Crystal structure of ponazuril, C18H14F3N3O6S

The crystal structure of ponazuril has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. Ponazuril crystallizes in space group P21/c (#14) with a = 8.49511(6), b = 12.38696(6), c = 18.84239(17) Å, β = 96.7166(4)°, V = 1969.152(12) Å3, and Z = 4. N–H⋯O hydrogen bonds link the molecules into chains along the a-axis, with a graph set C1,1(6). The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).

A powder pattern of crystalline ponazuril has been reported by Li et al. (2022), in the context of a study of preparation of co-amorphous formulations of toltrazuril and ponazuril, but no crystal structure of ponazuril was reported.
This work was carried out as part of a project (Kaduk et al., 2014) to determine the crystal structures of large-volume commercial pharmaceuticals, and include high-quality powder diffraction data for them in the Powder Diffraction File (Gates-Rector and Blanton, 2019).

II. EXPERIMENTAL
Ponazuril was a commercial reagent, purchased from TargetMol (Lot #131432), 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., 2008;Wang et al., 2008) of the Advanced Photon Source at Argonne National Laboratory using a wavelength of 0.458208(2) Å from 0.5 to 50°2θ with a step size of 0.0009984375 and a counting time of 0.1 s per step. The high-resolution powder diffraction data were collected using twelve silicon crystal analyzers that allow for high angular resolution, high precision, and accurate peak positions. A mixture of silicon (NIST SRM 640c) and The suggested space group was P2 1 /c, which was confirmed by successful solution and refinement of the structure. A diclazuril molecule was downloaded from PubChem (Kim et al., 2019) as Conformer3D_CID_3050408.sdf. It was converted to a *.mol2 file using Mercury (Macrae et al., 2020). The structure was solved by Monte Carlo simulated annealing as implemented in EXPO2014 (Altomare et al., 2013).
Rietveld refinement was carried out using GSAS-II (Toby and Von Dreele, 2013). Only the 2.0-27.0°portion of the Figure 2. The Rietveld plot for the refinement of ponazuril. 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 > 9.2°, and by a factor of 40× for 2θ > 18.4°. The row of blue tick marks indicates the calculated reflection positions. Figure 3. Comparison of the synchrotron pattern from this study of ponazuril (black) to that reported by Li et al. (2022;green). The literature pattern, measured using Cu Kα radiation, was digitized using UN-SCAN-IT (Silk Scientific, 2013), and converted to the synchrotron wavelength of 0.458208 Å using JADE Pro (MDI, 2022). Image generated using JADE Pro (MDI, 2022). pattern was included in the refinement (d min = 0.981 Å). All non-H bond distances and angles were subjected to restraints, based on a Mercury/Mogul Geometry Check (Bruno et al., 2004;Sykes et al., 2011). The Mogul average and standard deviation for each quantity were used as the restraint parameters. The restraints contributed 4.0% to the final χ 2 . The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault, 2021). The U iso of the heavy atoms were grouped by chemical similarity. The U iso for the H atoms were fixed at 1.2× the U iso of the heavy atoms to which they are attached. A second-order spherical harmonic preferred orientation model was included in the refinement. The refined texture index was 1.007(0). The peak profiles were described using the generalized microstrain model. The background was modeled using a 6-term shifted Chebyshev polynomial, and a peak at 5.72°2θ to model the scattering from the Kapton capillary and any amorphous component.
The final refinement of 121 variables using 25 040 observations and 84 restraints yielded the residuals R wp = 0.0662 and GOF = 1.49. The largest peak (1.11 Å from F4) and hole (1.14 Å from O8) in the difference Fourier map were 0.32(8) and −0.32(8) eÅ −3 , respectively. The largest errors in the difference plot (Figure 2) are in the shapes of some of the strong low-angle peaks.
The crystal structure was optimized using density functional techniques as implemented in VASP (Kresse and Furthmüller, 1996) (fixed experimental unit cell) 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 ∼28.5 h. A single-point density functional calculation (fixed experimental cell) and population analysis were carried out using CRYSTAL17 (Dovesi et al., 2018). The basis sets for the H, C, N, and O atoms in the calculation were those of Gatti et al. (1994), and those for F and Cl were those of Peintinger et al. (2013). The calculations were run on a 3.5 GHz PC using 8 k-points and the B3LYP functional, and took ∼2.8 h.

III. RESULTS AND DISCUSSION
The synchrotron powder pattern of this study matches the pattern measured by Li et al. (2022) well enough to conclude that they represent the same material, and that our sample is representative (Figure 3). The root-mean-square (rms) Cartesian displacement between the Rietveld-refined and DFT-optimized structures of ponazuril is 0.066 Å (Figure 4). The excellent agreement provides strong evidence that the refined structure is correct (van de Streek and Neumann, 2014). This discussion concentrates on the DFT-optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 5. The best view of the crystal structure is Figure 5. The asymmetric unit of ponazuril, with the atom numbering. The atoms are represented by 50% probability spheroids. Image generated using Mercury (Macrae et al., 2020). down the a-axis (Figure 6). The crystal structure consists of normally packed molecules with hydrogen bonds parallel to the a-axis.
All of the bond distances, bond angles, and torsion angles fall within the normal ranges indicated by a Mercury/Mogul Geometry Check (Macrae et al., 2020). Quantum chemical geometry optimization of the ponazuril molecule (DFT/ B3LYP/6-31G*/water) using Spartan '18 (Wavefunction, 2020) indicated that the observed conformation is in a local minimum. A conformational analysis (MMFF force field) indicates that the minimum-energy conformation is only 0.1 kcal mol −1 lower in energy, but has a very different conformation (Figure 7). The molecule is thus apparently flexible, and intermolecular interactions are important in determining the solid-state conformation.
Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault, 2021) suggests that the intramolecular deformation energy is dominated by angle and torsion distortion terms. The intermolecular energy is dominated by electrostatic attractions, which in this force field analysis include hydrogen bonds. The hydrogen bonds are better analyzed using the results of the DFT calculation.
There is only one classical hydrogen bond in the structure, N13-H42⋯O6 (Table I). This interaction between NH and carbonyl groups results in chains along the a-axis, with a graph set C1,1(6) (Etter, 1990;Bernstein et al., 1995;Shields et al., 2000). By the correlation of Wheatley and Kaduk (2019), this hydrogen bond has an energy of 5.2 kcal mol −1 . Several C-H⋯O hydrogen bonds also contribute to the lattice energy.
The volume enclosed by the Hirshfeld surface of ponazuril (Figure 8, Hirshfeld, 1977;Turner et al., 2017) is 484.29 Å 3 , 98.37% of 1/4 the unit cell volume. The packing density is thus fairly typical. The only significant-close contacts (red in Figure 8) involve the hydrogen bonds, and a short C-H⋯ring distance. The volume/non-hydrogen atom is smaller than usual at 15.9 Å 3 . The Bravais-Friedel-Donnay-Harker (Bravais, 1866;Friedel, 1907;Donnay and Harker, 1937) morphology suggests that we might expect blocky morphology for ponazuril. A second-order spherical harmonic preferred orientation   model was included in the refinement. The texture index was 1.007(0), indicating that preferred orientation was not significant for this rotated capillary specimen.

IV. DEPOSITED DATA
The Crystallographic Information Framework (CIF) files containing the results of the Rietveld refinement (including the raw data) and the DFT geometry optimization were deposited with the ICDD. The data can be requested at pdj@icdd.com. Figure 8. The Hirshfeld surface of ponazuril. 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. Image generated using CrystalExplorer (Turner et al., 2017).