Polymeric additives to sustain the dissolution enhancement of niclosamide nanocrystals formed via freeze drying

Abstract

Nanocrystal formation is an effective method to increase the dissolution of drug compounds with limited solubilities. Niclosamide is a sparingly soluble compound, and it also tends to become an even less soluble monohydrate upon contact with dissolution media. We utilized freeze drying to successfully generate niclosamide nanocrystals, which displayed rapid initial dissolution but also suffered from the expedited formation of the monohydrate. Therefore, we explored some pharmaceutically acceptable polymers to overcome the unfavorable anhydrate-to-monohydrate transformation. Poly(vinylpyrrolidone-co-vinyl acetate) (Mw 45000–70000) effectively retarded the monohydrate formation in a concentration-dependent manner, and 3–5% in the drug-polymer mixture was enough to sustain the enhanced initial dissolution of niclosamide nanocrystals. The area under the dissolution curve tripled due to the combined effect of the nanocrystal formation and the monohydrate inhibition. This study demonstrates an example of the one-pot freeze-drying process to form an optimized drug-additive mixture to realize the full potential of drug nanocrystals.