Crystal structure of a mixed solvated form of amoxapine acetate

The mixed solvated salt 4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-ium acetate–acetic acid–cyclohexane (2/2/1), crystallizes with one molecule of protonated amoxapine (AXPN), an acetate anion and a molecule of acetic acid together with half a molecule of cyclohexane. In the crystal, the various components are linked via N—H⋯O and O—H⋯O hydrogen bonds, forming a layered structure with the solvent molecules occupying the spaces between the layers.


Chemical context
2-Chloro-11-(piperazin-1-yl)dibenzo [b,f] [1,4]oxazepine (Amoxapine, AXPN) is a benzodiazepine derivative and exhibits anti-depressant properties (Greenbla & Osterber, 1968) with one reported crystal structure (CSD refcode: AMOXAP; Cosulich & Lovell, 1977). AXPN acetate acetic acid cyclohexane was obtained as a part of a wider investigation that couples experimental crystallization techniques with computational methods in order to obtain a better understanding of the factors underpinning the solid-state structure and diversity of structurally related compounds, i.e. olanzapine, clozapine, loxapine and AXPN Bhardwaj, Price et al., 2013). The sample of AXPN acetate acetic acid cyclohexane was isolated during an experimental physical form screen of AXPN. The sample was identified as a novel form using multi-sample foil transmission X-ray powder diffraction analysis (Florence et al., 2003). A suitable sample for single crystal X-ray diffraction analysis was obtained from slow evaporation of a saturated solution of AXPN in a 1:1 molar ratio of acetic acid and cyclohexane at room temperature. ISSN 2056-9890

Structural commentary
The title compound crystallizes with one molecule of protonated AXPN and an acetate anion each with a molecule of acetic acid and a half molecule of cyclohexane (which lies across a center of inversion) as solvent of crystallization in the asymmetric unit (Fig. 1). The dioxazepine ring of AXPN exists in a puckered conformation between the planes of the benzene rings [the benzene rings fused to the central ring make a dihedral angle of 58.63 (6) ], and the piperazine ring adopts a chair conformation, as observed in the AXPN free base (CSD refcode: AMOXAP; Cosulich and Lovell, 1977) and structurally related analogues Bhardwaj, Price et al., 2013).

Supramolecular features
In the crystal, opposite enantiomers of protonated AXPN molecules stack along the c-axis direction. A view of the molecular structure of the asymmetric unit of the title molecular salt, showing the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
The crystal packing of the title molecular salt, viewed down the b axis. The cyclohexane molecules are shown as a blue space-fill model. Hydrogen bonds are shown as green lines (see Table 1 for details; atom colour code: C, N, O, Cl and H are blue, violet, red, green and black, respectively; H atoms not involved in hydrogen bonding have been omitted for clarity). Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) x; Ày þ 1 2 ; z þ 1 2 ; (ii) Àx; y À 1 2 ; Àz þ 1 2 ; (iii) x; y À 1; z. AXPN molecule forms two N-HÁ Á ÁO hydrogen bonds with two acetate anions, which connect it to an adjacent protonated AXPN molecule along the b axis, creating a sheet-like structure parallel to (100); see Fig. 2 and Table 1. The acetic acid molecules act as hydrogen-bond donors to acetate anions and are present between the protonated AXPN molecules along the c-axis direction. There are also C-HÁ Á ÁO hydrogen bonds present within the sheets (Table 1). These sheets stack along the a axis and the cyclohexane molecules occupy the space between the sheets (Fig. 2).

Synthesis and crystallization
Rod-shaped crystals were grown from a saturated solution of AXPN in a 1:1 molar ratio of acetic acid and cyclohexane by isothermal solvent evaporation at 298 K.

Refinement
Crystal data, data collection and structure refinement details are summarized in

Special details
Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.