Physicochemical Stability - Lipid Nanoparticles: Production, Characterization and Stability - page 80

bound particles with little to no water separating them, and is largely irreversible
due to the deep energy well “stuck” particles are now in. Furthermore, because the
particle surface is solid, they are not likely to coalesce so remain as discrete parti-
cles, but so tightly bound that they cannot be re-dispersed.
In both the cases of flocculation and coagulation, particles size now has two
meanings—the intrinsic particle size of the individual particle and the effective
particle size of the agglomerate (floc or coagulum). The effective particle size
increasing results in creaming, sedimentation and/or gelling and results in disper-
sion instability.

Creaming and Sedimentation
Lipid nanoparticles either settle (sedimentation) or float (creaming) depending on
their density relative to the density of the dispersion medium. Although flocculated
dispersions do not necessarily result in serious instabilities, a settled or a creamed
product is considered to be pharmaceutically and cosmetically inelegant, and may
result in administration of an inadequate dose. Creaming or sedimentation, when
the result of coagulation, is always serious.
The particles suspended in the dispersion are in a constant state of Brownian
motion and collisions between the particles cause those particles to either settle or
cream. The drag in the dispersion medium, however, causes the particles to resist
settling. The resistance provided by the dispersion medium is proportional to the
velocity of sedimentation. The gravitational force acting on the particle balances
the resistance offered by the dispersion medium. The phenomenon of creaming or
sedimentation can be explained according to Stokes' Law (Eq. 5.5 ),

d 2 (ρ 1 − ρ 2 ) g
18 η

V =

(5.5)

where V is the velocity of sedimentation, d is the diameter of the particle, ρ 1 , and
ρ 2 are the densities of the particle and dispersion medium, respectively, η is the
viscosity of the dispersion medium and g is the acceleration due to gravity.
According to Stokes' Law, the particle size, medium viscosity and the dif-
ference in densities of particles and medium are the main factors that influence
the sedimentation rate of particles (Kim 2004 ). Decreasing the particle size
or increasing the medium viscosity are the most common strategies to reduce
particle sedimentation. The difference in densities of particles and dispersion
medium also has an influence on the rate of sedimentation. Although the density
of lipid nanoparticles cannot be changed, the density of the dispersion medium
can be increased slightly by addition of density modifiers (such as mannitol and
sorbitol). Since the density of the dispersion medium can rarely be increased
above 1.3, it is practically impossible to eliminate the density difference (Nutan
and Reddy 2009 ).
Dispersion instability can thus be mitigated by either (a) increasing the primary
maximum (Fig. 5.1 ) leading to kinetic stability of the dispersion, or (b) slowing
the rate of sedimentation or creaming.