Controlling Nucleation and Fabricating Nanoparticulate Formulation of Sorafenib Using a High-Gravity Rotating Packed Bed

Nucleation is the initial step of the crystallization process and is the significant step to prepare nanometer-sized crystalline materials. In this work, we systematically investigated the nucleation kinetics of poorly water-soluble drug sorafenib when precipitated by liquid antisolvent precipitation in high-gravity rotating packed bed. We found that high-gravity field tremendously promoted the nucleation rate, and the nucleation rate was increased by 2–3 orders of magnitude over that in the stirred tank reactor. Moreover, polymer excipients have a significant impact on nucleation; especially, poly­(vinylpyrrolidone) (PVP) could increase the nucleation rate by 3 orders of magnitude over that without excipient. Finally, stable amorphous sorafenib nanoparticulate formulation with a particle size of 80 nm was obtained by controlling nucleation in RPB. Compared to the coarse drug, the nanoparticulate formulation performed faster drug release and had much better cytotoxicity. In vivo pharmacokinetics of the nanoparticulate formulation displayed the increase in plasma concentration time curve (AUC_0–∞) and maximum plasma concentration (<i>C</i>_max), which demonstrated nanoparticulate formulation could enhance the bioavailability and exhibit extensive potential in the pharmaceutical industry