722	0.6003	0.039*
C12	0.3804 (7)	0.840 (3)	0.808 (3)	0.039 (4)
C13	0.3082 (7)	0.622 (3)	0.553 (3)	0.045 (4)
H13A	0.2674	0.6257	0.4980	0.067*
H13B	0.3117	0.4810	0.6508	0.067*
H13C	0.3375	0.6229	0.4089	0.067*
C14	0.0525 (8)	1.046 (4)	1.902 (3)	0.066 (5)
H14A	0.0189	1.0375	2.0304	0.099*
H14B	0.0506	1.1874	1.8040	0.099*
H14C	0.0907	1.0475	1.9797	0.099*
O1A	0.5869 (5)	0.316 (2)	0.1437 (19)	0.043 (3)
O2A	0.6036 (5)	−0.0646 (18)	0.1311 (17)	0.040 (3)
O3A	0.9508 (5)	0.318 (2)	−0.714 (2)	0.056 (3)
C1A	0.8587 (7)	0.432 (3)	−0.476 (3)	0.040 (4)
H1A	0.8555	0.5650	−0.5756	0.048*
C2A	0.8146 (6)	0.383 (3)	−0.280 (3)	0.037 (4)
C3A	0.7664 (8)	0.517 (3)	−0.227 (3)	0.052 (5)
H3A	0.7627	0.6523	−0.3225	0.062*
C4A	0.7226 (7)	0.460 (3)	−0.035 (3)	0.050 (4)
H4A	0.6902	0.5584	0.0024	0.060*
C5A	0.7270 (7)	0.255 (3)	0.101 (3)	0.035 (4)
C6A	0.7730 (7)	0.122 (3)	0.055 (3)	0.045 (4)
H6A	0.7759	−0.0096	0.1579	0.054*
C7A	0.8183 (7)	0.166 (3)	−0.141 (3)	0.035 (4)
C8A	0.8672 (7)	0.030 (3)	−0.198 (3)	0.053 (5)
H8A	0.8715	−0.1059	−0.1038	0.064*
C9A	0.9085 (7)	0.088 (3)	−0.383 (3)	0.055 (5)
H9A	0.9407	−0.0107	−0.4213	0.066*
C10A	0.9052 (7)	0.295 (3)	−0.525 (3)	0.045 (4)
C11A	0.6763 (7)	0.198 (3)	0.314 (3)	0.042 (4)
H11A	0.6712	0.3375	0.4191	0.050*
C12A	0.6157 (7)	0.146 (3)	0.182 (3)	0.031 (4)
C13A	0.6892 (7)	−0.001 (3)	0.476 (3)	0.051 (4)
H13D	0.6966	−0.1366	0.3747	0.076*
H13E	0.6545	−0.0343	0.5955	0.076*
H13F	0.7248	0.0384	0.5651	0.076*
C14A	0.9494 (8)	0.531 (3)	−0.866 (3)	0.062 (5)
H14D	0.9825	0.5337	−0.9958	0.092*
H14E	0.9539	0.6664	−0.7611	0.092*
H14F	0.9109	0.5340	−0.9411	0.092*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Na1	0.066 (4)	0.031 (4)	0.039 (3)	−0.001 (3)	−0.007 (3)	−0.001 (3)
Na2	0.059 (4)	0.034 (4)	0.028 (3)	0.003 (3)	−0.002 (3)	0.015 (3)
O1W	0.065 (6)	0.039 (6)	0.033 (5)	0.003 (5)	−0.007 (5)	−0.003 (5)
O2W	0.060 (6)	0.042 (6)	0.048 (6)	0.004 (5)	−0.013 (5)	−0.004 (5)
O3W	0.065 (6)	0.071 (7)	0.037 (6)	0.002 (5)	−0.009 (5)	0.018 (5)
O4W	0.067 (6)	0.026 (5)	0.043 (6)	0.003 (5)	−0.016 (5)	0.009 (5)
O1	0.065 (6)	0.052 (7)	0.038 (6)	0.016 (5)	−0.016 (5)	−0.009 (5)
O2	0.066 (6)	0.056 (7)	0.047 (6)	−0.014 (5)	−0.017 (5)	0.006 (5)
O3	0.064 (6)	0.073 (8)	0.062 (7)	0.003 (6)	−0.001 (6)	0.006 (6)
C1	0.054 (8)	0.053 (9)	0.046 (7)	0.006 (7)	−0.008 (6)	−0.002 (7)
C2	0.042 (7)	0.039 (8)	0.038 (7)	0.003 (6)	−0.009 (6)	0.005 (6)
C3	0.053 (8)	0.027 (8)	0.050 (8)	0.000 (6)	−0.008 (6)	−0.003 (7)
C4	0.049 (8)	0.051 (9)	0.053 (7)	−0.006 (7)	0.000 (7)	0.011 (7)
C5	0.044 (7)	0.029 (8)	0.037 (7)	0.002 (6)	−0.012 (6)	0.003 (6)
C6	0.045 (7)	0.034 (8)	0.042 (7)	0.004 (6)	−0.009 (6)	−0.007 (6)
C7	0.038 (7)	0.019 (7)	0.043 (7)	0.009 (6)	−0.015 (6)	0.001 (6)
C8	0.071 (9)	0.067 (10)	0.063 (9)	−0.009 (8)	−0.005 (7)	−0.003 (8)
C9	0.048 (7)	0.042 (8)	0.048 (8)	0.009 (6)	−0.003 (6)	0.009 (7)
C10	0.051 (8)	0.055 (9)	0.043 (7)	−0.004 (7)	0.000 (7)	0.002 (7)
C11	0.044 (7)	0.026 (7)	0.027 (7)	0.001 (6)	−0.008 (6)	0.002 (6)
C12	0.060 (8)	0.027 (8)	0.030 (7)	0.004 (7)	−0.003 (6)	0.006 (6)
C13	0.044 (7)	0.053 (9)	0.038 (7)	0.003 (6)	−0.011 (6)	−0.002 (7)
C14	0.065 (9)	0.065 (10)	0.066 (8)	0.003 (7)	0.004 (7)	−0.002 (8)
O1A	0.059 (6)	0.042 (6)	0.031 (5)	0.016 (5)	−0.009 (5)	0.004 (5)
O2A	0.056 (6)	0.039 (6)	0.026 (5)	0.003 (5)	−0.008 (4)	0.002 (5)
O3A	0.062 (6)	0.047 (7)	0.058 (6)	0.001 (5)	0.001 (5)	0.010 (6)
C1A	0.046 (7)	0.033 (8)	0.042 (7)	0.004 (6)	−0.008 (6)	0.002 (6)
C2A	0.039 (7)	0.032 (8)	0.042 (7)	0.006 (6)	−0.008 (6)	0.016 (6)
C3A	0.064 (8)	0.048 (9)	0.043 (7)	−0.001 (7)	−0.008 (6)	0.021 (7)
C4A	0.043 (7)	0.051 (9)	0.055 (8)	0.009 (7)	0.005 (6)	0.010 (7)
C5A	0.044 (7)	0.036 (8)	0.023 (6)	−0.008 (6)	−0.011 (6)	0.007 (6)
C6A	0.046 (7)	0.045 (8)	0.046 (7)	0.000 (7)	−0.017 (6)	0.004 (7)
