Venlafaxine besylate monohydrate

Carolina H Corvalan; Daniel R Vega

doi:10.1107/S1600536813027542

. 2013 Nov 6;69(Pt 12):o1737–o1738. doi: 10.1107/S1600536813027542

Venlafaxine besylate monohydrate

Carolina H Corvalan ^a,^*,^‡, Daniel R Vega ^b,^c

PMCID: PMC3885021 PMID: 24454196

Abstract

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.

Related literature

For background information, see: Venu et al. (2008 ▶); Tessler & Goldberg (2004 ▶); Van Eupen et al. (2008 ▶); Yardley et al. (1990 ▶); Banjeree et al. (2005 ▶); Vega et al. (2000 ▶); Sivalakshmidevi et al. (2002 ▶); Roy et al. (2007 ▶). For ring-puckering calculations, see: Cremer & Pople (1975 ▶). For graph-set notation, see: Bernstein et al. (1995 ▶). For a description of the Cambridge Structural Database, see: Allen (2002 ▶). graphic file with name e-69-o1737-scheme1.jpg

Experimental

Crystal data

C₁₇H₂₈NO₂ ⁺·C₆H₅O₃S⁻·H₂O
M _r = 453.58
Triclinic,
a = 10.1163 (5) Å
b = 10.2176 (4) Å
c = 13.8162 (6) Å
α = 72.074 (4)°
β = 70.108 (4)°
γ = 63.889 (5)°
V = 1184.53 (11) Å³
Z = 2
Mo Kα radiation
μ = 0.17 mm⁻¹
T = 293 K
0.70 × 0.30 × 0.10 mm

Data collection

Agilent Xcalibur (Eos, Gemini) diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2010 ▶) T _min = 0.842, T _max = 1.000
10063 measured reflections
5366 independent reflections
3072 reflections with I > 2σ(I)
R _int = 0.020

Refinement

R[F ² > 2σ(F ²)] = 0.053
wR(F ²) = 0.163
S = 1.02
5366 reflections
292 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.54 e Å⁻³
Δρ_min = −0.44 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2010 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012 ▶); software used to prepare material for publication: WinGX (Farrugia, 2012 ▶) and PLATON (Spek, 2009 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536813027542/gg2130sup1.cif

e-69-o1737-sup1.cif^{(32.2KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813027542/gg2130Isup2.hkl

e-69-o1737-Isup2.hkl^{(262.7KB, hkl)}

Click here for additional data file.^{(9.1KB, cml)}

Supplementary material file. DOI: 10.1107/S1600536813027542/gg2130Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

Cg1 is the centroid of the C1–C6 ring.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O2—H2A⋯O1W	0.81 (3)	1.87 (3)	2.673 (3)	173 (3)
O1W—H1WB⋯O3B	0.83 (3)	1.92 (3)	2.711 (4)	159 (3)
O1W—H1WA⋯O2B ⁱ	0.88 (3)	1.91 (3)	2.785 (4)	175 (3)
N1—H1⋯O2	0.78 (3)	2.05 (3)	2.719 (2)	143 (3)
C15—H15C⋯O2B	0.96	2.68	3.468 (4)	140
C16—H16A⋯O1B ⁱⁱ	0.96	2.44	3.395 (4)	172
C2—H2⋯Cg1	0.93	3.17	3.928	140

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

We are grateful to Gador S.A. for providing the raw material. We also acknowledge PIP-11220090100889 and ANPCyT (project No. PME 2006–01113) for the purchase of the Oxford Gemini CCD diffractometer.

supplementary crystallographic information

1. 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 R₄⁴(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, determining a chain of alternate dimmers and venlafaxine cations along the b axis.

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).