Particle design of itraconazole by evaporative recrystallization for dissolution improvement

Abstract

The aim of this study was to improve dissolution of a poorly water-soluble drug, itraconazole (ITZ), by evaporative recrystallization under vacuum using lyophilizer and rotary evaporator, and compared with that prepared under the ambient conditions. Different organic solvents were used as crystallizing solvent. The amorphous ITZ was obtained by vacuum evaporation using lyophilizer and rotary evaporator. Immediate evaporation of chloroform or methylene chloride out from the drug solution caused the rapid crystallization, leading to amorphous phase formation. Using chloroform as crystallizing solvent caused the complete amorphous ITZ while some ITZ crystals were still found when using methylene chloride. Thus, the dissolution of amorphous ITZ obtained from chloroform showed better dissolution than that from methylene chloride. The crystallization method also influenced the properties of ITZ powders. The ITZ powders prepared from vacuum evaporation using both rotary evaporator and lyophilizer showed a significant increase in drug dissolution. By using lyophilizer, the ITZ powders with faster dissolution were obtained. This is because extremely low temperatures can limit molecular mobility, therefore, the nucleation of the drug is prevented, and crystallization cannot occur, leading to complete amorphous phase formation. After 1-year storage at ambient conditions, both ITZ powders were partially crystallized, leading to a decrease in dissolution. However, ITZ powders obtained from vacuum crystallization using lyophilization showed less change and still provided higher drug dissolution. The instability of the amorphous ITZ was expected and confirmed by these experiments. Therefore, stabilization of the amorphous ITZ is necessary to maintain the drug effectiveness through a long-term storage.