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Acta Crystallogr Sect E Struct Rep Online. 2009 September 1; 65(Pt 9): o2294.
Published online 2009 August 29. doi:  10.1107/S1600536809033996
PMCID: PMC2970009

Duloxetine hydro­chloride

Abstract

The title compound [systematic name: N-methyl-3-(1-naphth­yloxy)-3-(2-thien­yl)propan-1-aminium chloride], C18H20NOS+·Cl, was crystallized from 1,4-dioxane. Twofold rotational disorder exhibited by the thio­phene ring in a 0.580 (5):0.420 (5) ratio represents two different conformations of the mol­ecule that exist in the same crystal form. The crystal structure contains strong N—H(...)Cl hydrogen bonds.

Related literature

For therapeutic properties of duloxetine hydro­chloride, see Waitekus & Kirkpatrick (2004 [triangle]). For related structures, see: Brenna et al. (2007 [triangle]); Tao et al. (2008 [triangle]). The title compound is reported to have different polymorphs on the basis of X-ray powder diffraction data, see: Ini et al. (2006 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-65-o2294-scheme1.jpg

Experimental

Crystal data

  • C18H20NOS+·Cl
  • M r = 333.86
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-65-o2294-efi1.jpg
  • a = 9.7453 (10) Å
  • b = 6.9227 (7) Å
  • c = 13.4247 (16) Å
  • β = 109.432 (4)°
  • V = 854.09 (16) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.35 mm−1
  • T = 150 K
  • 0.38 × 0.08 × 0.03 mm

Data collection

  • Bruker Kappa APEXII CCD area-detector diffractometer
  • Absorption correction: multi-scan (SADABS; Sheldrick, 2003 [triangle]) T min = 0.879, T max = 0.990
  • 6386 measured reflections
  • 2947 independent reflections
  • 2255 reflections with I > 2σ(I)
  • R int = 0.058

Refinement

  • R[F 2 > 2σ(F 2)] = 0.044
  • wR(F 2) = 0.131
  • S = 0.79
  • 2947 reflections
  • 237 parameters
  • 110 restraints
  • H-atom parameters constrained
  • Δρmax = 0.17 e Å−3
  • Δρmin = −0.21 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 1309 Friedel pairs
  • Flack parameter: −0.05 (10)

Data collection: APEX2 (Bruker, 2007 [triangle]); cell refinement: SAINT (Bruker, 2007 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL-Plus (Sheldrick, 2008 [triangle]); software used to prepare material for publication: SHELXL97.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809033996/bg2289sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809033996/bg2289Isup2.hkl

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

Acknowledgments

We are grateful to Professor Grainne Moran for her encouragement and interest in this work.

supplementary crystallographic information

Comment

Duloxetine hydrochloride (1) is a new generation drug indicated for the management of major depressive disorders as well as for neuropathic pain (Waitekus, et al., 2004). The compound 1 is reported to have different polymorphs on the basis of X-ray powder diffraction data (Ini et al., 2006), but no single-crystal structure has as yet been presented. The only structures reported are that of a related racemic precursor (Tao, et al., 2008) and of a regioisomer (Brenna et al., 2007). Herein we report the structure of the drug itself (Fig. 1).

In the crystal structure, the thiophene ring is disordered over two positions obtained by 180 degree rotation about C11—C12 bond in a 0.580/0.420 (5) ratio. The same disorder with similar occupancies was also observed in the structure of an impurity (Brenna et al., 2007). These two orientations represent two different molecular conformations that exist in the same crystal structure; in one of them (minor occupancy) the S atom makes a short intramolecular contact with the oxygen atom (S···O = 2.957 Å). The thiophene and naphthyl units are almost perpendicular to each other (angle between their mean planes 87.9 (1) °).

The crystal packing (Fig. 2) shows that both the H-atoms attached to the N atom of the side chain make strong almost linear H-bonding contacts with the chloride ion.

Experimental

Microcrystalline powder of (1) was supplied by Arrow Laboratories Ltd.,Croydon, Australia. Recrystallization of this powder by slow evaporation was attempted in acetonitrile, 1,4-dioxane,chlorobenzene and 2-propanol. Suitable single crystals in the form of thin plates were grown from the first three solvents, crystals from chlorobenzene were very thin silky fibres unsuitable for single-crystal analysis. Crystals from the first three solvents yielded the same monoclinic P2(1) form having unit-cell parameters as given in Table 1. Amongst these, better quality crystals were obtained from 1,4-dioxane, which were used for further structural analysis.

Refinement

The twofold disorder of the thiophene ring noted first in the E-map at the structure solution stage (two strong peaks and two long bonds instead of one), was confirmed subsequently in the full-matrix least-squares refinement. The molecular geometry for this ring was refined with restrained bond and angles. H atoms were idealized at their expected positions and allowed to ride both in coordinates (C—H = 0.96–0.99, N–H = 0.92 Å), as well as in their isotropic displacement factors (Uĩso~(H) = 1.2/1.5× U~equiv~(host).

