4-(3-Methylanilino)-N-[N-(1-methylethyl)carbamoyl]pyridinium-3-sulfonamidate (torasemide T–N): a low temperature redetermination

The structure [Danilovski et al. (2001 ▶). Croat. Chim. Acta 74, 103–120] of the T–N (non-solvated) polymorph of torasemide, C16H20N4O3S, a diuretic drug used in the treatment of hypertension, has been redetermined at low temperature. The zwitterionic form of the molecule is confirmed, although GAUSSIAN03 calculations suggest that this form is less stable in the gas phase. The unit-cell contraction between 298 and 100 K is approximately isotropic and the largest structual change is in a C—N—C—C torsion angle, which differs by 11.4 (3)° between the room-temperature and low-temperature structures. There are two molecules in the asymmetric unit, both of which contain an intramolecular N—H⋯N hydrogen bond. In the crystal structure, both molecules form inversion dimers linked by pairs of N—H⋯N hydrogen bonds. Further N—H⋯N and N—H⋯O hydrogen bonds lead to a three-dimensional network. The different hydrogen-bond arrangements and packing motifs in the polymorphs of torasemide are discussed in detail.

The structure [Danilovski et al. (2001). Croat. Chim. Acta 74, 103-120] of the T-N (non-solvated) polymorph of torasemide, C 16 H 20 N 4 O 3 S, a diuretic drug used in the treatment of hypertension, has been redetermined at low temperature. The zwitterionic form of the molecule is confirmed, although GAUSSIAN03 calculations suggest that this form is less stable in the gas phase. The unit-cell contraction between 298 and 100 K is approximately isotropic and the largest structual change is in a C-N-C-C torsion angle, which differs by 11.4 (3) between the room-temperature and low-temperature structures. There are two molecules in the asymmetric unit, both of which contain an intramolecular N-HÁ Á ÁN hydrogen bond. In the crystal structure, both molecules form inversion dimers linked by pairs of N-HÁ Á ÁN hydrogen bonds. Further N-HÁ Á ÁN and N-HÁ Á ÁO hydrogen bonds lead to a threedimensional network. The different hydrogen-bond arrangements and packing motifs in the polymorphs of torasemide are discussed in detail.

