supplementary materials


gw2140 scheme

Acta Cryst. (2013). E69, o1794-o1795    [ doi:10.1107/S1600536813030377 ]

A triclinic polymorph of (-)-(S)-N-benzyl-2-[(R)-6-fluoro­chroman-2-yl]-2-hy­droxy­ethanaminium bromide

Y. Rousselin, H. Laureano and A. Clavel

Abstract top

The title salt, C18H21FNO2+·Br-, determined at 115 K, crystallizes in the triclinic space group P1. The previously reported polymorph occurs in the monoclinic space group P21 and has two independent mol­ecules in the asymmetric unit [Peeters et al. (1993). Acta Cryst. C49, 2157-2160]. In the title molecule, the pyran rings adopt half-chair conformations. The absolute configuration is S for the hy­droxy-bearing C atom and R for the asymmetric C atom in the di­hydro­pyran unit. In the crystal, the components are linked by N-H...Br and O-H...Br hydrogen bonds, forming chains along the c-axis direction. The crystal studied was refined as an inversion twin.

Introduction top

The asymmetric unit of title compound is a key building block for the synthesis of dl-nebivolol. This active pharmaceutical ingredient is a highly cardioselective vasodilatory β-receptor blocker used in treatment of hypertension. The chemical structure of nebivolol contains four asymmetric carbon atoms (chiral centers), the combination of all the centers results in 16 theoretical isomers and the total number of isomeric structures is reduced to 10 due to the symmetry plane through the N atom of the molecule. All isomeric structures are currently known (Tuchalski et al. (2006), Rousselin et al. (2012)). This paper confirms absolute configuration of one possible amino inter­mediate formed during the synthesis of dl-nebivolol. This structure is a polymorphic form (Bernstein, 2002) of a previous structure determined by Peeters et al. (1993).

Experimental top

Synthesis and crystallization top

2-chloro-1-(6-fluoro-chroman-2-yl)-1-ethanol were prepared as enanti­opure products in order to obtain the 2-benzyl­amino-1-(6-fluoro-chroman-2-yl)-1-ethanol by addition of benzyl­amine (Jas et al. (2011)). A subsequent addition of (R)-2-chloro-1-((S)-6-fluoro-chroman-2-yl)-1-ethanol would then be used to yield the corresponding protected nebivolol. The crude 2-benzyl­amino-1-(6-fluoro-chroman-2-yl)-1-ethanol was then recrystallized at 60°C in a mixture of ethanol and aqueous hydro­bromic acid.

The X-ray, mass spectrometry and NMR analyzes was recorded in the "Pôle Chimie Moléculaire", the technological platform for chemical analysis and molecular synthesis (http://www.wpcm.fr) which relies on the Institute of the Molecular Chemistry of University of Burgundy and Welience"TM", a Burgundy University private subsidiary. The analytical results concerning identity (NMR and optical rotation) and purity (HPLC and chiral HPLC) are listed below. 1H and 13C NMR measurements were performed in deuterated DMSO on Bruker Avance III, recorded at 300 MHz and 75.5 MHz, respectively. DMSO-d6 has been used as inter­nal reference. Chemical shifts (δ) and coupling constants are reported respectively in p.p.m. and hertz (Hz). The optical rotation was measured using a UV Visible Perkin Elmer Lambda 12, polarimeter at 589 nm. High-resolution mass spectrometry (HRMS) was performed in ESI a positive mode. The infrared spectrum (IR) was generated by ATR using a Spectrometer Infrared Avatar 370. A scan range of 4000 - 400 cm-1 was used.

(S)-2-benzyl­amino-1-((R)-6-fluoro-chroman-2-yl)-1-ethanol characterization:

δ(1H, DMSO-d6, 300 MHz, ppm): 1.69 (1H, m); 2.04 (2H, m); 2.58 (1H, m); 2.74 (3H, m); 3.65 – 3.78 (1H, m); 3.73 (2H, s); 3.88 (1H, m); 5.00 (1H, bs); 6.68 (1H, m); 6.88 (2H, m); 7.17 – 7.37 (5H, m).

