Influence of precursor solvent properties on matrix crystallinity and drug release rates from nanoparticle aerosol lipid matrices

Abstract

The crystallinity of drug-loaded lipid nanoparticles is believed to affect drug release rates; however, effective control over lipid crystallinity has not been achieved by current lipid nanoparticle preparation methods. The present study investigates control over the crystallinity of drug-loaded Nanoparticle Aerosol Lipid Matrices (NALM) through differences in evaporation rates of precursor solution drops and the subsequent control over drug release rates from these matrices. Gefitinib-loaded NALM were synthesized in an aerosol reactor using precursor solutions of gefitinib and stearic acid at a ratio of 1:4 w/w in organic solvents with high (dichloromethane) and low (ethyl acetate and chloroform) vapor pressures. Mean mobility diameter measured using a scanning mobility particle sizer was in the range of 123–132 nm with a unimodal distribution and a geometric standard deviation of 1.6–1.9. A layered particle structure was observed using transmission electron microscopy, which suggests partial drug enrichment in the surface layer. Higher drug loading (20% w/w) and uniform entrapment efficiencies (∼100%) were achieved. The initial drug to lipid ratio (1:4 w/w) of the precursor solution was preserved in the synthesized lipid matrices. The crystallinity of the gefitinib-loaded lipid matrix was measured using X-ray diffraction and differential scanning calorimetry. In vitro drug release from gefitinib-loaded NALM in phosphate buffered saline (pH 7.2) over 10 days showed an initial fast release period followed by a prolonged sustained release period with varying release rates. Gefitinib-loaded NALM synthesized at higher evaporation rates exhibited lower degrees of crystallinity and faster drug releases. These results suggest the determinant role of lipid crystallinity manipulated by differing evaporation rates during aerosol synthesis on drug releases from nanometer-sized lipid matrices.