I. INTRODUCTION
Solifenacin hydrogen succinate [C23H27N2O2(HC4H4O4)], marketed as VESIcare® by Astellas, is a medicine of the antimuscarinic class used for treating contraction of overactive bladder with urge incontinence. The systematic name (CAS Registry number 242478-38-2) is [(8R)-1-azabicyclo[2.2.2]oct-8-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate, hydrogen succinate salt. A two-dimensional molecular diagram of the cation is shown in Figure 1.
The molecular structure of the solifenacin cation.
The presence of high-quality reference powder patterns in the Powder Diffraction File (PDF; ICDD, Reference Kabekkodu2014) is important for phase identification, particularly by pharmaceutical, forensic, and law enforcement scientists. The crystal structures of a significant fraction of the largest dollar volume pharmaceuticals have not been published, and thus the calculated powder patterns are not present in the PDF-4 databases. Sometimes experimental patterns are reported, but they are generally of low quality. This structure is a result of collaboration among ICDD, Illinois Institute of Technology (IIT), Poly Crystallography Inc., and Argonne National Laboratory to measure high-quality synchrotron powder patterns of commercial pharmaceutical ingredients; include these reference patterns in the PDF; and determine the crystal structures of these active pharmaceutical ingredients (APIs).
Even when the crystal structure of an API is reported, the single-crystal structure was often determined at low temperature. Most powder measurements are performed at ambient conditions. Thermal expansion (often anisotropic) means that the peak positions calculated from a low-temperature single-crystal structure often differ significantly from those measured at ambient conditions. These peak shifts can result in failure of default search/match algorithms to identify a phase, even when it is present in the sample. High-quality reference patterns measured at ambient conditions are thus critical for easy identification of APIs using standard powder diffraction practices.
II. EXPERIMENTAL
Solifenacin hydrogen succinate was commercial “solifenacin succinate” reagent, purchased from Toronto Research Chemicals Inc. and 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 the Argonne National Laboratory using a wavelength of 0.413 685 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 using DICVOL06 (Boultif and Louer, Reference Boultif and Louer2004) on a primitive monoclinic unit cell having a = 6.473, b = 7.829, c = 23.847 Å, β = 90.2°, and V = 1208.5 Å3. The space group was suggested to be P21 or P21/m by ChekCell (Laugier and Bochu, Reference Laugier and Bochu2000). Assuming Z = 2 and 17 Å3/non-hydrogen atom yields 71 atoms cell−1. A 1:1 solifenacin:succinate ratio yields 35 atoms/asymmetric unit, or 70 atoms cell−1, suggesting P21 must be the correct space group on the basis of general multiplicity. Since the nitrogen in the isoquinoline ring is unlikely to be protonated, and the only other basic site is the nitrogen in the azabicyclo[2.2.2]octane, the unit-cell volume indicates that the compound is a hydrogen succinate salt. A reduced cell search in the Cambridge Structural Database (Allen, Reference Allen2002) yielded 52 hits, but no crystal structure for solifenacin hydrogen succinate.
A solifenacin molecule was extracted from the CSD entry DESNAR for solifenacin phosphoric acid (Naito, et al., Reference Naito, Yonetoku, Okamoto, Toyoshima, Ikeda and Takeuchi2005). Succinic acid from CSD Refcode SUCACB11 (Thalladi, et al., Reference Thalladi, Nüsse and Boese2000) was used as the succinate fragment. Both molecules were converted to Fenske–Hall Z-matrices using OpenBabel (O'Boyle et al., Reference O'Boyle, Banck, James, Morley, Vandermeersch and Hutchison2011). These two fragments were used to solve the structure using FOX (Favre-Nicolin and Černý, Reference Favre-Nicolin and Černý2002). The solution used 35 set of parallel tempering with 2 × 106 trials per run, with a maximum sinθ/λ = 0.35. Approximately one-third of the trials yielded solutions with cost functions ~25 000 (an exceptionally good/low value).
Rietveld refinement was carried out using GSAS (Larson and Von Dreele, Reference Larson and Von Dreele2004; Toby, Reference Toby2001). Only the 0.8°–25° portion of the pattern was included in the refinement. The C20–H30 phenyl group was refined as a rigid body. All other non-hydrogen 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 3.11% to the final χ 2. Isotropic displacement coefficients were refined, grouped by chemical similarity. Initial hydrogen positions were deduced by the analysis of potential hydrogen-bonding patterns. The hydrogen atoms were included in calculated positions, which were recalculated during the refinement. The U iso of each hydrogen atom was constrained to be 1.3× that of the heavy atom to which it is attached. The peak profiles were described using profile function #4, which includes the Stephens (Reference Stephens1999) anisotropic strain broadening model. The background was modeled using a three-term shifted Chebyshev polynomial and a six-term diffuse scattering (Debye) function, to model the scattering from the Kapton capillary and any amorphous component of the sample. A second-order spherical harmonic preferred orientation correction was included in the model, but the refined texture index was only 1.002. The final refinement of 107 variables using 24 285 observations (24 203 data points and 82 restraints) yielded the residuals R wp = 0.0835, R p = 0.0646, and χ 2 = 2.142. The largest peak (1.59 Å from C9) and hole (1.37 Å from C20) in the difference Fourier map were 0.48 and −0.52 e (Å−3), respectively. The Rietveld plot is included as Figure 2. The largest errors are in the shapes of some low-angle peaks, which may indicate subtle changes in the specimen during the measurement.
