II. EXPERIMENTAL

Metolazone was a commercial reagent, purchased from United States Pharmacopeial Convention (Lot #G0B246) and was used as received. The white powder was packed into a 1.5 mm diameter Kapton capillary and rotated during the measurement at ~50 Hz. The powder pattern was measured at 295 K at beamline 11-BM (Lee et al., Reference Lee, Shu, Ramanathan, Preissner, Wang, Beno, Von Dreele, Ribaud, Kurtz, Antao, Jiao and Toby2008; Wang et al., Reference Wang, Toby, Lee, Ribaud, Antao, Kurtz, Ramanathan, Von Dreele and Beno2008) of the Advanced Photon Source at Argonne National Laboratory using a wavelength of 0.414157 Å from 0.5° to 50° 2θ with a step size of 0.001° and a counting time of 0.1 s step⁻¹.

The pattern was initially indexed on a primitive monoclinic unit cell with a = 8.0524, b = 8.1940, c = 25.2517 Å, β = 98.910°, V = 1646.03 Å³, and Z = 4 using DICOL14 (Louër and Boultif, Reference Louër and Boultif2014). Analysis of the systematic absences using EXPO2014 (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013) suggested the space group P2₁/c. An unindexed sharp peak at 1.556°2θ shows that the sample contains an impurity. This peak disappears on re-crystallization, as shown by measurement of the pattern on a laboratory diffractometer. The structure solution using FOX (Favre-Nicolin and Černý, Reference Favre-Nicolin and Černý2002) was straightforward, but the U _iso of the Cl atom refined to a high value (0.164 Å²), and the agreement of the Rietveld refinement and the DFT optimization was poor; the root-mean-square Cartesian displacement of the non-hydrogen atoms was 0.555 Å, well outside the range of correct structures (van de Streek and Neumann, Reference van de Streek and Neumann2014).

More-careful (manual) peak location allowed N-TREOR (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013) to find a higher-quality triclinic cell with a = 8.1976(5), b = 14.4615(69), c = 16.0993(86) Å, α = 115.009(18), β = 90.096(7), γ = 106.264(4)°, V = 1644.52(9) Å³, and Z = 4. The space group was assumed to be P-1. A reduced cell search in the Cambridge Structural Database (Groom et al., Reference Groom, Bruno, Lightfoot and Ward2016) combined with the chemistry C, H, Cl, N, and O and S only yielded no hits. The structure was solved using Monte Carlo simulated annealing techniques as implemented in EXPO2014.

Rietveld refinement was carried out using GSAS-II (Toby and Von Dreele, Reference Toby and Von Dreele2013). Only the 1.7°–25.0° portion of the pattern was included in the refinement (d _min = 0.956 Å). All non-H-bond distances and angles were subjected to restraints, based on a Mercury/Mogul Geometry Check (Bruno et al., Reference Bruno, Cole, Kessler, Luo, Motherwell, Purkis, Smith, Taylor, Cooper, Harris and Orpen2004; Sykes et al., Reference Sykes, McCabe, Allen, Battle, Bruno and Wood2011) of the molecule. The results were exported to a csv file. The Mogul average and standard deviation for each quantity were used as the restraint parameters and were incorporated using the new feature Restraints/Edit Restraints/Add MOGUL Restraints, which reads the bond distance and angle restraints from the csv file. The restraints contributed 4.6% to the final χ ². The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault, 2019). Positions of the active hydrogens were derived by analysis of potential hydrogen bonding patterns. The U _iso were grouped by chemical similarity, and the U _iso in the two molecules were constrained to be equal. The background was modeled using a 3-term shifted Chebyshev polynomial.

The final refinement of 178 variables using 23 302 observations and 132 restraints yielded the residuals R _wp = 0.1069 and GOF = 2.09. The largest peak (1.48 Å from O9) and hole (2.00 Å from O10) in the difference Fourier map were 0.34 and −0.28(7) eÅ⁻³, respectively. The Rietveld plot is included in Figure 2. The largest errors in the fit are at the broad peak at 3.42°.

Figure 2.

(Colour online) The Rietveld plot for the refinement of metolazone. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot. The vertical scale has been multiplied by a factor of 10× for 2θ > 13.0°.

