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The synergistic effect of nanosizing and lipid-based drug delivery systems (LBDDS) was explored to enhance formulation drug loading levels and improve drug solubilisation in the gastrointestinal environment. A novel formulation combining drug nanocrystals and silica-lipid hybrid (SLH) microparticles as a solid-state LBDDS was developed for the challenging poorly water-soluble drug, ziprasidone. A ziprasidone nanosuspension was fabricated via high-pressure homogenisation, achieving a mean particle size of 280 nm. In vitro dissolution studies revealed the nanosuspension to exhibit a significant 2.4-fold increase in the extent of drug dissolution, relative to pure drug. Novel ziprasidone nanocrystal-loaded SLH microparticles (ncSLH) were formulated by freeze-drying a precursor drug-loaded emulsion with drug nanocrystals and silica nanoparticles. Drug loading levels were increased at least 17-fold relative to conventional SLH microparticles, resulting in an increase in crystalline drug content and a change in surface atomic composition. The in vitro performance was evaluated by quantifying solubilisation levels during simulated intestinal lipolysis studies. Novel ncSLH significantly improved the in vitro fasted state solubilisation of ziprasidone (up to 4.7-fold), thus indicating the potential for such a formulation to overcome some of the various challenges faced by poorly water-soluble, brick-dust drug molecules.