Production Techniques - Lipid Nanoparticles: Production, Characterization and Stability - page 33

Organic solvent-in-water
emulsion

Solid lipid nanoparticles

Water-saturated organic
solvent
(and solubilising drug)

Step 2: Mixing organic
and aq. phases

Step 3: Precipitation by
quick addition of water

Solvent-saturated
aq. phase

Step 1: Equilibration
of two phases

Fig. 3.7 Schematic steps involved in the solvent diffusion technique

3.2.6 Solvent Diffusion

The solvent diffusion method was first introduced in the production of polymeric
nanoparticles by Leroux et al. ( 1995 ). The method was developed and patented by
Quintanar-Guerrero et al. ( 1996 ). Hu et al. ( 2002 ) introduced a novel solvent diffu-
sion technique in the preparation of lipid nanoparticles.
A schematic protocol for preparation of lipid nanoparticles using the solvent
diffusion technique is shown in Fig. 3.7 . Partially water-miscible solvents are used
to solubilize the solid lipids. A number of solvents partially soluble in water such
as benzyl alcohol, butyl lactate, isobutyric acid, isovaleric acid and tetrahydrofuran
have been used in the preparation of lipid nanoparticles (Battaglia et al. 2007 ;
Shahgaldian et al. 2003a , b , c ; Trotta et al. 2003 , 2005 ). Prior to lipid solubili-
zation, the water-miscible solvents are saturated with water to ensure preliminary
thermodynamic equilibrium between the two liquids. The drug may be added to
the organic solvent phase. The organic phase is then emulsified with a solvent-
saturated aqueous phase containing an emulsifier. Water is added to the primary
emulsion to extract the solvent into the external water phase and this generate
SLNs. Typical emulsion:water ratios are 1:5 or 1:10.

3.2.7 Solvent Injection (or Displacement)

Solvent injection is a well-established technique from its use in preparation of
liposomes and polymeric nanoparticles (Batzri and Korn 1973 ; Fessi et al. 1989 ).
Solvent injection is a modification of a solvent diffusion technique.
In the solvent injection technique, the lipid is solubilized in a semi-polar water-
miscible solvent or water-soluble solvent mixture while the drug is dissolved in
the organic phase. The organic phase is rapidly injected, under constant stirring,