I. INTRODUCTION
Valbenazine (marketed under the trade name Ingrezza®) is used to treat tardive dyskinesia, a disorder that results in involuntary repetitive body movements. The systematic name (CAS Registry Number 1025504-45-3) is [(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl] (2S)-2-amino-3-methylbutanoate. A two-dimensional molecular diagram of valbenazine is shown in Figure 1.
Figure 1. The two-dimensional structure of valbenazine.
X-ray powder diffraction patterns of several polymorphs of valbenazine ditosylate and dihydrochloride are reported in International Patent Application WO 2017/075340 A1 (McGee et al., Reference McGee, Zook, Carr and Bonnaud2017; Neurocrine Biosciences) and the equivalent US application US 2017/0145008 A1. A powder pattern for valbenazine free base is reported in WO 2018/130345 A1 (Langes and Reissmann, Reference Langes and Reissmann2018; Sandoz); however, no crystal structure was reported.
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 (Gates-Rector and Blanton, Reference Gates-Rector and Blanton2019).
II. EXPERIMENTAL
Valbenazine was a commercial reagent, purchased from AchemBlock (Batch #8384), and was used as-received. The yellowish 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 beam line 11-BM (Antao et al., Reference Antao, Hassan, Wang, Lee and Toby2008; 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 0.459744(2) Å from 0.5 to 40° 2θ with a step size of 0.001° and a counting time of 0.1 s/step. The high-resolution powder diffraction data were collected using 12 silicon crystal analyzers that allow for high angular resolution, high precision, and accurate peak positions. A mixture of silicon (NIST SRM 640c) and alumina (NIST SRM 676a) standards (ratio Al2O3:Si = 2:1 by weight) was used to calibrate the instrument and refine the monochromatic wavelength used in the experiment.
The pattern was indexed using N-TREOR (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013) on a primitive orthorhombic unit cell with a = 5.26085, b = 17.77338, c = 26.16453 Å, V = 2446.5 Å3, and Z = 4. The suggested space group was P212121, 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 19 hits, but no structures of valbenazine or its derivatives.
The valbenazine molecule was downloaded from PubChem (Kim et al., Reference Kim, Chen, Cheng, Gindulyte, He, He, Li, Shoemaker, Thiessen, Yu, Zaslavsky, Zhang and Bolton2023) as Conformer3D_CID_24795069.sdf. It was converted to a *.mol2 file using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020), and to a Fenske–Hall Z-matrix using OpenBabel (O'Boyle et al., Reference O'Boyle, Banck, James, Morley, Vandermeersch and Hutchison2011). The crystal structure was solved using Monte Carlo simulated annealing techniques as implemented in FOX (Favre-Nicolin and Černý, Reference Favre-Nicolin and Černý2002), using (sinθ/λ)max = 0.3 Å−1.
Rietveld refinement (Figure 2) was carried out with GSAS-II (Toby and Von Dreele, Reference Toby and Von Dreele2013). Only the 1.7–22.0° portion of the pattern was included in the refinements (d min = 1.205 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 phenyl ring was restrained to be planar. The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault, 2022) using the Adjust Hydrogen tool. The Uiso of the heavy atoms were grouped by chemical similarity. The Uiso for the H atoms was 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 final Rietveld plot is shown in Figure 2. The largest features in the normalized error plot represent subtle shifts in peak positions and may represent change to the specimen during the measurement.
Figure 2. The Rietveld plot for the refinement of valbenazine. 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 (counts) has been multiplied by a factor of 10× for 2θ > 9.5°, and 40× for 2θ > 16.5°.
The crystal structure of valbenazine 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, 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 3 × 1 × 1 mesh, and took ~9.5 days. Single-point density functional theory calculations (fixed experimental cell) and population analysis were carried out using CRYSTAL23 (Erba et al., Reference Erba, Desmaris, 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 14 k-points and the B3LYP functional and took ~3.6 h.
III. RESULTS AND DISCUSSION
The powder pattern of this study is similar enough to that reported by Langes and Reissmann (Reference Langes and Reissmann2018; Figure 3) to conclude that they represent the same material. The material analyzed in this study is probably representative of that used in commerce. The root-mean-square Cartesian displacement of the non-H atoms in the Rietveld-refined and VASP-optimized molecules is 0.142 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 with the atom numbering is presented in Figure 5. The remainder of this discussion will emphasize the VASP-optimized structure.
Figure 3. Comparison of the synchrotron pattern of valbenazine (black) from this study to that reported by Langes and Reissmann (Reference Langes and Reissmann2018; 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 0.459744(2) Å using JADE Pro (MDI, 2023). Image generated using JADE Pro (MDI, 2023).
Figure 4. Comparison of the Rietveld-refined (red) and VASP-optimized (blue) structures of the valbenazine. The rms Cartesian displacement is 0.142 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 valbenazine, 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 of the bond distances and bond 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). The torsion angles involving rotation about the C7–C12 and C23–C25 bonds are flagged as unusual, but they lie in the middle of broad distributions with few hits. Quantum chemical geometry optimization of the isolated molecule (DFT/B3LYP/6-31G*/water) using Spartan ‘20 (Wavefunction, 2022) indicated that the solid-state conformation is 3.1 kcal/mol higher in energy than a local minimum, which has a very similar conformation. The global minimum energy conformation is 8.9 kcal/mol lower in energy and has different orientations of the methoxy and peripheral groups. The difference shows that, while weak, the hydrogen bonds affect the observed conformation.
The crystal structure (Figure 6) consists of discrete molecules. The mean plane of the molecule is approximately (8,−2,15). There are no obvious strong intermolecular interactions. Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault Systèmes, 2022) suggests that bond, angle, and torsion distortion terms contribute significantly to the intramolecular deformation energy, but that angle terms are the most important, as expected for a molecule containing a fused ring system. The intermolecular energy is dominated by electrostatic repulsions, with a significant contribution from van der Waals attractions.
Figure 6. The crystal structure of valbenazine, viewed down the a-axis. Image generated using Diamond (Crystal Impact, 2022).
There is only one classical hydrogen bond in the structure (Table I), from the amino group N6 to the ether oxygen atom O3. This hydrogen bond is weak, and its energy was calculated using the correlation of Wheatley and Kaduk (Reference Wheatley and Kaduk2019). Two intramolecular and one intermolecular C–H⋯O hydrogen bonds also contribute to the lattice energy.
TABLE I. Hydrogen bonds (CRYSTAL23) in valbenazine
a Intramolecular.
The volume enclosed by the Hirshfeld surface of valbenazine (Figure 7, Hirshfeld, Reference Hirshfeld1977; Spackman et al., Reference Spackman, Turner, McKinnon, Wolff, Grimwood, Jayatilaka and Spackman2021) is 603.16 Å3, 98.64% 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, at 20.4 Å3.
Figure 7. The Hirshfeld surface of valbenazine. 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 needlelike morphology for valbenazine, as expected for stacking of the molecules along the short <100> axis. No preferred orientation model was necessary, indicating that preferred orientation was not present in this rotated capillary specimen.
IV. DEPOSITED DATA
The powder pattern of valbenazine 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
Use of the Advanced Photon Source at Argonne National Laboratory was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. This work was partially supported by the International Centre for Diffraction Data. We thank Saul Lapidus for his assistance in the data collection.
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
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