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Volume 61 
Part 8 
Pages o2520-o2522  
August 2005  

Received 23 June 2005
Accepted 7 July 2005
Online 13 July 2005

Key indicators
Single-crystal X-ray study
T = 123 K
Mean [sigma](C-C) = 0.002 Å
R = 0.034
wR = 0.084
Data-to-parameter ratio = 23.1
Details

Hydrochlorothiazide-aniline (1/1)

aDepartment of Pharmaceutical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, Scotland, and bWestCHEM, Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland
Correspondence e-mail: alastair.florence@strath.ac.uk

Hydrochlorothiazide forms a 1:1 solvate with aniline, C7H8ClN3O4S2·C6H7N. The crystal structure contains a hydrogen-bonding network comprising two N-H...N and three N-H...O contacts.

Comment

Hydrochlorothiazide (HCT) is a thiazide diuretic which is known to crystallize in at least one non-solvated form (Dupont & Dideberg, 1972[Dupont, L. & Dideberg, O. (1972). Acta Cryst. B28, 2340-2347.]). The aniline solvate, (I)[link], was produced during an automated parallel crystallization polymorph screen on HCT. The sample was identified as a novel form using multisample X-ray powder diffraction analysis of all recrystallized samples (Florence et al., 2003[Florence, A. J., Baumgartner, B., Weston, C., Shankland, N., Kennedy, A. R., Shankland, K. & David, W. I. F. (2003). J. Pharm. Sci. 92, 1930-1938.]). Subsequent manual recrystallization from a saturated 1:1 acetone-aniline solution by slow evaporation at 278 K yielded samples of (I)[link] suitable for single-crystal X-ray analysis (Fig. 1[link]).

[Scheme 1]

In (I)[link], the N1-S1-C1-N2-C2-C7 six-membered ring in HCT adopts a non-planar conformation, with atoms S1 and N1 having deviations of 0.271 (1) and 0.843 (1) Å, respectively, from the least-squares plane through atoms C2-C7. The sulfonamide side chain adopts a torsion angle N3-S2-C5-C4 of 69.05 (12)°, such that atom O4 eclipses H6 and atoms O3 and N3 are staggered with respect to Cl1. In the non-solvated structure (Dupont & Dideberg, 1972[Dupont, L. & Dideberg, O. (1972). Acta Cryst. B28, 2340-2347.]), this group is rotated by approximately 130° compared to (I)[link] such that the amine group lies on the opposite side of the benzothiadiazine moiety. The aniline molecule is planar, the greatest deviation of any non-H atom from the least-squares plane through C8-C13/N4 being 0.013 (1) Å for C8.

The crystal structure is stabilized by a network of hydrogen bonds interconnecting (a) HCT molecules (Fig. 2[link], contacts 1 and 2) and (b) HCT and solvent molecules (contacts 3, 4 and 5). Two C-H...O contacts also exist between HCT molecules (contacts 6 and 7). Contact 1 (N3-H3N...O2) forms a centrosymmetric R22(16) motif between molecules of HCT, whilst contacts 4 and 5 (N4-H5N...N3 and N4-H6N...O4) combine to form an R44(12) motif between aniline and HCT (Fig. 3[link]). Hydrophobic interactions between HCT and aniline include a C-H...[pi] contact and an offset face-to-face (off) [pi]-[pi] approach (Fig. 4[link]).

[Figure 1]
Figure 1
Plot of the asymmetric unit contents with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
[Figure 2]
Figure 2
A packing diagram of (I)[link]. Dashed lines indicate hydrogen bonds and unique contacts are labelled as follows: 1 = N3...O2 [2.9725 (16) Å, O2 in the molecule at (1 - x, 1 - y, 2 - z)]; 2 = N3...O1 [2.9390 (15) Å, O1 in the molecule at ([{1\over 2}] + x, [{1\over 2}] - y, -[{1\over 2}] + z)]; 3 = N1...N4 [2.9652 (17) Å]; 4 = N4...N3 [3.3944 (18) Å, in the molecule at (-1 + x, y, z)]; 5 = N4...O4 [3.1000 (17) Å, O4 in the molecule at (1 - x, 1 - y, 2 - z)]; 6 = C1...O3 [3.2535 (18) Å, O3 in the molecule at (1 - x, -y, 2 - z)]; 7 = C1...O3 [3.2852 (17) Å, O3 in the molecule at (-1 + x, y, z)]. Contacts calculated and illustrated using PLATON (Spek, 2003[Spek, A. L. (2003). J. Appl. Cryst. 36, 7-13.]; program version 280604)
[Figure 3]
Figure 3
The R22(16) (left) and R44(12) hydrogen-bond motifs in the crystal structure of (I)[link].
[Figure 4]
Figure 4
Hydrophobic interactions in (I)[link], showing a C3-H3...centroid contact to the centroid of the benzene ring of aniline [C3...centroid = 3.618 (2) Å] (top) and a [pi]-[pi] off-stacking interaction between HCT and aniline with a centroid-centroid distance of 3.6955 (8) Å (bottom). Contacts are illustrated using dashed lines.