C7A	0.041 (7)	0.019 (7)	0.046 (7)	0.002 (6)	−0.008 (6)	0.003 (6)
C8A	0.051 (8)	0.057 (9)	0.054 (8)	0.002 (7)	−0.013 (7)	0.014 (7)
C9A	0.050 (8)	0.055 (9)	0.061 (8)	0.009 (7)	−0.006 (7)	0.005 (7)
C10A	0.055 (8)	0.043 (8)	0.038 (7)	−0.006 (7)	−0.007 (7)	−0.002 (7)
C11A	0.047 (7)	0.047 (8)	0.033 (7)	0.002 (6)	−0.008 (6)	0.000 (7)
C12A	0.042 (7)	0.034 (8)	0.017 (6)	−0.002 (6)	−0.005 (5)	−0.006 (6)
C13A	0.058 (8)	0.058 (9)	0.036 (7)	0.004 (7)	−0.002 (6)	0.010 (7)
C14A	0.063 (8)	0.062 (9)	0.058 (8)	0.002 (7)	0.007 (7)	0.001 (8)

Geometric parameters (Å, º)

Na1—O1	2.292 (13)	C9—C10	1.32 (3)
Na1—O2^i	2.308 (12)	C9—H9	0.9500
Na1—O1W	2.320 (13)	C11—C12	1.46 (2)
Na1—O3W	2.385 (14)	C11—C13	1.55 (2)
Na1—O4W	2.444 (11)	C11—H11	1.0000
Na1—Na2	3.412 (7)	C13—H13A	0.9800
Na1—H1W	2.6270	C13—H13B	0.9800
Na1—H6W	2.5929	C13—H13C	0.9800
Na2—O2A^ii	2.305 (11)	C14—H14A	0.9800
Na2—O1A	2.317 (13)	C14—H14B	0.9800
Na2—O3W	2.337 (12)	C14—H14C	0.9800
Na2—O4W	2.415 (13)	O1A—C12A	1.228 (19)
Na2—O2W	2.427 (13)	O2A—C12A	1.280 (19)
Na2—H8W	2.6745	O2A—Na2^i	2.305 (11)
O1W—H1W	0.8501	O3A—C10A	1.38 (2)
O1W—H2W	0.8499	O3A—C14A	1.49 (2)
O2W—H3W	0.8499	C1A—C10A	1.35 (2)
O2W—H4W	0.8499	C1A—C2A	1.41 (2)
O3W—H5W	0.8500	C1A—H1A	0.9500
O3W—H6W	0.8501	C2A—C3A	1.37 (2)
O4W—H7W	0.8500	C2A—C7A	1.476 (19)
O4W—H8W	0.8501	C3A—C4A	1.40 (2)
O1—C12	1.289 (19)	C3A—H3A	0.9500
O2—C12	1.28 (2)	C4A—C5A	1.41 (2)
O2—Na1^ii	2.308 (12)	C4A—H4A	0.9500
O3—C10	1.41 (2)	C5A—C6A	1.32 (2)
O3—C14	1.43 (2)	C5A—C11A	1.58 (2)
C1—C10	1.34 (2)	C6A—C7A	1.42 (2)
C1—C2	1.44 (2)	C6A—H6A	0.9500
C1—H1	0.9500	C7A—C8A	1.39 (2)
C2—C3	1.39 (2)	C8A—C9A	1.34 (2)
C2—C7	1.43 (2)	C8A—H8A	0.9500
C3—C4	1.35 (2)	C9A—C10A	1.43 (2)
C3—H3	0.9500	C9A—H9A	0.9500
C4—C5	1.42 (2)	C11A—C13A	1.50 (2)
C4—H4	0.9500	C11A—C12A	1.60 (2)
C5—C6	1.40 (2)	C11A—H11A	1.0000
C5—C11	1.52 (2)	C13A—H13D	0.9800
C6—C7	1.38 (2)	C13A—H13E	0.9800
C6—H6	0.9500	C13A—H13F	0.9800
C7—C8	1.44 (2)	C14A—H14D	0.9800
C8—C9	1.40 (2)	C14A—H14E	0.9800
C8—H8	0.9500	C14A—H14F	0.9800
O1—Na1—O2^i	102.8 (5)	C6—C7—C2	119.0 (13)
O1—Na1—O1W	164.3 (5)	C6—C7—C8	123.1 (17)
O2^i—Na1—O1W	90.8 (5)	C2—C7—C8	117.8 (15)
O1—Na1—O3W	101.6 (5)	C9—C8—C7	118.1 (19)
O2^i—Na1—O3W	93.1 (5)	C9—C8—H8	120.9
O1W—Na1—O3W	85.3 (5)	C7—C8—H8	120.9
O1—Na1—O4W	86.5 (4)	C10—C9—C8	122.0 (18)
O2^i—Na1—O4W	170.2 (5)	C10—C9—H9	119.0
O1W—Na1—O4W	79.6 (4)	C8—C9—H9	119.0
O3W—Na1—O4W	88.1 (4)	C9—C10—C1	123.6 (17)
O1—Na1—Na2	98.0 (4)	C9—C10—O3	114.7 (15)
O2^i—Na1—Na2	134.8 (4)	C1—C10—O3	121.7 (19)
O1W—Na1—Na2	77.3 (3)	C12—C11—C5	110.7 (13)
O3W—Na1—Na2	43.2 (3)	C12—C11—C13	113.0 (13)
O4W—Na1—Na2	45.0 (3)	C5—C11—C13	114.7 (12)
O1—Na1—H1W	155.5	C12—C11—H11	105.9
O2^i—Na1—H1W	100.5	C5—C11—H11	105.9
O1W—Na1—H1W	18.5	C13—C11—H11	105.9
O3W—Na1—H1W	69.4	O2—C12—O1	121.3 (16)
O4W—Na1—H1W	70.8	O2—C12—C11	120.4 (15)
Na2—Na1—H1W	59.4	O1—C12—C11	118.1 (14)
O1—Na1—H6W	114.1	C11—C13—H13A	109.5
O2^i—Na1—H6W	76.4	C11—C13—H13B	109.5
O1W—Na1—H6W	76.5	H13A—C13—H13B	109.5
O3W—Na1—H6W	19.1	C11—C13—H13C	109.5
O4W—Na1—H6W	102.9	H13A—C13—H13C	109.5
Na2—Na1—H6W	58.4	H13B—C13—H13C	109.5
H1W—Na1—H6W	64.4	O3—C14—H14A	109.5
O2A^ii—Na2—O1A	102.3 (4)	O3—C14—H14B	109.5
O2A^ii—Na2—O3W	170.2 (5)	H14A—C14—H14B	109.5
O1A—Na2—O3W	83.6 (5)	O3—C14—H14C	109.5
O2A^ii—Na2—O4W	96.7 (4)	H14A—C14—H14C	109.5
O1A—Na2—O4W	99.7 (4)	H14B—C14—H14C	109.5
O3W—Na2—O4W	89.9 (4)	C12A—O1A—Na2	131.4 (10)
O2A^ii—Na2—O2W	96.0 (4)	C12A—O2A—Na2^i	130.2 (9)
O1A—Na2—O2W	161.3 (4)	C10A—O3A—C14A	114.5 (13)
O3W—Na2—O2W	77.8 (5)	C10A—C1A—C2A	121.9 (13)
O4W—Na2—O2W	82.0 (4)	C10A—C1A—H1A	119.1
O2A^ii—Na2—Na1	142.3 (3)	C2A—C1A—H1A	119.1
O1A—Na2—Na1	89.8 (3)	C3A—C2A—C1A	123.3 (13)
O3W—Na2—Na1	44.3 (3)	C3A—C2A—C7A	118.9 (13)
O4W—Na2—Na1	45.7 (3)	C1A—C2A—C7A	117.6 (14)
