Venlafaxine besylate monohydrate

The title compound {systematic name: [2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl]dimethylazanium benzenesulfonate monohydrate}, C17H28NO2 +·C6H5O3S−·H2O, is a besylate salt hydrate of the antidepressant drug venlafaxine. In the crystal, besylate anions and water molecules self-assemble, forming hydrogen-bonded dimers linked around inversion centers, with graph set R 4 4(6). The crystal packing features a chain of alternate dimers and venlafaxine cations in the b-axis direction with the components linked by O—H⋯O hydrogen bonds and C—H⋯O and C—H⋯π interactions. This is the first example of a venlafaxine cation with a closed conformation, as it features an intramolecular N—H⋯O interaction involving the protonated N atom.

The title compound {systematic name: [2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl]dimethylazanium benzenesulfonate monohydrate}, C 17 H 28 NO 2 + ÁC 6 H 5 O 3 S À ÁH 2 O, is a besylate salt hydrate of the antidepressant drug venlafaxine. In the crystal, besylate anions and water molecules selfassemble, forming hydrogen-bonded dimers linked around inversion centers, with graph set R 4 4 (6). The crystal packing features a chain of alternate dimers and venlafaxine cations in the b-axis direction with the components linked by O-HÁ Á ÁO hydrogen bonds and C-HÁ Á ÁO and C-HÁ Á Á interactions. This is the first example of a venlafaxine cation with a closed conformation, as it features an intramolecular N-HÁ Á ÁO interaction involving the protonated N atom.

Comment
The title compound (I) is a monohydrate of the 1:1 salt of 1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol with benzenesulphonic acid. Venlafaxine besylate is an antidepressant drug belonging to the class of serotonin norepinephrine reuptake inhibitors. The asymmetric unit consists of a venalfaxine cation, a besylate anion and a water molecule (Fig. 1).
The dimethylaminomethyl group of the venlafaxine cation is protonated by besylic acid. The hydroxy group lies in an axial position with respect to the cyclohexane ring and C7 is located at an equatorial position. Inspecting CSD (Allen, 2002), different conformations could be found for Venlafaxine. An open conformation -T shaped geometry- (Venu et al., 2008), with the dimethylaminomethyl and cyclohexanol groups representing the arms, is observed when venlafaxine is protonated (cation), whereas a closed conformation can be seen when venlafaxine is a free base. The closed conformation observed in the free base molecule is mainly due to the presence of an intra-molecular hydrogen bond provided by O2-H2···N1, then the torsion angle C8-C7-C14-N1 assumes a value that allows the approaching of H2 to N1. The mean value of the torsion angle C8-C7-C14-N1 obtained on seven free molecules is 62 (1)° (refcodes OCALAG, two molecules in OCALAG01, OCALAG02, YISFOW, YISFOW01 and YISFOW02) (Tessler & Goldberg, 2004, Van Eupen et al., 2008. This intramolecular hydrogen bond is absent in the Venlafaxine cation, probably due to the presence of an extra hydrogen atom at N1. The mean value of the torsion angle C8-C7-C14-N1 on six cation molecules is 138 (7)° (refcodes KIDGUZ, VAWQAM, WOBMUV, WOBMUV01 and two molecules in WOBMUV02) (Yardley et al., 1990, Banjeree et al., 2005, Vega et al., 2000, Sivalakshmidevi et al., 2002, Roy et al., 2007, featuring the open conformation for cations. However, the crystal structure introduced here is the first case where a Venlafaxine cation is in a closed conformation. The torsion angle C8-C7-C14-N1 is 71.9 (2)°. Although the closed conformation is provided by an intramolecular hydrogen bond, in this opportunity a different hydrogen bond is present because it is provided by the protonated nitrogen atom N1, where O2 acts as an acceptor (Fig 1) The cyclohexyl ring assumes a chair conformation, with puckering amplitude Q T =0.564 Å, τ=0.67° and φ=262.3° (Cremer & Pople, 1975), where C8 and C11 are located at 0.666 (3) Å from the C9/C10/C12/C13 mean plane. On average, the endocyclic bonds have angles close to the tetrahedral value [110.7 (8)°] and torsion angles of 55.3 (4)°.
Besylate anions and water molecules are self-assembled to determine a dimer-like hydrogen-bonded link around an inversion center. Two centrosymmetric water molecules are bonded to a couple of also centrosymmetric besylate anions (Fig 2). Each water molecule acts as a donor of two hydrogen bonds determining a graph set R 4 4 (6) in the dimer.
Venlafaxine cation is located between two b-translated dimers, generating several interactions. On one side, O2-H2A···O1W, C15-H15C···O2B and C2-H2···CG1 join a Venlafaxine cation to the water molecule and the besylate anion of one of the dimmers. On the other side, C16-H16A···O1B(x,y -1,z) and C6-H6···CG1(x,y -1,z) link a Venlafaxine cation to the besylate anion belonging to the other dimmer (CG1 is defined as the centroid of the ring C1, C2, C3, C4, C5 and C6 atoms). These interactions, some very weak in character, give cohesion to the crystal packing, The water molecules are held in the crystal structure in a way that desolvation occurs as an isolated event. A differential scanning calorimetry trace shows a single endotherm with a mid-point temperature of around 387 (2) K (heating rate 10 K min -1 ). The water molecule is involved in the formation of as many as three strong hydrogen bonds, bridging the besylate and venlafaxine ions ( Fig. 2 and Table 1).

Refinement
The O atoms in the besylate anion exhibited some disorder, with U eq values for O2B and O3B large in relation to the rest of the molecule, thus giving larger U eq (max)/U eq (min) ratios. Attempts to refine a split model of these atoms gave no better results. The H atoms were refined using a riding model while keeping their isotropic displacement parameters constrained to 1.2 (H attached to aromatic, methine and methylene C atoms) and 1.5 (H atoms attached to methyl C and N) times larger than those of their carrier atoms. The H atoms in water molecule were refined keeping their isotropic displacement parameters constrained to 1.4 times larger than the O carrier atom. H1 and H2A were found in the Fourier Difference Map and refined keeping their isotropic displacement parameters constrained to 1.2 and 1.5 times larger than the carrier atoms respectively. Data from two different single crystals were collected and similar positions were obtained for H1 and H2A atoms.

Figure 2
Besylate anions and water molecules around an inversion center, determining a dimmer-like hydrogen-bonded.  Alternate dimmers and venlafaxine cations determining a chain running along c axis. 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 > σ(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.