Dimethylated β-cyclodextrin inclusion complexes containing the guest steroid hormones progesterone and 17β-estradiol: syntheses, crystal structures, thermal analyses and steroid solubility enhancements

The aim of the present study was to complex the potent steroidal hormones progesterone (PRO) and 17β-estradiol (BES) with heptakis(2,6-di-O-methyl)-β-cyclodextrin (DIMEB), and to characterize the resulting complexes for assessment of their potential utility. Complex synthesis using co-precipitation methods yielded single crystals of the desired complexes, which were subsequently characterized by thermal analysis, single-crystal X-ray analyses and solubility measurements. ¹H NMR spectroscopy indicated 1:1 host–guest stoichiometries for both of the hydrated complexes DIMEB·PRO and DIMEB·BES. Thermal analysis showed that the dehydrated DIMEB·PRO complex remained intact up to a temperature of ∼180 °C, when complex decomposition commenced. However, following the dehydration of DIMEB·BES, loss of the guest BES occurred in the approximate range 180–325 °C. Major findings were evident from X-ray analyses, which revealed only a single mode of API inclusion in the DIMEB·PRO crystal, but instead, the relatively rare phenomenon of bimodal API inclusion within the crystal of DIMEB·BES. Measurements of complex dissolution in a biorelevant medium at 27 °C showed significant API solubility enhancements of ∼25-fold for PRO and ∼40-fold for BES as a result of their inclusion in DIMEB.

For the DIMEB·PRO complex, partial encapsulation of PRO in the guest cavity was evident, with guest orientation D-ring up. However the DIMEB·BES complex featured the unusual occurrence of bimodal inclusion manifested in a single crystal, with one of the two crystallographically independent DMB·BES complex units displaying partial guest inclusion and guest orientation D-ring up, while the other features full guest encapsulation, with guest orientation A-ring up. 

Alexios I. Vicatos, Zakiena Hoossen, Cesarina Edmonds-Smith and Mino R. Caira (2026) Dimethylated β-cyclodextrin inclusion complexes containing the guest steroid hormones progesterone and 17β-estradiol: syntheses, crystal structures, thermal analyses and steroid solubility enhancements. DOI: 10.1039/D5CE01106J