Inclusion complexes of the steroid hormones 17β-estradiol and progesterone with β- and γ-cyclodextrin hosts: syntheses, X-ray structures, thermal analyses and API solubility enhancements

Abstract

Overcoming the challenges of poor aqueous solubility of active pharmaceutical ingredients (APIs) is necessary to render them bioavailable. This study addresses the poor solubility of two potent steroid hormones, 17β-estradiol (BES) and progesterone (PRO), via their complexation with two water-soluble native cyclodextrins (CDs) namely β-CD and γ-CD. The hydrated inclusion complexes β-CD·BES, β-CD·PRO, γ-CD·BES and γ-CD·PRO were prepared via kneading and co-precipitation, and 1H NMR spectroscopic analysis of solutions of their pure complex crystals yielded the host–guest stoichiometries 2:1, 2:1, 1:1 and 3:2, respectively. Both powder X-ray diffraction (PXRD) and single-crystal X-ray diffraction (SCXRD) were employed for focused studies of the isostructurality of the CD complexes with known complexes and structural elucidation of the new complexes, respectively. SCXRD analyses of β-CD·BES, β-CD·PRO and γ-CD·PRO at 100(2) K yielded the first crystal structures of CD complexes containing the hormones BES and PRO, while the complex γ-CD·BES was readily shown to be isostructural with γ-CD·PRO by PXRD. Severe disorder of the encapsulated steroid molecules in the respective channels of the CD molecular assemblies was evident, however, preventing their modelling, but combination of the host–guest stoichiometries and water contents of the four hydrated inclusion complexes enabled accurate assignment of the chemical formulae of these ternary systems. Predicted electron counts for the complexed molecules BES and PRO correlated reasonably well with the complex compositions indicated by 1H NMR spectroscopy. Subsequent measurements of the aqueous solubilities of the four complexes confirmed significant solubility improvements effected by encapsulation of the steroids within the CDs, yielding solubility enhancement factors for BES and PRO in the approximate range 5–20.

17-β-Estradiol—β-Cyclodextrin Complex as Solid: Synthesis, Structural and Physicochemical Characterization

“…It has also been shown that the complexation of EST with this particular cyclodextrin decreased toxicity of the studied hormone [23]. Moreover, the combination of EST and ß-CD was found to improve the bioavailability of the API by increasing its solubility [28].…”

“…As was mentioned above, a single crystal analysis of the EST/ß-CD complex has been presented in a previous work [28] where only the host and the water oxygen atoms were located via the collected diffraction data using a Mo X-ray source, whereas the encapsulated hormone was not possible to be modeled as the residual electron density appearing within the host cavity was very low (∆ρ ≤ 1 e•Å 3 ) due to the high disorder of the included estradiol. Similar to that work, the EST/ß-CD crystal structure presented here was found to belong to the monoclinic system with space group C2, with roughly the same lattice parameters (Table 1).…”

“…The properties and structures of the complexes of EST with various CDs have been studied extensively for the last 30 years [20][21][22][23][24][25][26][27]. For example, in a recent work [28], single-crystal X-ray diffraction (SCXRD) results of the EST/ß-CD complex were presented, determining the unit cell and the crystallographic space group of the crystal structure. In this work, only the atomic coordinates of the host molecule were determined, whereas the encapsulated hormone was not possible to be modeled due to its high disorder.…”

A Review on Cyclodextrins/Estrogens Inclusion Complexes

“…Storing the complex for further use should be carried out at low temperature; for example, at 4 • C [98]. The current state of knowledge regarding the stoichiometry of the complexes indicates a 1:1 [98][99][100] value for HP-β-CD and β-CD or a 2:1 [99,100] for β-CD in the form of polymer-based materials. The 1:1 stoichiometry with β-CD was also shown to be stable in a molecular modeling study [101].…”

Solid Forms and β-Cyclodextrin Complexation of Oxymetholone and Crystal Structure of Metribolone

“…Some diffraction lines of the pure steroid and for the oxymetholone-beta-cyclodextrin complex appear by random coincidence at similar 2ϴ, but still they are slightly shifted, which suggests that the inclusion of the steroid, which is a small molecule, is easily fitted inside the cyclodextrin cavity. Some preparations of beta-cyclodextrin with other steroidal compounds such as methyltestosterone [38], estradiol [39], and progesterone [40] have been recently reported.…”