O2W—Na2—Na1	78.0 (3)	C2A—C3A—C4A	121.8 (14)
O2A^ii—Na2—H8W	81.7	C2A—C3A—H3A	119.1
O1A—Na2—H8W	113.2	C4A—C3A—H3A	119.1
O3W—Na2—H8W	103.3	C3A—C4A—C5A	119.0 (15)
O4W—Na2—H8W	18.3	C3A—C4A—H4A	120.5
O2W—Na2—H8W	73.2	C5A—C4A—H4A	120.5
Na1—Na2—H8W	60.8	C6A—C5A—C4A	120.8 (14)
Na1—O1W—H1W	101.7	C6A—C5A—C11A	122.0 (14)
Na1—O1W—H2W	136.2	C4A—C5A—C11A	117.2 (14)
H1W—O1W—H2W	110.2	C5A—C6A—C7A	123.1 (15)
Na2—O2W—H3W	121.4	C5A—C6A—H6A	118.4
Na2—O2W—H4W	124.5	C7A—C6A—H6A	118.4
H3W—O2W—H4W	112.4	C8A—C7A—C6A	125.4 (14)
Na2—O3W—Na1	92.5 (5)	C8A—C7A—C2A	118.4 (13)
Na2—O3W—H5W	126.1	C6A—C7A—C2A	116.0 (14)
Na1—O3W—H5W	127.6	C9A—C8A—C7A	121.2 (15)
Na2—O3W—H6W	137.1	C9A—C8A—H8A	119.4
Na1—O3W—H6W	94.4	C7A—C8A—H8A	119.4
H5W—O3W—H6W	80.3	C8A—C9A—C10A	121.6 (17)
Na2—O4W—Na1	89.2 (4)	C8A—C9A—H9A	119.2
Na2—O4W—H7W	131.6	C10A—C9A—H9A	119.2
Na1—O4W—H7W	115.0	C1A—C10A—O3A	128.1 (15)
Na2—O4W—H8W	98.4	C1A—C10A—C9A	119.2 (15)
Na1—O4W—H8W	140.1	O3A—C10A—C9A	112.6 (16)
H7W—O4W—H8W	88.7	C13A—C11A—C5A	114.1 (14)
C12—O1—Na1	125.6 (10)	C13A—C11A—C12A	110.7 (14)
C12—O2—Na1^ii	136.1 (10)	C5A—C11A—C12A	106.0 (12)
C10—O3—C14	118.0 (14)	C13A—C11A—H11A	108.6
C10—C1—C2	118.8 (18)	C5A—C11A—H11A	108.6
C10—C1—H1	120.6	C12A—C11A—H11A	108.6
C2—C1—H1	120.6	O1A—C12A—O2A	128.9 (15)
C3—C2—C7	117.7 (14)	O1A—C12A—C11A	114.9 (15)
C3—C2—C1	122.7 (17)	O2A—C12A—C11A	116.2 (14)
C7—C2—C1	119.5 (14)	C11A—C13A—H13D	109.5
C4—C3—C2	122.1 (18)	C11A—C13A—H13E	109.5
C4—C3—H3	119.0	H13D—C13A—H13E	109.5
C2—C3—H3	119.0	C11A—C13A—H13F	109.5
C3—C4—C5	122.0 (15)	H13D—C13A—H13F	109.5
C3—C4—H4	119.0	H13E—C13A—H13F	109.5
C5—C4—H4	119.0	O3A—C14A—H14D	109.5
C6—C5—C4	115.6 (15)	O3A—C14A—H14E	109.5
C6—C5—C11	122.6 (16)	H14D—C14A—H14E	109.5
C4—C5—C11	121.7 (13)	O3A—C14A—H14F	109.5
C7—C6—C5	123.4 (17)	H14D—C14A—H14F	109.5
C7—C6—H6	118.3	H14E—C14A—H14F	109.5
C5—C6—H6	118.3
O1—Na1—Na2—O2A^ii	−70.5 (6)	C8—C9—C10—C1	4 (3)
O2^i—Na1—Na2—O2A^ii	172.5 (8)	C8—C9—C10—O3	−178.0 (15)
O1W—Na1—Na2—O2A^ii	94.3 (6)	C2—C1—C10—C9	−1 (3)
O3W—Na1—Na2—O2A^ii	−168.9 (8)	C2—C1—C10—O3	−179.0 (14)
O4W—Na1—Na2—O2A^ii	6.3 (7)	C14—O3—C10—C9	177.5 (15)
O1—Na1—Na2—O1A	179.4 (5)	C14—O3—C10—C1	−4 (2)
O2^i—Na1—Na2—O1A	62.3 (6)	C6—C5—C11—C12	−123.5 (15)
O1W—Na1—Na2—O1A	−15.9 (4)	C4—C5—C11—C12	60.7 (19)
O3W—Na1—Na2—O1A	81.0 (6)	C6—C5—C11—C13	6 (2)
O4W—Na1—Na2—O1A	−103.8 (5)	C4—C5—C11—C13	−170.0 (13)
O1—Na1—Na2—O3W	98.4 (6)	Na1^ii—O2—C12—O1	135.8 (14)
O2^i—Na1—Na2—O3W	−18.6 (7)	Na1^ii—O2—C12—C11	−50 (2)
O1W—Na1—Na2—O3W	−96.8 (6)	Na1—O1—C12—O2	−113.5 (16)
O4W—Na1—Na2—O3W	175.2 (8)	Na1—O1—C12—C11	72.0 (17)
O1—Na1—Na2—O4W	−76.8 (5)	C5—C11—C12—O2	−81.7 (17)
O2^i—Na1—Na2—O4W	166.1 (7)	C13—C11—C12—O2	148.2 (14)
O1W—Na1—Na2—O4W	88.0 (5)	C5—C11—C12—O1	92.9 (18)
O3W—Na1—Na2—O4W	−175.2 (8)	C13—C11—C12—O1	−37.3 (19)
O1—Na1—Na2—O2W	13.7 (4)	O2A^ii—Na2—O1A—C12A	122.9 (13)
O2^i—Na1—Na2—O2W	−103.4 (6)	O3W—Na2—O1A—C12A	−49.1 (13)
O1W—Na1—Na2—O2W	178.4 (5)	O4W—Na2—O1A—C12A	−138.0 (13)
O3W—Na1—Na2—O2W	−84.7 (6)	O2W—Na2—O1A—C12A	−44 (2)
O4W—Na1—Na2—O2W	90.5 (5)	Na1—Na2—O1A—C12A	−93.1 (13)
O1A—Na2—O3W—Na1	−96.4 (5)	C10A—C1A—C2A—C3A	−179.2 (18)
O4W—Na2—O3W—Na1	3.4 (6)	C10A—C1A—C2A—C7A	−5 (2)
O2W—Na2—O3W—Na1	85.2 (5)	C1A—C2A—C3A—C4A	178.2 (15)
O1—Na1—O3W—Na2	−89.4 (5)	C7A—C2A—C3A—C4A	4 (3)
O2^i—Na1—O3W—Na2	166.9 (5)	C2A—C3A—C4A—C5A	−2 (3)
O1W—Na1—O3W—Na2	76.4 (5)	C3A—C4A—C5A—C6A	2 (3)
O4W—Na1—O3W—Na2	−3.4 (6)	C3A—C4A—C5A—C11A	−179.7 (14)
O2A^ii—Na2—O4W—Na1	−176.1 (4)	C4A—C5A—C6A—C7A	−4 (3)
O1A—Na2—O4W—Na1	80.1 (4)	C11A—C5A—C6A—C7A	178.0 (14)
O3W—Na2—O4W—Na1	−3.3 (6)	C5A—C6A—C7A—C8A	−179.5 (18)
O2W—Na2—O4W—Na1	−81.0 (4)	C5A—C6A—C7A—C2A	5 (2)
O1—Na1—O4W—Na2	105.0 (4)	C3A—C2A—C7A—C8A	179.5 (17)
O1W—Na1—O4W—Na2	−82.3 (4)	C1A—C2A—C7A—C8A	5 (2)
O3W—Na1—O4W—Na2	3.3 (5)	C3A—C2A—C7A—C6A	−5 (2)