Experimental

A single-crystal sample of the title compound was recrystallized from a 1:1 acetone-aniline solution by slow evaporation at 278 K.

Crystal data
  • C7H8ClN3O4S2·C6H7N

  • Mr = 390.86

  • Monoclinic, P 21 /n

  • a = 9.7757 (3) Å

  • b = 10.5004 (3) Å

  • c = 15.6093 (4) Å

  • [beta] = 91.692 (2)°

  • V = 1601.58 (8) Å3

  • Z = 4

  • Dx = 1.621 Mg m-3

  • Mo K[alpha] radiation

  • Cell parameters from 5824 reflections

  • [theta] = 1.0-32.0°

  • [mu] = 0.53 mm-1

  • T = 123 (2) K

  • Prism, colourless

  • 0.38 × 0.30 × 0.18 mm

Data collection
  • Nonius KappaCCD diffractometer

  • [omega] and [varphi] scans

  • Absorption correction: none

  • 10766 measured reflections

  • 5573 independent reflections

  • 4379 reflections with I > 2[sigma](I)

  • Rint = 0.027

  • [theta]max = 32.0°

  • h = -14 [rightwards arrow] 14

  • k = -15 [rightwards arrow] 15

  • l = -23 [rightwards arrow] 23

Refinement
  • Refinement on F2

  • R[F2 > 2[sigma](F2)] = 0.034

  • wR(F2) = 0.084

  • S = 1.02

  • 5573 reflections

  • 241 parameters

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

  • w = 1/[[sigma]2(Fo2) + (0.036P)2 + 0.781P] where P = (Fo2 + 2Fc2)/3

  • ([Delta]/[sigma])max = 0.002

  • [Delta][rho]max = 0.48 e Å-3

  • [Delta][rho]min = -0.53 e Å-3

Table 1
Hydrogen-bond geometry (Å, °)[link]

D-H...A D-H H...A D...A D-H...A
N1-H1N...N4 0.87 (2) 2.10 (2) 2.9652 (17) 174 (2)
N3-H3N...O2i 0.85 (2) 2.13 (2) 2.9725 (16) 169 (2)
N3-H4N...O1ii 0.90 (2) 2.09 (2) 2.9390 (15) 157 (2)
N4-H5N...N3iii 0.89 (2) 2.52 (2) 3.3944 (18) 169 (2)
N4-H6N...O4i 0.83 (2) 2.28 (2) 3.1000 (17) 173 (2)
C1-H1A...O3iv 0.99 2.37 3.2535 (18) 148
C1-H1B...O3iii 0.99 2.47 3.2852 (17) 139
C6-H6...O4 0.95 2.38 2.8101 (16) 107
Symmetry codes: (i) -x+1, -y+1, -z+2; (ii) [x+{\script{1\over 2}}, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]; (iii) x-1, y, z; (iv) -x+1, -y, -z+2.

The N-bound H atoms were found in difference maps and refined freely [N-H = 0.77 (2)-0.90 (2) Å]. The remaining H atoms were positioned geometrically at distances of 0.95 (CH) and 0.99 Å (CH2) from the parent C atoms; a riding model was used [Uiso(H) = 1.2Ueq(C)] during the refinement process.

Data collection: COLLECT (Hooft, 1988[Hooft, R. (1988). COLLECT. Nonius BV, Delft, The Netherlands.]) 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.]); cell refinement: DENZO and COLLECT; data reduction: DENZO; 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: PLATON (Spek, 2003[Spek, A. L. (2003). J. Appl. Cryst. 36, 7-13.]); software used to prepare material for publication: SHELXL97.

Acknowledgements

The authors thank the Basic Technology programme of the UK Research Councils for funding this work under the project Control and Prediction of the Organic Solid State (URL: www.cposs.org.uk).

References

Dupont, L. & Dideberg, O. (1972). Acta Cryst. B28, 2340-2347. [details]
Florence, A. J., Baumgartner, B., Weston, C., Shankland, N., Kennedy, A. R., Shankland, K. & David, W. I. F. (2003). J. Pharm. Sci. 92, 1930-1938. [ISI] [CSD] [CrossRef] [PubMed] [ChemPort]
Hooft, R. (1988). 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.
Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Göttingen, Germany.
Spek, A. L. (2003). J. Appl. Cryst. 36, 7-13. [details]


Acta Cryst (2005). E61, o2520-o2522   [ doi:10.1107/S1600536805021914 ]