Crystal structure of naltrexone chloride solvates with ethanol, propan-2-ol, and 2-methylpropan-2-ol

Naltrexone [systematic name: 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one] is an opioid receptor competitive antagonist that has been widely used to prevent relapse in opioid- and alcohol-dependent subjects. Its chloride salt forms non-isomorphic solvates with ethanol (C20H24O4 +·Cl−·C2H5OH) (I), propan-2-ol (C20H24O4 +·Cl−·C3H7OH) (II), and 2-methylpropan-2-ol (C20H24O4 +·Cl−·C4H9OH) (III). In all these structures, the alcohol molecules occupy infinite solvent-filled channels. All three compounds described are attractive crystalline forms for unambiguous identification of naltrexone chloride after isolation from a pharmaceutical form.

Naltrexone [systematic name: 17-(cyclopropylmethyl)-3,14-dihydroxy-4,5epoxymorphinan-6-one] is an opioid receptor competitive antagonist that has been widely used to prevent relapse in opioid-and alcohol-dependent subjects. Its chloride salt forms non-isomorphic solvates with ethanol (C 20 H 24 NO 4 + ÁCl À Á-ÁC 2 H 5 OH) (I), propan-2-ol (C 20 H 24 NO 4 + ÁCl À ÁC 3 H 7 OH) (II), and 2-methylpropan-2-ol (C 20 H 24 NO 4 + ÁCl À ÁC 4 H 9 OH) (III). The naltrexone cation can be described as a T-shape made out of two ring systems, a tetrahydro-2Hnaphtho [1,8-bc]furan system and a decahydroisoquinolinium subunit, that are nearly perpendicular to one another. The flexible cyclopropylmethyl group can adopt various different conformations in response to its surroundings: an increase of available space around cyclopropylmethyl group may allow it to adopt a more favorable conformation. In all these structures, the alcohol molecules occupy infinite solvent-filled channels. All three compounds described are attractive crystalline forms for unambiguous identification of naltrexone chloride after isolation from a pharmaceutical form. Compound (III) was refined as a two-component twin.

Chemical context
Alcohol and opiate dependence are potentially life-threatening disorders associated with adverse physical and societal effects including poor social functioning, familial problems, and crime (Compton & Volkow, 2006). One strategy suggested to address these issues is the inclusion of receptor antagonists that reduce, and can even reverse, the euphoric effects of the drug sought by abusers. Naltrexone [systematic name: 17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxy-morphinan-6one] is an opioid receptor competitive antagonist that has been widely used to prevent relapse in heroin and other opioiddependent subjects, and has been found to reduce cravings in alcohol-dependent subjects (Roozen et al., 2006). Its structurerelated analogue oxymorphone is a potent -agonist, which differs from naltrexone only in having an N-methyl group in place of an N-cyclopropylmethyl group (Amato et al., 1990). Elucidation of the conformational profile of naltrexone is of fundamental importance in order to determine molecular requirements for the specific binding affinities of this drug, particularly through the possible position of groups responsible for pharmacological action.
The most common pharmaceutical form of this compound is naltrexone hydrochloride tablets. The introduction of new crystalline forms of an active pharmaceutical compound provides an opportunity to improve the performance characteristics of a pharmaceutical product. There is a need for new crystalline forms of naltrexone hydrochloride (Nichols et ISSN 2056-9890 al., 2013) as well for new analytical methods of its unambiguous identification. This communication is a continuation of our work on analytical crystallography of opiate compounds (Gauchat & Nazarenko, 2017).

Structural commentary
In all cases, interaction with the alcohol molecules does not affect the geometry of the methorphan ring system (Fig. 1), leaving the shape of the organic molecule intact. The bond lengths and angles in the alcohol solvates are not far from expected values and are generally close to those reported for the hydrate structure (Ledain et al., 1992).
There are four six-membered rings and a five-membered ring in a naltrexone molecule. The aromatic ring is close to planar, with deviations less than 0.03 Å in all cases. The cyclohexadiene ring can be described as a half-chair shifted towards an envelope conformation: atoms C10, C11, C12 and C13 are adjacent to the aromatic ring and therefore almost planar while C9 and C14 deviate from this plane in opposite directions (see Table 1 for puckering parameters). A similar observation is true for the dihydrofurane five-membered ring, which is almost intermediate between an envelope and a halfchair with C5 and C13 deviating from the mean plane in opposite directions.
The cyclohexanone and piperidine rings both have chair conformations, with cyclohexanone visibly shifted towards half-chair. These two rings are nearly coplanar. As a result, the naltrexone cation can be described as having two ring systems: a phenyl ring with adjacent epoxy and cyclohexadiene rings  Table 1 Ring puckering analysis (Å , ) of five-and six-membered rings.

