II. EXPERIMENTAL

Citalopram hydrobromide was commercial reagent, purchased from Sigma-Aldrich (Lot No. SLBG5276V), 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 0.413 676 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 = 10.872, b = 33.274, c = 10.933 Å, β = 90.884°, V = 3955.0 Å³, and Z = 8 using N-TREOR in EXPO2013 (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013). Analysis of the systematic absences in EXPO2009 suggested the space group P2₁/c, which was confirmed by successful solution and refinement of the structure. A reduced cell search in the Cambridge Structural Database (Allen, Reference Allen2002) combined with the chemistry “C H Br F N O only” yielded no hits. A name search on “citalopram” yielded (S)-citalopram oxalate oxalic acid hydrate (Harrison et al., Reference Harrison, Yathirajan, Bindya and Anilkumar2007, CSD Refcode SETVUJ; de Diego et al., Reference de Diego, Bond and Dancer2011, WASGAA) and (RS)-citalopram oxalate oxalic acid (de Diego et al., Reference de Diego, Bond and Dancer2011, WASGEE, and WASGEE01), and a connectivity search yielded the same four Refcodes.

A citalopram cation was built and its conformation optimized using Spartan '14 (Wavefunction, 2013), and saved as a mol2 file. This 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). Using the cation and a Br atom as fragments, the structure was solved with DASH (David et al., Reference David, Shankland, van de Streek, Pidcock, Motherwell and Cole2006).

Rietveld refinement was carried out using GSAS (Toby, Reference Toby2001; Larson and Von Dreele, Reference Larson and Von Dreele2004). Only the 1.0–25.0° portion of the pattern was included in the refinement (d _min = 0.955 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) of the molecule. The Mogul average and standard deviation for each quantity were used as the restraint parameters. The rings C1–C6 (plus C7 and N8), C12–C16, C24 (plus F23), C25–C30 (plus C31 and N32), and C36–C41 (plus F48) were subjected to planar restraints. The restraints contributed 7.16% to the final χ ². Isotropic displacement coefficients were refined, grouped by chemical similarity. 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 (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 refinement yielded the residuals R _wp = 0.0792, R _p = 0.0649, and χ ² = 2.950, but there were several unusual torsion angles in the side chain of one of the molecules. The final refinement of 184 variables [started from the results of the density functional theory (DFT) calculation] using 24 141 observations (24 003 data points and 138 restraints) yielded the residuals R _wp = 0.0634, R _p = 0.0524, and χ ² = 1.860. The largest peak (1.16 Å from F48) and hole (1.65 Å from C19) in the difference Fourier map were 0.34 and −0.35 e(Å)⁻³, respectively. The Rietveld plot is included as Figure 2. The largest errors are in the positions and shapes of the low-angle peaks, and may indicate subtle changes in the sample during the measurement. The beamline staff indicated that the specimen darkened slightly during the measurement. A Le Bail fit yielded the residuals R _wp = 0.0573, R _p = 0.0469, and χ ² = 1.520. The Rietveld plot of the Le Bail fit is included as Supplementary Material. The largest errors in the fit were in the positions of certain strong low-angle peaks.

Figure 2. (Color online) The Rietveld plot for the refinement of citalopram hydrobromide. 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 > 8.7°, and by a factor of 20 for 2θ > 15.4°.

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 F was that of Nada et al. (Reference Nada, Catlow, Pisani and Orlando1993), and the basis set for Br was that of Peintinger et al. (Reference Peintinger, Vilela Oliveira and Bredow2012). 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, used 8 k-points and the B3LYP functional, and took ~5 days. The optimization changed the positions of one of the N–H hydrogen atoms significantly, resulting in a chemically more-reasonable structure.

