Naloxegol hydrogen oxalate displaying a hydrogen-bonded layer structure

Abstract

In the salt (5 ,6 )-6- [(2,5,8,11,14,17,20-heptaoxadocosan-22-yl)oxy]-3,14-dihydroxy-17-(prop-2-en-1-yl)-4,5-epoxymorphinan-17-ium hydrogen oxalate, C 34 H 54 NO 11 + ÁC 2 HO 4 À the polyether unit of the naloxegol cation adopts the shape of a squashed open letter 'O'. In the crystal, the hydrogen oxalate anions are linked into a chain by O-HÁ Á ÁO hydrogen bonds. Each naloxegol unit is hydrogen bonded to three hydrogen oxalate ions via two O-HÁ Á ÁO and one N-HÁ Á ÁO interactions. The resulting hydrogen-bonded two-dimensional layer structure is 3,5-connected and has the 3,5 L50 topology. Chemical contextNaloxegol {(5 ,6 )-17-allyl-6- [(20-hydroxy-3,6,9,12,15,18-hexaoxaicos-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 commentaryThe 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. ISSN 2056-9890 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 sequenceAll 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 featuresThe naloxegol cation contains one NH group and two OH groups, which can serve as hydrogen-bond don...

Oxalic Acid, a Versatile Coformer for Multicomponent Forms with 9-Ethyladenine

“…Curiously, it was found through a small-scale screening due to the difficulties in preparing naloxegol in solid form [3]. As a result, two polymorphic forms were described, and the crystal structure resolution of Form B showed that it contained hydrogen oxalate anions [4]. In spite of the low incidence of oxalic acid in the list of the most used anions in APIs [5], many other examples have also been described in the literature exhibiting the interest of the scientific community for this coformer [6][7][8][9].…”