Powder study of hydrochlorothiazide – methyl acetate ( 1 / 1 )

# 2005 International Union of Crystallography Printed in Great Britain – all rights reserved A polycrystalline sample of the title compound, C7H8ClN3O4S2 C3H6O2, was produced during an automated parallel crystallization search on hydrochlorothiazide (HCT). The crystal structure was solved by simulated annealing from laboratory X-ray powder diffraction data collected at room temperature to 1.75 Å resolution. Subsequent Rietveld refinement yielded an Rwp value of 0.0182 to 1.54 Å resolution. The compound crystallizes with one molecule of HCT and one of methyl acetate in the asymmetric unit and displays an extensive hydrogen-bonding network.

A polycrystalline sample of the title compound, C 7 H 8 ClN 3 O 4 S 2 ÁC 3 H 6 O 2 , was produced during an automated parallel crystallization search on hydrochlorothiazide (HCT). The crystal structure was solved by simulated annealing from laboratory X-ray powder diffraction data collected at room temperature to 1.75 Å resolution. Subsequent Rietveld refinement yielded an R wp value of 0.0182 to 1.54 Å resolution. The compound crystallizes with one molecule of HCT and one of methyl acetate in the asymmetric unit and displays an extensive hydrogen-bonding network.

Comment
Hydrochlorothiazide (HCT) is a thiazide diuretic which is known to crystallize in at least two non-solvated forms; form I (Dupont & Dideberg, 1972) and form II (Florence et al., 2005). During an automated parallel crystallization search on HCT, multi-sample X-ray powder diffraction analysis (Florence et al., 2003) of all recrystallized samples revealed a novel pattern which was identified as the methyl acetate solvate (I).
The crystal structure of (I) was solved by simulated annealing using laboratory X-ray powder diffraction data. The compound crystallizes in the space group P2 1 /c with one molecule of hydrochlorothiazide (HCT) and one of methyl acetate in the asymmetric unit (Fig. 1). In (I), the sixmembered ring N2/S1/C1/C2/N1/C3 in HCT displays a nonplanar conformation, atom N2 having the largest deviation [0.646 (2) Å ] from the least-squares plane through the aromatic ring. The sulfonamide side chain displays a torsion angle N3-S2-C5-C6 of 65.1 (4) , such that atom O1 eclipses H4, and atoms O4 and N3 are staggered with respect to Cl1.
Hydrophobic interactions within the structure of (I) include a C-HÁ Á Á approach between C10-H10A and the centroid of the ring C1/C2/C4-C7 [C10Á Á Ácentroid distance of 3.364 (2) Å ]. The structure also contains a short OÁ Á ÁC intermolecular contact of 2.915 (4) Å between atom O1 of the HCT sulfonamide side chain and C9 i [symmetry code: (i) x, 3 2 À y, À 1 2 + z], the carbonyl C atom of methyl acetate. This type of contact is not unique, and a search of the Cambridge Structural Database (Version 5.26; Allen, 2002) for (O)S OÁ Á ÁC O(ester) intermolecular contacts less than the sum of the van der Waals radii yielded 38 structures comprising 41 contacts within the range 2.83-3.21 Å . It is reasonable to consider this contact to be an attractive dipoledipole interaction of the type S O( À )Á Á ÁC( + ) O, similar to those described elsewhere for carbonyl-carbonyl interactions (Allen et al., 1998).

Experimental
A polycrystalline sample of (I) was recrystallized by cooling a saturated methyl acetate-acetone (50:50) solution from 313 to 283 K. The sample was lightly ground in a mortar, loaded into a 0.7 mm borosilicate glass capillary and mounted on the diffractometer. Data were collected from a sample in a rotating 0.7 mm borosilicate glass capillary using a variable count time scheme (Shankland et al., 1997;Hill & Madsen, 2002).
organic papers The crystal structure of (I), viewed along the b axis. Dashed lines indicate hydrogen bonds.

Figure 1
The atomic arrangement in (I), showing the contents of the asymmetric unit and the atom-numbering scheme. Isotropic displacement ellipsoids are shown at the 50% probability level.
The diffraction pattern indexed to a monoclinic cell [M(20)= 34.0, F(20)= 81.2; DICVOL-91; Boultif & Louer, 1991] and the space group P2 1 /c was assigned from volume considerations and a statistical consideration of the systematic absences (Markvardsen et al., 2001). The data set was background subtracted and truncated to 52.2 2 for Pawley fitting (Pawley, 1981; 2 Pawley = 1.64) and the structure solved using the simulated annealing (SA) global optimization procedure, described previously (David et al., 1998), that is now implemented in the DASH computer program . The internal coordinate descriptions (including H atoms) of the molecules were constructed from standard bond lengths, angles and torsions where appropriate. The structure was solved using data to 52.23 2, comprising 291 reflections. The structure was refined against data in the range 7.5 to 60.0 2 (430 reflections). The restraints were set such that bonds and angles did not deviate more than 0.01 Å and 1 , respectively, from their initial values during the refinement. Atoms C1, C2, C4, C5, C6, C7, H4, H7, Cl1 and S2 of HCT were restrained to be planar, as were atoms C8, C9, C10, O5 and O6 of the methyl acetate. The SA structure solution involved the optimization of one molecule of HCT plus one molecule of methyl acetate, totaling 13 degrees of freedom (six positional, six orientational and one torsional). All degrees of freedom were assigned random values at the start of the simulated annealing. The best SA solution had a favourable 2 SA / 2 Pawley ratio of 5.2, a chemically reasonable packing arrangement and exhibited no significant misfit to the data. Prior to Rietveld refinement, atoms H31 and H32 (attached to N3) were set to positions which satisfied the hydrogen-bonding contacts within the structure. The solved structure was subsequently refined against data in the range 7.5-60.0 2 using a restrained Rietveld method (Rietveld, 1969) as implemented in TOPAS (Coelho, 2003), with the R wp value falling to 0.0182 during the refinement. All atomic positions (including H atoms) for the structure of (I) were refined, subject to a series of restraints on bond lengths, angles and planarity. A spherical harmonics (8th order) correction of intensities for preferred orientation was applied in the final refinement (Jä rvinen, 1993). The observed and calculated diffraction patterns for the refined crystal structure are shown in Fig. 4   taken from the software, and it is worth noting that the s.u. values derived from the Rietveld refinement are, in common with the majority of Rietveld refinements, significantly underestimated.