Febuxostat solubilization and stabilization approach using solid dispersion method: Synergistic effect of dicalcium phosphate dehydrate and chitosan

Abstract

Drug solubilization studies are continuously being conducted. Febuxostat (FBX) has a low solubility in water. This study aims to develop a stable FBX-solid dispersion (SD) formulation using a solvent evaporation method. The solubilization strategy of FBX is to develope an optimal FBX-SD formulation by selecting a solubilizer and carrier through the screening method. The final selected solubilizer, macrogol 15 hydroxystearate and polyoxyl 15 hydroxystearate (Kolliphor® HS-15), is widely used in the pharmaceutical industry as a nonionic solubilizing and emulsifying agent and has low toxicity. Especially when commonly used in developing lipophilic drug formulations, it dissolves well in water and ethyl alcohol. The optimal composition ratio of the formulation (SD4) was FBX:HS-15®:granular dicalcium phosphate dehydrate (DCP-D): A synthetic magnesium aluminometasilicate (Neusilin®UFL2):chitosan = 1:3:3:1:1 (w/w) and showed 3.0-, 2.3-, and 1.1-fold higher dissolution (%) of FBX compared to that of the Feburic tab® in pH 1.2 media, distilled water (DW), and pH 6.8 buffer, respectively. Also, in vitro release and in vitro permeability in SD4 formulation showed higher than that of Feburic tab®. Based on its stability over 6 months, it was confirmed that chitosan acted as a stabilizer. Moreover, due to weak intermolecular interactions, FBX in the SD4 formulation was considered to exist in a mixed state of amorphous and crystalline FBX. In conclusion, the improved dissolution (%) and stability of FBX in SD4 formulation were secured through the synergistic effect of excipients.

Keywords: Febuxostat; Solid dispersion (SD); Synergistic effect.