The first single-crystal XRD-based structure of enantiopure (R)-baclofen, a commonly used spasmolytic drug, without any co-crystallized molecules is reported in this article.
Keywords: crystal structure, (R)-baclofen, enantiopure, hydrogen bonds
Abstract
This article provides the first single-crystal XRD-based structure of enantiopure (R)-baclofen (form C), C10H12ClNO2, without any co-crystallized substances. In the enantiopure title compound, the molecules arrange themselves in an orthorhombic crystal structure (space group P212121). In the crystal, strong hydrogen bonds and C—H⋯Cl bonds interconnect the zwitterionic molecules.
Chemical context
(R)-Baclofen, an unnatural β-amino acid and artificial GABA receptor agonist, is a frequently used non-addictive drug to treat muscle spasticity (Dario & Tomei, 2004 ▸). Although baclofen is conventionally applied as a racemic mixture, only the (R)-enantiomer actually mediates a therapeutic effect (Olpe et al., 1978 ▸). In addition, baclofen has been recently approved in France as an alternative medication to treat alcohol dependence (Reade, 2021 ▸). Considering those new developments, the establishment of synthetic routes towards enantiopure (R)-baclofen were discussed recently (Córdova-Villanueva et al., 2018 ▸; Gendron et al., 2019 ▸).
Structural commentary
The molecular structure of the title compound is shown in Fig. 1 ▸. A partial packing diagram is shown in Fig. 2 ▸.
Figure 1.
The molecular structure of (R)-baclofen with displacement ellipsoids shown at the 50% probability level.
Figure 2.
Partial packing diagram of (R)-baclofen form C.
A prediction of crystal forms of the title compound was previously presented by Couvrat et al. (2021 ▸), which is based on detailed XRPD-studies and Rietveld refinement. Based on the available XRPD-data, three forms, A, B and C, were observed, of which form C is considered to be the most stable form at higher temperatures. The (R)-baclofen crystal analyzed in this work corresponds to the newly predicted polymorphic form C presented by Couvrat et al. (2021 ▸).
The molecules crystallize in a zwitterionic configuration, forming an ammonium and a carboxylate residue. The N-bound hydrogen atoms were located and refined freely. Bond lengths and angles fall into the typically observed ranges for organic molecules without any strain.
Supramolecular features
In the crystal of enantiopure (R)-baclofen form C, short N—H⋯O hydrogen bonds occur between the carboxylate and the ammonium group of the neighboring baclofen molecule. In parallel, additional hydrogen bonding occurs with neighboring baclofen molecules, resulting in a two-dimensional network parallel to (001), which yields a layered formation of baclofen molecules. Parallel to the hydrogen bonding, T-shaped C—H⋯π interactions occur along the layers of aromatic rings within the molecules [C9—H9 ⋯ Cg1viii= 2.74 Å; C6—H6 ⋯ Cg1ix= 3.24 Å; symmetry codes: (viii) −x + 2, y −
, −z +
; (ix) −x + 1, y +
, −z +
; Cg1 is the centroid of the C5–C10 benzene ring] . The interaction planes both form angles of 67° with the plane of the corresponding benzene ring (C5–C10).
The combination of both effects yields the observed structure of form C of (R)-baclofen. In contrast, the cohesion of the apparently less stable form A is ensured by π–π interactions.
Hydrogen-bond geometry data as well as non-classical C—H⋯Cl interaction data are summarized in Table 1 ▸.
Table 1. Hydrogen-bond geometry (Å, °).
| D—H⋯A | D—H | H⋯A | D⋯A | D—H⋯A |
|---|---|---|---|---|
| N1—H1A⋯O2i | 0.91 (3) | 1.91 (3) | 2.820 (2) | 176 (3) |
| N1—H1B⋯O2ii | 0.93 (3) | 1.80 (3) | 2.7149 (19) | 168 (2) |
| N1—H1C⋯O1iii | 0.85 (3) | 1.93 (3) | 2.775 (2) | 174 (3) |
| N1—H1B⋯Cl1iv | 0.93 (3) | 2.95 (2) | 3.3192 (14) | 105.3 (16) |
| C4—H4A⋯Cl1v | 0.99 | 2.73 | 3.6306 (19) | 152 |
| C4—H4B⋯Cl1vi | 0.99 | 2.81 | 3.5668 (19) | 134 |
Symmetry codes: (i) x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1; (ii) x, y+1, z; (iii) x-{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1; (iv) -x+{\script{3\over 2}}, -y+1, z-{\script{1\over 2}}; (v) -x+1, y+{\script{1\over 2}}, -z+{\script{3\over 2}}; (vi) -x+2, y+{\script{1\over 2}}, -z+{\script{3\over 2}}.
