II. EXPERIMENTAL

“Rivastigmine tartrate” was a commercial reagent, purchased from Tocris Bioscience (Batch No. 1A/129729), 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 0.413 891 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 = 17.509, b = 8.358, c = 7.299 Å, β = 98.866°, V = 2190 Å³, and Z = 2 using Jade 9.5 (MDI, 2014) and N-TREOR in EXPO2009 (Altomare et al., Reference Altomare, Camalli, Cuocci, Giacovazzo, Moliterni and Rizzi2009). Analysis of the systematic absences in EXPO2009 suggested the space group P2₁, 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 chemistry “C H N O only” yielded 34 hits, but no structure for rivastigmine hydrogen tartrate. A name search on “rivastigmine” yielded (S)-rivastigmine (+)di(p-toluoyl)-D-tartaric acid (Chen et al., Reference Chen, Wen, Jin and Mi2009; CSD Refcode MAKKEQ), as did a connectivity search on rivastigmine.

A rivastigmine dication and a tartrate dianion were built and their conformations optimized using Spartan ‘14 (Wavefunction, 2013), and saved as mol2 files. These files were converted into Fenske–Hall Z-matrix files using OpenBabel (O'Boyle et al., Reference O'Boyle, Banck, James, Morley, Vandermeersch and Hutchison2011). Using these two fragments, the structure was solved with DASH (David et al., Reference David, Shankland, van de Streek, Pidcock, Motherwell and Cole2006). In the best solution, it was clear that N20 participated in a strong hydrogen bond, but that N14 did not. In addition, the tartrate oxygen atoms O48 and O51 were close (~2.50 Å), suggesting that they formed a very strong hydrogen bond, and that a hydrogen atom was present between them. The compound is thus not rivastigmine tartrate, but rivastigmine hydrogen tartrate, as expected from the patent literature.

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).

The C1–H10 benzene ring was refined as a rigid body. The y-coordinate of O11 was fixed to determine the origin. 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 6.78% 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 using Materials Studio 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. Initial positions of the active hydrogens were deduced from an analysis of potential hydrogen bonding patterns. 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 15-term diffuse scattering function to model the Kapton capillary and any amorphous component. The final refinement (started from the result of the density functional theory (DFT) calculation) of 95 variables using 24 050 observations (23 999 data points and 51 restraints) yielded the residuals R _wp = 0.1091, R _p  = 0.0915, and χ ² = 2.405. The largest peak (0.21 Å from N14) and hole (0.76 Å from C12) in the difference Fourier map were 0.62 and −0.50 eÅ⁻³, respectively. The Rietveld plot is included as Figure 2. The largest errors are in the shapes and positions of the low-angle peaks, and may indicate subtle changes in the sample during the measurement.

Figure 2. (Color online) The Rietveld plot for the refinement of rivastigmine hydrogen tartrate Form I. 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 scale as the other patterns, and the green line is the background. The vertical scale has been multiplied by a factor of 5 for 2θ > 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 8 k-points and the B3LYP functional, and took ~13 days on a 2.4 GHz PC.

III. RESULTS AND DISCUSSION

The experimental pattern corresponds to that of Form I reported by Benkic et al. (Reference Benkic, Smrkolj, Pecavar, Stropnik, Vrbinc, Vrecer and Pelko2008). The refined atom coordinates of rivastigmine hydrogen tartrate are reported in Table I, and the coordinates from the DFT optimization in Table II. The root-mean-square (rms) deviation of the non-hydrogen atoms in the rivastigmine is 0.206 Å (Figure 3), and the rms deviation in the tartrate is 0.091 Å. The largest difference (0.360 Å) is at the methyl group C17. This good 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 rivastigmine hydrogen tartrate. The Rietveld refined structure is in red, and the DFT-optimized structure is in blue.

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

Figure 5. (Color online) The crystal structure of rivastigmine hydrogen tartrate, viewed down the b-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 displacement coefficients of the methylethylamino group N14–C17 are large, perhaps indicating that this group is disordered. There is no obvious sign of disorder in the difference Fourier map, and since the refined structure was to be used as input to an (ordered) DFT calculation, any disorder was not pursued further.

A quantum mechanical conformation examination (Hartree-Fock/6-21G*/water) using Spartan ‘14 indicated that the observed conformation of the rivastigmine cation is ~6.9 kcal mole⁻¹ higher in energy than a local minimum. A molecular mechanics (MMFF) sampling of conformational space indicated that the solid state conformation is within 1.2 kcal mole⁻¹ of the minimum energy conformation, which is very different than the observed one. The rivastigmine cation appears to be flexible, and has distorted to accommodate the formation of hydrogen bonds. Compared with MAKKEQ (Chen et al., Reference Chen, Wen, Jin and Mi2009), both methylethylamine ends of the molecule have different conformations.

Analysis of the contributions to the total crystal energy using the Forcite module of Materials Studio (Accelrys, 2013) suggests that the intramolecular deformation energy contains small contributions from bond and angle distortion terms. The intermolecular energy is dominated by 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.

The un-ionized end of the hydrogen tartrate anions forms a very strong (17.4 kcal mole⁻¹) O48–H23⋯O51 hydrogen bond with the ionized end of another anion to form a chain (Table III). The graph set is C1,1(7) (Etter, Reference Etter1990; Bernstein et al., Reference Bernstein, Davis, Shimoni and Chang1995; Shields et al., Reference Shields, Raithby, Allen and Motherwell2000). The ammonium ion N20–H36 forms a strong discrete (graph set D1,1(2)) hydrogen bond with the carbonyl oxygen O47 of the un-ionized end of the tartrate anion. Both of these strong hydrogen bonds participate in a discrete pattern with graph set D3,3(12). These hydrogen bonds form a corrugated network in the bc-plane. Both hydroxyl groups of the tartrate anion form intramolecular O–H⋯O hydrogen bonds. Several C–H⋯O hydrogen bonds appear to contribute to the crystal energy.

The volume enclosed by the Hirshfeld surface (Figure 6; 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 516.62 Å³, 98.6% of half the unit cell volume. The molecules are thus not tightly packed. The only significant close contacts (red in Figure 6) involve the hydrogen bonds.

Figure 6. (Color online) The Hirshfeld surface of rivastigmine hydrogen tartrate. 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 rivastigmine hydrogen tartrate, with {100} as the principal faces (Figure 7). A second-order spherical harmonic preferred orientation model was included in the refinement; the texture index was 1.016, indicating that preferred orientation was not significant in this rotated capillary specimen. The powder pattern of rivastigmine hydrogen tartrate has been submitted to ICDD for inclusion in the PDF as entry 00-064-1501.

Figure 7. (Color online) The Bravais–Friedel–Donnay–Harker morphology of rivastigmine hydrogen tartrate Form I. The morphology is platy, with {100} as the major faces.