δ(13C DMSO-d6, 75.47 MHz, ppm): 22.1; 23.8; 51.3; 53.0; 70.7; 77.3; 113.5 (d, 22.5 Hz); 115.2 (d, 22.5 Hz); 117.2 (d, 8.3 Hz); 123.8 (d, 7.5 Hz); 126.4; 127.8; 128.0; 140.9; 150.6 (d, 2.3 Hz); 155.7 (d, 234 Hz).

HRMS (ESI) for C18H21FNO2[M+H]+ m/z =302.15508, found m/z = 302.1537.

IR (cm-1) 3137, 2821, 1489, 1215, 810.

Refinement top

Crystal data, data collection and structure refinement details are summarized in Table 1. Anisotropic thermal parameters were used for non-hydrogen atoms. All H atoms, on carbon atom or oxygen atom, were placed at calculated positions using a riding model with C—H = 1 Å (methine), 0.99 Å (methyl­ene), 0.95 Å (aromatic), N—H = 0.99 Å or O—H = 0.84 Å with Uiso(H) = 1.2Ueq(CH), Uiso(H) = 1.2Ueq(CH2), Uiso(H) = 1.2Ueq(NH) or Uiso(H) = 1.5Ueq(OH). TWIN/BASF refinement type was used to determine absolute configuration from anomalous scattering using the Flack method.

Results and discussion top

The asymmetric unit of the title compound, C18H21FNO2+.Br-, contains one molecule. Contrary to the previous structure (Peeters et al., 1993) which crystallized in monoclinic with P21 symmetry, we found a polymophic form which crystallize in triclinic with P1 symmetry. The overlay of the molecules obtained in two different crystal systems clearly shows that they possess the same conformation with RMSD of 0.1329 Å, 0.1088 Å and a maximum deviation of 0.2823 Å, 0.1789 Å. The pyran rings adopt half-chair conformations with total puckering amplitutdes QT of 0.5041 (28) (with Θ = 129.10 (33)° and φ = 84.59 (39)°) (Cremer & Pople, (1975)). The protonation of the amine is confimed by the distance C11—N1 and C12—N1 of 1.502 (3) and 1.513 (4) respectively. The structure is stabilized by a network of hydrogen bonds between N, O and Br atoms. The absolute configuration is R for the asymmetric C atom in the di­hydro­pyran ring and S for the hydroxyl-bearing C atom. Chains are formed in the c axis.

Concerning the crystal packing features, each aromatic group are parallel unlike the previously determined structure (Peeters et al., 1993) wherein aromatic rings between two adjacent molecules possess dihedral angle close to 35° and 55° respectively.

Related literature top

For the synthesis of the enantiopure title product, see: Jas et al. (2011). For studies of related isomers, see: Cini et al. (1990); Tuchalski et al. (2006, 2008); Rousselin et al. (2012). for the monoclinic polymorph, see: Peeters et al. (1993). The title compound is a key intermediate in the synthesis of the beta blocker dl-nebivolol [systematic name: 1-(6-fluorochroman-2-yl)-{[2-(6-fluorochroman-2-yl)-2-hydroxy-ethyl]amino}ethanol. For the pharmacological properties of nebivolol, see: Van Lommen et al. (1990). For puckering parameters, see: Cremer & Pople (1975). For background to polymorphism, see: Bernstein (2002).

Computing details top

Data collection: APEX2 (Bruker, 2012); cell refinement: SAINT (Bruker, 2012); data reduction: SAINT (Bruker, 2012); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