Database survey
Using the CSD database (version 5.42 updates 2 and 3; Groom et al., 2016 ▸), a search for the title compound’s structure and names used in this article was conducted with CONQUEST (version 2021.2.0; Bruno et al., 2002 ▸).
While the crystal structures of (R)- and (S)-baclofenium hydrochloride were reported in the early 1980s (Chang et al., 1981 ▸, 1982 ▸; refcodes: CRBMZB, CRBMZC10), studies on the phase behavior of pure baclofen have gained attention just recently. This is particularly relevant for the crystal structure of enantiomerically pure (R)-baclofen since X-ray powder diffraction studies were recently described by Couvrat et al. (2021 ▸). A total of three polymorphic forms (A, B and C) of (R)-baclofen were analyzed by X-ray powder diffraction, form C being identified as previously unknown. Based on this nomenclature, the crystal structure of form C is reported in this study. For the crystal structure of racemic baclofen, see Maniukiewicz et al. (2016 ▸; refcode: AQEKUE). A further array of racemic baclofenium co-crystal structures with various carboxylic acids were published by Báthori & Kilinkissa (2015 ▸; refcodes: LUSXAA, LUSXEE, LUSXII, LUSXUU, LUSXOO, LUSYAB) and Malapile et al. (2021 ▸; refcodes: LABJIL, LABJOR, LABJUX, LABKAE, LABKEI, LABKIM, LABKOS). Additionally, Gendron et al. (2019 ▸; refcode: WONSIE01) presented the crystal structure of (R)-baclofen hydrogenium maleate.
Synthesis and crystallization
Crystals of the title compound were grown from a saturated aqueous solution containing enantiopure (R)-baclofen, which was evaporated slowly by a stream of dry argon at 313 K. The purity of the (R)-baclofen was verified via 1H NMR. Enantiopure (R)-baclofen was purchased from abcr GmbH (Karlsruhe, Germany) under the name (R)-4-amino-3-(4-chlorophenyl)butanoic acid.
Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. The N-bound hydrogen atoms were found in difference syntheses, and refined freely. All C-bound H atoms were positioned geometrically and refined using a riding model, with C—H = 0.99 Å (methylene groups), 1.00 Å (methine groups) or 0.95 Å (aryl CH) and with U iso(H) = 1.2U eq(C) (methylene groups, aryl CH, methine groups). The structure was refined as a two-component inversion twin (BASF 0.04470).
Table 2. Experimental details.
| Crystal data | |
| Chemical formula | C10H12ClNO2 |
| M r | 213.66 |
| Crystal system, space group | Orthorhombic, P212121 |
| Temperature (K) | 123 |
| a, b, c (Å) | 6.8913 (5), 7.6898 (5), 19.7527 (14) |
| V (Å3) | 1046.75 (13) |
| Z | 4 |
| Radiation type | Mo Kα |
| μ (mm−1) | 0.34 |
| Crystal size (mm) | 0.27 × 0.19 × 0.16 |
| Data collection | |
| Diffractometer | Bruker D8 QUEST diffractometer |
| Absorption correction | Multi-scan (SADABS2016/2; Krause et al., 2015 ▸) |
| T min, T max | 0.662, 0.747 |
| No. of measured, independent and observed [I > 2σ(I)] reflections | 23624, 3796, 3447 |
| R int | 0.042 |
| (sin θ/λ)max (Å−1) | 0.756 |
| Refinement | |
| R[F 2 > 2σ(F 2)], wR(F 2), S | 0.033, 0.082, 1.07 |
| No. of reflections | 3796 |
| No. of parameters | 140 |
| H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
| Δρmax, Δρmin (e Å−3) | 0.36, −0.30 |
| Absolute structure | Refined as an inversion twin |
| Absolute structure parameter | 0.04 (6) |
Supplementary Material
Crystal structure: contains datablock(s) I. DOI: 10.1107/S2056989021012809/yz2013sup1.cif
Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989021012809/yz2013Isup2.hkl
Supporting information file. DOI: 10.1107/S2056989021012809/yz2013Isup3.cml
CCDC reference: 2125567
Additional supporting information: crystallographic information; 3D view; checkCIF report
Acknowledgments
Funding by the Central SME Innovation Programme (ZIM, project No. ZF4402103CR9) is gratefully acknowledged. The authors thank Isabel Schicht and Sandra Diederich for experimental and technical support.
