Supersaturated Liquid Formulation of Pazopanib Hydrochloride Loaded with Synergistic Precipitation Inhibitors

초록

This study aimed to develop a supersaturated liquid formulation (SSLF) to enhance the solubility and dissolution of pazopanib hydrochloride (PZH). SSLFs were prepared by a simple stirring method in a heated silicon oil bath (70 degrees C). PZH showed highly pH-dependent solubility (pH 1.2 > water >> pH 4.0 and pH 6.8) at 37 degrees C. The SSLF containing glycerol and polyvinylpyrrolidone K30 (PVP K30) increased PZH dispersion solubility (273.66 +/- 48.91 mu g/mL) at pH 6.8 by more than 50-fold compared with that of glycerol alone (<5 mu g/mL), and the PZH precipitate particle size was considerably small (<100 nm). Moreover, the dispersion solubility of PZH from SSLF containing additional propylene glycol (PG) increased to 364.41 +/- 2.47 mu g/mL. The optimized SSLF10 (PZH/glycerol/PG/PVP K30 = 10/50/20/20, w/w) exhibited a high dissolution rate at pH 4.0 (>90%) and 6.8 (>55%) until 360 min, whereas PZH powder and PZH glycerol solution showed pH-dependent, low dissolution rates (<10%) under similar conditions. The supersaturation ratio of SSLF10 was very high at 29.88 and 18.36 at pH 6.8 and 4.0, respectively, indicating a stable PZH supersaturation solution. In the transmission electron microscopy analysis, PVP K30 and PG in SSLF10 synergistically suppressed PZH precipitation and recrystallization with small amorphous particles (<200 nm). Therefore, SSLF10 would be a promising formulation with enhanced solubility and dissolution rates regardless of medium pH.

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