CHARACTERIZATION AND BIOAVAILABILITY OF DANAZOL-HYDROXYPROPYL BETA-CYCLODEXTRIN COPRECIPITATES

Danazol, a steroid with very low aqueous solubility and poor bioavaila bility, and its coprecipitates were characterized for solubility, diss olution rate and bioavailability. Solubility diagrams of danazol in aq ueous hydroxypropyl beta-cyclodextrin (HPCD) solutions and isopropanol /water solutions were constructed with concentration of HPCD solutions ranging between 0.65 and 65.0 mM. Coprecipitates of danazol and HPCD at ratios ranging from 1:1 to 1:10 were prepared by solvent evaporatio n method using ethanol and by freeze drying method. Solubility diagram s indicated the existence of a complex between danazol and HPCD, and s howed a remarkable increase in danazol solubility. Stability constants of the complex and thermodynamic parameters of complexation were calc ulated in both aqueous and aqueous / organic solvents; the presence of isopropanol appeared to have negative effect on the stability of the complex. Dissolution profiles of the coprecipitates demonstrated highe r dissolution rates than pure danazol. Characterization of coprecipita tes by DSC and X-ray diffraction techniques showed that danazol existe d almost exclusively in crystalline form in coprecipitates a low danaz ol to HPCD ratios; while at high ratios, danazol appeared to exist in a nan-crystalline form. No distinct differences in the product charact eristics could be attributed to the method of preparation. Oral bioava ilability of the coprecipitate (danazol: HPCD, 1:10) and a marketed da nazol were tested in Wistar rats in a two-way, randomized cross-over s tudy. The area under the curve (AUC) of plasma concentration versus ti me was significantly higher(P < 0.05) for the complex than the commerc ial formulation, with mean AUC value more than two-fold higher for the complex. The bioavailability of the coprecipitate relative to the com mercial formulation was calculated to be 237%. The peak plasma concent ration (C-max) of the coprecipitate was higher and the time to reach t he peak (T-max) was lower for the complex. The greater rate and extent of absorption of danazol from the complex makes it a formulation with the potential to decrease the oral dose of danazol. Absolute bioavail ability of the coprecipitate and commercial formulation was 14.2% and 6.2%, respectively.