supplementary crystallographic information
Crystal data
| C10H12ClNO2 | Dx = 1.356 Mg m−3 |
| Mr = 213.66 | Mo Kα radiation, λ = 0.71073 Å |
| Orthorhombic, P212121 | Cell parameters from 9871 reflections |
| a = 6.8913 (5) Å | θ = 2.8–33.0° |
| b = 7.6898 (5) Å | µ = 0.34 mm−1 |
| c = 19.7527 (14) Å | T = 123 K |
| V = 1046.75 (13) Å3 | Block, colourless |
| Z = 4 | 0.27 × 0.19 × 0.16 mm |
| F(000) = 448 |
Data collection
| Bruker D8 QUEST diffractometer | 3796 independent reflections |
| Radiation source: microfocus sealed tube | 3447 reflections with I > 2σ(I) |
| Detector resolution: 10.4167 pixels mm-1 | Rint = 0.042 |
| phi and ω scans | θmax = 32.5°, θmin = 2.1° |
| Absorption correction: multi-scan (SADABS2016/2; Krause et al., 2015) | h = −10→10 |
| Tmin = 0.662, Tmax = 0.747 | k = −11→11 |
| 23624 measured reflections | l = −29→29 |
Refinement
| Refinement on F2 | Hydrogen site location: mixed |
| Least-squares matrix: full | H atoms treated by a mixture of independent and constrained refinement |
| R[F2 > 2σ(F2)] = 0.033 | w = 1/[σ2(Fo2) + (0.0372P)2 + 0.2629P] where P = (Fo2 + 2Fc2)/3 |
| wR(F2) = 0.082 | (Δ/σ)max = 0.001 |
| S = 1.07 | Δρmax = 0.36 e Å−3 |
| 3796 reflections | Δρmin = −0.30 e Å−3 |
| 140 parameters | Absolute structure: Refined as an inversion twin |
| 0 restraints | Absolute structure parameter: 0.04 (6) |
| Primary atom site location: dual |
Special details
| Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Least-squares planes (x,y,z in crystal coordinates) and deviations from them (* indicates atom used to define plane) 3.7985 (0.0046) x + 6.4064 (0.0034) y + 0.9085 (0.0146) z = 5.2962 (0.0108) * 0.0030 (0.0012) C5 * -0.0067 (0.0012) C6 * 0.0039 (0.0013) C7 * 0.0025 (0.0013) C8 * -0.0062 (0.0014) C9 * 0.0035 (0.0014) C10 2.7365 (0.0020) H9_$8 3.2353 (0.0036) H6_$9 Rms deviation of fitted atoms = 0.0046 3.7985 (0.0045) x - 6.4064 (0.0034) y + 0.9085 (0.0145) z = 0.4604 (0.0136) Angle to previous plane (with approximate esd) = 67.162 ( 0.045 ) * -0.0030 (0.0012) C5_$8 * 0.0067 (0.0012) C6_$8 * -0.0039 (0.0013) C7_$8 * -0.0025 (0.0014) C8_$8 * 0.0062 (0.0014) C9_$8 * -0.0035 (0.0014) C10_$8 Rms deviation of fitted atoms = 0.0046 3.7985 (0.0045) x + 6.4064 (0.0034) y - 0.9085 (0.0145) z = 7.2622 (0.0039) Angle to previous plane (with approximate esd) = 66.899 ( 0.045 ) * -0.0030 (0.0012) C5_$6 * 0.0067 (0.0012) C6_$6 * -0.0039 (0.0013) C7_$6 * -0.0025 (0.0013) C8_$6 * 0.0062 (0.0014) C9_$6 * -0.0035 (0.0014) C10_$6 Rms deviation of fitted atoms = 0.0046 |
| Refinement. Refined as a 2-component inversion twin (BASF 0.04470). |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)
