The purpose of this research was to study the effect of the lipid matrix on the entrapment of olanzapine (OL). OL-loaded solid lipid nanoparticles (SLNs) were prepared using lipids like glyceryl monostearate (GMS), Precirol ATO 5 (PRE), glyceryl tristearate (GTS), and Witepsol E85 (WE 85)--and poloxamer 407 and hydrogenated soya phosphatidylcholine as stabilizers--using a hot melt emulsification high-pressure homogenization technique, and then characterized by particle size analysis, zeta potential, differential scanning calorimetry (DSC), and powder X-ray diffraction (pXRD). Homogenization at 10,000 psi for 3 cycles resulted in the formation of SLNs with a mean particle size of approximately 190 nm for the 4 lipids investigated. The highest partition coefficient for OL between the melted lipid and pH 7.4 phosphate buffer (pH 7.4 PB) was obtained with GTS. The entrapment efficiency was in the following order: GTS SLNs > PRE SLNs > WE 85 SLNs > GMS SLNs. DSC and pXRD showed that much of the incorporated fraction of OL existed in the amorphous state after incorporation into SLNs. A sharp increase in the flocculation of the SLN dispersions was observed upon addition of 0.6 M aqueous sodium sulfate solution. Nanoparticle surface hydrophobicity was in the following order: GTS SLNs > PRE SLNs > WE 85 SLNs > GMS SLNs. A significant increase in size and zeta potential was observed for GTS SLN and WE 85 SLN dispersions stored at 40 degrees C. Release of OL from the SLNs was sustained up to 48 hours in pH 7.4 PB and obeyed Higuchi's release kinetics.