Figures

Fig. 1.
Molecular view of 1. Displacement ellipsoids drawn at 50% level.
Fig. 2.
Packing view of1 showing N—H···Cl interactions.

Crystal data

C18H20NOS+·ClF(000) = 352
Mr = 333.86Dx = 1.298 Mg m3
Monoclinic, P21Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ybCell parameters from 1635 reflections
a = 9.7453 (10) Åθ = 2.3–22.1°
b = 6.9227 (7) ŵ = 0.35 mm1
c = 13.4247 (16) ÅT = 150 K
β = 109.432 (4)°Thin Plates, colourless
V = 854.09 (16) Å30.38 × 0.08 × 0.03 mm
Z = 2

Data collection

Bruker Kappa APEXII CCD area-detector diffractometer2947 independent reflections
Radiation source: fine-focus sealed tube2255 reflections with I > 2σ(I)
graphiteRint = 0.058
[var phi] scans, and ω scans with κ offsetsθmax = 25.0°, θmin = 1.6°
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)h = −10→11
Tmin = 0.879, Tmax = 0.990k = −8→8
6386 measured reflectionsl = −15→15

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.044H-atom parameters constrained
wR(F2) = 0.131w = 1/[σ2(Fo2) + (0.1P)2 + 0.0292P] where P = (Fo2 + 2Fc2)/3
S = 0.79(Δ/σ)max = 0.005
2947 reflectionsΔρmax = 0.17 e Å3
237 parametersΔρmin = −0.21 e Å3
110 restraintsAbsolute structure: Flack (1983), 1309 Friedel pairs
Primary atom site location: structure-invariant direct methodsFlack parameter: −0.05 (10)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

xyzUiso*/UeqOcc. (<1)
C10.7076 (5)1.0388 (6)0.3732 (3)0.0414 (10)
H10.64731.05460.30180.050*
C20.8113 (5)1.1721 (7)0.4181 (3)0.0559 (13)
H20.82221.28040.37790.067*
C30.9031 (5)1.1525 (7)0.5234 (3)0.0498 (12)
H30.97691.24560.55380.060*
C40.8856 (4)0.9990 (6)0.5818 (3)0.0404 (10)
H40.94650.98770.65340.048*
C50.7784 (4)0.8557 (6)0.5376 (2)0.0333 (8)
C60.7619 (5)0.6944 (7)0.5957 (3)0.0488 (12)
H60.82170.68040.66740.059*
C70.6613 (5)0.5596 (7)0.5500 (3)0.0594 (14)
H70.65180.45080.59040.071*
C80.5696 (5)0.5748 (7)0.4444 (3)0.0453 (11)
H80.50070.47640.41340.054*
C90.5811 (4)0.7331 (5)0.3870 (3)0.0302 (9)
C100.6874 (4)0.8761 (5)0.4309 (3)0.0285 (8)
C110.3962 (4)0.6244 (5)0.2248 (3)0.0287 (8)
H110.35060.55430.27090.034*
C160.2800 (4)0.7340 (5)0.1395 (3)0.0334 (9)
H16A0.22330.64160.08510.040*
H16B0.32770.82630.10510.040*
C170.1769 (4)0.8439 (7)0.1826 (3)0.0395 (9)
H17A0.19880.81110.25810.047*
H17B0.19250.98440.17760.047*
C18−0.0810 (4)0.8802 (6)0.1698 (3)0.0449 (10)
H18A−0.06340.82650.24050.067*
H18B−0.18020.84830.12460.067*
H18C−0.06941.02090.17460.067*
Cl10.02776 (10)0.35210 (15)0.11567 (7)0.0385 (3)
N10.0237 (3)0.7976 (4)0.1242 (2)0.0334 (7)
H1A0.00150.84160.05600.040*
H1B0.01310.66550.12140.040*
O10.4920 (3)0.7711 (3)0.28494 (18)0.0335 (6)
C120.4783 (4)0.4840 (6)0.1806 (3)0.0304 (9)
S1A0.4000 (4)0.2836 (6)0.1112 (4)0.0390 (8)0.580 (5)
C13A0.5587 (15)0.220 (3)0.088 (2)0.043 (2)0.580 (5)
H13A0.57030.10750.05080.051*0.58
C14A0.6634 (16)0.353 (2)0.1292 (18)0.045 (2)0.580 (5)
H14A0.75750.34910.12270.054*0.58
C15A0.6158 (17)0.500 (3)0.184 (2)0.042 (4)0.580 (5)
H15A0.67740.60270.21990.051*0.58
S1B0.6515 (6)0.5208 (10)0.1826 (7)0.0410 (14)0.420 (5)
C13B0.656 (2)0.310 (3)0.119 (2)0.042 (3)0.420 (5)
H13B0.73900.26240.10430.051*0.42
C14B0.526 (2)0.221 (4)0.091 (3)0.045 (3)0.420 (5)
H14B0.50300.10620.04980.054*0.42
C15B0.427 (2)0.318 (3)0.131 (2)0.053 (5)0.420 (5)
H15B0.33250.26910.12370.063*0.42