Related literature
For the crystal structures of polymorphs of torasemide, see: Dupont et al. (1978); Danilovski et al. (2001). For the structure of the water-methanol solvated T-II form of torasemide, see: Bartolucci et al. (2009 T min = 0.541, T max = 1.000 (expected range = 0.412-0.761) 53231 measured reflections 6941 independent reflections 6840 reflections with I > 2(I) R int = 0.029 Refinement R[F 2 > 2(F 2 )] = 0.043 wR(F 2 ) = 0.117 S = 1.07 6941 reflections 458 parameters H atoms treated by a mixture of independent and constrained refinement Á max = 0.64 e Å À3 Á min = À0.36 e Å À3 Table 1 Hydrogen-bond geometry (Å , ). Data collection: CrysAlisPro CCD (Oxford Diffraction, 2006); cell refinement: CrysAlisPro CCD; data reduction: CrysAlisPro RED (Oxford Diffraction, 2006); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: SHELXL97, WinGX (Farrugia, 1999), GAUSSIAN03 (Frisch et al., 2004) and PARST (Nardelli, 1995). Three polymorphs of torasemide have been reported up to now, respectively denoted T-I, T-II (Dupont et al., 1978) and T-N (Danilovski et al., 2001). In addition, the structure of a water-methanol solvate, isomorphous with form T-II has now been determined (Bartolucci et al., 2009). Since crystals of the T-N form were repeatedly obtained in the course of an investigation on torasemide polymorphic forms, it was deemed worthwhile to collect a set of low-temperature (100 K) data on this structure (I), in order to enable comparisons with the results of the previous, accurate, room-temperature study of the same T-N form. Also, it appeared that a new, unified, approach to the description of hydrogen bonding in the T-N, T-II and T-II solvate structures would be useful. The asymmetric unit of the monoclinic unit cell of I ( Fig. 1) contains two symmetry-independent molecules of torasemide (as for form T-II; however, no solvent molecules are present in the T-N structure). As already pointed out by Danilovski et al., the T-N form has the highest density among all known polymorphs. Moreover, there is a 3% decrease in the cell volume going from room temperature to 100 K, the decrease being rather isotropic, possibly due to the rather uniform, three-dimensional, distribution of hydrogen-bond linkages (hydrogen bonds and the effects on their distances due to the decrease in temperature are considered below). As far as the molecular conformation is concerned, only the most flexible parts are significantly affected by the temperature decrease, with a 11.4 (3)°c hange in the value of the C6-N4-C7-C8 torsion angle and a 4.1° variation for the C22-N8-C23-C24 one (labelling criteria are consistent with those of the accompanying paper on the T-II solvated form: the molecules formed by carbon atoms C1 to C16 and C17 to C32 respectively correspond to the A and B molecules in Danilovski's notation). Other conformational changes are smaller, the largest one, 3.2 (3)°, being found for the torsion angle of the S1-N3-C6-N4 chain. The values of the angles between the best planes through the aromatic rings of the two molecules, 81.60 (5)° (A) and 63.21 (6)° (B), are close to those found in the room-temperature study [80.3 (2)° and 62.8 (3)°, respectively]. The N-H amine bonds are oriented as in the structure of the T-II solvate and the large difference (ca 0.09 Å) between the lengths of the two N-C bonds formed by N1 and, separately, by N5, discussed in connection with the T-II solvate structure, is found also for the T-N polymorph.
Since all recent torasemide structure determinations have unambiguously shown that the molecule adopts the zwitterionic form, it was interesting to compare the energy of this arrangement with that of the tautomer where the N3, or N7, nitrogen is protonated, instead of the pyridine nitrogen. Geometry optimizations performed with the GAUSSIAN03 programs suite at the B3LYP/6-31 G(d,p) level, followed by single-point calculations on the optimized geometries, using the 6-311++G(d,p) basis set, yielded the zwitterionic form as definitely less stable than the other one (by as much as 56.6 kJ/mol) in the gas phase.
However, the energy gap reduces to 5.3 kJ/mol if the presence of a dielectric environment is simulated by the PCM model, suggesting that the zwitterionic form is actually stabilized by the hydrogen bond interactions existing in water solution as well as in the solid state. Both optimized geometries showed the appreciable difference in the lengths of the two N-C bonds formed by the amine N1, or N5, atom (this point, recalled above, is discussed in the accompanying paper).

Experimental
Samples of torasemide were kindly provided by SIMS (SIMS srl, Reggello Firenze, Italy). Crystals of (I), suitable for X-ray diffraction analysis, were obtained by slow evaporation from methanol solutions.

Refinement
H atoms bound to carbon atoms were in geometrically generated positions, riding, whereas the coordinates of those bound to the N atoms were refined freely. The constraint U(H) = 1.2U eq (C,N) on hydrogen temperature factors was applied [U(H) = 1.5U eq (C) for the H atoms of methyl groups]. The N-H bond distances formed by refined hydrogen atoms were in the range 0.85 -0.93 Å. Fig. 1. A view of the content of the asymmetric unit of (I). Displacement ellipsoids are drawn at the 50% probability level.

Figures
supplementary materials sup-3 Fig. 2. A view of the crystal packing in the structure of (I), in proximity of the ab face. Hydrogen bonds are denoted by dashed lines. Only hydrogen atoms involved in the formation of hydrogen bonds are shown. The A and B labels denote centrosymmetric molecule dimers, respectively formed by the symmetry-independent molecules of the two types, present in the structure. The dimers, joined by hydrogen bonds, form chains parallel to the [1-10] direction (or to the [110] direction, on parallel planes at c/2 distance from the one shown).   (5)  C22 0.0259 (7) 0.0247 (7) 0.0236 (7) 0.0052 (6) 0.0024 (6) 0.0006 (6)