O2^i—Na1—O1—C12	−147.7 (12)	C1A—C2A—C7A—C6A	−179.9 (14)
O1W—Na1—O1—C12	1 (3)	C6A—C7A—C8A—C9A	−178.5 (17)
O3W—Na1—O1—C12	116.4 (13)	C2A—C7A—C8A—C9A	−4 (3)
O4W—Na1—O1—C12	29.1 (13)	C7A—C8A—C9A—C10A	2 (3)
Na2—Na1—O1—C12	72.7 (13)	C2A—C1A—C10A—O3A	178.5 (15)
C10—C1—C2—C3	−177.8 (15)	C2A—C1A—C10A—C9A	3 (3)
C10—C1—C2—C7	−3 (2)	C14A—O3A—C10A—C1A	5 (3)
C7—C2—C3—C4	4 (2)	C14A—O3A—C10A—C9A	−179.8 (15)
C1—C2—C3—C4	178.6 (15)	C8A—C9A—C10A—C1A	−2 (3)
C2—C3—C4—C5	−5 (2)	C8A—C9A—C10A—O3A	−177.8 (15)
C3—C4—C5—C6	5 (2)	C6A—C5A—C11A—C13A	7 (2)
C3—C4—C5—C11	−178.7 (14)	C4A—C5A—C11A—C13A	−170.7 (15)
C4—C5—C6—C7	−6 (2)	C6A—C5A—C11A—C12A	−114.8 (17)
C11—C5—C6—C7	178.5 (14)	C4A—C5A—C11A—C12A	67.3 (19)
C5—C6—C7—C2	5 (2)	Na2—O1A—C12A—O2A	139.0 (13)
C5—C6—C7—C8	−178.2 (15)	Na2—O1A—C12A—C11A	−40.7 (18)
C3—C2—C7—C6	−4 (2)	Na2^i—O2A—C12A—O1A	−103.1 (16)
C1—C2—C7—C6	−178.7 (14)	Na2^i—O2A—C12A—C11A	76.6 (15)
C3—C2—C7—C8	179.2 (15)	C13A—C11A—C12A—O1A	147.8 (14)
C1—C2—C7—C8	4 (2)	C5A—C11A—C12A—O1A	−88.1 (16)
C6—C7—C8—C9	−178.5 (15)	C13A—C11A—C12A—O2A	−31.9 (19)
C2—C7—C8—C9	−2 (2)	C5A—C11A—C12A—O2A	92.2 (14)
C7—C8—C9—C10	−2 (2)

Symmetry codes: (i) x, y−1, z; (ii) x, y+1, z.

(DH2)

Crystal data

C14H13O3^−·Na^+·2(H2O)	γ = 92.11 (6)°
Mr = 288.27	V = 1405.2 (8) Å^3
Triclinic, P1	Z = 4
Hall symbol: P 1	F(000) = 608
a = 22.750 (6) Å	Dx = 1.363 Mg m^−3
b = 5.747 (3) Å	Cu Kα radiation, λ = 1.5418 Å
c = 10.866 (3) Å	T = 298 K
α = 89.61 (4)°	white
β = 98.20 (1)°

Data collection

Panalytical X'Pert Pro diffractometer	Data collection mode: reflection
Radiation source: sealed tube	Scan method: continuous
None monochromator	2θmin = 5.003°, 2θmax = 39.947°, 2θstep = 0.026°
Specimen mounting: flat plate

Refinement

Rp = 0.039	1345 data points
Rwp = 0.053	Profile function: pseudo-Voigt
Rexp = 0.020
R(F) = 0.017	Background function: Chebyshev polynomial
χ^2 = 6.667	Preferred orientation correction: none

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
Na1	0.4382 (5)	0.4222 (13)	0.5097 (7)	0.062 (5)
Na2	0.5601 (5)	0.6793 (15)	0.4438 (7)	0.062 (5)
O1W	0.4755 (7)	0.189 (3)	0.3537 (12)	0.062 (5)
O2W	0.5545 (7)	0.962 (4)	0.6089 (12)	0.062 (5)
O3W	0.5424 (5)	0.392 (2)	0.5907 (6)	0.062 (5)
O4W	0.4570 (5)	0.713 (2)	0.3622 (7)	0.062 (5)
H1W	0.493 (2)	0.311 (17)	0.303 (6)	0.074 (5)
H2W	0.4404 (17)	0.122 (19)	0.297 (5)	0.074 (5)
H3W	0.5213 (17)	0.91 (2)	0.653 (5)	0.074 (5)
H4W	0.5914 (16)	0.97 (2)	0.672 (6)	0.074 (5)
H5W	0.568 (2)	0.44 (2)	0.667 (8)	0.074 (5)
H6W	0.5473 (17)	0.223 (19)	0.590 (5)	0.074 (5)
H7W	0.4323 (18)	0.68 (2)	0.282 (6)	0.074 (5)
H8W	0.4538 (18)	0.884 (17)	0.374 (5)	0.074 (5)
O1A	0.3978 (9)	0.700 (3)	0.6273 (18)	0.062 (5)
O2A	0.4143 (10)	1.084 (3)	0.608 (3)	0.062 (5)
O3A	0.0465 (7)	0.912 (3)	0.9149 (15)	0.062 (5)
C1A	0.2189 (5)	0.803 (3)	0.6061 (12)	0.062 (5)
C2A	0.1739 (5)	0.826 (3)	0.6828 (9)	0.062 (5)
C3A	0.1236 (5)	0.670 (3)	0.6814 (11)	0.062 (5)
C4A	0.0817 (5)	0.697 (3)	0.7568 (12)	0.062 (5)
C5A	0.0872 (5)	0.886 (4)	0.8393 (12)	0.062 (5)
C6A	0.1336 (5)	1.045 (3)	0.8471 (11)	0.062 (5)
C7A	0.1792 (4)	1.023 (3)	0.7697 (8)	0.062 (5)
C8A	0.2294 (5)	1.178 (3)	0.7694 (12)	0.062 (5)
C9A	0.2708 (6)	1.145 (3)	0.6913 (12)	0.062 (5)
C10A	0.2670 (5)	0.956 (4)	0.6098 (12)	0.062 (5)
C11A	0.3144 (5)	0.936 (3)	0.5269 (11)	0.062 (5)
C12A	0.3784 (6)	0.907 (4)	0.5989 (19)	0.062 (5)
C13A	0.2990 (5)	0.749 (3)	0.4322 (10)	0.062 (5)
C14A	0.0604 (5)	1.116 (3)	0.9914 (10)	0.062 (5)
H1A	0.2147 (17)	0.659 (18)	0.543 (6)	0.074 (5)
H3A	0.1187 (19)	0.53 (2)	0.619 (6)	0.074 (5)
H4A	0.0445 (16)	0.576 (15)	0.755 (6)	0.074 (5)
H6A	0.1362 (18)	1.190 (16)	0.914 (6)	0.074 (5)
H8A	0.2349 (17)	1.326 (16)	0.832 (6)	0.074 (5)
H9A	0.3086 (19)	1.267 (16)	0.693 (5)	0.074 (5)
