Pharmaceutical Manufacturing Handbook: Production and

NANOTECHNOLOGY FOR DRUG DELIVERY 1265
The nanoprecipitation method is commonly adopted to entrap lipophilic drugs,
and low polydispersity is probably achieved [42] . In general, the organic solution
containing drugs and polymers is added a nonsolvent to lead to polymers precipitating
together with drugs. The size of formed nanoparticles can be adjusted by the
polymer and nonsolvent amounts in the organic phase. Nanoparticles can be separated
from solvents and unincorporated drugs with centrifugation followed by spray
drying or freeze drying when needed. The stability and drug recovery yield of
nanoparticles depend on the ratio of drugs to polymers [98] . Recently, this technique
has also been used to entrap hydrophilic compounds into PLGA and PLA
nanoparticles [99, 100] , especially peptides and proteins [101] .
Another common method to manufacture polymeric nanoparticles is the emulsion
diffusion or solvent evaporation technique, which is used to entrap hydrophobic
or hydrophilic drugs. Generally, the polymer and hydrophobic drugs are dissolved
in a partially water miscible organic phase (e.g., benzyl alcohol, propylene carbonate,
and ethyl acetate). The organic solution is emulsifi ed in aqueous media containing
a suitable surfactant [i.e., anionic sodium dodecyl sulfate (SDS), nonionic
poly(vinyl alcohol) (PVA) or cationic didodecyl dimethyl ammonium bromide
(DMAB)] under stirring. The diffusion of the organic solvent and the counterdiffusion
of water into the emulsion droplets induce polymeric nanoparticle formation.
The organic solvent is evaporated. Also hydrophilic drugs could be entrapped into
a water - in - oil (W/O) emulsion containing polymers and then undergo the above
process. Then a water - in - oil - in - water (W/O/W) emulsion is obtained. After evaporation
of total organic solvent, the drug - loaded nanoparticles can be separated.
Polymer nature, polymer concentration, solvent nature, surfactant molecular mass,
viscosity, phase ratio, stirring rate, temperature, and fl ow of water all affect nanoparticle
size [102] .
The salting - out method is also used. Polymers are dissolved in water - miscible
organic solvents such as acetone or tetrahydrofuran (THF). The organic phase is
emulsifi ed in an aqueous phase that contains the emulsifi er and salts of high concentration.
Typically, the salt solution used contains 60% (w/w) magnesium chloride
hexahydrate or magnesium acetate tetrahydrate with a polymer - to - salt ratio of 1 : 3.
In contrast to the emulsion diffusion method, no diffusion of solvents occurs due
to the presence of high concentrated salts. The fast addition of pure water to the
O/W emulsion under mild stirring reduces the ionic strength and leads to the migration
of the organic solvent to the aqueous phase, inducing nanoparticle formation.
The fi nal step is purifi cation by cross - fl ow fi ltration or centrifugation to remove the
salting - out agent. Common salting - out agents are electrolytes (sodium chloride,
magnesium acetate, or magnesium chloride) or nonelectrolytes, such as sucrose.
Polymer concentration and molecular weight, stirring rate and time, and the nature
and concentration of surfactant and solvent are all important parameters. This
method would allow avoiding the use of organic chlorinated solvents and large
amounts of surfactants [102] . Furthermore, formulation of nanoparticles with
natural polymers is performed by ionic gelation (chitosan), coacervation (chitosan,
gelatin), and desolvation (gelatin) [102, 103] . These mild methods have the advantage
of producing organic solvent - free formulations.
Additional advantages can be obtained by changing nanoparticle surface properties,
for example, good stability, mucoadhesion, and long circulation time.
For example, the in vivo long - circulating effect is achieved either by coating