Processing and Scale-up of Polymeric Nanoparticles - Intracellular Delivery: Fundamentals and Applications - page 442

Multiple emulsions can be prepared with microfluidizer (Sani et al. 2009 ), high pres-
sure homogeniser (Lamprecht et al. 1999 , 2000 ) and ultrasounds (Perez et al. 2001 ) by
re-emulsifying the simple emulsion prepared above into a new continuous phase.
Surfactants such as pluronic and span are often used to prepare stable emulsions.
However new polymer surfactants were synthesized to formulate suitable emul-
sions for nanoparticle preparation. In general these polymer surfactants include
polymer chains of the same nature than that composing the nanoparticle. The
hydrophilic moiety required to achieve the stability of the nanoparticles which
protruded in the aqueous phase is composed either of polyethylene glycol (Gref
et al. 1994 ; Bazile et al. 1995 ; Avgoustakis 2004 ; Qui and Bae 2006 ) or of various
polysaccharides (Lemarchand et al. 2003 ; Chauvierre et al. 2004 ).

2.2.2 Conversion of an Emulsion into Nanoparticle Dispersion

Several artefacts can be used to convert the emulsion into nanoparticle dispersion.
For instance, it can be achieved by inducing the precipitation of the polymer dis-
solved in the emulsion droplets. The simplest methods inducing polymer precipi-
tation consists in removing the solvent contained in the emulsion droplets by
evaporation of the solvent composing the dispersed phase of O/W and W/O/W
emulsions (Avgoustakis 2004 ; Vauthier and Bouchemal 2009 ). This corresponds
to the original method of preparation of pseudolatexes by Gurny et al. ( 1981 ). To
achieve this, it is required that the emulsion was prepared with an organic volatile
solvent such as dichloromethane and ethyl-acetate. Because solvent evaporation is
a slow process, formation of nanoparticles takes more then a few minutes. Polymer
concentration increases gradually over time in the emulsion droplets thanks to
solvent removal until polymer starts precipitation (Desgouilles et al. 2003 ).
Diameter and size distribution of the nanoparticles depends on the diameter and
size distribution of the emulsion droplets. However, no general relationship can be
drawn between droplet and nanoparticle size because this depends on the extend
of emulsion droplet coalescence occurrence during the solvent removal step which
in turn depends on surface active properties of the polymer and may be affected
by the presence of surfactant.
A second method consists in a rapid extraction of the solvent contained in the
emulsion droplets by diffusion toward the continuous phase of the emulsion. This
method was named the emulsification-solvent extraction method or the emulsifica-
tion-solvent diffusion method. Typically, suitable conditions are obtained by
dilution of the emulsion by adding more continuous phase if the polymer solvent
contained in emulsion droplets is partly miscible with the continuous phase
(i.e. ethylacetate for instance). Instead of diluting the continuous phase, solvents in
which both the continuous and the dispersed phase are miscible can be added to
displace the polymer solvent from the dispersed phase towards the continuous phase
causing polymer precipitation (Leroux et al. 1995 ; Quintanard-Guerrero et al. 1999 ;
Perez et al. 2001 ; Guinebretiere et al. 2002 ; Moinard-Chécot et al. 2006, 2008 ).