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Volume 63 
Part 2 
Pages o129-o131  
February 2007  

Received 18 December 2006
Accepted 19 December 2006
Online 23 January 2007

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© International Union of Crystallography 2007

Escitalopram oxalate: co-existence of oxalate dianions and oxalic acid molecules in the same crystal

William T. A. Harrison,a* H. S. Yathirajan,b S. Bindya,b H. G. Anilkumarb and Devarajub

aDepartment of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland, and bDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
Correspondence e-mail: w.harrison@abdn.ac.uk

The title compound {systematic name: (+)-(S)-3-[5-cyano-2-(4-fluorophenyl)-1,3-dihydroisobenzofuran-2yl]propanaminium oxalate oxalic acid 0.325-hydrate}, 2C20H22FN2O+·C2O42-·C2H2O4·0.325H2O, is a molecular salt of the N-protonated escitalopram cation. As well as charge-balancing oxalate dianions, neutral molecules of oxalic acid are present. The component species interact by way of N-H...O and short O-H...O hydrogen bonds, resulting in supramolecular chains.

Comment

(+)-(S)-1-[3-(Dimethylammonio)propyl]-1-(4-fluorophenyl)-5-phthalan-5-carbonitrile oxalate (C20H21FN2O), common names escitalopram or S-(+)-citalopram, is a widely prescribed drug used to treat depression and related conditions (Burke, 2002[Burke, W. J. (2002). Expert Opin. Invest. Drugs, 11, 1477-1486.]). It is conveniently introduced as an oxalate salt, with a nominal formula usually given as C20H21FN2O·C2H2O4, i.e. the presumed proton-transfer reaction is not specified (Sorbera et al., 2001[Sorbera, L. A., Revel, L., Martin, L. & Castaner, J. (2001). Drugs Future, 26, 115-120.]). As part of our ongoing crystallographic studies of pharmaceutical molecules (Harrison et al., 2005[Harrison, W. T. A., Yathirajan, H. S., Anilkumar, H. G., Sarojini, B. K., Narayana, B. & Lobo, K. G. (2005). Acta Cryst. E61, o3810-o3812.]), we now report the structure of the title compound, (I)[link], in which two N-protonated escitalopram cations (C20H22FN2O+) and a C2O42- oxalate dianon are accompanied by a neutral molecule of oxalic acid and a partially occupied water molecule (Fig. 1[link]).

[Scheme 1]

The bond lengths and angles in (I)[link] fall within their expected ranges (Cambridge Structural Database, Version 5.27; Allen, 2002[Allen, F. H. (2002). Acta Cryst. B58, 380-388.]). There are two C20H22FN2O+ cations in the asymmetric unit; atoms C8 and C28 are assumed to possess S configurations, consistent with the known absolute structure of the biologically active enantiomer of citalopram (Sanchez et al., 2004[Sanchez, C., Bogeso, K. P., Ebert, B., Reines, E. H. & Braestrup, C. (2004). Psychopharmacology, 174, 163-176.]). For the C1-containing molecule, the dihedral angle between the mean planes of the C2-C7 and C9-C14 benzene rings is 62.83 (13)°, and the C1/C2/C7/C8/O1 five-membered ring displays an envelope conformation with atom O1 in the flap position [the displacement from the C-atom mean plane is 0.435 (5) Å]. In the C21-containing molecule, the dihedral angle between the C22-C27 and C29-C34 mean planes is 81.99 (13)°, and the envelope conformation for C21/C22/C27/C28/O2 is less pronounced, with atom O2 displaced from the C-atom mean plane by 0.113 (6) Å. The oxalate species are both approximately planar; the dihedral angle between the C41/O3/O4 and C42/O5/O6 groupings is 4.4 (3)°, and the equivalent value for C43/O7/O8 and C44/O9/O10 is 2.8 (6)°.