| x | y | z | Uiso*/Ueq | ||
| Cl1 | 0.90826 (7) | 0.16066 (7) | 0.88304 (2) | 0.02370 (11) | |
| N1 | 0.5842 (2) | 0.60260 (18) | 0.52352 (7) | 0.0134 (2) | |
| O1 | 0.76064 (19) | 0.02092 (17) | 0.54492 (7) | 0.0194 (3) | |
| O2 | 0.45342 (19) | −0.06602 (16) | 0.53636 (7) | 0.0178 (3) | |
| C1 | 0.5825 (3) | 0.0466 (2) | 0.54937 (7) | 0.0123 (3) | |
| C2 | 0.5085 (2) | 0.2255 (2) | 0.57066 (9) | 0.0147 (3) | |
| H2A | 0.4081 | 0.2098 | 0.6060 | 0.018* | |
| H2B | 0.4454 | 0.2809 | 0.5311 | 0.018* | |
| C3 | 0.6643 (2) | 0.3497 (2) | 0.59801 (8) | 0.0124 (3) | |
| H3 | 0.7818 | 0.3378 | 0.5687 | 0.015* | |
| C4 | 0.5966 (3) | 0.5388 (2) | 0.59429 (8) | 0.0139 (3) | |
| H4A | 0.4674 | 0.5490 | 0.6159 | 0.017* | |
| H4B | 0.6882 | 0.6130 | 0.6199 | 0.017* | |
| C5 | 0.7231 (2) | 0.3034 (2) | 0.67012 (8) | 0.0134 (3) | |
| C6 | 0.6148 (2) | 0.3582 (2) | 0.72594 (8) | 0.0160 (3) | |
| H6 | 0.5005 | 0.4248 | 0.7190 | 0.019* | |
| C7 | 0.6719 (3) | 0.3166 (2) | 0.79192 (8) | 0.0173 (3) | |
| H7 | 0.5986 | 0.3560 | 0.8297 | 0.021* | |
| C8 | 0.8370 (3) | 0.2172 (2) | 0.80119 (8) | 0.0176 (3) | |
| C9 | 0.9459 (3) | 0.1590 (3) | 0.74684 (9) | 0.0223 (4) | |
| H9 | 1.0580 | 0.0896 | 0.7540 | 0.027* | |
| C10 | 0.8886 (3) | 0.2037 (2) | 0.68165 (8) | 0.0200 (3) | |
| H10 | 0.9639 | 0.1655 | 0.6442 | 0.024* | |
| H1A | 0.701 (5) | 0.586 (4) | 0.5031 (16) | 0.044 (8)* | |
| H1B | 0.555 (4) | 0.721 (3) | 0.5245 (11) | 0.022 (6)* | |
| H1C | 0.490 (4) | 0.557 (4) | 0.5021 (14) | 0.029 (7)* |
Atomic displacement parameters (Å2)
| U11 | U22 | U33 | U12 | U13 | U23 | |
| Cl1 | 0.02181 (19) | 0.0335 (2) | 0.01578 (16) | 0.0041 (2) | −0.00328 (16) | 0.00057 (16) |
| N1 | 0.0134 (6) | 0.0094 (6) | 0.0174 (6) | 0.0003 (5) | −0.0012 (5) | 0.0000 (4) |
| O1 | 0.0152 (6) | 0.0173 (6) | 0.0258 (6) | 0.0016 (5) | 0.0031 (5) | −0.0055 (5) |
| O2 | 0.0167 (6) | 0.0096 (5) | 0.0272 (6) | −0.0011 (4) | −0.0027 (5) | −0.0011 (5) |
| C1 | 0.0156 (7) | 0.0097 (6) | 0.0117 (6) | 0.0006 (6) | 0.0003 (6) | 0.0009 (5) |
| C2 | 0.0147 (7) | 0.0091 (6) | 0.0202 (7) | 0.0006 (6) | −0.0025 (6) | −0.0018 (6) |
| C3 | 0.0130 (6) | 0.0099 (6) | 0.0144 (6) | 0.0013 (6) | −0.0013 (5) | −0.0010 (5) |
| C4 | 0.0159 (7) | 0.0104 (6) | 0.0155 (6) | 0.0015 (6) | −0.0012 (6) | −0.0012 (5) |
| C5 | 0.0133 (7) | 0.0100 (7) | 0.0169 (7) | 0.0006 (5) | −0.0013 (5) | −0.0010 (5) |
| C6 | 0.0146 (7) | 0.0146 (7) | 0.0187 (7) | 0.0028 (6) | 0.0015 (5) | 0.0012 (6) |
| C7 | 0.0186 (7) | 0.0171 (8) | 0.0163 (7) | 0.0010 (7) | 0.0029 (6) | 0.0004 (6) |
| C8 | 0.0188 (8) | 0.0188 (8) | 0.0151 (7) | 0.0001 (6) | −0.0025 (6) | 0.0002 (6) |
