(638d) Processing Pathway to Enhance Nanoparticle Stability

Formulation of hydrophobic drug compounds into nanoparticle form through the rapid precipitation technique has proven an attractive processing scheme for laboratory studies (Horn & Rieger, 2001; Hu et al., 2004; Johnson & Prud'homme, 2003) as well as for large scale operations (US Patent, BASF Aktiengesellschaft, 1999). In all of these approaches organic solvents must be employed in the processing to solubilize the active compound and then must be removed in the final dosage form for toxicological as well as nanoparticle stability reasons (Liu et al., 2007). The presence of organic solvent during the formulation often induces Ostwald ripening and secondary crystallization, which lead to the coarsening of the particle size distribution. Normal processing schemes include dialysis, which can require hours or days (Kim & Lee, 2001; Shuai et al., 2004) for solvent removal are too slow, and lyophilization is problematic for relatively high concentrations of organic solvent.

In this study we demonstrate the use of flash evaporation to rapidly remove tetrahydrofuran (THF) from a mixed solvent stream used to produce block copolymer stabilized nanoparticles by Flash NanoPrecipitation (Johnson & Prud'homme, 2003). The effectiveness of the solvent removal by flash evaporation is, in part, due to the strong non-ideality in the THF:water vapor-liquid equilibrium. The application has been demonstrated for the nanoparticle-formulation of model hydrophobic solute, β-carotene stabilized by PEO-b-PS (3k-b-1k) block copolymer. The dependence of stability of nanoparticles on the fraction of solvent present and degree of supersaturation have been analyzed.

Vacuum flash evaporation is especially well suited as the solvent removal process coupled with nanoparticle formation by Flash NanoPrecipitation. The process can easily scale from the laboratory-scale preparation of research samples, to large scale production.