Studies on cyclodextrin complexation of a poorly water soluble anti-hyperlipidemic drug, tablet formulation and characterization

The aims of the present study were to study the complexation of a poorly water-soluble anti-hyperlipidemic drug, bezafibrate (BF), with different cyclodextrins (CDs) and to formulate the complexes as tablet dosage form. Alpha-cyclodextrin (αCD), beta-cyclodextrin (βCD), gamma-cyclodextrin (γCD), and hydroxypropyl-β-cyclodextrin (HPβCD) were used for these purposes. Continuous stirring of drug with CD solutions followed by filtration and lyophilization was performed for the complexation. Initial studies showed BF solubility increase with all the CDs and equilibrium complexation period was 2 days. Experiments with aqueous medium of pH 7.0, 4.0, and 1.5 showed that acidic pH drastically reduced intrinsic solubility of BF but increases complexation efficiency. Experiment at 60˚C increased complexation solubility but reduced the stability of the complexes. Overall, βCD and HPβCD showed better solubilization than αCD and γCD. As solubility of HPβCD is much higher (> 33 g/100 mL water) than 25 mM tested, solubility of BF can presumably be increased proportionally. FTIR, DSC and SEM studies confirmed complexation of BF with all the CDs tested. The complexes of BF with βCD (BFβCD) and HPβCD (BFHPβCD) were formulated with two different directly compressible vehicles, namely, Avicel PH102 (microcrystalline cellulose) and DiPac (compressible sugar). Both types of tablets were of good quality when evaluated by quality attributes like thickness, diameter, hardness, friability, disintegration time and dissolution characteristics. In tablets, cyclodextrin played the dual roles of solubility enhancer and filler reducing the requirement of directly compressible vehicles. Lyophilized BFHPβCD produced very hard and non-friable tablets without negatively affecting disintegration or dissolution. Finally, dissolution test showed that complexation of bezafibrate with βCD and HPβCD exhibited an enhanced dissolution rate in comparison to pure drug. The same observation were also found with tablets; both Avicel and DiPac tablets with complexes showed superior dissolution profiles compared to tablets with pure drug or physical mixture of drug with cyclodextrins. These dissolution profiles were tested with similarity factor, f2, which showed the similarity of dissolution between βCD and HPβCD complexes or tablets containing these complexes but both were different from those of non-complex powder or tablet formulation.