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C120.030 (2)0.034 (2)0.0272 (18)−0.0013 (18)0.0086 (16)0.0036 (16)
S1A0.0360 (14)0.0354 (13)0.0453 (18)0.0021 (11)0.0130 (14)−0.0108 (10)
C13A0.046 (6)0.048 (5)0.038 (5)0.018 (5)0.019 (6)−0.002 (4)
C14A0.039 (4)0.060 (7)0.042 (5)0.009 (4)0.021 (4)−0.001 (5)
C15A0.044 (9)0.049 (6)0.042 (5)−0.005 (6)0.025 (6)−0.001 (4)
S1B0.024 (2)0.056 (2)0.042 (2)−0.0013 (18)0.0099 (19)0.0093 (17)
C13B0.042 (5)0.051 (6)0.037 (7)0.009 (5)0.017 (5)0.015 (5)
C14B0.045 (7)0.050 (6)0.036 (6)0.005 (6)0.010 (6)0.003 (5)
C15B0.043 (7)0.062 (12)0.055 (11)0.005 (7)0.018 (8)0.003 (8)
C10.047 (2)0.038 (2)0.0303 (19)−0.007 (2)0.0003 (18)0.0082 (18)
C20.062 (3)0.048 (3)0.043 (2)−0.020 (3)−0.002 (2)0.010 (2)
C30.051 (3)0.045 (3)0.043 (2)−0.017 (2)0.002 (2)−0.003 (2)
C40.040 (2)0.046 (2)0.0269 (19)−0.002 (2)−0.0007 (17)−0.0027 (19)
C50.034 (2)0.0372 (19)0.0269 (17)−0.003 (2)0.0081 (15)−0.001 (2)
C60.046 (3)0.058 (3)0.032 (2)−0.010 (2)−0.0012 (19)0.019 (2)
C70.060 (3)0.061 (3)0.042 (2)−0.020 (3)−0.004 (2)0.028 (2)
C80.044 (2)0.043 (2)0.040 (2)−0.014 (2)0.0024 (19)0.010 (2)
C90.032 (2)0.032 (2)0.0261 (18)0.0051 (17)0.0090 (15)0.0010 (15)
C100.0295 (19)0.031 (2)0.0250 (16)0.0001 (17)0.0092 (14)−0.0023 (16)
C110.026 (2)0.031 (2)0.0268 (18)−0.0037 (15)0.0066 (16)0.0011 (14)
C160.029 (2)0.035 (2)0.0308 (19)0.0003 (18)0.0029 (16)−0.0060 (16)
C170.033 (2)0.040 (2)0.0382 (19)0.002 (2)0.0021 (16)−0.015 (2)
C180.039 (2)0.040 (2)0.060 (2)0.003 (2)0.023 (2)0.000 (2)
Cl10.0438 (6)0.0345 (5)0.0345 (5)−0.0070 (5)0.0095 (4)0.0009 (4)
N10.0348 (17)0.0295 (17)0.0335 (16)−0.0006 (14)0.0080 (14)0.0003 (13)
O10.0365 (14)0.0308 (13)0.0254 (12)−0.0054 (12)−0.0003 (11)−0.0003 (10)

Geometric parameters (Å, °)

