Impact of nanosizing on solubility and dissolution rate of poorly soluble pharmaceuticals

The quantitative determination of solubility and the initial dissolution rate enhancement of crystalline nanoparticles were critically investigated using a separation-based approach (ultracentrifugation and filtration). Four poorly soluble model compounds (griseofulvin, celecoxib, compound-X, and fenofibrate) were used in this investigation. The effect of the stabilizer concentration on the solubility of the unmilled compound was determined first to quantify its impact on the solubility and used for comparing solubility enhancement upon nanosizing. Methodologies were established for ultracentrifugation, ensuring satisfactory separation of crystalline nanoparticles. The data obtained using separation-based methodologies proved to be accurate, reproducible, and were in fair agreement with what would be predicted from the Ostwald-Freundlich equation. The dissolution studies under sink conditions were proved to be less efficient in quantifying the initial dissolution rate of crystalline nanoparticles. Nonsink dissolution experiments were able to reduce the high-dissolution velocity of nanoparticles and generated the best discriminative dissolution profile. The enhancement in initial dissolution rate was significantly less than that expected from the Noyes-Whitney equation based on surface area change. This discriminatory dissolution method can potentially be used further in the modeling of crystalline nanoparticles during drug development.