| C9 | 0.0200 (9) | 0.0276 (9) | 0.0194 (7) | 0.0115 (8) | −0.0034 (6) | 0.0002 (7) |
| C10 | 0.0188 (8) | 0.0243 (9) | 0.0169 (7) | 0.0090 (7) | −0.0015 (6) | −0.0030 (6) |
Geometric parameters (Å, º)
| Cl1—C8 | 1.7445 (17) | C3—H3 | 1.0000 |
| N1—C4 | 1.484 (2) | C4—H4A | 0.9900 |
| N1—H1A | 0.91 (3) | C4—H4B | 0.9900 |
| N1—H1B | 0.93 (3) | C5—C10 | 1.394 (2) |
| N1—H1C | 0.85 (3) | C5—C6 | 1.396 (2) |
| O1—C1 | 1.247 (2) | C6—C7 | 1.398 (2) |
| O2—C1 | 1.268 (2) | C6—H6 | 0.9500 |
| C1—C2 | 1.526 (2) | C7—C8 | 1.383 (3) |
| C2—C3 | 1.535 (2) | C7—H7 | 0.9500 |
| C2—H2A | 0.9900 | C8—C9 | 1.384 (2) |
| C2—H2B | 0.9900 | C9—C10 | 1.390 (2) |
| C3—C5 | 1.523 (2) | C9—H9 | 0.9500 |
| C3—C4 | 1.529 (2) | C10—H10 | 0.9500 |
| C4—N1—H1A | 109 (2) | C3—C4—H4A | 109.2 |
| C4—N1—H1B | 108.4 (14) | N1—C4—H4B | 109.2 |
| H1A—N1—H1B | 110 (3) | C3—C4—H4B | 109.2 |
| C4—N1—H1C | 112.1 (19) | H4A—C4—H4B | 107.9 |
| H1A—N1—H1C | 114 (2) | C10—C5—C6 | 118.31 (15) |
| H1B—N1—H1C | 104 (2) | C10—C5—C3 | 119.94 (14) |
| O1—C1—O2 | 124.61 (16) | C6—C5—C3 | 121.76 (14) |
| O1—C1—C2 | 119.43 (15) | C5—C6—C7 | 121.13 (15) |
| O2—C1—C2 | 115.95 (15) | C5—C6—H6 | 119.4 |
| C1—C2—C3 | 115.09 (14) | C7—C6—H6 | 119.4 |
| C1—C2—H2A | 108.5 | C8—C7—C6 | 118.76 (15) |
| C3—C2—H2A | 108.5 | C8—C7—H7 | 120.6 |
| C1—C2—H2B | 108.5 | C6—C7—H7 | 120.6 |
| C3—C2—H2B | 108.5 | C7—C8—C9 | 121.46 (16) |
| H2A—C2—H2B | 107.5 | C7—C8—Cl1 | 119.47 (13) |
| C5—C3—C4 | 110.37 (13) | C9—C8—Cl1 | 119.07 (14) |
| C5—C3—C2 | 111.71 (14) | C8—C9—C10 | 119.01 (16) |
| C4—C3—C2 | 111.18 (13) | C8—C9—H9 | 120.5 |
| C5—C3—H3 | 107.8 | C10—C9—H9 | 120.5 |
| C4—C3—H3 | 107.8 | C9—C10—C5 | 121.32 (16) |
| C2—C3—H3 | 107.8 | C9—C10—H10 | 119.3 |
| N1—C4—C3 | 112.15 (12) | C5—C10—H10 | 119.3 |
| N1—C4—H4A | 109.2 | ||
| O1—C1—C2—C3 | −11.2 (2) | C10—C5—C6—C7 | 0.9 (3) |
| O2—C1—C2—C3 | 169.78 (14) | C3—C5—C6—C7 | −179.16 (16) |
| C1—C2—C3—C5 | −76.36 (17) | C5—C6—C7—C8 | −1.0 (3) |
| C1—C2—C3—C4 | 159.86 (13) | C6—C7—C8—C9 | 0.1 (3) |
| C5—C3—C4—N1 | 165.95 (14) | C6—C7—C8—Cl1 | −178.86 (14) |
| C2—C3—C4—N1 | −69.51 (18) | C7—C8—C9—C10 | 0.8 (3) |
| C4—C3—C5—C10 | −138.39 (16) | Cl1—C8—C9—C10 | 179.81 (16) |
| C2—C3—C5—C10 | 97.37 (19) | C8—C9—C10—C5 | −0.9 (3) |
| C4—C3—C5—C6 | 41.7 (2) | C6—C5—C10—C9 | 0.0 (3) |
| C2—C3—C5—C6 | −82.53 (19) | C3—C5—C10—C9 | −179.86 (18) |
Hydrogen-bond geometry (Å, º)
| D—H···A | D—H | H···A | D···A | D—H···A |
| N1—H1A···O2i | 0.91 (3) | 1.91 (3) | 2.820 (2) | 176 (3) |
| N1—H1B···O2ii | 0.93 (3) | 1.80 (3) | 2.7149 (19) | 168 (2) |
| N1—H1C···O1iii | 0.85 (3) | 1.93 (3) | 2.775 (2) | 174 (3) |
| N1—H1B···Cl1iv | 0.93 (3) | 2.95 (2) | 3.3192 (14) | 105.3 (16) |
