II. EXPERIMENTAL

Paliperidone palmitate was a commercial reagent, purchased from Toronto Research Chemicals (Lot #14-SDJ-99-1), 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 cycles s⁻¹. The powder pattern was measured at 295 K at beam line 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 0.413 342 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 indexed on a primitive monoclinic unit cell having a = 34.453, b = 10.097, c = 10.907 Å, β = 94.4°, V = 3783.3 Å³, and Z = 4 using Jade (MDI, 2014). 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 (consistent with a racemate), which was confirmed by successful solution and refinement of the structure. A reduced cell search in the Cambridge Structural Database (Groom et al., Reference Groom, Bruno, Lightfoot and Ward2016) combined with the chemistry “C H F N O only” yielded no hits.

The structure of the paliperidone molecule was taken from our previous determination (Kaduk et al., Reference Kaduk, Zhong, Gindhart and Blanton2016). The structure of palmitic acid was taken from CSD Refcode YEFWEM01 (Moreno-Calvo et al., Reference Moreno-Calvo, Gbabode, Cordobilla, Calvet, Cuevas Diarte, Negrier and Mondieig2009). The structure was solved with FOX (Favre-Nicolin & Černý, 2002). The maximum sinθ/λ used in the structure solution was 0.25 Å⁻¹. Initial attempts used separate paliperidone and palmitic acid fragments. These attempts yielded what was ultimately the correct orientation and position of the paliperidone, but a “flipped” orientation of the palmitate (the carboxylic acid end was pointed away from the paliperidone). The two fragments were joined to form the ester in Materials Studio (Dassault, 2014), and the geometry was optimized using both the Forcite module and Spartan ‘14 (Wavefunction, 2013). Both optimizations of the isolated molecule led to “curled up” conformations of the palmitate chain, so the chain torsion angles were manually reset to 180°. The resulting .mol2 file was converted into a Fenske-Hall Z-matrix file using OpenBabel (O'Boyle et al., Reference O'Boyle, Banck, James, Morley, Vandermeersch and Hutchison2011). In FOX, use of the default flexibility model of “Automatic from Restraints, relaxed” yielded solutions with a “curled up” palmitate chain, so the dihedral angles in the palmitate chain were restrained to 180°. Inclusion of these restraints yielded a chemically reasonable structure solution.

Initial refinement yielded the residuals R _wp = 0.1779, R _p = 0.1422, and χ ² = 12.89 (Figure 2). Comparison of the refined structure to a density functional theory (DFT)-optimized model revealed that the root-mean-square deviation of the non-hydrogen atoms in the paliperidone palmitate molecules was 1.09 Å (Figure 3). The poor agreement between the refined and optimized structures was evidence that the experimental structure was incorrect (van de Streek and Neumann, Reference van de Streek and Neumann2014). Additional cycles of structure solution using FOX yielded an improved model, in which the general orientation of the molecule was the same, but the orientation of the O6–C31 fused 5/6-ring portion of the molecule was rotated by ~180°. This model was the basis of a successful refinement and DFT optimization.

Figure 2.

(Colour online) The Rietveld plot for the incorrect refinement of paliperidone palmitate. The red crosses represent the observed data points, and the green line is the calculated pattern. The magenta curve is the difference pattern, plotted at the same vertical scale as the other patterns.

Figure 3.

(Colour online) Comparison of the incorrect refined and optimized structures of paliperidone palmitate. The Rietveld refined structure is in red, and the DFT-optimized structure is in blue.

Rietveld refinement was carried out using General Structure Analysis System (GSAS) (Toby, Reference Toby2001; Larson and Von Dreele, Reference Larson and Von Dreele2004). Only the 0.5–20.0° portion of the pattern was included in the refinement (d _min = 1.190 Å). The large size of the molecule and the limited data range made this a difficult refinement. In addition, the beamline staff noted peak shifts during the exposure, shifts which indicated change in the specimen during the measurement of the pattern. 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 Mogul average and standard deviation for each quantity were used as the restraint parameters. The restraints contributed 4.5% to the final χ ². The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio. The U _iso of each hydrogen atom was fixed at 1.3× that of the heavy atom to which it is attached. The peak profiles were described using profile function #4 (Thompson et al., Reference Thompson, Cox and Hastings1987; Finger et al., Reference Finger, Cox and Jephcoat1994), which includes the Stephens (Reference Stephens1999) anisotropic strain broadening model. The background was modeled using a three-term shifted Chebyshev polynomial, with a five-term diffuse scattering function to model the Kapton capillary and any amorphous component. The final refinement of 168 variables using 19 133 observations (19 002 data points and 131 restraints) yielded the residuals R _wp = 0.0783, R _p = 0.0664, and χ ² = 1.979. The largest peak (0.68 Å from C15) and hole (1.35 Å from C2, near the center of the C₄N₂ ring) in the difference Fourier map were 0.16 and −0.16 eÅ⁻³, respectively. The Rietveld plot is included as Figure 4. The largest errors in the fit are in the shapes of some of the low-angle peaks, and may reflect the visible specimen decomposition.

Figure 4.

(Colour online) The Rietveld plot for the correct refinement of paliperidone palmitate. The red crosses represent the observed data points, and the green line is the calculated pattern. The magenta curve is the difference pattern, plotted at the same vertical scale as the other patterns. The vertical scale has been multiplied by a factor of 5 for 2θ > 1.0°, and by a factor of 40 for 2θ > 7.5°.

