Development and evaluation of febuxostat solid dispersion through screening method

Abstract

Febuxostat (Febux) is a BCS II drug and has a very low solubility. In order to overcome this shortcoming, the purpose of study is to increase the in vitro dissolution (%) and drug release (%) of Febux by using a screening method. The Febux-SD formulation was prepared by screening solubilizers, pH agents, and carriers using with a solvent evaporation method. The novel Febux SD formulation was successfully developed. The dissolution (%) of Febux of optimal formulation (SD3) was higher than that of Feburic® tab in pH 1.2, distilled water (DW), and pH 6.8 buffer by 6.3-, 2.6-, and 1.1-fold, respectively, at 60 min. The in vitro drug release (%) and permeability (μg/cm²) of SD3 formulation were improved compared to those of Feburic® tab in the pH shifting method and PBS (7.4), respectively. The SD3 formulation was well maintained the stability for 6 months, and that of physicochemical properties were altered. In conclusion, the Febux solubilization study with meglumine was first attempted and successfully performed. Through the improved dissolution (%) of Febux, high bioavailability of SD3 formulation is expected in animal and human studies.

Keywords: Dissolution (%); Febuxostat; In vitro drug release; In vitro permeability; Meglumine; Stability.

Fig. 1

Pre-dissolution study of the B formulations. Pre-dissolution (%) of B formulations (B1–24) in distilled water was tested at 37 ± 1 °C for 60 min. Data are expressed as mean ± standard deviation (sd, n = 3).

Fig. 2

Pre-dissolution study of the F and SD (solid dispersion) formulations. Pre-dissolution (%) of F formulations (F1-12) in distilled water was tested at 37 ± 1 °C for 60 min (a). Pre-dissolution (%) of SD formulations (SD1-9) in distilled water was tested at 37 ± 1 °C for 60 min (b).

Fig. 3

Dissolution study of the optimal formulation. Dissolution (%) of pure Febux, Feburic® tab, physical mixture (PM3), and solid dispersion (SD3) was tested in pH 1.2 (a), distilled water (DW) (b), and pH 6.8 buffer (c) at 37 ± 1 °C for 60 min. Data are expressed as mean ± standard deviation (sd, n = 6).

Fig. 4

In vitro drug release test. The in vitro drug release test of pure Febux, Feburic® tab, physical mixture (PM3), and solid dispersion (SD3) was evaluated in pH shifting method. Data are expressed as mean ± standard deviation (sd, n = 3).

Fig. 5

In vitro permeability test. The in vitro permeability test of Feburic® tab, physical mixture (PM3), and solid dispersion (SD3) was evaluated with PBS (pH 7.4) in Franz diffusion cell system. Data are expressed as mean ± standard deviation (sd, n = 3).

Fig. 6

Physicochemical properties. DSC images of pure Febux, Feburic® tab, physical mixture (PM3), and solid dispersion (SD3) (a). FT-IR spectra of pure Febux, Feburic® tab, physical mixture (PM3), and solid dispersion (SD3) (b). PXRD images of pure Febux, Feburic® tab, physical mixture (PM3), and solid dispersion (SD3) (c).

Fig. 7

Stability test. Composition of Febux-solid dispersion (SD) formulations by excluding each variable to identify main factors. SD3 (Febux, meglumine, P407® and mannitol in a 1:2:1:1), SD3-1 (Febux, meglumine, P407® and mannitol in a 1:0:1:1), SD3-2 (Febux, meglumine, P407® and mannitol in a 1:2:0:1) and SD3-3 (Febux, meglumine, P407® and mannitol in a 1:2:1:0)(a). Moreover, stability test was performed for 6 months. The pre-dissolution (%) of Febux in SD3 formulations was performed in DW at 37 ± 1 ℃ at 60 min (b). Graph represents the mean ± standard deviation (n = 3).