A study of the complexation between danazol and hydrophilic cyclodextrin derivatives

Complexation between danazol, a steroid used for endometriosis, and both hydroxypropyl-beta-cyclodextrin (HPCD) and sulfobutyl ether-beta-cyclodextrin (SEE) was studied in solution and solid state. Complexation was evaluated in solution using solubility studies and proton magnetic resonance (H-1 NMR) spectroscopy, and in the solid state using x-ray diffraction, Fourier-transform infrared spectroscopy (FTIR), and dissolution studies. Solubility studies suggested the existence of a 1:1 complex between danazol and either HPCD or SEE. H-1 MMR showed that complexation occurs by inclusion of the isoxazole ring of danazol into the cyclodextrin cavity in both cases. Powder x-ray diffraction indicated that danazol existed in a crystalline noncomplexed form at low danazol-to-cyclodextrin ratios in the coprecipitates prepared by solvent evaporation method, while at higher ratios danazol existed in an amorphous completed form. This ratio was 1:10 w/w for HPCD and 1:20 for SBE; the higher ratio in the case of SBE is attributed to early precipitation of danazol from the solvent used for preparation. FTIR studies showed that the complexation was accompanied by a shift of the O-H stretching of danazol hydroxyl group to a higher frequency, which is attributed to the disruption of the intermolecular hydrogen bonding. The dissolution rate of danazol from HPCD coprecipitates was higher than crystalline danazol in aqueous-isopropanolic medium, while SBE coprecipitates showed reduced dissolution rates due to the low solubility of SBE in isopropanol. However, SBE coprecipitates showed higher dissolution rates in water than in the isopropanolic medium.