(Color online) The Rietveld plot for the refinement of solifenacin hydrogen succinate. The black crosses represent the observed data points, and the red line is the calculated pattern. The blue curve is the difference pattern, plotted at the same vertical scales as the other patterns. The vertical scale has been multiplied by a factor of 5 for 2 θ > 8.0°, and by a factor of 20 for 2θ > 13.0°.
A density functional geometry optimization (fixed experimental unit cell) was carried out using CRYSTAL09 (Dovesi et al., Reference Dovesi, Orlando, Civalleri, Roetti, Saunders and Zicovich-Wilson2005). The basis sets for the H, C, N, and O atoms were those of Gatti et al. (Reference Gatti, Saunders and Roetti1994). The calculation used eight k-points and the B3LYP functional.
III. RESULTS AND DISCUSSION
The refined atom coordinates of solifenacin hydrogen succinate are reported in Table I, and the coordinates from the density functional theory (DFT) optimization in Table II. The root-mean-square deviation of the non-hydrogen atoms is 0.078 Å, and the maximum deviation is 0.155 Å, at O61 in the succinate anion (Figure 3). The excellent agreement between the refined and optimized structures is strong evidence that the structure is correct (van de Streek and Neumann, Reference van de Streek and Neumann2014). The discussion of the geometry uses the DFT-optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 4, and the crystal structure is presented in Figure 5.
(Color online) Comparison of the refined and optimized structures of solifenacin hydrogen succinate. The experimental (Rietveld refined) structure is colored red, and the DFT-optimized structure is in blue.
(Color online) The molecular structure of solifenacin hydrogen succinate, with the atom numbering. The atoms are represented by 50% probability spheroids.
(Color online) The crystal structure of solifenacin hydrogen succinate, viewed down the a-axis.
Rietveld refined crystal structure of solifenacin hydrogen succinate.
Density functional theory optimized (CRYSTAL09) crystal structure of solifenacin hydrogen succinate.
All bond distances, angles, and torsion angles fall within the normal ranges indicated by a Mercury Mogul Geometry Check. Conformational analyses using Spartan ‘14 (Wavefunction, 2013) using both molecular mechanics and quantum chemical techniques (Hartree–Fock/3-21G/water) indicated that both the solifenacin cation and hydrogen succinate anion are close to their minimum-energy conformations (<10 kcal mol−1). An analysis of the contributions to the total crystal energy using the Forcite module of Materials Studio (Accelrys, 2013) suggests that bond and torsion distortion terms contribute little to the crystal energy. The energy appears to be dominated by angle distortion terms, as might be expected in such a fused-ring system. The hydrogen bonds are better analyzed using the results of the DFT calculation.
Two very strong hydrogen bonds are important to the crystal packing (Table III). The cationic N36–H45 makes a discrete D1,1(2) hydrogen bond to O61 of the ionized end of the succinate (Etter, Reference Etter1990; Bernstein et al., Reference Bernstein, Davis, Shimoni and Chang1995; Shields et al., Reference Shields, Raithby, Allen and Motherwell2000). The un-ionized O59–H67 end of the succinate forms a strong hydrogen bond with O62 of the ionized end to make a C1,1(7) chain parallel to the a-axis. The discrete hydrogen bonds lie on the sides of this chain. The result is a layer parallel to the ab-plane rich in hydrogen bonds. Halfway between these layers, the molecules meet in a herringbone stacking of aromatic rings (Figure 5). Two weak C–H···O hydrogen bonds also link the cations and anions.
Hydrogen bonds in solifenacin hydrogen succinate.
The Bravais–Friedel–Donnay–Harker (Bravais, Reference Bravais1866; Friedel, Reference Friedel1907; Donnay and Harker, Reference Donnay and Harker1937) morphology suggests that we might expect platy morphology for solifenacin hydrogen succinate, with {001} as the principal faces. A second-order spherical harmonic preferred orientation model was included in the refinement; the texture index was 1.002, indicating that preferred orientation was not significant for this rotated capillary specimen. The powder pattern of solifenacin hydrogen succinate is has been submitted to ICDD for inclusion in future releases of the PDF.
ACKNOWLEDGMENTS
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 Lynn Ribaud for his assistance in data collection.
SUPPLEMENTARY MATERIALS AND METHODS
The supplementary material for this article can be found at http://www.journals.cambridge.org/PDJ
