Naloxegol hydrogen oxalate displaying a hydrogen-bonded layer structure

Nodes representing hydrogen-bonded naloxegol and hemioxalate units form a 3,5-connected net which has the 3,5 L50 topology.


Chemical context
Naloxegol {(5,6)-17-allyl-6- [(20-hydroxy-3,6,9,12,15,18hexaoxaicos-1-yl)oxy]-4,5-epoxymorphinan-3,14-diol} is a pegylated derivative of naloxone which serves as a peripherally acting m-opioid receptor antagonist. This compound was developed for the oral treatment of opioid-induced constipation in adults with chronic non-cancer pain, and is currently marketed under the trade name Movantik by AstraZeneca. Å slund et al. (2012) have described two forms, denoted as A and B, of naloxegol oxalate. Form B was reported as showing 'a sharp endothermic peak at 92.5 C' (365.5 K) in the DSC thermogram with a heat of fusion of Á fus H = 96.1 J g À1 (71.29 kJ mol À1 ). Herein we report the crystal structure of naloxegol hydrogen oxalate (I) (C 34 H 54 NO 11 + C 2 HO 4 À ), which is identical with form B described by Å slund et al. (2012). The unequivocal identity with form B is evidenced by the match of the X-ray powder diffraction data and the good agreement of the melting data [T fus(onset) = 363.9 AE 0.3 K, T fus(peak) = 366.7 AE 0.3 K, Á fus H = 70.4 AE 0.6 kJ mol À1 ] with those reported by Å slund et al. .

Structural commentary
The geometry of the morphine scaffold in the title structure (I) is very similar to that of the parent molecule in the naloxone hydrochloride dihydrate structure (Klein et al., 1987), except for the conformation of the cyclohexyl ring (C2-C6/C11) (Figs. 1 and 2). In (I), the puckering parameters for this ring of q = 85.3 (2) and = 76.6 (3) indicate a conformation between boat and twist boat (Cremer & Pople, 1975;Boeyens, 1978). The conformation of the 2-propenyl group at N8 is characterised by the torsion angle N8-C43-C44-C45 of 133.6 (4) , which differs substantially from the corresponding value, À96.2 , in the naloxone hydrochloride dihydrate. The polyether unit adopts the shape of a squashed open letter O. Using the nomenclature for torsion angles recommended by Markley et al. (1998), the conformation of the fragment (C3, O19-C41) can be described by the sequence tg + t tg À [[t]] ttg À g À g À g + g + g À t tg À t tg À t. All O-C-C-O angles are gauche except for O25-C26-C27-O28. Six consecutive gauchetype torsion angles are associated with a 180 turn within the chain section (C26-O34) (Fig. 1, Table 1). The hydrogen oxalate anion displays a twisted conformation with a torsion angle O1O-C2O-C4O-O5O of À143.3 (3) .

Supramolecular features
The naloxegol cation contains one NH group and two OH groups, which can serve as hydrogen-bond donor groups, and the hydrogen oxalate contains another OH group. Neighbouring hydrogen oxalate ions are hydrogen bonded (Table 2) to one another (O6O-H6OÁ Á ÁO1O iii ), so that a chain structure parallel to the b axis is formed. Each naloxegol unit serves as a bridge between two such hydrogen oxalate chains in that it provides two bonds, O42-H42Á Á ÁO3O ii and N8-H8Á Á ÁO1O i , to two different anions belonging to one hydrogen-bonded hydrogen oxalate chain, The third bond, O46-H46Á Á ÁO5O, connects to a second anion chain (Fig. 3). Altogether, each naloxegol cation forms three hydrogen bonds to three hydrogen oxalate ions, and each anion is engaged in five one-point hydrogen-bonding interactions with two hydrogen oxalate and three naloxegol units. The 3,5connected layer structure (Fig. 4) resulting from these interactions lies in the ab plane. It possesses the 3,5L50 topology and has the point symbol (3.5 2 )(3 2 .5 3 .6 4 .7), wherein the naloxegol and hydrogen oxalate nodes are represented by the string (3.5 2 ) and (3 2 .5 3 .6 4 .7), respectively.

Figure 1
The asymmetric unit of (I), with displacement ellipsoids drawn at the 50% probability level and H atoms drawn as spheres of arbitrary size.
Heptaglyme (heptaethyleneglycol dimethyl ether) has been used as a multidentate ligand in Ba (FIXKAY; Wei et al., 1987), Ca (RUFWUK; Arunasalam et al., 1997) and Gd (YOMBUX; Baxter et al., 1995) complexes. The heptaglyme conformations in these crystals differ substantially from the chain geometry found in (I). For example, the heptaglyme complex with barium thiocyanate displays a regular sequence tg + t tg À t tg + t tg À t tg + t tg À tg + t with sign alternation (Wei et al., 1987).

Synthesis and crystallization
Naloxegol was obtained as a viscous transparent yellow oil (purity 95.05%). Approximately 4000 mg (6.14 mmol) of the free base were dissolved in 30 ml of ethylacetate and 774 mg (1 meq) of oxalic acid dihydrate (Merck) suspended in 20 ml of ethylacetate. The free-base solution was added dropwise to the suspended counter-ion. Stirring at room temperature for 15 minutes transformed the gel-like material into a suspension. The oxalate salt formation was complete after continued stirring for 12 h at ambient temperature. The slurry was then separated from the mother liquor by centrifuge and then dried in vacuo at ambient temperature (yield 3700 mg = 4.99 mmol = 81% of theory). The PXRD pattern of the dried product was found to match that of form B reported in Å slund et al. (2012).
A sample of form B (50 mg) was dissolved in 0.3 ml of 2-propanol under slight heating. Filtration through a syringe filter (pore size 0.44 microns) yielded a clear solution. The solution was allowed to cool to room temperature. Crystallization in a closed vial yielded single crystals suitable for a crystal structure determination. Typical crystal morphologies of (I) obtained by evaporation from different organic solvents are shown in Fig. S1 of the Supporting information.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. All H atoms were identified in difference maps. Methyl H atoms were idealized and included as rigid groups allowed to rotate but not tip and refined with U iso set to 1.5U eq (C) of the parent carbon atom. All other H Topological representation in the manner proposed by Hursthouse et al. (2015) of the hydrogen-bonded layer structure with the 3,5 L50 topology (Nal = naloxegol, Hox = hydrogen oxalate). The net is viewed along the c axis. Note that the naloxegol nodes are placed at the centroid of the molecule rather than the center of its morphine scaffold.

Figure 3
Hydrogen-bonded layer structure of (I), viewed along the c axis. H and O atoms directly engaged in hydrogen bonding are drawn as balls. All other H atoms and the polyether group are omitted for clarity. atoms bound to carbon atoms were positioned geometrically and refined with U iso set to 1.2U eq (C) of the parent carbon atom. Hydrogen atoms in OH and NH groups were refined with restrained distances [O-H = 0.84 (1) Å ; N-H = 0.88 (1) Å ] and their U iso parameters were refined freely. The absolute structure was established by anomalous-dispersion effects.
The largest residual peak of 0.73 e Å À3 is located 1.00 Å from C30. An alternative refinement of a disorder model with a split C30 position was attempted, but resulted in a few unreasonably short intramolecular HÁ Á ÁH distances for the minor disorder fragment. This feature could not be eliminated even with the aplication of a suitable anti-bumping restraint.
The topology of the hydrogen-bonded structures was determined and classified with the programs ADS and IsoTest of the TOPOS package (Blatov, 2006) in the manner described by Baburin & Blatov (2007).

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.