H11A	0.316 (2)	1.107 (14)	0.481 (5)	0.074 (5)
H13A	0.2573 (16)	0.782 (19)	0.371 (6)	0.074 (5)
H13B	0.335 (2)	0.74 (3)	0.374 (6)	0.074 (5)
H13C	0.2939 (17)	0.582 (15)	0.480 (5)	0.074 (5)
H14A	0.0186 (19)	1.182 (19)	1.011 (7)	0.074 (5)
H14B	0.0826 (19)	1.253 (13)	0.941 (7)	0.074 (5)
H14C	0.0898 (18)	1.080 (19)	1.079 (5)	0.074 (5)
O1B	0.5782 (11)	0.337 (3)	0.342 (2)	0.062 (5)
O2B	0.6056 (11)	−0.034 (3)	0.333 (2)	0.062 (5)
O3B	0.9496 (7)	0.398 (3)	0.1293 (15)	0.062 (5)
C1B	0.7668 (5)	0.162 (2)	0.4157 (13)	0.062 (5)
C2B	0.8143 (5)	0.220 (3)	0.3435 (10)	0.062 (5)
C3B	0.8679 (5)	0.091 (3)	0.3454 (12)	0.062 (5)
C4B	0.9111 (5)	0.155 (3)	0.2746 (12)	0.062 (5)
C5B	0.9051 (5)	0.351 (4)	0.1974 (12)	0.062 (5)
C6B	0.8555 (5)	0.483 (3)	0.1899 (12)	0.062 (5)
C7B	0.8085 (4)	0.426 (3)	0.2608 (8)	0.062 (5)
C8B	0.7565 (5)	0.551 (3)	0.2598 (12)	0.062 (5)
C9B	0.7134 (5)	0.487 (3)	0.3328 (13)	0.062 (5)
C10B	0.7176 (5)	0.293 (3)	0.4101 (13)	0.062 (5)
C11B	0.6667 (5)	0.242 (3)	0.4815 (10)	0.062 (5)
C12B	0.6117 (7)	0.170 (3)	0.3830 (17)	0.062 (5)
C13B	0.6814 (5)	0.076 (3)	0.5900 (10)	0.062 (5)
C14B	0.9421 (5)	0.597 (3)	0.0510 (10)	0.062 (5)
H1B	0.7706 (17)	0.014 (18)	0.478 (6)	0.074 (5)
H3B	0.8744 (19)	−0.061 (16)	0.404 (5)	0.074 (5)
H4B	0.9503 (17)	0.056 (16)	0.276 (6)	0.074 (5)
H6B	0.8514 (19)	0.63 (2)	0.129 (6)	0.074 (5)
H8B	0.7507 (17)	0.701 (17)	0.199 (6)	0.074 (5)
H9B	0.6736 (18)	0.585 (19)	0.330 (6)	0.074 (5)
H11B	0.6556 (19)	0.407 (15)	0.520 (5)	0.074 (5)
H13D	0.6814 (19)	−0.104 (15)	0.558 (6)	0.074 (5)
H13E	0.7260 (15)	0.119 (19)	0.638 (6)	0.074 (5)
H13F	0.6492 (17)	0.090 (18)	0.656 (6)	0.074 (5)
H14D	0.9857 (19)	0.65 (2)	0.028 (7)	0.074 (5)
H14E	0.9113 (16)	0.56 (2)	−0.034 (6)	0.074 (5)
H14F	0.9246 (17)	0.737 (15)	0.100 (6)	0.074 (5)
Na3	0.4455 (5)	−0.1021 (14)	1.0216 (7)	0.062 (5)
Na4	0.5658 (5)	0.1423 (16)	0.9522 (7)	0.062 (5)
O5W	0.4682 (7)	−0.394 (3)	0.8745 (12)	0.062 (5)
O6W	0.5457 (7)	0.440 (3)	1.1009 (12)	0.062 (5)
O7W	0.5476 (5)	−0.1270 (18)	1.1104 (8)	0.062 (5)
O8W	0.4642 (5)	0.172 (2)	0.8607 (7)	0.062 (5)
H9W	0.496 (2)	−0.306 (19)	0.827 (5)	0.074 (5)
H10w	0.4319 (17)	−0.436 (18)	0.814 (6)	0.074 (5)
H11w	0.5206 (18)	0.353 (18)	1.155 (5)	0.074 (5)
H12w	0.5839 (19)	0.48 (2)	1.158 (6)	0.074 (5)
H13w	0.570 (2)	−0.09 (3)	1.194 (8)	0.074 (5)
H14w	0.5505 (17)	−0.300 (17)	1.101 (5)	0.074 (5)
H15w	0.4425 (17)	0.14 (2)	0.777 (6)	0.074 (5)
H16w	0.4616 (17)	0.34 (2)	0.871 (6)	0.074 (5)
O1C	0.4208 (9)	0.249 (3)	1.109 (2)	0.062 (5)
O2C	0.3891 (9)	0.611 (3)	1.119 (3)	0.062 (5)
O3C	0.0572 (7)	0.382 (3)	1.4146 (15)	0.062 (5)
C1C	0.2476 (5)	0.216 (2)	1.1622 (12)	0.062 (5)
C2C	0.1993 (4)	0.255 (3)	1.2270 (9)	0.062 (5)
C3C	0.1792 (5)	0.086 (3)	1.3107 (12)	0.062 (5)
C4C	0.1306 (6)	0.127 (2)	1.3737 (12)	0.062 (5)
C5C	0.1016 (5)	0.343 (4)	1.3526 (13)	0.062 (5)
C6C	0.1189 (5)	0.513 (3)	1.2734 (11)	0.062 (5)
C7C	0.1681 (3)	0.475 (3)	1.2087 (8)	0.062 (5)
C8C	0.1884 (5)	0.639 (3)	1.1265 (12)	0.062 (5)
C9C	0.2368 (6)	0.592 (3)	1.0656 (13)	0.062 (5)
C10C	0.2665 (5)	0.381 (3)	1.0841 (12)	0.062 (5)
C11C	0.3160 (5)	0.332 (3)	1.0140 (11)	0.062 (5)
C12C	0.3788 (6)	0.400 (3)	1.086 (2)	0.062 (5)
C13C	0.3090 (5)	0.083 (2)	0.9688 (11)	0.062 (5)
C14C	0.0370 (5)	0.610 (3)	1.3851 (11)	0.062 (5)
H1C	0.2701 (17)	0.05 (2)	1.175 (6)	0.074 (5)
H3C	0.2026 (17)	−0.08 (2)	1.323 (6)	0.074 (5)
H4C	0.1146 (16)	−0.001 (18)	1.439 (5)	0.074 (5)
H6C	0.0958 (18)	0.678 (18)	1.260 (5)	0.074 (5)
H8C	0.165 (2)	0.802 (17)	1.112 (6)	0.074 (5)
H9C	0.2524 (17)	0.719 (17)	1.002 (6)	0.074 (5)
H11C	0.3108 (19)	0.450 (15)	0.934 (5)	0.074 (5)
H13G	0.2639 (17)	0.033 (16)	0.929 (7)	0.074 (5)
H13H	0.337 (2)	0.059 (17)	0.895 (6)	0.074 (5)
H13I	0.321 (2)	−0.036 (17)	1.046 (6)	0.074 (5)