The component species in (I)[link] interact by way of N-H...O and O-H...O hydrogen bonds (Table 1[link]), such that both C20H22FN2O+ cations make bifurcated N-H...(O,O) hydrogen bonds to the same oxalate dianion. Then, the 2C20H22FN2O+·C2O42- units are linked into [001] chains by way of the oxalic acid molecules, i.e. the oxalate dianions and oxalic acid molecules alternate in the chains (Fig. 2[link]). The short H...O separations of the oxalic acid-to-oxalate hydrogen bonds suggests that they are strong interactions.

Although it is not expected from a consideration of the pKa values of oxalic acid (pKa1 = 1.23 and pKa2 = 4.19; Newkome et al., 1985[Newkome, G. R., Theriot, K. J. & Fronczek, F. R. (1985). Acta Cryst. C41, 1642-1644.]) the co-existence of oxalate dianions and oxalic acid molecules in the same crystal has been observed in a number of compounds, three examples being bis(pyridinium) oxalate oxalic acid (Newkome et al., 1985[Newkome, G. R., Theriot, K. J. & Fronczek, F. R. (1985). Acta Cryst. C41, 1642-1644.]), barium oxalate oxalic acid dihydrate (Chaix-Pluchery et al., 1989[Chaix-Pluchery, O., Mutin, J. C., Bouillot, J. & Niepce, J. C. (1989). Acta Cryst. C45, 1699-1705.]) and 1-([alpha]-pyrrolidiniobenzyl)-2-naphthol oxalate oxalic acid (Periasamy et al., 2004[Periasamy, M., Reddy, M. N. & Anwar, S. (2004). Tetrahedron Asymmetry, 15, 1809-1812.]). These three compounds show the same alternating oxalate-oxalic acid hydrogen-bonded chains seen in (I)[link].

[Figure 1]
Figure 1
The molecular structure of (I)[link], showing 50% probability displacement ellipsoids (arbitrary spheres for H atoms). All H atoms, except those involved in hydrogen bonds (dashed lines), have been omitted for clarity.
[Figure 2]
Figure 2
A view along [010] of part of an [001] chain in (I)[link], with hydrogen bonds shown as dashed lines. Atoms labelled with an asterisk (*) are generated by the symmetry operation (x, y, z - 1).

Experimental

The title compound was obtained as a gift sample from Jubilant Organosys, Nanjangud, India. The sample of (I)[link] was recrystallized from ethanol (m.p. 420 K).

Crystal data

  • 2C20H22FN2O+·C2O42-·C2H2O4·0.325H2O

  • Mr = 834.05

  • Monoclinic, P 21

  • a = 7.9355 (3) Å

  • b = 24.7376 (9) Å

  • c = 11.1332 (5) Å

  • [beta] = 106.589 (2)°

  • V = 2094.54 (14) Å3

  • Z = 2

  • Dx = 1.324 Mg m-3

  • Mo K[alpha] radiation

  • [mu] = 0.10 mm-1

  • T = 120 (2) K

  • Block, colourless

  • 0.32 × 0.24 × 0.18 mm
Data collection

  • Nonius KappaCCD diffractometer

  • [omega] and [varphi] scans

  • Absorption correction: multi-scan (SADABS; Bruker, 2003[Bruker (2003). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]) Tmin = 0.969, Tmax = 0.982

  • 7581 measured reflections

  • 3609 independent reflections

  • 2652 reflections with I > 2[sigma](I)

  • Rint = 0.037

  • [theta]max = 25.5°
Refinement

  • Refinement on F2

  • R[F2 > 2[sigma](F2)] = 0.042

  • wR(F2) = 0.095

  • S = 1.02

  • 3609 reflections

  • 562 parameters

  • H atoms treated by a mixture of independent and constrained refinement

  • w = 1/[[sigma]2(Fo2) + (0.0473P)2] where P = (Fo2 + 2Fc2)/3

  • ([Delta]/[sigma])max = 0.008

  • [Delta][rho]max = 0.17 e Å-3

  • [Delta][rho]min = -0.21 e Å-3

  • Extinction correction: SHELXL97

  • Extinction coefficient: 0.0118 (16)