Ring parameter (I) (II) (III) cation 1 (III) cation 2
A Q 0.341 (2) 0.340 ( The numbering scheme of the naltrexone cation in the ethanol solvate structure (I), with 50% probability ellipsoids. All other naltrexone cations have the same numbering scheme (100 added to each atom number in a second naltrexone cation in structure III).

Figure 2
Overlay of all four naltrexone cations studied in this work with the cyclopropyl group omitted.
(tetrahydro-2H-naphtho [1,8-bc]furan system, atoms O2/C1-C4/ C9-C13) and cyclohexanone plus piperidine rings (decahydroisoquinolinium moiety, atoms N1/C5-C9/C13-C16). They are nearly perpendicular to each other, thus forming the well-established T-shape common to morphine, naloxene, and numerous similar molecules (Darling et al., 1982;Klein et al., 1987;Gelbrich et al., 2012). The angle between two mean planes is 83.9 (1) for EtOH (I), 83.4 (1) for i-PrOH (II) and 82.5 (1) and 84.3 (1) for the two cations in t-BuOH (III) solvate. What is responsible for switching from a potent opiate agonist (morphine and oxymorphone) to a potent competitive antagonist (naloxene and naltrexone)? It seems certain that changes in a relatively rigid oxymorphone cation are not liable. Overlay calculations show that all three naltrexone solvates fit the same shape (Fig. 2), with r.m.s. deviations being 0.09 (EtOH/i-PrOH), 0.06 and 0.11 Å (EtOH/t-BuOH). The same overlay with an oxymorphone cation (refcode BIZGAS) shows r.m.s. deviations of 0.10 to 0.13 Å and 0.13 Å for naloxene (refcode NALOXC02). It should be taken into account that, in these cases, the temperature of the experiment was different, which obviously increases the discrepancy. Even when we compare morphine (refcode EFASAH; Gelbrich et al., 2012) and oxymorphone and morphine and naltrexone, the fit is almost identical: r.m.s. deviations of 0.36 and 0.35 Å , respectively, with larger discrepancies coming from obvious structural differences between the phenol group of morphine and a cyclohexanone fragment in oxymorphone and naltrexone. The only flexible locations in the oxymorphone cation are oxygen O1 of the carbonyl group and the orientation of two hydroxyl groups (oxygen atoms O3 and O4), which all potentially form strong hydrogen bonds. Therefore, the simplest explanation of antagonist activity is the presence of a small 'flat' fragment attached to an N-methyl Overlay of both naltrexone cations of the tert-butanol solvate (III) (red and green) and of the propan-2-ol solvate (II) (usual color scheme). The orientation of the cyclopropyl group is similar in all three cases.

Figure 4
Overlay of the naltrexone cations of the ethanol solvate (I) and the tetrahydrate (refcode PABCEA). The orientation of the cyclopropyl group is similar in both cases.

Figure 5
Overlay of the naltrexone cations of the ethanol solvate (I) and propanol solvate (II). The orientation of the cyclopropyl group is visibly different. group: cyclopropyl in naltrexone or vinyl in naloxene. The link between this small rigid fragment and the oxymorphone cation is flexible: as a result, we see different orientations of the cyclopropane ring in various solvates of naltrexone. These orientations can be systemized in two groups. First, an overlay of the hydrate (refcode PABCEA) and the ethanol solvate (this work) shows very similar conformations for these two structures (Fig. 3). The orientation of the cyclopropyl group in the iso-propanol and tert-butanol solvates is also almost the same (Fig. 4). However, these two groups significantly differ from each other (Fig. 5). The angle between the cyclopropyl group plane and the mean plane of the cyclohexanone and piperidine rings can serve as a quantitative measure of the methylcyclopropyl fragment orientation. This angle is 36.1 (formate, H 2 O), 38.6 (H 2 O), 48.6 (EtOH), 71.7 (i-PrOH), 83.5 and 84.6 Å (t-BuOH); the first two values were calculated from Scheins et al. (2007) and Ledain et al. (1992). Thus, the conformation of the methylcyclopropyl fragment is very sensitive to its environment.