Figures top
[Figure 1] Fig. 1. View of the molecular structure of (I) with 50% probability displacement ellipsoids for the non-hydrogen atoms.
[Figure 2] Fig. 2. View of the hydrogen-bonding in (I). Dashed lines indicate O—H···Br and N—H···Br hydrogen bonds.
[Figure 3] Fig. 3. Packing features in (I).
(-)-(S)-N-Benzyl-2-[(R)-6-fluorochroman-2-yl]-2-hydroxyethanaminium bromide top
Crystal data top
C18H21FNO2+·BrV = 441.48 (3) Å3
Mr = 382.27Z = 1
Triclinic, P1F(000) = 196
a = 4.9248 (2) ÅDx = 1.438 Mg m3
b = 5.5117 (2) ÅMo Kα1 radiation, λ = 0.71073 Å
c = 16.3894 (7) ŵ = 2.35 mm1
α = 83.721 (2)°T = 115 K
β = 89.038 (2)°Prism, clear light colourless
γ = 86.765 (2)°0.25 × 0.2 × 0.2 mm
Data collection top
Nonius KappaCCD
diffractometer with APEXII detector
3903 independent reflections
Radiation source: X-ray tube, Siemens KFF Mo 2K-1803886 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.020
Detector resolution: 9 pixels mm-1θmax = 27.6°, θmin = 3.7°
CCD rotation images, thick slices scansh = 66
Absorption correction: multi-scan
(SADABS; Bruker, 2012)
k = 76
Tmin = 0.61, Tmax = 0.74l = 2121
10328 measured reflections
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.021 w = 1/[σ2(Fo2) + (0.0317P)2 + 0.0488P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.052(Δ/σ)max < 0.001
S = 1.11Δρmax = 0.37 e Å3
3903 reflectionsΔρmin = 0.18 e Å3
210 parametersAbsolute structure: Flack (1983); refined as an inversion twin
3 restraintsAbsolute structure parameter: 0.013 (7)
0 constraints
Crystal data top
C18H21FNO2+·Brγ = 86.765 (2)°
Mr = 382.27V = 441.48 (3) Å3
Triclinic, P1Z = 1
a = 4.9248 (2) ÅMo Kα1 radiation
b = 5.5117 (2) ŵ = 2.35 mm1
c = 16.3894 (7) ÅT = 115 K
α = 83.721 (2)°0.25 × 0.2 × 0.2 mm
β = 89.038 (2)°
Data collection top
Nonius KappaCCD
diffractometer with APEXII detector
3903 independent reflections
Absorption correction: multi-scan
(SADABS; Bruker, 2012)
3886 reflections with I > 2σ(I)
Tmin = 0.61, Tmax = 0.74Rint = 0.020
10328 measured reflectionsθmax = 27.6°
Refinement top
R[F2 > 2σ(F2)] = 0.021H-atom parameters constrained
wR(F2) = 0.052Δρmax = 0.37 e Å3
S = 1.11Δρmin = 0.18 e Å3
3903 reflectionsAbsolute structure: Flack (1983); refined as an inversion twin
210 parametersAbsolute structure parameter: 0.013 (7)
3 restraints
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refined as a 2-component inversion twin.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.0450 (9)0.1145 (8)0.4454 (2)0.0432 (10)
C20.1300 (8)0.3000 (9)0.4294 (2)0.0438 (11)
H20.19740.38100.47250.053*
C30.2056 (7)0.3656 (7)0.3481 (2)0.0336 (7)
H30.32600.49320.33480.040*
C40.1030 (6)0.2425 (5)0.28630 (16)0.0208 (5)
C50.0712 (6)0.0542 (6)0.30396 (17)0.0229 (6)
C60.1462 (7)0.0085 (7)0.3862 (2)0.0350 (8)
H60.26660.13560.40030.042*
C70.1764 (6)0.0806 (7)0.2368 (2)0.0220 (6)
H7A0.36730.02410.22460.026*
H7B0.17210.25800.25510.026*
C80.0012 (6)0.0345 (6)0.15966 (19)0.0155 (6)
H8A0.17750.12480.16760.019*
H8B0.09110.09320.11250.019*