Table 1
Hydrogen-bond geometry (Å, °)

D-H...A D-H H...A D...A D-H...A
N1-H1...O6 0.93 1.91 2.768 (4) 152
N1-H1...O4 0.93 2.22 2.886 (4) 128
N3-H2...O3 0.93 1.91 2.764 (4) 152
N3-H2...O5 0.93 2.22 2.884 (4) 127
O7-H3...O5 0.91 (3) 1.56 (3) 2.466 (4) 177 (4)
O9-H4...O4i 0.91 (3) 1.57 (3) 2.465 (4) 173 (4)
Symmetry code: (i) x, y, z+1.

Anomalous dispersion effects were negligible and Friedel pairs were merged before refinement. The absolute structure of (I)[link] was assigned on the basis of the known chirality of escitalopram (Sanchez et al., 2004[Sanchez, C., Bogeso, K. P., Ebert, B., Reines, E. H. & Braestrup, C. (2004). Psychopharmacology, 174, 163-176.]). The C- and N-bound H atoms were placed in idealized locations (C-H = 0.95-0.99 Å and N-H = 0.93 Å) and refined as riding with Uiso(H) values of 1.2Ueq(carrier) or 1.5Ueq(methyl C). The oxalic acid H atoms were located in a difference map and refined with the restraint O-H = 0.90 (1) Å and the constraint Uiso(H) = 1.2Ueq(O). The H atoms of the partially occupied water molecule could not be located.

Data collection: COLLECT (Nonius, 1998[Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.]); cell refinement: SCALEPACK (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]); data reduction: SCALEPACK and DENZO (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]), and SORTAV (Blessing, 1995[Blessing, R. H. (1995). Acta Cryst. A51, 33-38.]); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997[Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Göttingen, Germany.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997[Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Göttingen, Germany.]); molecular graphics: ORTEP-3 (Farrugia, 1997[Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.]); software used to prepare material for publication: SHELXL97.

Supplementary data for this paper are available from the IUCr electronic archives (Reference: GD3075 ). Services for accessing these data are described at the back of the journal.

Acknowledgements

We thank the EPSRC National Crystallography Service (University of Southampton) for data collection.

References

Allen, F. H. (2002). Acta Cryst. B58, 380-388. [ISI] [CrossRef] [details]
Blessing, R. H. (1995). Acta Cryst. A51, 33-38. [CrossRef] [details]
Bruker (2003). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.
Burke, W. J. (2002). Expert Opin. Invest. Drugs, 11, 1477-1486. [CrossRef] [ChemPort]
Chaix-Pluchery, O., Mutin, J. C., Bouillot, J. & Niepce, J. C. (1989). Acta Cryst. C45, 1699-1705. [CrossRef] [details]
Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565. [CrossRef] [details]
Harrison, W. T. A., Yathirajan, H. S., Anilkumar, H. G., Sarojini, B. K., Narayana, B. & Lobo, K. G. (2005). Acta Cryst. E61, o3810-o3812. [CrossRef] [details]
Newkome, G. R., Theriot, K. J. & Fronczek, F. R. (1985). Acta Cryst. C41, 1642-1644. [CrossRef] [details]
Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.
Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.
Periasamy, M., Reddy, M. N. & Anwar, S. (2004). Tetrahedron Asymmetry, 15, 1809-1812. [CrossRef] [ChemPort]
Sanchez, C., Bogeso, K. P., Ebert, B., Reines, E. H. & Braestrup, C. (2004). Psychopharmacology, 174, 163-176. [CrossRef] [PubMed] [ChemPort]
Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Göttingen, Germany.
Sorbera, L. A., Revel, L., Martin, L. & Castaner, J. (2001). Drugs Future, 26, 115-120. [CrossRef] [ChemPort]

Acta Cryst (2007). C63, o129-o131   [ doi:10.1107/S010827010605520X ]