Production Techniques - Lipid Nanoparticles: Production, Characterization and Stability - page 23

• Stability of the lipid nanoparticle dispersion
• Availability of the production equipment
A brief description of a variety of production techniques is discussed here.
Table 3.1 gives a brief outline of the mechanisms involved in lipid nanoparticle
formation by various techniques, and the major advantages and disadvantages
associated with those techniques.
3.2 Production of Lipid Nanoparticles
3.2.1 High Pressure Homogenization
Being the most reliable and influential technique, high pressure homogenization
has emerged as the industry choice of production technique for preparation of lipid
nanoparticle dispersions. The method was introduced by Siekmann and Westesen
( 1992 ) and Muller et al. ( 1993 ), and was later developed and patented for produc-
tion of SLNs by Müller and Lucks ( 1996 ).
Production of SLNs by high pressure homogenization can be achieved by two
approaches—the hot homogenization and the cold homogenization approaches.
3.2.1.1 Hot Homogenization
Hot homogenization is a well-established technique from its use in the prepara-
tion of fat (or parenteral) emulsions and in dairy processing. Parenteral emulsions
are generally produced in temperature controlled cabinets and high temperature
is essential for their preparation. Parenteral emulsions are prepared using liquid
lipids. Lipid nanoparticles can be drawn from fat emulsions by substituting the liq-
uid lipids (or oils) with solid lipids. Thus, existing production lines for fat emul-
sions can also be very well engaged in lipid nanoparticle production by the hot
homogenization technique (Müller et al. 2000 ).
Figure 3.1 gives a schematic depiction of the steps involved in the hot homog-
enization technique. The hot homogenization technique is often regarded as the
“homogenization of emulsions” because lipid nanoparticle dispersions are pre-
pared at temperatures above the melting point of the lipid used (Mehnert and
Mäder 2001 ). The solid lipids are melted and the drug is solubilized or dispersed
in the molten lipid. The drug-contained lipid melt is dispersed in a hot aqueous
surfactant solution, previously maintained at the same temperature, under high
speed stirring. Subsequent ultrasonication produces a pre-emulsion. Usually, a
piston-gap homogenizer or a jet-stream homogenizer is used to homogenize the
pre-emulsion to produce a hot colloidal emulsion. The droplets of the hot colloidal
emulsion are recrystallized by cooling the emulsion to room temperature in order
to generate SLNs. In some exceptional cases, specific thermal treatment of emul-
sions such as cooling to refrigeration conditions or even sub-zero temperatures
may be required (Bunjes et al. 1996 ; Lim and Kim 2002 ; Schwarz and Mehnert
1997 ; Unruh et al. 2001 ; Westesen et al. 1997 ).