I. INTRODUCTION
Atomoxetine is a drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD) in children age 6 and older, adolescents, and adults. It is marketed under the trade name Strattera by Eli Lilly and Company and is described as a norepinephrine re-uptake inhibitor. In 2011, it was among the top 200 s sold in the USA by total dollar value. The chemical formula for atomoxetine hydrochloride is C17H21NO•HCl and the IUPAC name for this molecule is (3R)-N-methyl-3-(2-methylphenoxy)-3-phenyl-1-propanamine hydrochloride (1:1). A two-dimensional structural diagram is shown in Figure 1.
Figure 1. Molecular structure of atomoxetine hydrochloride.
CSD entries YIGNEI and YIGNEI01 (Stephenson and Liang, Reference Stephenson and Liang2006) correspond to orthorhombic and monoclinic polymorphs of atomoxetine hydrochloride, but neither contains atom coordinates. The coordinates of the non-hydrogen atoms in the orthorhombic polymorph are reported in European Patent 1,798,215 (Malpezzi et al., Reference Malpezzi, Bedeschi and Pizzocaro2007).
The presence of high-quality reference powder patterns in the Powder Diffraction File (PDF) (ICDD, Reference Kabekkodu2013) 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 calculated powder patterns are not present in the PDF-4 Organics database. Sometimes experimental patterns are reported, but they are generally of low quality. Accordingly, a collaboration among the ICDD, IIT, Poly Crystallography Inc., and Argonne National Laboratory has been established 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 from those measured at ambient conditions. These peak shifts can result in failure of normal 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
The atomoxetine hydrochloride 99% was commercial material, purchased from AK Scientific, Inc. (Lot #LC24205), and was used as-received. The white powder was packed into a 1.5 mm diameter Kapton capillary, and rotated during the experiment at ~50 rotations per second. The powder pattern was measured at the beamline 11-BM (Lee et al., Reference Lee, Shu, Ramanathan, Preissner, Wang, Beno, Von Dreele, Ribaud, Jurtz, Antao and Toby2007; Wang et al., Reference Wang, Toby, Lee, Ribaud, Antao, Kurtz, Ramanathan, Von Dreele and Beno2008; Ribauld et al., Reference Ribaud, Kurtz, Antao, Jiao and Toby2008) of the Advanced Photon Source at the Argonne National Laboratory using a wavelength of 0.413 891 Å at 296 K from 0.5 to 50° 2θ with a step size of 0.001° and a counting time of 0.1 s per step. The pattern was indexed using Jade 9.5 (MDI, 2012). The systematic absences determined the space group to be P212121 (#19) (a common space group for chiral organic compounds), which was confirmed by successful solution and refinement of the structure. A protonated atomoxetine cation was built, and its conformation optimized, using Spartan ’10 (Wavefunction, 2011). It was saved as a mol2 file, and converted into a Fenske-Hall Z-matrix using OpenBabel (O'Boyle et al., Reference O'Boyle, Banck, James, Morley, Vandermeersch and Hutchison2011). The structure was solved with FOX (Favre-Nicolin and Černý, Reference Favre-Nicolin and Černý2002) using an atomoxetine cation and a chlorine atom as fragments.
The Rietveld refinement was carried out using GSAS (Larson and Von Dreele, Reference Larson and Von Dreele2004). Only the 2–25° portion of the pattern was included in the refinement. The phenyl groups were refined as rigid bodies, and 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 0.19% to the final χ 2. Isotropic displacement coefficients were refined, grouped by chemical similarity. 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 two-term shifted Chebyshev polynomial, and a six-term diffuse scattering function to describe the scattering from the Kapton capillary and any amorphous content of the sample. The final refinement of 54 variables using 22 999 observations yielded the residuals wRp = 0.1040, Rp = 0.0892, and χ 2 = 2.745. The largest peak and hole in the difference Fourier map were 0.57 and −0.59 eÅ−3, respectively. The largest peak lies in one of the C–C bonds of a phenyl ring, and the largest holes lie between pairs of hydrogen but not close to either of them. The Rietveld plot is included as Figure 2. The largest errors are in the positions and shapes of low-angle peaks, and probably indicate non-uniformity in the crystallites.