H14G	0.0223 (19)	0.68 (2)	1.469 (7)	0.074 (5)
H14H	0.001 (2)	0.603 (17)	1.307 (5)	0.074 (5)
H14I	0.0740 (18)	0.724 (16)	1.361 (6)	0.074 (5)
O1D	0.5837 (12)	−0.205 (3)	0.8599 (18)	0.062 (5)
O2D	0.5965 (13)	−0.575 (3)	0.8136 (18)	0.062 (5)
O3D	0.9395 (7)	−0.191 (3)	0.5939 (15)	0.062 (5)
C1D	0.7388 (5)	−0.422 (3)	0.8205 (11)	0.062 (5)
C2D	0.7901 (3)	−0.355 (3)	0.7668 (9)	0.062 (5)
C3D	0.8037 (5)	−0.471 (4)	0.6597 (11)	0.062 (5)
C4D	0.8552 (5)	−0.405 (3)	0.6075 (12)	0.062 (5)
C5D	0.8943 (5)	−0.224 (3)	0.6598 (12)	0.062 (5)
C6D	0.8833 (5)	−0.102 (3)	0.7628 (11)	0.062 (5)
C7D	0.8308 (4)	−0.164 (3)	0.8202 (9)	0.062 (5)
C8D	0.8132 (5)	−0.061 (2)	0.9252 (12)	0.062 (5)
C9D	0.7607 (6)	−0.135 (3)	0.9731 (12)	0.062 (5)
C10D	0.7233 (5)	−0.312 (3)	0.9196 (12)	0.062 (5)
C11D	0.6709 (5)	−0.397 (3)	0.9778 (11)	0.062 (5)
C12D	0.6116 (7)	−0.397 (3)	0.8819 (17)	0.062 (5)
C13D	0.6881 (5)	−0.638 (2)	1.0275 (11)	0.062 (5)
C14D	0.9804 (5)	−0.008 (3)	0.6296 (10)	0.062 (5)
H1D	0.7100 (18)	−0.56 (2)	0.779 (6)	0.074 (5)
H3D	0.7736 (16)	−0.615 (17)	0.619 (6)	0.074 (5)
H4D	0.8666 (19)	−0.491 (18)	0.523 (6)	0.074 (5)
H6D	0.9133 (17)	0.036 (15)	0.800 (6)	0.074 (5)
H8D	0.842 (2)	0.08 (2)	0.969 (5)	0.074 (5)
H9D	0.7480 (17)	−0.057 (18)	1.055 (5)	0.074 (5)
H11D	0.6664 (19)	−0.283 (17)	1.057 (5)	0.074 (5)
H13J	0.7320 (17)	−0.624 (17)	1.081 (6)	0.074 (5)
H13K	0.6580 (18)	−0.708 (18)	1.091 (6)	0.074 (5)
H13L	0.6907 (19)	−0.755 (17)	0.949 (6)	0.074 (5)
H14J	1.0254 (16)	−0.07 (2)	0.628 (5)	0.074 (5)
H14K	0.9717 (16)	0.134 (19)	0.564 (6)	0.074 (5)
H14L	0.9752 (17)	0.050 (14)	0.722 (6)	0.074 (5)

Geometric parameters (Å, º)

Na1—O1W	2.433 (17)	Na3—O5W	2.444 (18)
Na1—O3W	2.420 (14)	Na3—O7W	2.395 (14)
Na1—O4W	2.375 (13)	Na3—O8W	2.417 (13)
Na1—O1A	2.34 (2)	Na3—O1C	2.36 (2)
Na1—O2A^i	2.30 (2)	Na3—O2C^i	2.39 (2)
Na2—O2W	2.446 (19)	Na4—O6W	2.461 (17)
Na2—O3W	2.353 (13)	Na4—O7W	2.375 (13)
Na2—O4W	2.401 (15)	Na4—O8W	2.394 (14)
Na2—O1B	2.34 (2)	Na4—O1D	2.31 (2)
Na2—O2B^ii	2.33 (2)	Na4—O2D^ii	2.36 (2)
O1W—H1W	1.00 (8)	O5W—H9W	0.99 (8)
O1W—H2W	1.01 (5)	O5W—H10W	1.00 (5)
O2W—H3W	0.99 (6)	O6W—H11W	1.00 (6)
O2W—H4W	1.00 (5)	O6W—H12W	1.01 (6)
O3W—H5W	0.98 (8)	O7W—H13W	0.99 (8)
O3W—H6W	0.98 (11)	O7W—H14W	1.00 (10)
O4W—H7W	0.99 (5)	O8W—H15W	0.99 (6)
O4W—H8W	1.00 (10)	O8W—H16W	1.00 (14)
O1A—C12A	1.30 (3)	O1C—C12C	1.31 (2)
O2A—C12A	1.28 (3)	O2C—C12C	1.27 (2)
O3A—C5A	1.34 (2)	O3C—C5C	1.32 (2)
O3A—C14A	1.44 (2)	O3C—C14C	1.42 (2)
C1A—C2A	1.420 (17)	C1C—C2C	1.412 (16)
C1A—C10A	1.37 (2)	C1C—C10C	1.37 (2)
C1A—H1A	1.07 (9)	C1C—H1C	1.08 (11)
C2A—C3A	1.426 (19)	C2C—C3C	1.432 (19)
C2A—C7A	1.47 (2)	C2C—C7C	1.47 (2)
C3A—C4A	1.355 (19)	C3C—C4C	1.409 (19)
C3A—H3A	1.05 (10)	C3C—H3C	1.09 (12)
C4A—C5A	1.40 (2)	C4C—C5C	1.43 (2)
C4A—H4A	1.08 (6)	C4C—H4C	1.10 (8)
C5A—C6A	1.36 (2)	C5C—C6C	1.38 (2)
C6A—C7A	1.434 (16)	C6C—C7C	1.428 (15)
C6A—H6A	1.10 (8)	C6C—H6C	1.10 (9)
C7A—C8A	1.421 (19)	C7C—C8C	1.402 (19)
C8A—C9A	1.372 (19)	C8C—C9C	1.398 (19)
C8A—H8A	1.08 (8)	C8C—H8C	1.09 (9)
C9A—C10A	1.40 (2)	C9C—C10C	1.41 (2)
C9A—H9A	1.09 (7)	C9C—H9C	1.09 (8)
C10A—C11A	1.510 (18)	C10C—C11C	1.482 (19)
C11A—C12A	1.565 (18)	C11C—C12C	1.566 (19)
C11A—C13A	1.49 (2)	C11C—C13C	1.509 (19)
C11A—H11A	1.10 (8)	C11C—H11C	1.09 (7)
C13A—H13A	1.10 (5)	C13C—H13G	1.08 (4)
C13A—H13B	1.10 (6)	C13C—H13H	1.11 (6)
C13A—H13C	1.10 (8)	C13C—H13I	1.09 (8)
C14A—H14A	1.09 (7)	C14C—H14G	1.10 (8)
C14A—H14B	1.10 (7)	C14C—H14H	1.09 (5)
C14A—H14C	1.11 (5)	C14C—H14I	1.11 (7)
O1B—C12B	1.29 (2)	O1D—C12D	1.30 (2)
O2B—C12B	1.29 (2)	O2D—C12D	1.28 (2)
O3B—C5B	1.35 (2)	O3D—C5D	1.34 (2)
O3B—C14B	1.42 (2)	O3D—C14D	1.40 (2)
C1B—C2B	1.452 (18)	C1D—C2D	1.416 (16)
C1B—C10B	1.367 (19)	C1D—C10D	1.35 (2)
C1B—H1B	1.08 (9)	C1D—H1D	1.07 (9)
C2B—C3B	1.449 (19)	C2D—C3D	1.423 (19)