III. RESULTS AND DISCUSSION

The powder pattern is similar enough to those reported by Ikemoto et al. (Reference Ikemoto, Arai and Igi2001) to conclude that this citalopram hydrobromide is the same material crystallized by Sumika Fine Chemicals Co. Ltd in European Patent application 1,152,000. The refined atom coordinates (from the present study) of citalopram hydrobromide are reported in Table I, and the coordinates from the DFT optimization in Table II. The root-mean-square deviation of the non-hydrogen atoms in the citalopram cations are 0.126 and 0.057 Å respectively (Figure 3). The largest differences are in the cationic side chain of molecule 1. This 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 4, and the crystal structure is presented in Figure 5.

Figure 3. (Color online) Comparison of the refined and optimized structures of citalopram hydrobromide. The Rietveld refined structure is in red, and the DFT-optimized structure is in blue. (a) Cation 1. (b) Cation 2.

Figure 4. (Color online) The molecular structure of citalopram hydrobromide, with the atom numbering. The atoms are represented by 50% probability spheroids.

Figure 5. (Color online) The crystal structure of citalopram hydrobromide, viewed down the c-axis. The hydrogen bonds are shown as dashed lines.

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). The root-mean-square displacement of the non-hydrogen atoms in the two independent cations is 0.500 Å (Figure 6). The largest differences are in the conformation of the cationic side chains and the fluorinated phenyl groups.

Figure 6. (Color online) Comparison of the two independent citalopram cations in the structure of citalopram hydrobromide. Cation 1 is in red and cation 2 is colored green.

Quantum mechanical conformation examinations (Hartree–Fock/6-31G*/water) using Spartan '14 indicated that the observed conformations of the citalopram cations are within 3.0 kcal mole⁻¹ in energy, and converge to the same minimum, which a molecular mechanics (MMFF) sampling of conformational space indicated was the minimum energy conformation.

Just as in this structure, there are two independent citalopram cations in the SETVUJ (Harrison et al., Reference Harrison, Yathirajan, Bindya and Anilkumar2007) and WASGAA (de Diego et al., Reference de Diego, Bond and Dancer2011) structures. The WASGEE and WASGEE01 structures (de Diego et al., Reference de Diego, Bond and Dancer2011) exhibit disorder, and will not be discussed further. The observed conformations in this structure are similar (but not identical) to the two conformations in SETVUJ and WASGAA.

Analysis of the contributions to the total crystal energy using the Forcite module of Materials Studio (Dassault, 2014) suggests that the intramolecular deformation energy is dominated by bond and angle distortion terms, as might be expected in a fused ring structure. The intermolecular energy contains significant contributions from both van der Waals and electrostatic contributions, which in this force-field-based analysis includes hydrogen bonds. The hydrogen bonds are better analyzed using the results of the DFT calculation (Table III).

As expected, both N–H cationic groups form discrete hydrogen bonds to the bromide cations, with graph sets D1,1(2) (Etter, Reference Etter1990; Bernstein et al., Reference Bernstein, Davis, Shimoni and Chang1995; Shields et al., Reference Shields, Raithby, Allen and Motherwell2000). A C–H⋯O hydrogen bond between a phenyl carbon and the ring oxygen O34 apparently also contributes significantly to the crystal energy.

The volume enclosed by the Hirshfeld surface (Figure 7; 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 955.26 Å³, 98.53% of 1/4 the unit-cell volume. The molecules are thus not tightly packed. The only significant close contacts (red in Figure 7) involve the hydrogen bonds.

Figure 7. (Color online) The Hirshfeld surface of citalopram hydrobromide. 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 platy morphology for citalopram hydrobromide, with {010} as the principal faces (Figure 8). A forth-order spherical harmonic preferred orientation model was included in the refinement; the texture index was only 1.002, indicating that preferred orientation was not significant in this rotated capillary specimen. The powder pattern of citalopram hydrobromide has been published in the ICDD Powder Diffraction File, entry 00-065-1422.

Figure 8. (Color online) The Bravais–Friedel–Donnay–Harker morphology of citalopram hydrobromide. The morphology is platy, with {010} as the major faces.