Effect of surfactant on the in vitro dissolution and the oral bioavailability of a weakly basic drug from an amorphous solid dispersion

Abstract

This study aimed to investigate the effect of a surfactant on the liquid-liquid phase separation, dissolution, diffusion, and the oral bioavailability of a weakly basic drug (l-tetrahydropalmatine; l-THP) from an amorphous solid dispersion (ASD). The carrier used in the ASD was optimized by the application of casting film, solvent shift, and pH shift methods. The interaction between the optimized carrier (HPMCP) and l-THP was then evaluated by Fourier transform-infrared spectroscopy and powder X-ray diffraction. The impact of the surfactant on ASD prepared by the spray-drying method was evaluated by both in vitro and in vivo studies. The results of in vitro studies, including liquid-liquid phase separation, drug diffusion, and pH-shift dissolution, indicated that the addition of a surfactant at a certain concentration below critical micelle concentration to ASD caused the precipitation of and a reduction in the membrane diffusion of l-THP in pH 6.8. This observation was confirmed in an in vivo study in which the drug concentration of l-THP in rabbit plasma was determined by the LC-MS/MS analysis method. Then the absolute and relative bioavailability of l-THP was calculated from the obtained pharmacokinetic parameters. Specifically, the addition of 1.5% surfactant (Poloxamer 188) to the binary ASD decreased the relative bioavailability of l-THP by approximately 2.4 times compared with the original binary ASD. Besides, the study proved that l-THP had low absolute bioavailability (around 1.24%), and the application of binary ASD was meaningful in enhancing the oral bioavailability of l-THP by around 334.77% compared to the raw material. The study is expected to provide a better understanding of how different dosage forms influence the bioavailability of l-THP, thereby allowing the selection of the optimal approach for this weakly basic drug.

Keywords: Bioavailability; Diffusion; Dissolution; Liquid-liquid phase separation; Surfactant; l-tetrahydropalmatine;∙Amorphous solid dispersion.