C1—C21.353 (6)C17—H17A0.9900
C1—C101.418 (5)C17—H17B0.9900
C1—H10.9500C18—N11.469 (5)
C2—C31.406 (5)C18—H18A0.9800
C2—H20.9500C18—H18B0.9800
C3—C41.364 (6)C18—H18C0.9800
C3—H30.9500N1—H1A0.9200
C4—C51.420 (6)N1—H1B0.9200
C4—H40.9500C12—C15A1.332 (14)
C5—C61.402 (6)C12—C15B1.341 (16)
C5—C101.418 (4)C12—C111.501 (5)
C6—C71.344 (6)C12—S1B1.699 (7)
C6—H60.9500C12—S1A1.703 (5)
C7—C81.406 (5)S1A—C13A1.734 (10)
C7—H70.9500C13A—C14A1.351 (10)
C8—C91.365 (5)C13A—H13A0.9500
C8—H80.9500C14A—C15A1.420 (14)
C9—O11.381 (4)C14A—H14A0.9500
C9—C101.413 (5)C15A—H15A0.9500
C11—O11.433 (4)S1B—C13B1.699 (14)
C11—C161.519 (5)C13B—C14B1.351 (11)
C11—H111.0000C13B—H13B0.9500
C16—C171.520 (5)C14B—C15B1.421 (15)
C16—H16A0.9900C14B—H14B0.9500
C16—H16B0.9900C15B—H15B0.9500
C17—N11.472 (4)
C2—C1—C10121.2 (3)N1—C17—H17B109.3
C2—C1—H1119.4C16—C17—H17B109.3
C10—C1—H1119.4H17A—C17—H17B107.9
C1—C2—C3120.9 (4)N1—C18—H18A109.5
C1—C2—H2119.5N1—C18—H18B109.5
C3—C2—H2119.5H18A—C18—H18B109.5
C4—C3—C2119.5 (4)N1—C18—H18C109.5
C4—C3—H3120.2H18A—C18—H18C109.5
C2—C3—H3120.2H18B—C18—H18C109.5
C3—C4—C5121.3 (3)C18—N1—C17114.6 (3)
C3—C4—H4119.3C18—N1—H1A108.6
C5—C4—H4119.3C17—N1—H1A108.6
C6—C5—C10119.5 (4)C18—N1—H1B108.6
C6—C5—C4121.9 (3)C17—N1—H1B108.6
C10—C5—C4118.6 (3)H1A—N1—H1B107.6
C7—C6—C5120.0 (4)C9—O1—C11120.0 (3)
C7—C6—H6120.0C15A—C12—C15B107.3 (10)
C5—C6—H6120.0C15A—C12—C11126.5 (7)
C6—C7—C8122.0 (4)C15B—C12—C11126.2 (8)
C6—C7—H7119.0C15B—C12—S1B110.1 (8)
C8—C7—H7119.0C11—C12—S1B123.7 (3)
C9—C8—C7119.0 (4)C15A—C12—S1A110.5 (7)
C9—C8—H8120.5C11—C12—S1A122.9 (3)
C7—C8—H8120.5S1B—C12—S1A113.1 (3)
C8—C9—O1124.8 (3)C12—S1A—C13A92.4 (4)
C8—C9—C10120.9 (3)C14A—C13A—S1A110.4 (8)
O1—C9—C10114.4 (3)C14A—C13A—H13A124.8
C9—C10—C1123.0 (3)S1A—C13A—H13A124.8
C9—C10—C5118.5 (3)C13A—C14A—C15A111.8 (10)
C1—C10—C5118.5 (3)C13A—C14A—H14A124.1
O1—C11—C12110.4 (3)C15A—C14A—H14A124.1
O1—C11—C16104.7 (3)C12—C15A—C14A114.8 (11)
C12—C11—C16112.8 (3)C12—C15A—H15A122.6
O1—C11—H11109.6C14A—C15A—H15A122.6
C12—C11—H11109.6C13B—S1B—C1293.3 (7)
C16—C11—H11109.6C14B—C13B—S1B110.6 (11)
C11—C16—C17112.6 (3)C14B—C13B—H13B124.7
C11—C16—H16A109.1S1B—C13B—H13B124.7
C17—C16—H16A109.1C13B—C14B—C15B112.1 (12)
C11—C16—H16B109.1C13B—C14B—H14B124.0
C17—C16—H16B109.1C15B—C14B—H14B124.0
H16A—C16—H16B107.8C12—C15B—C14B113.7 (12)
N1—C17—C16111.7 (3)C12—C15B—H15B123.2
N1—C17—H17A109.3C14B—C15B—H15B123.2
C16—C17—H17A109.3

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N1—H1A···Cl1i0.922.233.113 (3)161
N1—H1B···Cl10.922.183.087 (3)170

Symmetry codes: (i) −x, y+1/2, −z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: BG2289).

References

  • Brenna, E., Frigoli, S., Fronza, G., Fuganti, C. & Malpezzi, L. (2007). J. Pharm. Biomed. Anal.43, 1573–1575. [PubMed]
  • Bruker (2007). APEX2 andSAINT Bruker AXS Inc., Madison, Wisconsin, USA.
  • Flack, H. D. (1983). Acta Cryst. A39, 876–881.
  • Ini, S., Shmueli, Y., Koltai, T. & Gold, A. (2006). Duloxetine. HCl Polymorphs WO/2006/081515, International Application No. PCT/US2006/003126. Publication Date: 03.08.2006.
  • Sheldrick, G. M. (2003). SADABS University of Göttingen, Germany.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Tao, X., Zhang, X.-Q., Yuan, L. & Wang, J.-T. (2008). Acta Cryst. E64, o553. [PMC free article] [PubMed]
  • Waitekus, A. B. & Kirkpatrick, P. (2004). Nat. Rev. Drug Discov.3, 907–908. [PubMed]

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