Figure 2. (Color online) Observed, calculated, and difference patterns of atomoxetine hydrochloride. The red crosses represent the observed data points, the green solid line the calculated pattern, and the magenta line the difference (observed – calculated) pattern. The vertical scale is multiplied by a factor of 5 above 9° 2θ and by a factor of 20 above 13.5°.
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 basis set for Cl was that of (Apra et al., Reference Apra, Causa, Prencipe, Dovesi and Saunders1993). The calculation used eight k-points and the B3LYP functional.
III. RESULTS AND DISCUSSION
The refined atom coordinates of orthorhombic atomoxetine hydrochloride are reported in Table I, and the coordinates from the density functional theory (DFT) optimization in Table II. The root-mean-square (rms) deviation of the non-hydrogen atoms is 0.07 Å, and the maximum deviation is 0.14 Å (Figure 3). The rms deviation of the non-hydrogen atoms in the DFT structure and that reported in Malpezzi et al. (Reference Malpezzi, Bedeschi and Pizzocaro2007) is 0.06 Å, and the maximum deviation is 0.12 Å. The discussion of the geometry uses the optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 4, and the crystal structure is presented in Figure 5.
Figure 3. (Color online) Comparison of the Rietveld-refined and DFT-optimized structures of atomoxetine hydrochloride. The RMS difference between the non-hydrogen atom positions is 0.07 Å.
Figure 4. (Color online) The asymmetric unit of atomoxetine hydrochloride, with the atom numbering.
Figure 5. (Color online) Crystal structure of atomoxetine hydrochloride. The view is approximately down the a-axis.
Table I. Rietveld refined structure of orthorhombic atomoxetine hydrochloride. Space group P212121 (#19), with a = 7.362 554(12), b = 13.340 168(27), c = 16.701 887(33) Å, V = 1640.421(5) Å3, and Z = 4.
Table II. Density functional optimized structure of atomoxetine hydrochloride. Space group P212121 (#19), with a = 7.362 554, b = 13.340 168, c = 16.701 887 Å, V = 1640.421 Å3, and Z = 4.
All bond distances, angles, and torsion angles fall within the normal ranges indicated by a Mercury Geometry Check. There are no voids in the crystal structure. The most prominent features of the crystal structure are the N–H···Cl hydrogen bonds (Table III). They form a zigzag chain parallel to the a-axis. The graph set (Etter, Reference Etter1990; Bernstein et al., Reference Bernstein, Davis, Shimoni and Chang1995; Motherwell et al., Reference Motherwell, Shields and Allen2000) is C1,2(4) > a < b. The symbol means that the pattern is a four-atom chain containing one acceptor and two donors; traversing the chain, one hydrogen bond is encountered donor-to-acceptor and the other is acceptor-to-donor. The Mulliken overlap populations indicate that these hydrogen bonds are normal strength. The average N···Cl in such hydrogen bonds in the CSD is 3.15(33) Å, so these hydrogen bonds are geometrically typical. The Mulliken overlap populations indicate that none of the other potential short intermolecular contacts (such as C–H···Cl) represent real bonding interactions. Other than the hydrogen bonds, the crystal structure is dominated by van der Waals contacts.
Table III. Hydrogen bonds in orthorhombic atomoxetine hydrochloride.
The Bravais–Friedel–Donnay–Harker (Bravais, Reference Bravais1866; Friedel, Reference Friedel1907; Donnay and Harker, Reference Donnay and Harker1937) crystal morphology is not especially anisotropic. There might be a slight tendency to form needles with 〈100〉 as the long axis, or plates with {01-1} as the principal faces. We would not expect preferred orientation to be significant for this compound.
The powder pattern of atomoxetine hydrochloride has been submitted to the ICDD for inclusion in future releases of the PDF.
ACKNOWLEDGMENTS
Use of the Advanced Photon Source at the Argonne National Laboratory was supported by the US 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, and Silvina Pagola for her participation in the early stages of this project.
