Microenvironmental pH-modified solid dispersions to enhance the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate cancer drug: Preparation, characterization and evaluation in vivo

The aim of the present work was to design a pH-modified solid dispersion (pHM-SD) that can improve the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate cancer drug. To select the appropriate acidifiers, a solubility test was carried out first. Solid dispersions (SDs) containing GT0918 and polyvinylpyrrolidone (PVP) were prepared using a solvent evaporation method and were characterized using dissolution studies in different media. The solid states of the SDs were investigated using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transformed infrared spectroscopy (FTIR). The in vivo pharmacokinetics of the pHM-SDs tablets were also studied in beagle dogs compared to the conventional tablets. The optimized pHM-SD (GT0918/PVP/citric acid, 1:2:2 weight ratio) exhibited a significant improvement in the dissolution behavior compared to both the physical mixture and the binary SDs. Solid-state characterization revealed that the amorphous formation of GT0918 in the SDs and the strong H-bonding were only found in the pHM-SDs containing citric acid. Furthermore, the GT0918-loaded pHM-SD tablets showed a higher AUC and a lower tmax compared to the conventional tablets. Accordingly, the pHM-SD might be an efficient route for enhancing the dissolution and bioavailability of poorly water-soluble GT0918.

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