II. EXPERIMENTAL

Niraparib tosylate monohydrate was a commercial reagent, purchased from TargetMol (Batch #T9497), 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 Diffraction 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 minutes. The high-resolution powder diffraction data were collected using eight Dectris Mythen2 X series 1K 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 N-TREOR (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013) on a primitive triclinic unit cell with a = 7.22904, b = 12.77595, c = 13.38682 Å, α = 88.738, β = 88.065, γ = 82.233°, V = 1,224.1 Å³, and Z = 2. The space group was assumed to be P-1, 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 seven hits but no niraparib derivatives.

The niraparib molecule was downloaded from PubChem (Kim et al., Reference Kim, Chen, Cheng, Gindulyte, He, He and Li2023) as Conformer3D_COMPOUND_CID_24958200.sdf. It was converted to a *.mol2 file using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock and Platings2020). A tosylate anion was built using Spartan ‘24 (Wavefunction, 2023). The crystal structure was solved using Monte Carlo simulated annealing techniques as implemented in EXPO2014 (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013), using a niraparib molecule, a tosylate anion, and an O atom (water molecule) as fragments, with a bump penalty. Analysis of potential hydrogen bonds (short intermolecular distances) suggested that the amide atom was protonated, so a H atom was added there using Materials Studio (Dassault Systèmes, 2023). This was surprising, as a chemist would expect the amine nitrogen atom in the piperidine ring to be more basic. A similar analysis led to approximate positions of the H atoms on the water molecule along the O···O vectors.

This model was refined using GSAS-II (Toby and Von Dreele, Reference Toby and Von Dreele2013) and optimized using VASP (Kresse and Furthmüller, Reference Kresse and Furthmüller1996). The refinement yielded a residual R _wp = 0.05374 (Figure 2). The root-mean-square Cartesian displacements of the non-H atoms in the Rietveld-refined and VASP-optimized cations and anions were 0.199 and 0.204 Å. The agreement is within the normal range for correct structures (van de Streek and Neumann, Reference van de Streek and Neumann2014). A Mercury Mogul Geometry check (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock and Platings2020) indicated that the C–N bond distance of 1.524 Å in the protonated amide was highly unusual (average = 1.314(20) Å; Z-score = 10.4), but that the other geometrical features were normal.

Figure 2. The Rietveld plot for the first refinement of niraparib tosylate monohydrate Form I (R _wp = 0.0537). 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 3× for 2θ > 17.0̊ and by a factor of 10× for 2θ > 32.0̊.

Coincidentally, a single-crystal structure of niraparib tosylate monohydrate has been published by Mudda et al. (Reference Mudda, Devarapalli, Das, Lakkireddy, Reddy and Chennuru2024) – 3 days before we became aware of it. In the Mudda et al. structure, the N atom in the piperidine ring is protonated, as expected. The piperidine ring was modeled as a 50/50 disordered model of two orientations. Each orientation was optimized using VASP. One orientation was 174.308 kJ/mol lower in energy than our model, and the other was 144.397 kJ/mol lower than our model. (The two orientations differed in energy by 29.9 kJ/mol.) The lower-energy orientation based on the Mudda et al. structure was used to begin another Rietveld refinement on the data in our study.

Rietveld refinement was carried out with GSAS-II (Toby and Von Dreele, Reference Toby and Von Dreele2013). Only the 3.4 to 65.0° portion of the pattern was included in the refinements (d _min = 0.763 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 and Smith2004, 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 aromatic rings were restrained to be planar. The restraints contributed 6.7% to the overall χ ². The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault Systèmes, 2023). The U _iso of the heavy atoms were grouped by chemical similarity. The U _iso for the H atoms were fixed at 1.3× the U _iso 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 larger and more complex than is typical and was modeled using a six-term shifted Chebyshev polynomial, with broad peaks at 9.90, 14.06, and 41.59° to model the scattering from the Kapton capillary and an apparent amorphous component.

The final refinement of 159 variables using 24,641 observations and 95 restraints also yielded the residual R _wp = 0.0537; the two models yielded the same residual, but the second model is more chemically reasonable. The largest peak (1.08 Å from O2) and hole (1.86 Å from C13) in the difference Fourier map were 0.98(22) and −1.07(22) eÅ⁻³, respectively. The final Rietveld plot is shown in Figure 3. The largest features in the normalized error plot are in the shapes and positions of some of the low-angle peaks.

