Structural Diversity of Ethinyl Estradiol Solvates

824 Crystal Growth & Design, Vol. 8, No. 3, 2008 Guguta et al.
Table 2. Crystal Data for the Investigated Pseudo-Polymorphs
hemihydrate methanolate ACN dioxane nitromethane ethanolate DMF
system monoclinic monoclinic orthorhombic orthorhombic monoclinic monoclinic monoclinic
space group C2 P2 1 P2 12 12 1 P2 12 12 1 P2 1 P2 1 P2 1
a (Å) 21.0163(7) 6.6449(7) 7.2604(5) 6.7531(9) 12.2381(5) 7.7250(4) 7.0732(3)
b (Å) 6.5877(5) 16.5425(14) 20.4231(17) 12.2300(14) 6.7999(7) 14.6810(13) 11.2715(6)
c (Å) 12.0946(5) 8.6480(4) 23.6356(16) 50.824(7) 21.4221(14) 23.9456(16) 30.645(2)
β (°) 91.099(3) 106.090(7) 90 90 94.878(4) 94.327(4) 94.895(6)
V (Å 3 ) 1674.18(16) 913.38(13) 3504.6(8) 4197.5(8) 1776.2(2) 2708.0(3) 2434.2(8)
Z′ 1 1 2 2 2 3 2
density (mg/m 3 ) 1.212 1.1942(2) 1.2013(1) 1.2168(3) 1.2225(1) 1.1868(1) 1.2076(1)
F(000) 660 356 1368 1664 704 1048.6 960
final R 0.0509 0.0412 0.0514 0.0565 0.0588 0.0643 0.1306
crystal dimensions
(mm 3 )
0.55 × 0.15
× 0.1
0.2 × 0.29
× 0.3
0.45 × 0.35
× 0.4
0.16 × 0.23
× 0.3
0.55 × 0.5
× 0.25
0.3 × 0.5
× 0.06
0.3 × 0.3
× 0.4
The crystal structures of three of them are described in the
literature, and the hemihydrate structure is available from the
Cambridge Structural Database (CSD). 3 In 1987, van Geerestein
reported the crystal structure of the hemihydrate form (CSD
refcode FISWIN). 4 It crystallizes in the monoclinic system with
space group C2 and cell parameters a ) 20.99(1) Å, b )
6.647(7) Å, c ) 12.124(2) Å, β ) 90.51°, and V ) 1691.4(8)
Å 3 . In 1989, Ishida et al. redetermined the hemihydrate structure
and also determined the structures of the methanolate and
acetonitrile (ACN) solvates. 5 The methanolate crystallizes in
the monoclinic system with space group P2 1 and cell parameters
a ) 6.685(2) Å, b ) 16.631(6) Å, c ) 8.665(3) Å, β )
106.27(5)°, and V ) 924.8(6) Å 3 . The ACN solvate crystallizes
in the orthorhombic system with space group P2 1 2 1 2 1 and cell
parameters a ) 20.531(9) Å, b ) 7.283(2) Å, c ) 23.815(9)
Å, and V ) 3561(2) Å 3 .
Here, we are presenting the crystal structures of four new
ethinyl estradiol solvates (the dioxane, nitromethane, ethanolate,
and N,N-dimethylformamide (DMF) solvates), the redeterminations
of the hemihydrate, methanol, and ACN solvates, and an
attempt to characterize an unstable solvate formed from toluene.
In order to understand the diversity in the solvate formation of
ethinyl estradiol, structural details like H-bond formation and
isostructurality were investigated.
Experimental Section
1. Material. Ethinyl estradiol was obtained from Organon commercial
supply. The preparation of the individual pseudo-polymorphic
forms of ethinyl estradiol is described below.
2. Preparation of the Solvates. A large number of solvents were
used for possible solvents formation, but only a few of them gave
solvate crystals or the already known hemihydrate form. All the obtained
solvates were prepared from saturated solutions of the commercially
available ethinyl estradiol in the corresponding solvents (methanol,
ACN, dioxane, nitromethane, DMF, ethanol, and toluene) that were
heated to temperatures about 10 °C below their boiling points and
cooled to room temperature.
3. Single-Crystal X-ray Diffraction. Crystals were mounted on
glass needles (Table 2). The intensity data were collected at -65 °C
on a Nonius Kappa CCD single-crystal diffractometer, using Mo KR
radiation and applying φ and ω scan modes. The intensity data were
corrected for Lorentz and polarization effects. A semi-empirical
multiscan absorption correction was applied (SADABS). 11 Direct
methods (CRUNCH) 9 and Patterson search methods (DIRDIF) 10 were
applied for structure determination. The structures were refined with
standard methods (refinement against F 2 of all reflections with
SHELXL97) 12 with anisotropic displacement parameters for the nonhydrogen
atoms. When possible, the hydrogen atoms were obtained
from a difference Fourier map and refined independently. In other cases,
they were placed at calculated positions and refined riding on the parent
atoms.
4. Hot-Humidity Stage X-ray Powder Diffraction (XRPD). The
XRPD employed for investigating the dehydration/desolvation behavior
of the pseudo-polymorphs was performed with a Bruker D8 AXS
Advance X-ray diffractometer configured with a hot-humidity stage
and controlled by an Ansyco humidity and temperature control unit.
The samples were scanned from 25 to 150 °C ina2θ range from 5° to
40°, with a 0.01° step size and a counting time of 0.1 s per step. Several
measurements were done with the same characteristics using a
Panalytical X′Pert Pro Diffractometer and an Anton Paar TTK 450 cell.
5. Differential Scanning Calorimetry (DSC). The DSC curves
were obtained by using a Mettler Toledo 822 differential scanning
Figure 2. Projection of the hemihydrate form along (a) the b-axis and (b) the c-axis.