Mg-Al layered double hydroxide (LDH) nanohybrids intercalated with ibuprofen (IBU) with particle sizes of 150-530 nm have been synthesized through hydrothermal and coprecipitation treatment in aqueous solution without any organic solvent. The in vitro drug release properties of as-prepared IBU-LDH nanohybrids are systematically studied and the kinetic simulation to the release profiles suggests that the release processes of the larger nanohybrids are mainly controlled by intraparticle diffusion. The morphology changes from thick sheet-like into thin margin-curved platelets for the larger nanohybrid particles, induced by the hydrophobic IBU anions aggregations located in the edge region of interlayer via ion-exchange diffusion process, is firstly observed during the release process. Based on the SEM, HRTEM, XRD, FTIR, and UV-vis analyses of the samples recovered at different release time, a release mechanism model of the as-prepared IBU-LDH nanohybrids is tentatively proposed along with their morphology changes during the whole release process. (C) 2010 American Institute of Chemical Engineers AIChE J, 57: 1936-1946, 2011