C90.0379 (5)0.2363 (5)0.14248 (15)0.0135 (5)
H90.14480.32540.13900.016*
C100.2004 (5)0.3138 (5)0.06472 (15)0.0142 (5)
H100.23120.49170.06420.017*
C110.0363 (5)0.2836 (6)0.01119 (18)0.0122 (6)
H11A0.01660.11250.00920.015*
H11B0.13180.39110.01200.015*
C120.0371 (6)0.3492 (6)0.1649 (2)0.0174 (7)
H12A0.03000.18450.16810.021*
H12B0.12250.46620.16330.021*
C130.2086 (6)0.4206 (5)0.23948 (16)0.0186 (5)
C140.4109 (6)0.2578 (6)0.26486 (18)0.0263 (6)
H140.43970.10120.23490.032*
C150.5715 (8)0.3220 (8)0.3336 (2)0.0394 (8)
H150.71170.21070.34940.047*
C160.5283 (9)0.5446 (9)0.3784 (2)0.0438 (10)
H160.63580.58680.42600.053*
C170.3274 (12)0.7082 (9)0.3541 (2)0.0481 (13)
H170.29890.86340.38510.058*
C180.1655 (10)0.6482 (8)0.2847 (2)0.0332 (10)
H180.02770.76150.26850.040*
N10.2011 (4)0.3481 (4)0.08768 (13)0.0128 (4)
H1A0.35840.22870.08930.015*
H1B0.27250.51180.08590.015*
O10.1885 (4)0.3208 (4)0.20789 (11)0.0191 (4)
O20.4597 (3)0.1871 (4)0.06423 (12)0.0191 (4)
H2A0.44770.05740.04230.029*
F10.1223 (7)0.0501 (6)0.52531 (13)0.0673 (9)
Br10.56053 (2)0.82061 (2)0.92529 (2)0.02213 (8)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.055 (2)0.058 (3)0.0135 (14)0.0171 (19)0.0071 (14)0.0006 (14)
C20.058 (3)0.055 (3)0.0186 (15)0.016 (2)0.0064 (19)0.0170 (16)
C30.0379 (18)0.042 (2)0.0223 (15)0.0058 (15)0.0052 (13)0.0137 (14)
C40.0202 (13)0.0257 (14)0.0158 (12)0.0085 (10)0.0025 (10)0.0045 (10)
C50.0190 (13)0.0303 (15)0.0173 (13)0.0093 (11)0.0031 (10)0.0012 (11)
C60.0363 (18)0.043 (2)0.0228 (15)0.0080 (15)0.0072 (13)0.0047 (14)
C70.0181 (13)0.0259 (16)0.0207 (16)0.0041 (11)0.0036 (12)0.0049 (13)
C80.0139 (13)0.0169 (15)0.0157 (14)0.0014 (10)0.0005 (11)0.0009 (12)
C90.0117 (11)0.0151 (12)0.0142 (11)0.0001 (9)0.0005 (9)0.0038 (9)
C100.0106 (11)0.0166 (12)0.0161 (12)0.0021 (9)0.0005 (9)0.0042 (9)
C110.0065 (11)0.0168 (13)0.0135 (14)0.0025 (9)0.0012 (10)0.0017 (11)
C120.0136 (13)0.0244 (15)0.0152 (14)0.0036 (11)0.0040 (11)0.0055 (12)
C130.0214 (13)0.0216 (14)0.0140 (12)0.0088 (10)0.0044 (10)0.0022 (10)
C140.0285 (15)0.0325 (16)0.0190 (13)0.0058 (12)0.0027 (11)0.0060 (12)
C150.0361 (18)0.063 (3)0.0220 (15)0.0132 (17)0.0078 (13)0.0121 (16)
C160.050 (2)0.067 (3)0.0170 (14)0.034 (2)0.0022 (14)0.0008 (16)
C170.082 (3)0.037 (2)0.025 (2)0.030 (2)0.016 (2)0.0138 (18)
C180.047 (2)0.027 (2)0.0249 (19)0.0061 (16)0.0111 (16)0.0009 (15)
N10.0104 (10)0.0143 (10)0.0140 (10)0.0030 (8)0.0001 (8)0.0017 (8)
O10.0196 (9)0.0250 (10)0.0139 (8)0.0045 (7)0.0015 (7)0.0060 (7)
O20.0065 (8)0.0321 (11)0.0197 (9)0.0000 (7)0.0006 (7)0.0073 (8)
F10.101 (2)0.082 (2)0.0154 (10)0.0127 (17)0.0165 (12)0.0005 (11)
Br10.01948 (11)0.01430 (11)0.03333 (14)0.00276 (7)0.00045 (8)0.00482 (8)
Geometric parameters (Å, º) top
C1—C21.375 (7)C10—O21.421 (3)
C1—C61.360 (6)C11—H11A0.9900
C1—F11.372 (4)C11—H11B0.9900
C2—H20.9500C11—N11.502 (3)
C2—C31.392 (6)C12—H12A0.9900
C3—H30.9500C12—H12B0.9900
C3—C41.396 (4)C12—C131.503 (4)
C4—C51.387 (5)C12—N11.513 (4)
C4—O11.377 (3)C13—C141.392 (4)
C5—C61.403 (4)C13—C181.393 (5)