Supramolecular features
The way in which a solvate molecule interacts with a naltrexone cation is different in all cases studied. Obviously, the strongest possible interaction is a hydrogen bond associated with the hydroxyl group of the alcohol molecule. However, naltrexone hydrochloride is an ionic compound and electrostatic interaction between a positively charged bulk cation and a chloride ion plays an essential role in crystal formation. Electrostatic potential data (Scheins et al., 2007) show more or less uniform positive charge for most of the cation surface, with the obvious exception of the negatively charged oxygen atoms.
In the ethanol solvate (I), the ethanol molecule is disordered; however, both orientations show strong hydrogen bonds with the chloride anion and no direct interaction with the naltrexone cation. The chloride ion is surrounded by hydroxyl groups belonging to two different cations (Fig. 6, Table 1). Interestingly, there is no hydrogen bond between the chloride ion and the formally positively charged protonated ammonium nitrogen atom N1. Instead, there is a strong hydrogen bond between N1 and oxygen atom O1 of the carbonyl group belonging to another cation ( Table 2). As a result, the naltrexone cations form infinite chains along the [010] direction. These chains are bound together via hydrogen bonds involving a chloride ion (Fig. 6), forming a layer in the (001) Table 2 Hydrogen-bond geometry (Å , ) for (I). Symmetry codes: (i) x; y À 1; z; (ii) x þ 1; y À 1; z.

Figure 7
Packing diagram of the ion associates in the ethanol solvate (I), viewed along [010]. There is a visible gap between the bilayers. Chloride ions (green) and ethanol molecules are highlighted.

Figure 6
Hydrogen bonds around the chloride ion in the ethanol solvate (I). channel going along [010] axis containing the chloride ions and ethanol molecules (Fig. 7), thus forming a double layer in the (001) plane. These layers are bound to each other only by weak van der Waals interactions, despite the overall positive charge of the cation chains. The shortest contact involves an O2 oxygen atom of one layer and an H15A hydrogen atom of another, and has an O-H separation of 2.60 (2) Å , which is above threshold of hydrogen bonding.
In the propan-2-ol solvate (II), the alcohol molecule is also partially disordered. Both orientations make hydrogen bonds with ether oxygen atom, O2, of the dihydrofuran ring (Fig. 8).
In this structure, a chloride ion is surrounded by two hydroxyl groups and the protonated nitrogen atom N1, all belonging to different naltrexone cations ( Fig. 9, Table 3). These interactions result in a three-dimensional network, which has solvent-filled infinite channels oriented along the [100] direction ( Fig. 10).

Figure 10
Packing diagram of the naltrexone ion associates in the propan-2-ol solvate (II), viewed along [100]. The chloride ions (green) and solvent molecules are highlighted.

Figure 11
O-HÁ Á ÁO hydrogen bonds connecting the tert-butanol molecules in (III) to each other and to the ether group of a naltrexone cation.
Contrary to the ethanol solvate, in the propanol and tertbutanol solvates, sequences of chloride ions occupy locations which are separate from the solvent-filled channels.
In the tetrahydrate (refcode PABCEA; Ledain et al., 1992) and formate hydrate (refcode YIGREM; Scheins et al., 2007), naltrexone cations form a chain via the protonated nitrogen atom and an oxygen atom of a carbonyl group, similar to what we see in the ethanol solvate. Water molecules and chloride ions also occupy a channel, this time along [001]. However, contrary to the ethanol solvate, the tetrahydrate structure does not exhibit a layered layout.
It is worth mentioning that in the ethanol solvate of oxymorphone hydrochloride (Darling et al., 1982), the ethanol molecule makes a weak hydrogen bond with the phenolic hydroxy group (atom O3 in our numbering scheme).
A plausible assumption is that interaction with an alcohol solvate molecule (or absence of it) does not affect significantly the structure of the naltrexone cation. Obviously, the presence of a strong hydrogen bond at the cyclohexanone carbonyl oxygen atom O1 (e.g., hydrate and ethanol solvate) is important; this affects the geometry of the cyclohexanone moiety and, possibly, the orientation of the methylcyclopropyl residue. Another significant factor is the size of a solvent-filled void. An increase of available space around the cyclopropylmethyl group may allow it to adopt a more favorable conformation.