Figure 3. The Rietveld plot for the second refinement of niraparib tosylate monohydrate Form I (R _wp = 0.0537). 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 3× for 2θ > 17.0̊ and by a factor of 5× for 2θ > 36.0̊.

The crystal structure of niraparib tosylate monohydrate was optimized (fixed experimental unit cell) with density functional 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 × 1 × 1 mesh, and took ~5.4 hours. Single-point density functional calculations (fixed experimental cell) and population analysis were carried out using CRYSTAL23 (Erba et al., Reference Erba, Desmarais, Casassa, Civalleri, Donà, Bush and Searle2023). 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), and the basis set for S was that of Peintinger et al. (Reference Peintinger, Vilela Oliveira and Bredow2013). The calculations were run on a 3.5-GHz PC using eight k-points and the B3LYP functional and took ∼4.3 hours.

III. RESULTS AND DISCUSSION

The experimental powder pattern of niraparib tosylate monohydrate reported by Mudda et al. (Reference Mudda, Devarapalli, Das, Lakkireddy, Reddy and Chennuru2024) does not agree particularly well with that calculated from their crystal structure (Figure 4). The calculated pattern agrees reasonably well with the pattern reported by Wu et al. (Reference Wu, Chaber, McKeown and Foley2023) (Figure 5), accounting for the fact that the single crystal structure was done at 100 K and the patent pattern measured at ambient conditions and, thus, that the single-crystal cell is smaller. Mudda’s experimental pattern can be modeled by assuming a significant preferred orientation (sixth-order spherical harmonics), resulting in a texture index of 5.1. 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 niraparib tosylate monohydrate, with <010> as the long axis. We suspect that Mudda’s experimental pattern was measured from a poor specimen. The pattern from such an oriented specimen might not be useful for phase identification.

Figure 4. Comparison of the experimental powder pattern of niraparib tosylate monohydrate reported by Mudda et al. (Reference Mudda, Devarapalli, Das, Lakkireddy, Reddy and Chennuru2024) (black) with that calculated from their single-crystal structure (green). The literature pattern (measured using Cu K _α radiation) was digitized using UN-SCAN-IT (Silk Scientific, 2013). Image generated using JADE Pro (MDI, 2024).

Figure 5. Comparison of the experimental powder pattern of niraparib tosylate monohydrate reported by Wu et al. (Reference Wu, Chaber, McKeown and Foley2023) (green) with that calculated from the single-crystal structure of Mudda et al. (Reference Mudda, Devarapalli, Das, Lakkireddy, Reddy and Chennuru2024) (black). The literature pattern (measured using Cu K _α radiation) was digitized using UN-SCAN-IT (Silk Scientific, 2013). Image generated using JADE Pro (MDI, 2024).

The thermal expansion of niraparib tosylate monohydrate between 100 and 298 K is anisotropic (Table I). The expansion along the a-axis is 1.5%, while that along the b- and c-axes are 0.6% and 0.4%, respectively. The smaller unit cell at 100 K results in significant peak shifts compared with 298 K (Figure 6), meaning that the pattern calculated from the 100 K single crystal structure might not be useful for phase identification; the peak shifts may be outside the d-spacing tolerance used in the search/match methods for phase identification. As noted below, our sample exhibits a preferred orientation, resulting in some changes in peak intensities compared to the calculated pattern.

TABLE I. Lattice parameters of niraparib tosylate monohydrate. Space group P-1

Figure 6. Comparison of the experimental synchrotron powder pattern of niraparib tosylate monohydrate Form I (298 K; black) with that calculated from the single-crystal structure of Mudda et al. (Reference Mudda, Devarapalli, Das, Lakkireddy, Reddy and Chennuru2024) (100 K; black) (calculated using the synchrotron wavelength of 0.819563(2) Å). Image generated using JADE Pro (MDI, 2024).

The root-mean-square Cartesian displacement of the non-H atoms in the Rietveld-refined and VASP-optimized cations is 0.117 Å, and in the anions is 0.109 Å (Figure 7). The absolute difference in the position of the water molecule O64 is 0.300 Å. 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 8. The atom names of Mudda et al. (Reference Mudda, Devarapalli, Das, Lakkireddy, Reddy and Chennuru2024) have been used. Although the displacement coefficients of the atoms in the piperidine ring are slightly larger than those in the other fragments, the disorder noted in the single-crystal structure is not obvious. The remaining discussion will emphasize the VASP-optimized structure of our study.