C2B—C7B	1.48 (2)	C2D—C7D	1.481 (18)
C3B—C4B	1.370 (19)	C3D—C4D	1.412 (19)
C3B—H3B	1.08 (8)	C3D—H3D	1.11 (7)
C4B—C5B	1.40 (2)	C4D—C5D	1.41 (2)
C4B—H4B	1.07 (6)	C4D—H4D	1.11 (7)
C5B—C6B	1.37 (2)	C5D—C6D	1.381 (19)
C6B—C7B	1.431 (16)	C6D—C7D	1.456 (15)
C6B—H6B	1.08 (11)	C6D—H6D	1.07 (7)
C7B—C8B	1.406 (18)	C7D—C8D	1.404 (17)
C8B—C9B	1.386 (19)	C8D—C9D	1.420 (18)
C8B—H8B	1.08 (9)	C8D—H8D	1.08 (10)
C9B—C10B	1.39 (2)	C9D—C10D	1.38 (2)
C9B—H9B	1.08 (7)	C9D—H9D	1.08 (7)
C10B—C11B	1.503 (18)	C10D—C11D	1.493 (19)
C11B—C12B	1.571 (19)	C11D—C12D	1.583 (19)
C11B—C13B	1.516 (18)	C11D—C13D	1.53 (2)
C11B—H11B	1.09 (9)	C11D—H11D	1.11 (8)
C13B—H13D	1.10 (9)	C13D—H13J	1.08 (5)
C13B—H13E	1.09 (5)	C13D—H13K	1.10 (6)
C13B—H13F	1.10 (6)	C13D—H13L	1.10 (8)
C14B—H14D	1.09 (6)	C14D—H14J	1.10 (5)
C14B—H14E	1.10 (5)	C14D—H14K	1.09 (9)
C14B—H14F	1.09 (8)	C14D—H14L	1.09 (7)
O1W—Na1—O3W	76.9 (5)	O5W—Na3—O1C	162.7 (7)
O1W—Na1—O4W	79.0 (5)	O5W—Na3—O2C^i	90.0 (7)
O1W—Na1—O1A	168.6 (7)	O7W—Na3—O8W	95.2 (5)
O1W—Na1—O2A^i	88.7 (8)	O7W—Na3—O1C	101.0 (6)
O3W—Na1—O4W	93.3 (5)	O7W—Na3—O2C^i	108.1 (6)
O3W—Na1—O1A	108.3 (6)	O8W—Na3—O1C	79.2 (6)
O3W—Na1—O2A^i	91.5 (7)	O8W—Na3—O2C^i	155.5 (7)
O4W—Na1—O1A	90.4 (6)	O1C—Na3—O2C^i	103.2 (8)
O4W—Na1—O2A^i	165.5 (8)	O6W—Na4—O7W	84.8 (5)
O1A—Na1—O2A^i	101.1 (9)	O6W—Na4—O8W	86.6 (5)
O2W—Na2—O3W	86.2 (5)	O6W—Na4—O1D	164.0 (7)
O2W—Na2—O4W	92.6 (5)	O6W—Na4—O2D^ii	92.5 (7)
O2W—Na2—O1B	161.4 (7)	O7W—Na4—O8W	96.3 (5)
O2W—Na2—O2B^ii	89.5 (7)	O7W—Na4—O1D	79.4 (6)
O3W—Na2—O4W	94.4 (5)	O7W—Na4—O2D^ii	171.8 (7)
O3W—Na2—O1B	78.1 (6)	O8W—Na4—O1D	97.5 (7)
O3W—Na2—O2B^ii	162.9 (8)	O8W—Na4—O2D^ii	91.2 (7)
O4W—Na2—O1B	98.6 (7)	O1D—Na4—O2D^ii	102.9 (8)
O4W—Na2—O2B^ii	102.3 (7)	Na3—O5W—H9W	102 (6)
O1B—Na2—O2B^ii	102.5 (8)	Na3—O5W—H10W	110 (5)
Na1—O1W—H1W	102 (5)	H9W—O5W—H10W	106 (5)
Na1—O1W—H2W	108 (4)	Na4—O6W—H11W	103 (5)
H1W—O1W—H2W	104 (6)	Na4—O6W—H12W	109 (6)
Na2—O2W—H3W	106 (6)	H11W—O6W—H12W	105 (5)
Na2—O2W—H4W	112 (6)	Na4—O7W—Na3	84.7 (4)
H3W—O2W—H4W	107 (5)	Na4—O7W—H13W	115 (7)
Na2—O3W—Na1	86.2 (4)	Na4—O7W—H14W	123 (3)
Na2—O3W—H5W	104 (6)	Na3—O7W—H13W	134 (4)
Na2—O3W—H6W	130 (3)	Na3—O7W—H14W	97 (2)
Na1—O3W—H5W	135 (5)	H13W—O7W—H14W	104 (9)
Na1—O3W—H6W	102 (2)	Na4—O8W—Na3	83.8 (4)
H5W—O3W—H6W	103 (7)	Na4—O8W—H15W	134 (3)
Na2—O4W—Na1	86.1 (4)	Na4—O8W—H16W	97 (2)
Na2—O4W—H7W	135 (4)	Na3—O8W—H15W	116 (6)
Na2—O4W—H8W	99 (2)	Na3—O8W—H16W	123 (4)
Na1—O4W—H7W	110 (6)	H15W—O8W—H16W	104 (7)
Na1—O4W—H8W	125 (3)	Na3—O1C—C12C	136.7 (16)
H7W—O4W—H8W	105 (8)	C5C—O3C—C14C	108.6 (15)
Na1—O1A—C12A	131.4 (15)	C2C—C1C—C10C	121.3 (13)
C5A—O3A—C14A	110.6 (14)	C2C—C1C—H1C	119 (4)
C2A—C1A—C10A	122.9 (14)	C10C—C1C—H1C	119 (4)
C2A—C1A—H1A	118 (3)	C1C—C2C—C3C	122.2 (13)
C10A—C1A—H1A	119 (3)	C1C—C2C—C7C	119.4 (11)
C1A—C2A—C3A	124.3 (14)	C3C—C2C—C7C	118.3 (9)
C1A—C2A—C7A	118.1 (12)	C2C—C3C—C4C	121.4 (13)
C3A—C2A—C7A	118 (1)	C2C—C3C—H3C	118 (4)
C2A—C3A—C4A	122.5 (13)	C4C—C3C—H3C	121 (4)
C2A—C3A—H3A	119 (3)	C3C—C4C—C5C	118.3 (13)
C4A—C3A—H3A	119 (3)	C3C—C4C—H4C	122 (4)
C3A—C4A—C5A	119.5 (12)	C5C—C4C—H4C	119 (4)
C3A—C4A—H4A	121 (4)	C4C—C5C—O3C	117.8 (15)
C5A—C4A—H4A	119 (4)	C4C—C5C—C6C	123.2 (13)
C4A—C5A—O3A	119.5 (14)	O3C—C5C—C6C	119.0 (16)
C4A—C5A—C6A	122.3 (13)	C5C—C6C—C7C	119.5 (14)
O3A—C5A—C6A	118.1 (15)	C5C—C6C—H6C	121 (3)
C5A—C6A—C7A	120.3 (14)	C7C—C6C—H6C	119 (3)
C5A—C6A—H6A	120 (3)	C6C—C7C—C2C	119.3 (12)
C7A—C6A—H6A	120 (3)	C6C—C7C—C8C	123.1 (14)
C6A—C7A—C2A	117.9 (12)	C2C—C7C—C8C	117.6 (9)
C6A—C7A—C8A	125.3 (14)	C7C—C8C—C9C	120.5 (13)
C2A—C7A—C8A	117 (1)	C7C—C8C—H8C	118 (4)
C7A—C8A—C9A	121.6 (13)	C9C—C8C—H8C	122 (4)
C7A—C8A—H8A	119 (3)	C8C—C9C—C10C	121.6 (14)
C9A—C8A—H8A	119 (3)	C8C—C9C—H9C	120 (4)
C8A—C9A—C10A	122.3 (13)	C10C—C9C—H9C	118 (4)
C8A—C9A—H9A	120 (4)	C9C—C10C—C1C	119.7 (13)
