Lyophilization monophase solution technique for improvement of the physicochemical properties of an anticancer drug, flutamide

Flutamide (FLT), an anticancer drug for prostatic carcinoma, has poor aqueous solubility and low oral bioavailability. This study describes the ability of β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) to form complexes with flutamide with enhanced solubility and dissolution rate in vitro. FLT-CD lyophilized dispersions (LDs) were prepared via lyophilization monophase solution technique using tertiary butyl alcohol (TBA) as a cosolvent. FLT showed an AL-type phase solubility diagram consistent with a linear increase in drug solubility as a function of CD concentration. Gas chromatography indicated that the LDs contain 0.02-0.03% w/w residual TBA. Based on the data from differential scanning calorimetry (DSC) and X-ray diffractometry (XRD), FLT was fully amorphous in 1:5 FLT-HPβCD LD as indicated by complete disappearance of FLT endothermic and diffraction peaks. The Fourier transform infrared (FTIR) spectra indicated that a FLT-CD interaction took place in the lyophilized complex. The particle sizes of 1:1 FLT-βCD and FLT-HPβCD LDs were 0.92 and 0.82 μm, with a high surface area (484.55 and 705.68 m2/g) and porosity (769.46 and 1020.99 e-3ml/g), respectively. The dissolution rate of FLT from its CD complexes was enhanced significantly. After 30 min in 0.1 N HCl, about 73% and 86% of FLT were dissolved from 1:5 FLT-βCD and FLT-HPβCD LDs, respectively, compared to only 13.45% of pure drug. No endothermic peak corresponding to FLT melting was detected in 1:5 FLT-HPβCD LD after storage at 20 °C and 45% relative humidity for 90 days thus indicating the stability of this binary system. These data suggest that cyclodextrins might be useful adjuncts in preparation of immediate-release formulations of FLT. © 2009 Elsevier B.V. All rights reserved.