Structural Diversity of Ethinyl Estradiol Solvates

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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).
Structural Diversity of Ethinyl Estradiol Solvates Crystal Growth & Design, Vol. 8, No. 3, 2008 827 Figure 7. Projection of the DMF form along (a) the a-axis and (b) the b-axis. Figure 8. Projection of the ethanolate form along (a) the a-axis and (b) the b-axis. In the ACN solvate, the molecules of ethinyl estradiol are H-bonded in a head-to-head-to-tail fashion, forming a twodimensional network. The H-bonds are between the -OH groups attached to C(3) from different ethinyl estradiol molecules, as well as between the -OH groups attached to C(17) and C(3). The solvent molecule forms a H-bond between its N atom and the -OH group attached to C(17) of an ethinyl estradiol molecule (Figure 4). The dioxane solvate forms chains of ethinyl estradiol molecules in a head-to-tail fashion, with another molecule of ethinyl estradiol perpendicularly bonded to the chain (Figure 5). The space between neighboring chains of ethinyl estradiol molecules that are related by a two-fold screw axis is occupied by molecules of dioxane. One of those solvent molecules forms H-bonds with the -OH group attached to C(17). The second dioxane solvent molecule forms H-bonds with the ethinyl group of the ethinyl estradiol molecules (O ···H-C(51)). As Nangia and Desiraju concluded in 1999, 2 in most dioxane solvates, the acceptor O atom of the dioxane molecule is found in the neighborhood of a H donor. When being compared with the dioxane solvate, the nitromethane solvate shows similar chains of ethinyl estradiol molecules, and once again, other molecules of ethinyl estradiol are perpendicularly bonded to the chain (Figure 6). However, now, only one molecule of nitromethane occupies the space between neighboring chains. Nitromethane shows the same type of H-bonding to the -OH group of the ethinyl estradiol as dioxane does, but the ethinyl group is now involved in a H-bond
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Structural Diversity of Ethinyl Estradiol Solvates

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