Nanoflakes of itraconazole, a poorly-water-soluble antifungal drug, are produced by SAS-EM supercritical antisolvent solvent with enhanced mass transfer (SAS-EM) method. The nanoflakes show poor flowability and shelf-life; which are improved by mixing with silica nanoparticles. To intimately mix at nanoscale, macro mixture of itraconazole nanoflakes and silica nanoparticles is first pressurized with supercritical carbon dioxide, and then rapidly depressurized through a nozzle. The rapid depressurization of supercritical suspension (RDSS) causes deagglomeration and mixing, due to a high CO2 expansion velocity. Upon mixing, due to the presence of silica nanoparticles between itraconazole nanoflakes, growth of the drug particles during storage is avoided or reduced, and particle flow properties are significantly improved. The handling properties are characterized using angle of repose, compressibility index, and Hausner ratio. Physical stability (shelf-life) of drug and drug/silica mixture is tested by storing the samples for 25 days at 90 °C. Agglomeration and growth of pure drug nanoflakes during storage leads to substantial decrease in the dissolution rate. Whereas when the drug nanoflakes are mixed with silica nanoparticles, the dissolution rate almost remains constant during storage. Thus, effective deagglomeration and nanoscale mixing lead to increase in the shelf-life.