| C4—H4A···Cl1v | 0.99 | 2.73 | 3.6306 (19) | 152 |
| C4—H4B···Cl1vi | 0.99 | 2.81 | 3.5668 (19) | 134 |
Symmetry codes: (i) x+1/2, −y+1/2, −z+1; (ii) x, y+1, z; (iii) x−1/2, −y+1/2, −z+1; (iv) −x+3/2, −y+1, z−1/2; (v) −x+1, y+1/2, −z+3/2; (vi) −x+2, y+1/2, −z+3/2.
Funding Statement
This work was funded by Bundesministerium für Wirtschaft und Energie grant ZF4402103CR9 to Dr Jan von Langermann.
References
- Báthori, N. B. & Kilinkissa, O. E. Y. (2015). CrystEngComm, 17, 8264–8272.
- Bruker (2003). Apex, V7, 51A SADABS, SAINT, SHELXTL and SMART. Bruker AXS Inc., Madison, Wisconsin, USA.
- Bruno, I. J., Cole, J. C., Edgington, P. R., Kessler, M., Macrae, C. F., McCabe, P., Pearson, J. & Taylor, R. (2002). Acta Cryst. B58, 389–397. [DOI] [PubMed]
- Chang, C.-H., Yang, D. S. C., Yoo, C. S., Wang, B.-c., Pletcher, J. & Sax, M. (1981). Acta Cryst. A37, C71.
- Chang, C.-H., Yang, D. S. C., Yoo, C. S., Wang, B.-C., Pletcher, J., Sax, M. & Terrence, C. F. (1982). Acta Cryst. B38, 2065–2067.
- Córdova-Villanueva, E. N., Rodríguez-Ruiz, C., Sánchez-Guadarrama, O., Rivera-Islas, J., Herrera-Ruiz, D., Morales-Rojas, H. & Höpfl, H. (2018). Cryst. Growth Des. 18, 7356–7367.
- Couvrat, N., Sanselme, M., Poupard, M., Bensakoun, C., Drouin, S. H., Schneider, J.-M. & Coquerel, G. (2021). J. Pharm. Sci. 110, 3457–3463. [DOI] [PubMed]
- Dario, A. & Tomei, G. (2004). Drug Saf. 27, 799–818. [DOI] [PubMed]
- Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854.
- Gendron, F.-X., Mahieux, J., Sanselme, M. & Coquerel, G. (2019). Cryst. Growth Des. 19, 4793–4801.
- Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. [DOI] [PMC free article] [PubMed]
- Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3–10. [DOI] [PMC free article] [PubMed]
- Malapile, R. J., Nyamayaro, K., Nassimbeni, L. R. & Báthori, N. B. (2021). CrystEngComm, 23, 91–99.
- Maniukiewicz, W., Oracz, M. & Sieroń, L. (2016). J. Mol. Struct. 1123, 271–275.
- Olpe, H.-R., Demiéville, H., Baltzer, V., Bencze, W. L., Koella, W. P., Wolf, P. & Haas, H. L. (1978). Eur. J. Pharmacol. 52, 133–136. [DOI] [PubMed]
- Reade, M. C. (2021). JAMA, 325, 727–729. [DOI] [PubMed]
- Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8.
- Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8.
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Crystal structure: contains datablock(s) I. DOI: 10.1107/S2056989021012809/yz2013sup1.cif
Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989021012809/yz2013Isup2.hkl
Supporting information file. DOI: 10.1107/S2056989021012809/yz2013Isup3.cml
CCDC reference: 2125567
Additional supporting information: crystallographic information; 3D view; checkCIF report