C5—C71.508 (5)C14—H140.9500
C6—H60.9500C14—C151.390 (4)
C7—H7A0.9900C15—H150.9500
C7—H7B0.9900C15—C161.367 (6)
C7—C81.525 (4)C16—H160.9500
C8—H8A0.9900C16—C171.384 (7)
C8—H8B0.9900C17—H170.9500
C8—C91.511 (4)C17—C181.399 (7)
C9—H91.0000C18—H180.9500
C9—C101.527 (3)N1—H1A0.9900
C9—O11.446 (3)N1—H1B0.9900
C10—H101.0000O2—H2A0.8400
C10—C111.524 (4)
C6—C1—C2123.4 (3)O2—C10—H10107.5
C6—C1—F1118.2 (4)O2—C10—C11112.2 (2)
F1—C1—C2118.4 (4)C10—C11—H11A109.6
C1—C2—H2121.0C10—C11—H11B109.6
C1—C2—C3118.1 (4)H11A—C11—H11B108.1
C3—C2—H2121.0N1—C11—C10110.3 (2)
C2—C3—H3120.3N1—C11—H11A109.6
C2—C3—C4119.4 (4)N1—C11—H11B109.6
C4—C3—H3120.3H12A—C12—H12B108.1
C5—C4—C3121.5 (3)C13—C12—H12A109.6
O1—C4—C3115.2 (3)C13—C12—H12B109.6
O1—C4—C5123.2 (3)C13—C12—N1110.4 (2)
C4—C5—C6118.2 (3)N1—C12—H12A109.6
C4—C5—C7121.0 (2)N1—C12—H12B109.6
C6—C5—C7120.8 (3)C14—C13—C12120.2 (3)
C1—C6—C5119.4 (4)C14—C13—C18119.1 (3)
C1—C6—H6120.3C18—C13—C12120.7 (3)
C5—C6—H6120.3C13—C14—H14119.6
C5—C7—H7A109.7C15—C14—C13120.7 (3)
C5—C7—H7B109.7C15—C14—H14119.6
C5—C7—C8109.8 (3)C14—C15—H15119.9
H7A—C7—H7B108.2C16—C15—C14120.3 (4)
C8—C7—H7A109.7C16—C15—H15119.9
C8—C7—H7B109.7C15—C16—H16120.2
C7—C8—H8A109.9C15—C16—C17119.7 (3)
C7—C8—H8B109.9C17—C16—H16120.2
H8A—C8—H8B108.3C16—C17—H17119.5
C9—C8—C7109.1 (3)C16—C17—C18120.9 (4)
C9—C8—H8A109.9C18—C17—H17119.5
C9—C8—H8B109.9C13—C18—C17119.3 (4)
C8—C9—H9108.7C13—C18—H18120.4
C8—C9—C10115.5 (2)C17—C18—H18120.4
C10—C9—H9108.7C11—N1—C12112.5 (2)
O1—C9—C8110.5 (2)C11—N1—H1A109.1
O1—C9—H9108.7C11—N1—H1B109.1
O1—C9—C10104.45 (19)C12—N1—H1A109.1
C9—C10—H10107.5C12—N1—H1B109.1
C11—C10—C9110.3 (2)H1A—N1—H1B107.8
C11—C10—H10107.5C4—O1—C9115.5 (2)
O2—C10—C9111.7 (2)C10—O2—H2A109.5
C1—C2—C3—C40.1 (5)C10—C9—O1—C4171.2 (2)
C2—C1—C6—C50.1 (6)C10—C11—N1—C12173.5 (2)
C2—C3—C4—C50.6 (5)C12—C13—C14—C15179.8 (3)
C2—C3—C4—O1179.8 (3)C12—C13—C18—C17179.5 (4)
C3—C4—C5—C60.9 (4)C13—C12—N1—C11178.6 (2)
C3—C4—C5—C7178.8 (3)C13—C14—C15—C161.5 (5)
C3—C4—O1—C9166.3 (2)C14—C13—C18—C170.4 (5)
C4—C5—C6—C10.6 (5)C14—C15—C16—C171.3 (6)
C4—C5—C7—C817.2 (4)C15—C16—C17—C180.6 (6)
C5—C4—O1—C914.1 (4)C16—C17—C18—C130.1 (7)
C5—C7—C8—C947.7 (3)C18—C13—C14—C151.0 (5)
C6—C1—C2—C30.4 (6)N1—C12—C13—C1472.8 (3)
C6—C5—C7—C8162.5 (3)N1—C12—C13—C18108.0 (3)
C7—C5—C6—C1179.1 (3)O1—C4—C5—C6179.5 (3)
C7—C8—C9—C10177.6 (2)O1—C4—C5—C70.8 (4)
C7—C8—C9—O164.1 (3)O1—C9—C10—C11168.4 (2)
C8—C9—C10—C1170.0 (3)O1—C9—C10—O266.1 (2)
C8—C9—C10—O255.4 (3)O2—C10—C11—N152.0 (3)
C8—C9—O1—C446.4 (3)F1—C1—C2—C3179.5 (3)
C9—C10—C11—N1177.2 (2)F1—C1—C6—C5179.8 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1A···Br1i0.992.403.306 (2)152
N1—H1B···Br1ii0.992.303.258 (2)162
O2—H2A···Br1i0.842.473.2198 (19)149
Symmetry codes: (i) x, y1, z1; (ii) x, y, z1.
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1A···Br1i0.992.403.306 (2)152.4
N1—H1B···Br1ii0.992.303.258 (2)162.4
O2—H2A···Br1i0.842.473.2198 (19)148.5
Symmetry codes: (i) x, y1, z1; (ii) x, y, z1.
Acknowledgements top

