Inclusion complexes of the steroid hormones 1713-estradiol and progesterone with 13-and γ-cyclodextrin hosts: syntheses, X-ray structures, thermal analyses and API solubility enhancements

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, 1713-estradiol (BES) and progesterone (PRO), via their complexation with two water-soluble native cyclodextrins (CDs) namely 13-CD and gamma-CD. The hydrated inclusion com-plexes 13-CD center dot BES, 13-CD center dot PRO, gamma-CD center dot BES and gamma-CD center dot PRO were prepared via kneading and co-precipitation, and 1H NMR spectros-copic 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 13-CD center dot BES, 13-CD center dot PRO and gamma-CD center dot PRO at 100(2) K yielded the first crystal structures of CD complexes containing the hormones BES and PRO, while the complex gamma-CD center dot BES was readily shown to be isostructural with gamma-CD center dot 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 spectrosco-py. 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 approxi-mate range 5-20.

Automated summary

This study addresses the poor solubility of two potent steroid hormones by complexing them with water-soluble cyclodextrins. The structures and stoichiometries of the complexes were determined using various analysis methods. The aqueous solubilities of the complexes were significantly improved compared to the pure hormones.