A density functional geometry optimization (fixed experimental unit cell) was carried out 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 that for F was that of Nada et al. (Reference Nada, Catlow, Pisani and Orlando1993). 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 ~151 h.

III. RESULTS AND DISCUSSION

The refined atom coordinates of paliperidone palmitate and the coordinates from the DFT optimization are reported in the Crystallographic Information Framework files (CIFs) attached as online Supplementary Material. The root-mean-square deviation of the non-hydrogen atoms in the paliperidone palmitate molecules is 0.165 Å (Figure 5), and the largest difference is 0.354 Å at C48, the end of the palmitate chain. The excellent agreement between the refined and optimized structures is evidence that the experimental structure is correct (van de Streek and Neumann, Reference van de Streek and Neumann2014). This discussion uses the DFT-optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 6, and the crystal structure is presented in Figure 7.

Figure 5.

(Colour online) Comparison of the correct refined and optimized structures of paliperidone palmitate. The Rietveld refined structure is in red, and the DFT-optimized structure is in blue.

Figure 6.

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

Figure 7.

(Colour online) The crystal structure of paliperidone palmitate, viewed down the b-axis.

Almost 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., Reference Macrae, Bruno, Chisholm, Edington, McCabe, Pidcock, Rodriguez-Monge, Taylor, van de Streek and Wood2008). Only the C21–C22–C25–N10, C21–C22–C25–C26, C23–C22–C25–N10, and C23–C22–C25–C26 torsion angles are flagged as unusual, and they lie on the tails of the distributions of similar torsion angles. These angles represent the orientation of two portions of the paliperidone fragment. The paliperidone fragment in paliperidone palmitate has a different conformation than that in paliperidone (Kaduk et al., Reference Kaduk, Zhong, Gindhart and Blanton2016) (Figure 8); the root-mean-square difference in the non-H atom positions is 1.877 Å. This difference can be decreased to 0.28 Å by allowing flexibility in Mercury (Figure 9). Quantum chemical geometry optimizations (DFT/B3LYP/6-31G*/water) using Spartan ‘16 (Wavefunction, 2017) indicated that the observed conformation of paliperidone in paliperidone palmitate is <0.4 kcal mole⁻¹ lower in energy than that in paliperidone itself. The molecule is apparently fairly flexible. Both molecular mechanics and quantum conformational analyses indicated that the global minimum energy conformation is more compact, and that intermolecular interactions are important in determining the solid state conformation.

Figure 8.

(Colour online) The conformations of paliperidone (green) and the paliperidone fragment in paliperidone palmitate (red).

Figure 9.

(Colour online) The conformations of paliperidone (green) and the paliperidone fragment in paliperidone palmitate (red), after adjustment by the “flexibility” option in the Molecule Overlay module of Mercury.

The C–C–C–C torsion angles in the palmitate side chain are all nearly trans (180°), but indicate slight twists of the chain at low carbon numbers (close to the carboxyl group) and high carbon numbers (at the end of the chain) (Figure 10). The torsion angles increase with carbon number. Such twists in hydrocarbon chains have been observed in other systems (Nasrullah et al., Reference Nasrullah, Piranian, McCarthy and Kaduk2012).

Figure 10.

The C–C–C–C torsion angles in the palmitate chain of paliperidone palmitate.

Analysis of the contributions to the total crystal energy using the Forcite module of Materials Studio (Dassault, 2014) suggests that angle, bond, and torsion distortion terms are significant in the intramolecular deformation energy. The intermolecular energy contains significant contributions from van der Waals and 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.

As expected (since there are no normal hydrogen bond donors in the molecule), only C–H⋅⋅⋅O hydrogen bonds contribute to the crystal energy (Table I). The C3–H95⋅⋅⋅O37 and C13–H103⋅⋅⋅O5 hydrogen bonds are intramolecular, and probably help determine the conformation of the molecule. A short H81⋅⋅⋅H49 distance of 2.346 Å, with a Mulliken overlap population of 0.015 e, may indicate an additional intermolecular interaction.

Table I.

Hydrogen bonds in paliperidone palmitate.

^a Intramolecular.

The volume enclosed by the Hirshfeld surface (Figure 11; Hirshfeld, Reference Hirshfeld1977; McKinnon et al., Reference McKinnon, Spackman and Mitchell2004; Spackman and Jayatilaka, Reference Spackman and Jayatilaka2009; Wolff et al., Reference Wolff, Grimwood, McKinnon, Turner, Jayatilaka and Spackman2012) is 930.18 Å³, 98.5% of 1/4 the unit-cell volume. The molecules are thus not tightly packed. Some of the significant close contacts (red in Figure 11) involve the hydrogen bonds, while others indicate other close contacts.

Figure 11.

(Colour online) The Hirshfeld surface of paliperidone palmitate. 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 severe platy morphology for paliperidone palmitate, with {100} as the principal faces. An eighth-order spherical harmonic preferred orientation model was included in the refinement; the texture index was 1.019, indicating that preferred orientation was not significant in this rotated capillary specimen. The powder pattern of paliperidone palmitate is included in the Powder Diffraction File as entry 00-066-1614.

We have been told that the crystal structure of paliperidone palmitate has been determined using single-crystal techniques, but is unpublished. We look forward to its publication, so that those results can be compared with those obtained in this study.