We thank Ms Marie-Jose Penouilh for the NMR spectra and for ESI mass spectra.

references
References top

Bernstein, J. (2002). In Polymorphism in Molecular Crystals. Oxford: Clarendon Press.

Bruker (2012). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.

Cini, M., Crotti, P. & Macchia, F. (1990). Tetrahedron Lett. 31, 4661–4664.

Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354–1358.

Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339–341.

Flack, H. D. (1983). Acta Cryst. A 39, 876–881.

Jas, G., Freifeld, I. & Kesseler, K. (2011). Patent WO 2011091968 (Corden PharmaChem GmbH).

Peeters, O. M., Blaton, N. M. & De Ranter, C. J. (1993). Acta Cryst. C49, 2157–2160.

Rousselin, Y., Bruel, A. & Clavel, A. (2012). Acta Cryst. E68, o3352.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.

Tuchalski, G., Emmerling, F., Gröger, K., Hänsicke, A., Nagel, T. & Reck, G. (2006). J. Mol. Struct. 800, 28–44.

Tuchalski, G., Hansicke, A., Reck, G. & Emmerling, F. (2008). Acta Cryst. E64, o54.

Van Lommen, G. R. E., de Bruyn, M. F. L. & Schroven, M. F. J. (1990). J. Pharm. Belg. 45, 355–360.