Droplet-phase synthesis of nanoparticle aerosol lipid matrices with controlled properties

Abstract

Nanoparticle lipid matrices are being recently explored for controlled drug delivery applications. The degree of crystallinity of the lipid matrix governs drug loading capacity and release rates. Current methods of preparing nanoparticle lipid matrices, like high-pressure homogenization and solvent-emulsification evaporation, offer limited or poor control over lipid crystallinity. The present work explores a droplet-phase aerosol synthesis method to prepare Nanoparticle Aerosol Lipid Matrices (NALM). Control of evaporation rate was used to achieve control over crystallinity of NALM. NALM were synthesized in an aerosol reactor using precursor solutions of stearic acid in organic solvents with widely different vapour pressures, resulting in different rates of evaporation. Mean mobility diameter, measured using a Scanning Mobility Particle Sizer (SMPS), ranged from 94–127 nm, with a unimodal distribution and geometric standard deviation of 1.7–1.9. Aerodynamic diameters measured using gravimetric analysis of samples collected in a micro-orifice cascade impactor, ranged from 423–608 nm. Relatively higher peak intensities and peak areas in X-ray diffractograms and higher melting enthalpies in the Differential Scanning Calorimetry (DSC) thermograms were obtained for NALM synthesized under lower evaporation rates, using lower vapour pressure solvents, similar to that of bulk stearic acid. In contrast, NALM synthesized at higher evaporation rates, using higher vapour pressure solvents consistently showed a lower degree of crystallinity, evidenced by blunt X-ray diffraction peaks and lower melting enthalpies in DSC analysis. These results suggest the formation of non-equilibrium crystal structures within NALM, under the influence of faster evaporation rates, leading to a lower degree of crystallinity. The work demonstrates proof of concept of droplet-phase aerosol synthesis for preparing nanoparticle lipid matrices and for achieving control over their crystallinity.