Database survey
There are three reported naltrexone structures deposited in the Cambridge Structural Database (CSD Version 5.37; Groom et al., 2016). Of these, two report the structures of the chloride salt at room temperature (refcodes XINSAP and PABCEA), one of which (Sugimoto et al., 2007) is a powder structure of its anhydrous salt and the other (Ledain et al., 1992) a single-crystal investigation of tetrahydrate. A highquality charge-density investigation of the neutral naltrexone molecule and protonated naltrexone formate (refcodes YIGRAI and YIGREM; Scheins et al., 2007) was performed at 100 K. A room-temperature structure of naltrexone malonate (refcode JEXRAF; Amato et al., 1990) is also known. The existence of various solvates of naltrexone chloride was reported from powder data (Nichols et al., 2013); however, no structural results were provided.

Synthesis and crystallization
Naltrexone hydrochloride (INTAS Ltd, India) was obtained as a mixture with lactose. The target compound was extracted from its starting form by recrystallization in ethanol, isopropanol, and tert-butanol. FTIR and Raman spectra of purified samples were consistent with database data for naltrexone hydrochloride. A GC-MS study showed one single peak on the chromatogram with m/z: 341(M + ), 300 (M À C 3 H 5 ), 286 (M À C 4 H 7 ). A portion of the extracted naltrexone was then derivatized using pentafluoropropionic anhydride (PFPA), resulting in a corresponding dipentafluoropropionate (m/z): 633 (M), 592 (M À C 3 H 5 ), 486 (M À C 3 F 5 O). This is consistent with the existence of two hydroxyl groups in the naltrexone molecule and confirms the correct chemical formula.
Nevertheless, diffractograms obtained from the crystallized material were all different from each other and from known naltrexone hydrochloride hydrate and naltrexone hydrochloride crystals (Ledain et al., 1992;Sugimoto et al., 2007;Nichols et al., 2013). The quality of some of the solvate crystals was sufficient for single crystal investigation. Herein we report the results obtained.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 5.
In the ethanol solvate (I), the solvent molecules are disordered with occupancies being approximately in a 2:1 ratio [0.66 (3):0.34 (3)]. Rigid body restrains (RIGU) were applied during refinement. In the propanol solvate (II), the occupancy of the minor component of a disordered solvent molecule is only 0.178 (9), which required additional constraints (EXYZ and EADP) on the position of the hydroxy group atoms. The tert-butanol solvate structure (III) was refined as a twocomponent twin (twin matrix: À1.000 0.000 0.000 À0.001 À1.000 0.000 0.164 0.000 1.000). There is visible flexibility in positions of the methyl groups of the tertiary tert-butanol molecules, which results in larger displacement parameters and could be potentially treated as disorder. However, we do not see the need for additional over-complication of the refinement procedure.
Hydrogen atoms of the hydroxyl groups were refined with riding coordinates and stretchable bonds. Hydrogen atoms of the protonated amine were refined isotropically or with riding coordinates and stretchable bonds, with U iso = 1.2U iso (N) in all cases. All other hydrogen atoms were refined with riding coordinates, with U iso = 1.5U iso (C) for methyl groups and U iso = 1.2U iso (C) for all others.   For all compounds, data collection: APEX2 (Bruker, 2013); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b). Molecular graphics: OLEX2 (Dolomanov et al., 2009) and Mercury (Macrae et al., 2006) for (I); OLEX2 (Dolomanov et al., 2009) for (II), (III). Software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009) and PLATON (Spek, 2009) for (I); OLEX2 (Dolomanov et al., 2009) for (II), (III).   (18) 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.

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. (  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. Refinement. Refined as a 2-component twin.