A density functional geometry optimization (fixed experimental unit cell) was carried out using VASP (Kresse and Furthmüller, Reference Kresse and Furthmüller1996) through the MedeA graphical interface (Materials Design, 2016). The calculation was carried out on 16 2.4 GHz processors (each with 4 GB RAM) of a 64-processor HP Proliant DL580 Generation 7 Linux cluster at North Central College. The calculation used the GGA-PBE functional, a plane wave cutoff energy of 400.0 eV, and a k-point spacing of 0.5 Å⁻¹ leading to a 2 × 2 × 1 mesh, and took ~429 h. A density functional geometry optimization was carried out (starting from the not-quite-converged VASP output) using CRYSTAL14 (Dovesi et al., Reference Dovesi, Orlando, Erba, Zicovich-Wilson, Civalleri, Casassa, Maschio, Ferrabone, De La Pierre, D-Arco, Noël, Causà and Kirtman2014). The basis sets for the H, C, N, and O atoms were those of Gatti et al. (Reference Gatti, Saunders and Roetti1994), and the basis sets for S and Cl were those of Peintinger et al. (Reference Peintinger, Vilela Oliveira and Bredow2013). The calculation was run on eight 2.1 GHz Xeon cores (each with 6 GB RAM) of a 304-core Dell Linux cluster at IIT, using 8 k-points and the B3LYP functional, and took ~90 h.

III. RESULTS AND DISCUSSION

The powder pattern of metolazone (Figure 3) exhibits some similarities to that of Zhang et al. (Reference Zhang, Hui and Wang2014); it is not clear that the compound studied here is the same. The laboratory pattern of re-crystallized metolazone is essentially identical to the synchrotron pattern of the as-received material, except for the 1.556° peak. Re-crystallization is not the source of the differences between our material and Zhang's. The refined atom coordinates of metolazone and the coordinates from the DFT optimization are reported in the CIFs attached as Supplementary Material.

Figure 3.

(Colour online) Comparison of the synchrotron pattern (red) of metolazone with the laboratory diffraction pattern from Zhang et al. (Reference Zhang, Hui and Wang2014). The literature pattern (measured using CuKα radiation) was digitized using UN-SCAN-IT (Silk Scientific, 2013) and scaled to the synchrotron wavelength of 0.414157 Å using Jade 9.8 (MDI, 2018).

Comparing the Rietveld refined and the optimized structures, the root-mean-square Cartesian displacements of the non-hydrogen atoms in the metolazone molecules are 0.252 and 0.356 Å [Figures 4(a) and 4(b)]. The agreement between the refined and optimized structures is at the upper end of the range for correct structures (van de Streek and Neumann, Reference van de Streek and Neumann2014). This discussion concentrates on the CRYSTAL-optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 5, and the crystal structure is presented in Figure 6. The broad peak at 3.42° in the powder diffraction pattern (Figure 2) is the 02-1 peak. It is reasonable to expect stacking faults along this direction (Figure 7), but (given the objectives of this study), the nature of the faulting was not explored in detail. The crystal structure consists of alternating polar and hydrocarbon layers parallel to the ac-plane. Phenyl–phenyl interactions appear prominent but are not reflected in the population analysis.

Figure 4.

(Colour online) (a) Comparison of the Rietveld-refined (red) and CRYSTAL14-optimized (blue) structures of molecule 1 of metolazone. (b) Comparison of the Rietveld-refined (red) and CRYSTAL14-optimized (blue) structures of molecule 2 of metolazone.

Figure 5.

(Colour online) The asymmetric unit of metolazone, with the atom numbering. The atoms are represented by 50% probability spheres.

Figure 6.

(Colour online) The crystal structure of metolazone viewed down the a-axis.

Figure 7.

(Colour online) The crystal structure of metolazone viewed nearly down the a-axis, with the (02-1) plane indicated.

