Structural Diversity of Ethinyl Estradiol Solvates

826 Crystal Growth & Design, Vol. 8, No. 3, 2008 Guguta et al.
Figure 5. Projection of the dioxane form along (a) the a-axis and (b) the b-axis.
Figure 6. Projection of the nitromethane form along (a) the a-axis and (b) the b-axis.
lattices: participants in H-bonding networks, space fillers with
no strong interactions between solvent and solute molecules,
bridges between polar and apolar regions, and/or ligands
completing the coordination around a metal ion. The last
function will not be discussed here because it is not relevant
for ethinyl estradiol.
The crystal structures of the four new solvates obtained from
dioxane, nitromethane, ethanol, and DMF were determined from
single-crystal X-ray diffraction data. The most important crystal
data for the new solvates together with three redeterminations
are given in Table 2.
In 1989, Ishida et al. reported the existence of four pseudopolymorphs
of ethinyl estradiol: the hemihydrate, the methanolate,
the ACN, and the chloroform solvates, 5 and the crystal
structures of the hemihydrate, methanolate, and ACN forms
could be determined. The hemihydrate form was already
reported by van Geerestein two years earlier. 4 We redetermined
the crystal structures of the hemihydrate, the methanolate, and
the ACN forms at -65 °C, resulting in lower final R factors
(0.0509 for the hemihydrate, 0.0412 for the methanolate, and
0.0514 for ACN vs the values obtained by Ishida et al.: 5 0.057,
0.082, and 0.084, respectively). The main reason behind these
redeterminations was, however, the wish to obtain the positions
of the hydrogen atoms.
The structure determinations of the ethinyl estradiol solvates
showed a remarkable variety of structures with varying propensity
of H-bonding between the ethinyl estradiol and the
solvent guest molecules. Ethinyl estradiol forms different types
of H bonds, such as O-H ···O, N-H ···O, and C-H ···O.
H-bonds involving the -OH groups attached to C(3) and/or
C(17) of ethinyl estradiol and the corresponding solvent
molecules are found in all the investigated solvates (except the
toluate). Another type of H-bond appears between different
ethinyl estradiol molecules, namely, between the -OH groups
attached to C(3) and those attached to C(17). These H-bonds
are comparable to those found in the hemihydrate form. The
crystal structure of the hemihydrate form is presented in
Figure 2.
The water molecules in the hemihydrate structure form
H-bonds with four ethinyl estradiol molecules. For the methanolate
form, this is obviously impossible. The molecules of
ethinyl estradiol in the methanolate form are H-bonded in a
head-to-tail-to-methanol fashion forming a two-dimensional
network (Figure 3).