Hydro­chloro­thia­zide–aniline (1/1)

Johnston, A.; Florence, A.J.; Kennedy, A.R.

doi:10.1107/S1600536805021914

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 (C-C) = 0.002 Å
R = 0.034
wR = 0.084
Data-to-parameter ratio = 23.1
Details

Hydrochlorothiazide-aniline (1/1)

Andrea Johnston,^a Alastair J. Florence ^a ^* and Alan R. Kennedy ^b

^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-HN and three N-HO contacts.

Comment

Hydrochlorothiazide (HCT) is a thiazide diuretic which is known to crystallize in at least one non-solvated form (Dupont & Dideberg, 1972). The aniline solvate, (I), 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). Subsequent manual recrystallization from a saturated 1:1 acetone-aniline solution by slow evaporation at 278 K yielded samples of (I) suitable for single-crystal X-ray analysis (Fig. 1).

In (I), 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), this group is rotated by approximately 130° compared to (I) 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, contacts 1 and 2) and (b) HCT and solvent molecules (contacts 3, 4 and 5). Two C-HO contacts also exist between HCT molecules (contacts 6 and 7). Contact 1 (N3-H3NO2) forms a centrosymmetric R₂²(16) motif between molecules of HCT, whilst contacts 4 and 5 (N4-H5NN3 and N4-H6NO4) combine to form an R₄⁴(12) motif between aniline and HCT (Fig. 3). Hydrophobic interactions between HCT and aniline include a C-H [pi] contact and an offset face-to-face (off) [pi] - [pi] approach (Fig. 4).

Figure 1
Plot of the asymmetric unit contents with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
A packing diagram of (I)

. 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
The R₂²(16) (left) and R₄⁴(12) hydrogen-bond motifs in the crystal structure of (I)

Figure 4
Hydrophobic interactions in (I)

, 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]

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
M_r = 390.86
Monoclinic, P 2₁ /n
a = 9.7757 (3) Å
b = 10.5004 (3) Å
c = 15.6093 (4) Å
= 91.692 (2)°
V = 1601.58 (8) Å³
Z = 4
D_x = 1.621 Mg m^-3
Mo K radiation
Cell parameters from 5824 reflections
= 1.0-32.0°
= 0.53 mm^-1
T = 123 (2) K
Prism, colourless
0.38 × 0.30 × 0.18 mm

Data collection

Nonius KappaCCD diffractometer
and scans
Absorption correction: none
10766 measured reflections
5573 independent reflections
4379 reflections with I > 2(I)
R_int = 0.027
_max = 32.0°
h = -14 14
k = -15 15
l = -23 23

Refinement

Refinement on F²
R[F² > 2(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/[²(F_o²) + (0.036P)² + 0.781P] where P = (F_o² + 2F_c²)/3
(/)_max = 0.002
_max = 0.48 e Å^-3
_min = -0.53 e Å^-3

Table 1
Hydrogen-bond geometry (Å, °)

D-HA	D-H	HA	DA	D-HA
N1-H1NN4	0.87 (2)	2.10 (2)	2.9652 (17)	174 (2)
N3-H3NO2ⁱ	0.85 (2)	2.13 (2)	2.9725 (16)	169 (2)
N3-H4NO1ⁱⁱ	0.90 (2)	2.09 (2)	2.9390 (15)	157 (2)
N4-H5NN3ⁱⁱⁱ	0.89 (2)	2.52 (2)	3.3944 (18)	169 (2)
N4-H6NO4ⁱ	0.83 (2)	2.28 (2)	3.1000 (17)	173 (2)
C1-H1AO3^iv	0.99	2.37	3.2535 (18)	148
C1-H1BO3ⁱⁱⁱ	0.99	2.47	3.2852 (17)	139
C6-H6O4	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 [U_iso(H) = 1.2U_eq(C)] during the refinement process.

Data collection: COLLECT (Hooft, 1988) and DENZO (Otwinowski & Minor, 1997); cell refinement: DENZO and COLLECT; data reduction: DENZO; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2003); 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.
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.
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.

organic compounds