The aim of this study was to improve the oral bioavailability and diminish the food effect of a poorly soluble drug with pH-dependent solubility, lurasidone hydrochloride (LH), by fabricating its nanosuspensions using a facile nanoprecipitation method. Upon dilution with water, LH dissolved in pH 4 solution formed growing cores and aggregated into nanoparticles, due to the maximum solubility of LH at pH 4. Compared with the batches prepared with other stabilizers, the LH nanosuspensions (LH-NS) stabilized by HPMC E50 were found more stable and had a smaller particle size. A Box-Behnken design (BBD) was used to optimize the critical process and formulation parameters. Then the optimized LH-NS were lyophilized with 1% (w/v) mannitol for long-term stability. According to differential scanning calorimetry and X-ray diffraction analysis, the nanocrystals were still in crystalline state after the preparation procedure. Good physical stability was observed for nanoparticles kept for 6 months at 25 and 40 degrees C/75% RH. The in vitro dissolution rate of LH was significantly increased by reducing the particle size. The in vivo test demonstrated that the C-max and AUC(0-24) h values of nanocrystals in fasted rats were approximately 2.08-fold and 239-fold greater than that of raw drug, respectively. Besides, there was no significant difference in the oral bioavailability of nanoparticles between fasting and feeding. This nanoprecipitation technique is a promising method with a facile process and avoidance of toxic organic solvents and undesired byproducts for oral delivery of poorly soluble drugs with pH-dependent solubility. (C) 2017 Elsevier B.V. All rights reserved.