I. INTRODUCTION
Gepirone (marketed under the trade name Exxua) is used for the treatment of adults with major depressive disorder and is being investigated for use in the treatment of general anxiety disorder. The systematic name (CAS Registry Number 83928-76-1) is 4,4-Dimethyl-1-(4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl)piperidine-2,6-dione. A two-dimensional molecular diagram of gepirone is shown in Figure 1.
Figure 1. The two-dimensional structure of gepirone.
Two polymorphs of gepirone hydrochloride had been known previously, and a third form was discovered by differential scanning calorimetry and thermal microscopy (Behme et al., Reference Behme, Brooke, Farney and Kensler1985; Bristol-Myers). Single-crystal structures of Forms I and II of gepirone hydrochloride, as well as of gepirone-free base, were determined by Barbero (Reference Barbero2019), but no atom coordinates were published.
This work was carried out as part of a project (Kaduk et al., Reference Kaduk, Crowder, Zhong, Fawcett and Suchomel2014) to determine the crystal structures of large-volume commercial pharmaceuticals and include high-quality powder diffraction data for them in the Powder Diffraction File (Kabekkodu et al., Reference Kabekkodu, Dosen and Blanton2024).
II. EXPERIMENTAL
Gepirone was a commercial reagent, purchased from TargetMol (Batch 156703), and was used as-received. The white powder was packed into a 0.5 mm diameter Kapton capillary and rotated during the measurement at ~2 Hz. The powder pattern was measured at 298(1) K at the BXDS-WLE Wiggler Low Energy Beamline (Leontowich et al., Reference Leontowich, Gomez, Diaz Moreno, Muir, Spasyuk, King, Reid, Kim and Kycia2021) of the Brockhouse X-ray Diffraction and Scattering Sector of the Canadian Light Source using a wavelength of 0.819563(2) Å (15.1 keV) from 1.6 to 75.0° 2θ with a step size of 0.0025° and a collection time of 3 min. The high-resolution powder diffraction data were collected using eight Dectris Mythen2 X series 1 K linear strip detectors. NIST SRM 660b LaB6 was used to calibrate the instrument and refine the monochromatic wavelength used in the experiment.
The pattern was indexed with DICVOL06 (Louër and Boultif, Reference Louër and Boultif2007) as incorporated into EXPO2014 (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013) on a primitive monoclinic unit cell with a = 16.81970, b = 11.72400, c = 10.10370 Å, β = 95.702°, V = 1982.5 Å3, and Z = 4. The suggested space group was P2 1/a, which was confirmed by the successful solution and refinement of the structure. A reduced cell search of the Cambridge Structural Database (Groom et al., Reference Groom, Bruno, Lightfoot and Ward2016) yielded 20 hits but no gepirone derivatives.
The structure was solved by direct methods as implemented in EXPO2014 (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013) using the COVMAP option. A few atom types had to be reassigned manually. The initial hydrogen atom positions were calculated using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020).
Rietveld refinement was carried out with GSAS-II (Toby and Von Dreele, Reference Toby and Von Dreele2013). Only the 3.5–50° portion of the pattern was included in the refinements (d min = 0.969 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). The Mogul average and standard deviation for each quantity were used as the restraint parameters. The pyrimidine ring was restrained to be planar. The restraints contributed 4.2% to the overall χ 2. The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using the AddH item in Materials Studio (Dassault Systèmes, 2023); these H positions are calculated using a force field, so the X–H distances are longer than the usual crystallographic ones. The Uiso of the heavy atoms were grouped by chemical similarity. The Uiso for the H atoms were fixed at 1.3× the Uiso of the heavy atoms to which they are attached. The peak profiles were described using the generalized microstrain model (Stephens, Reference Stephens1999). The background was modeled using a 3-term shifted Chebyshev polynomial, with peaks at 10.38 and 41.94° to model the scattering from the Kapton capillary and an amorphous component.
The final refinement of 103 variables using 18,601 observations and 68 restraints yielded the residual R wp = 0.0445. The largest peak (2.33 Å from C22) and hole (1.92 Å from O2) in the difference Fourier map were 0.32(9) and −0.34(9) eÅ−3, respectively. The final Rietveld plot is shown in Figure 2. The largest features in the normalized error plot are in the shapes of some of the low-angle peaks and a few trace impurity peaks.
Figure 2. The Rietveld plot for the refinement of gepirone. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot, and the red line is the background curve. The vertical scale has been multiplied by a factor of 10× for 2θ > 17.4° and by a factor of 40× for 2θ > 30.0°.
The crystal structure of gepirone was optimized (fixed experimental unit cell) with density functional theory techniques using VASP (Kresse and Furthmüller, Reference Kresse and Furthmüller1996) through the MedeA graphical interface (Materials Design, 2024). The calculation was carried out on 32 cores of a 144-core (768 Gb memory) HPE Superdome Flex 280 Linux server 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 × 2 mesh, and took ~15.5 h. Single-point density functional theory calculations (fixed experimental cell) and population analysis were carried out using CRYSTAL23 (Erba et al., Reference Erba, Desmarais, Casassa, Civalleri, Donà, Bush, Searle, Maschio, Daga, Cossard, Ribaldone, Ascrizzi, Marana, Flament and Kirtman2023). The basis sets for the H, C, N, and O atoms in the calculation were those of Gatti et al. (Reference Gatti, Saunders and Roetti1994). The calculations were run on a 3.5 GHz PC using 8 k-points and the B3LYP functional and took ~4.5 h.
