One of the first methods to produce nanoparticles was the emulsification of an aqueous solution containing a dissolved macromolecule such as albumin [15-22, 158-171], gelatin [172, 173], chitosan , or a similar macromolecule together with the drug in an oil. The emulsion is then homogenized with a high sheer homogenizer or by ultrason-ication and poured into hot oil leading to the denaturation of the macromolecules and the formation of solid nanopar-ticles. Alternatively to heat denaturation the particles also may be hardened at much lower temperatures, even at room temperature, by cross-linking with an aldehyde [20, 172, 174] or by gelation . After solidification of the nanoparticles the oil is removed by washing with volatile organic solvents.
The particle size and the size distribution of the nanopar-ticles are influenced by the type of oil, macromolecule concentration, aqueous-to-nonaqueous phase concentration, emulsification temperature, and surfactant used [6, 7, 160166]. The time lapse between emulsification and hardening must be kept to a minimum to prevent an increase in particle size and distribution [6, 7]. Like nanoparticle formation by solvent evaporation, nanoparticle production in an oil emulsion is kinetically controlled and yields a relatively broad particle size distribution.
References [175-177] represent comprehensive reviews about these preparation methods.
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