C10A—C9A—H9A	118 (4)	C9C—C10C—C11C	120.3 (13)
C9A—C10A—C1A	118.2 (13)	C1C—C10C—C11C	119.9 (14)
C9A—C10A—C11A	118.3 (13)	C10C—C11C—C12C	113.5 (12)
C1A—C10A—C11A	123.4 (15)	C10C—C11C—C13C	108.9 (11)
C10A—C11A—C12A	114.1 (11)	C10C—C11C—H11C	106 (3)
C10A—C11A—C13A	111.7 (11)	C12C—C11C—C13C	114.5 (11)
C10A—C11A—H11A	105 (3)	C12C—C11C—H11C	104 (3)
C12A—C11A—C13A	110.8 (13)	C13C—C11C—H11C	109 (4)
C12A—C11A—H11A	105 (3)	C11C—C12C—O2C	117.9 (16)
C13A—C11A—H11A	110 (3)	C11C—C12C—O1C	122.3 (16)
C11A—C12A—O2A	118.1 (18)	O2C—C12C—O1C	119.8 (16)
C11A—C12A—O1A	120.4 (16)	C11C—C13C—H13G	113 (5)
O2A—C12A—O1A	120.2 (16)	C11C—C13C—H13H	110 (5)
C11A—C13A—H13A	112 (5)	C11C—C13C—H13I	110 (5)
C11A—C13A—H13B	109 (6)	Na3—C13C—H13G	143 (5)
C11A—C13A—H13C	109 (3)	Na3—C13C—H13H	57 (3)
H13A—C13A—H13B	108 (5)	Na3—C13C—H13I	61 (3)
H13A—C13A—H13C	109 (6)	H13G—C13C—H13H	106 (5)
H13B—C13A—H13C	111 (8)	H13G—C13C—H13I	106 (6)
O3A—C14A—H14A	107 (5)	H13H—C13C—H13I	111 (6)
O3A—C14A—H14B	111 (4)	O3C—C14C—H14G	107 (5)
O3A—C14A—H14C	113 (6)	O3C—C14C—H14H	110 (5)
H14A—C14A—H14B	108 (6)	O3C—C14C—H14I	110 (4)
H14A—C14A—H14C	110 (5)	H14G—C14C—H14H	112 (4)
H14B—C14A—H14C	108 (5)	H14G—C14C—H14I	108 (6)
Na2—O1B—C12B	128.3 (15)	H14H—C14C—H14I	109 (5)
C5B—O3B—C14B	115.2 (14)	Na4—O1D—C12D	142.0 (14)
C2B—C1B—C10B	121.7 (13)	C5D—O3D—C14D	117.5 (14)
C2B—C1B—H1B	120 (3)	C2D—C1D—C10D	122.6 (13)
C10B—C1B—H1B	119 (3)	C2D—C1D—H1D	119 (3)
C1B—C2B—C3B	124.9 (13)	C10D—C1D—H1D	118 (4)
C1B—C2B—C7B	118.7 (11)	C1D—C2D—C3D	120.7 (12)
C3B—C2B—C7B	116 (1)	C1D—C2D—C7D	121.1 (11)
C2B—C3B—C4B	122.1 (14)	C3D—C2D—C7D	118.2 (9)
C2B—C3B—H3B	120 (3)	C2D—C3D—C4D	120.3 (13)
C4B—C3B—H3B	118 (3)	C2D—C3D—H3D	119 (3)
C3B—C4B—C5B	120.7 (13)	C4D—C3D—H3D	121 (3)
C3B—C4B—H4B	121 (4)	C3D—C4D—C5D	121.2 (13)
C5B—C4B—H4B	118 (4)	C3D—C4D—H4D	122 (4)
C4B—C5B—O3B	116.3 (15)	C5D—C4D—H4D	117 (4)
C4B—C5B—C6B	120.8 (13)	C4D—C5D—O3D	110.4 (13)
O3B—C5B—C6B	122.9 (16)	C4D—C5D—C6D	121.5 (12)
C5B—C6B—C7B	121.5 (14)	O3D—C5D—C6D	128.1 (13)
C5B—C6B—H6B	120 (3)	C5D—C6D—C7D	119.5 (12)
C7B—C6B—H6B	119 (3)	C5D—C6D—H6D	120 (3)
C6B—C7B—C2B	118.5 (11)	C7D—C6D—H6D	121 (3)
C6B—C7B—C8B	125.4 (13)	C6D—C7D—C2D	119 (1)
C2B—C7B—C8B	116 (1)	C6D—C7D—C8D	127.1 (12)
C7B—C8B—C9B	121.9 (13)	C2D—C7D—C8D	113.6 (9)
C7B—C8B—H8B	118 (3)	C7D—C8D—C9D	122.2 (11)
C9B—C8B—H8B	120 (3)	C7D—C8D—H8D	116 (3)
C8B—C9B—C10B	123.0 (13)	C9D—C8D—H8D	121 (3)
C8B—C9B—H9B	120 (4)	C8D—C9D—C10D	122.5 (13)
C10B—C9B—H9B	117 (4)	C8D—C9D—H9D	122 (4)
C9B—C10B—C1B	118.6 (12)	C10D—C9D—H9D	116 (4)
C9B—C10B—C11B	117.0 (12)	C9D—C10D—C1D	118.0 (12)
C1B—C10B—C11B	124.4 (13)	C9D—C10D—C11D	121.0 (13)
C10B—C11B—C12B	106.5 (11)	C1D—C10D—C11D	120.7 (14)
C10B—C11B—C13B	114.0 (11)	C10D—C11D—C12D	111.6 (11)
C10B—C11B—H11B	107 (3)	C10D—C11D—C13D	103.9 (11)
C12B—C11B—C13B	116.5 (12)	C10D—C11D—H11D	109 (3)
C12B—C11B—H11B	105 (3)	C12D—C11D—C13D	114.3 (12)
C13B—C11B—H11B	107 (3)	C12D—C11D—H11D	109 (3)
C11B—C12B—O2B	122.0 (15)	C13D—C11D—H11D	109 (4)
C11B—C12B—O1B	115.5 (14)	C11D—C12D—O2D	119.4 (17)
O2B—C12B—O1B	121.6 (18)	C11D—C12D—O1D	119.7 (15)
C11B—C13B—H13D	111 (4)	O2D—C12D—O1D	120.0 (18)
C11B—C13B—H13E	110 (5)	C11D—C13D—H13J	109 (5)
C11B—C13B—H13F	110 (4)	C11D—C13D—H13K	112 (5)
H13D—C13B—H13E	107 (6)	C11D—C13D—H13L	109 (5)
H13D—C13B—H13F	109 (6)	H13J—C13D—H13K	107 (4)
H13E—C13B—H13F	109 (4)	H13J—C13D—H13L	107 (5)
O3B—C14B—H14D	107 (6)	H13K—C13D—H13L	112 (6)
O3B—C14B—H14E	112 (6)	O3D—C14D—H14J	108 (6)
O3B—C14B—H14F	110 (4)	O3D—C14D—H14K	108 (4)
H14D—C14B—H14E	110 (5)	O3D—C14D—H14L	110 (3)
H14D—C14B—H14F	110 (7)	H14J—C14D—H14K	110 (6)
H14E—C14B—H14F	108 (6)	H14J—C14D—H14L	111 (4)
O5W—Na3—O7W	85.2 (5)	H14K—C14D—H14L	110 (6)
O5W—Na3—O8W	84.2 (5)

Symmetry codes: (i) x, y−1, z; (ii) x, y+1, z.