III. RESULTS AND DISCUSSION
The powder pattern of this study is similar enough to that reported by Barbero (Reference Barbero2019) to conclude that they represent the same material (Figure 3). Further confirmation is provided by the similarities of the lattice parameters (Table I). The small differences presumably reflect the differences in the temperatures of data collection (298 in this study and 293 K for Barbero). The root-mean-square Cartesian displacement of the non-H atoms in the Rietveld-refined and VASP-optimized molecules is 0.055 Å (Figure 4). The agreement is within the normal range for correct structures (van de Streek and Neumann, Reference van de Streek and Neumann2014). The asymmetric unit is illustrated in Figure 5. The remaining discussion will emphasize the VASP-optimized structure.
Figure 3. Comparison of the synchrotron pattern of gepirone (black) to that reported by Barbero (Reference Barbero2019; 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 0.819563(2) Å using JADE Pro (MDI, 2024). Image generated using JADE Pro (MDI, 2024).
TABLE I. Lattice parameters (P2 1/a) of gepirone.
Figure 4. Comparison of the Rietveld-refined (red) and VASP-optimized (blue) structures of gepirone. The root-mean-square Cartesian displacement is 0.055 Å. Image generated using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020).
Figure 5. The asymmetric unit of gepirone, with the atom numbering. The atoms are represented by 50% probability spheroids. Image generated using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020).
All bond distances, bond angles, and torsion angles fall within the normal ranges indicated by a Mercury Mogul Geometry check (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020). Quantum chemical geometry optimization of the isolated molecule (DFT/B3LYP/6-31G*/water) using Spartan ‘24 (Wavefunction, 2023) indicated that the gepirone molecule is essentially in a local minimum-energy conformation; the rms Cartesian displacement is 0.298 Å. The global minimum-energy conformation is much more compact (folded on itself), indicating that intermolecular interactions are important to determining the solid-state conformation.
The crystal structure (Figure 6) consists of discrete gepirone molecules. The mean planes of the pyrimidine, piperazine, and piperidone dione rings are approximately −11,−6,−4; −4,−7,−12; and −3,2,−11, respectively. The mean plane of the entire molecule is approximately −4,−1,−5. There are no particularly strong aromatic–aromatic interactions; the shortest distance between the centroids of pyrimidine rings is 8.4 Å.
Figure 6. The crystal structure of gepirone, viewed down the b-axis. Image generated using Diamond (Crystal Impact, 2023).
Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault Systèmes, 2023) indicates that torsion, angle, and bond distortion terms are small and contribute about equally to the intramolecular energy (58.2 kcal/mol). The intermolecular energy is dominated by electrostatic attractions, which, in this force-field-based analysis, include hydrogen bonds. The hydrogen bonds are better discussed using the results of the density functional theory (DFT) calculation.
There are no classical hydrogen bonds in the crystal structure (Table II), but several intra- and intermolecular C–H⋯N and C–H–O hydrogen bonds contribute to the lattice energy.
TABLE II. Hydrogen bonds (CYSTAL23) in gepirone.
a intramolecular
The volume enclosed by the Hirshfeld surface of gepirone (Figure 7, Hirshfeld, Reference Hirshfeld1977; Spackman et al., Reference Spackman, Turner, McKinnon, Wolff, Grimwood, Jayatilaka and Spackman2021) is 487.19 Å3, which consitutes 98.36% of 1/4 of the unit cell volume. The packing density is thus fairly typical. The only significant close contacts (red in Figure 7) involve the hydrogen bonds. The volume/non-hydrogen atom is larger than normal, measuring 19.0 Å3.
Figure 7. The Hirshfeld surface of gepirone. 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 (Spackman et al., Reference Spackman, Turner, McKinnon, Wolff, Grimwood, Jayatilaka and Spackman2021).
The Bravais–Friedel–Donnay–Harker (Bravais, Reference Bravais1866; Friedel, Reference Friedel1907; Donnay and Harker, Reference Donnay and Harker1937) morphology suggests that we might expect isotropic morphology for gepirone. A second-order spherical harmonic model was included in the refinement. The texture index was 1.005(0), indicating that the preferred orientation was insignificant in this rotated capillary specimen.
IV. DEPOSITED DATA
The powder pattern of gepirone from this synchrotron data set has been submitted to ICDD for inclusion in the Powder Diffraction File. 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 [email protected].
Acknowledgements
The synchrotron data collection described in this paper was performed at the Canadian Light Source (CLS), a national research facility of the University of Saskatchewan, which is supported by the Canada Foundation for Innovation (CFI), the Natural Sciences and Engineering Research Council (NSERC), the Canadian Institute of Health Research (CIHR), the Government of Saskatchewan, and the University of Saskatchewan. This work was partially supported by the International Centre for Diffraction Data. We thank Adam Leontowich (CLS) for his assistance in the synchrotron data collection and Megan Rost (ICDD) for laboratory data collection before the gepirone specimen was sent to CLS.
Conflicts of interest
The authors have no conflicts of interest to declare.
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