The two independent metolazone molecules have different conformations (Figure 8). The largest differences are in the rings which contain C13 and C36 and the orientations of the sulfonamide groups. Most of the bond distances, bond angles, and torsion angles fall within the normal ranges indicated by a Mercury Mogul Geometry check (Macrae et al., Reference Macrae, Bruno, Chisholm, Edington, McCabe, Pidcock, Rodriguez-Monge, Taylor, van de Streek and Wood2008). The bond distances S7–N8, S7–O9, and S7–O10 (refined = 1.676, 1.499, 1.504 Å; averages = 1.600(20), 1.433(19), 1.433(19) Å; Z-scores = 3.8, 3.5, 3.5) and S31–N32, S31–O33, S31–O34 (refined = 1.746, 1.486, 1.493 Å; averages = 1.600(20), 1.433(19), 1.433(19); Z-scores = 7.3, 2.8, 3.2) are flagged as unusual. The bond angles C29–S31–N32 and O34–S31–C29 (refined = 100.2, 112.1; average = 108.2(18), 107.3(15); Z-scores = 4.3, 3.3) are flagged as unusual. The torsion angles C26–C29–S31–N32, C26–C29–S31–O34, C28–C29–S31–N32, and C28–C29–S31–O34 lie on the tails of a minority population of similar torsion angles.

Figure 8.

(Colour online) Comparison of the two independent metolazone molecules in the asymmetric unit. Molecule 1 is green, and molecule 2 is orange.

Quantum chemical geometry optimizations (DFT/B3LYP/6-31G*/water) using Spartan ‘18 (Wavefunction, 2018) indicated that the observed conformation of molecule 1 is 0.8 kcal mol⁻¹ lower in energy than that of molecule 2. The difference is close to the expected accuracy of such calculations, so the two conformations can be considered similar in energy. Molecular mechanics conformational analysis indicated that the two molecules are ~2 kcal mol⁻¹ higher in energy than the global minimum energy conformation (Figure 9). The conformational differences are relatively small and are spread throughout the molecules. Intermolecular interactions play a role in determining the observed solid-state conformations.

Figure 9.

(Colour online) Comparison of the two molecules of metolazone in the triclinic asymmetric unit (green and orange) with the single molecule of the monoclinic asymmetric unit (purple).

Analysis of the contributions to the total crystal energy using the Forcite module of Materials Studio (Dassault, 2019) suggests that angle distortion terms and torsion terms are significant in the intramolecular deformation energy, as might be expected for a fused ring system. The intermolecular energy is dominated by electrostatic attractions, which in this force-field-based analysis include hydrogen bonds. The hydrogen bonds are better analyzed using the results of the DFT calculation.

Several hydrogen bonds are present in the crystal structure (Table I). The energies of the N–H···O hydrogen bonds were calculated using the correlation of Wheatley and Kaduk (Reference Wheatley and Kaduk2019). Unusually, only one of the sulfonamide groups acts as a hydrogen bond donor. Both ring nitrogen atoms N36 and N12 act as hydrogen bond donors, but one forms an N–H···N hydrogen bond, while the other participates in an N–H···O bond. Three of the phenyl hydrogen atoms participate in C–H···O hydrogen bonds, one of which is intramolecular.

TABLE I.

Hydrogen bonds (CRYSTAL14) in metolazone.

^a Intramolecular.

The volume enclosed by the Hirshfeld surface (Figure 10; Hirshfeld, Reference Hirshfeld1977; Turner, et al., Reference Turner, McKinnon, Wolff, Grimwood, Spackman, Jayatilaka and Spackman2017) is 812.59 Å³, 98.82% of 1/2 the unit cell volume. The molecules are thus not tightly packed. All of the significant close contacts (red in Figure 10) involve the hydrogen bonds. The volume/non-hydrogen atom is 17.1 Å³.

Figure 10.

(Colour online) The Hirshfeld surface of metolazone. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white.

The Bravais–Friedel–Donnay–Harker (Bravais, Reference Bravais1866; Friedel, Reference Friedel1907; Donnay and Harker, Reference Donnay and Harker1937) morphology suggests that we might expect elongated morphology for metolazone, with <100> as the long axis, and {001}, {010}, and {011} as prominent side faces. A 2nd-order spherical harmonic model was included in the refinement. The texture index was 1.095, indicating that preferred orientation was significant in this rotated capillary specimen. The powder pattern of metolazone from this synchrotron data set in space group P2₁/c is included in the Powder Diffraction File™ as entry 00-066-1624 and will be replaced by one generated using the triclinic structure.