Effects of polysorbate 80 on the in-vitro precipitation and oral bioavailability of halofantrine from polyethylene glycol 400 formulations in rats

Objectives The aim of this study was to examine the effects of formulations of polysorbate 80 (PS 80) and polyethylene glycol 400 (PEG 400) on the precipitation and oral bioavailability of the hydrophobic drug halofantrine. Methods The in-vitro dilution profile of the formulations was evaluated in phosphate buffer and in simulated intestinal fluids using a standard dissolution apparatus. The pharmacokinetic profile of the formulations was investigated in fasted rats at two dose levels, 5 and 17.5 mg/kg, with blood sampling by vein puncture in the tail. Key findings The solubility of halofantrine was found to be highest in PS 80, and in co-mixtures there was a correlation with the content of PS 80. The in-vitro dilution profile revealed precipitation of halofantrine when dissolved in pure PEG 400, although the precipitation was smaller in the simulated intestinal fluid. Addition of 25% PS 80 to the PEG 400 significantly decreased precipitation. The animals dosed with the PEG 400 formulation had significant lower bioavailability than the PS 80-PEG 400 co-mixtures, possibly due to halofantrine precipitation in the gastrointestinal tract. Conclusions Addition of PS80 to the formulation increased the bioavailability of halofantrine and the more compound, the more PS80 was needed to prevent precipitation.