Figure 7. Comparison of the Rietveld-refined (red) and VASP-optimized (blue) structures of niraparib tosylate monohydrate Form I. The root-mean-square Cartesian displacements for the cation and the anion are 0.117 and 0.109 Å, respectively. Image generated using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock and Platings2020).

Figure 8. The asymmetric unit of niraparib tosylate monohydrate Form I, 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 and Platings2020).

All of the bond distances, bond angles, and most of the torsion angles fall within the normal ranges indicated by a Mercury Mogul Geometry check (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock and Platings2020). Only the C16B–C15B–C12–C11 torsion angle is flagged as unusual. This angle lies on the tail of a very broad distribution and represents the orientation of the piperidine ring with respect to the phenyl ring. Given that the piperidine ring is protonated and forms strong hydrogen bonds, we might expect the orientation of this ring to be slightly unusual.

Quantum chemical geometry optimization of the isolated cation (DFT/B3LYP/6-31G*/water) using Spartan ‘24 (Wavefunction, 2023) indicated that the observed conformation is 4.7 kcal/mol higher in energy than a local minimum, which has slightly different orientations of the phenyl and piperidine rings. The global minimum-energy conformation (MMFF force field) has a different orientation of the piperidine ring, showing that intermolecular interactions determine the solid-state conformation.

The crystal structure (Figure 9) consists of alternating double layers of cations and anions (including the water molecules) parallel to the ab-plane. Strong hydrogen bonds both parallel and perpendicular to the ab-plane link the fragments into a three-dimensional framework. The mean planes of the phenyl ring and the indazole ring system in the cation are approximately 9,7,1 and 9,6,−1, and the mean plane of the phenyl ring of the tosylate anion is approximately 0,3,7. The Mercury Aromatics Analyser indicates strong phenyl–phenyl interactions between the cations (distance = 3.63 and 3.77 Å), moderate interactions between the indazole ring systems (distance = 6.14 and 6.34 Å), and a weak phenyl–phenyl interaction of 7.77 Å. There are strong interactions between the anions (distance = 4.75 Å), as well as several weak cation–anion interactions.

Figure 9. The crystal structure of niraparib tosylate monohydrate Form I, viewed down the a-axis. Image generated using Diamond (Crystal Impact, Reference Putz and Brandenburg2023).

Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault Systèmes, 2023) indicates that angle distortion terms dominate the intramolecular energy, as might be expected for a molecule containing 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 discussed using the results of the density functional theory (DFT) calculation.

Hydrogen bonds are prominent in the crystal structure (Table II). The water molecule acts as a donor to two different O atoms of the tosylate anion and as an acceptor from one of the H atoms of the protonated piperidine ring. The other piperidyl N–H acts as a donor to the carbonyl group of another cation. Surprisingly, there are no cation–anion N–H···O hydrogen bonds. The amide group forms as a N–H···O hydrogen bond to the anion and an intramolecular N–H···N hydrogen bond to the indazole ring. The energies of the O–H···O hydrogen bonds were calculated using the correlation of Rammohan and Kaduk (Reference Rammohan and Kaduk2018) and the energies of the N–H···O hydrogen bonds using the correlation of Wheatley and Kaduk (Reference Wheatley and Kaduk2019). The hydrogen bonds form the piperidine ring and amide groups link four cations, two anions, and two water molecules into a cluster (Figure 10). Similar links from the other ends of the cations result in a complex chain along the b-axis (Figure 11), and these chains link to form a three-dimensional hydrogen-bonded framework. There are C–H···O hydrogen bonds between the cation and the anion and C–H···O and C–H···N hydrogen bonds between the anion and the cation.

TABLE II. Hydrogen bonds (CRYSTAL23) in the crystal structure of niraparib tosylate monohydrate. * = intramolecular.

Figure 10. The hydrogen-bonded clusters of niraparib cations, tosylate anions, and water molecules. Image generated using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock and Platings2020).

Figure 11. The complex hydrogen-bonded chains along the b-axis in niraparib tosylate monohydrate Form I. Image generated using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock and Platings2020).

As noted above, the Bravais–Friedel–Donnay–Harker (Bravais, Reference Bravais1866; Friedel, Reference Friedel1907; Donnay and Harker, Reference Donnay and Harker1937) algorithm suggests that we might expect elongated morphology for niraparib tosylate monohydrate, with <010> as the long axis. A fourth-order spherical harmonic model was included in the refinement. The texture index was 1.050(1), indicating that preferred orientation was slight in this rotated capillary specimen.