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

Abstract

Considerable ongoing research is aimed at enhancing the delivery of poorly soluble active pharmaceutical ingredients (APIs) via their complex formation with water-soluble cyclodextrin host compounds. 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 (DMB), 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 DMB·PRO and DMB·BES. Thermal analysis showed that the dehydrated DMB·PRO complex remained intact up to a temperature of ~180 degrees C, when complex decomposition commenced. However, following the dehydration of DMB·BES, loss of the guest BES occurred in the approximate range 180 - 325 degrees C. Major findings were evident from X-ray analyses, which revealed only a single mode of API inclusion in the DMB·PRO crystal, but instead, the relatively rare phenomenon of bimodal API inclusion within the crystal of DMB·BES. Measurements of complex dissolution in a biorelevant medium at 27 degrees C showed significant API solubility enhancements of ~25-fold for PRO and ~40-fold for BES as a result of their inclusion in DMB.