Physicochemical Stability - Lipid Nanoparticles: Production, Characterization and Stability - page 83

preferably towards a more perfect crystalline structure (evidence by increase in
melting enthalpy) can thus be theorized to expel encapsulated drug on storage.
Crystal reorientation has also been linked to changes other physical properties
such as zeta potential (Freitas and Müller 1999 ).
Gelation Phenomena
Lipid nanoparticle dispersions have the potential risk of transforming into a viscous
gel. The process, called gelation, is a very rapid and an unpredictable occurrence.
Particle aggregation may occur as a result of loss of colloidal particle stability and
precedes the gelling step. Typically, gelation results from long range particle inter-
action caused, for example, by polymeric material or large molecular weight non-
ionic surfactants. These link particles in such a way that a three dimensional network
across the entire sample is formed, and is more dependent on the nature of the cross-
linking material (gelling agent) than the particle itself. Gelation is thus a function of
the formulation more than a function of the nature of the particles within the SLNs.
Gelation can also occur as a result of an ordered dispersion where particles are in
sufficiently close contact that their random Brownian motion is restricted. In these
cases, zeta potential is very important. Particles are repelled from each other as a
result of the zeta potential, however if the dispersion is concentrated they cannot be
repelled because other particles are present in every direction, and these are just as
repelling. The result is a viscous ordered dispersion, akin to a gel. Physical charac-
teristics, such as temperature and salt concentration are important.
Different factors stimulate the gelation phenomena such as (Awad et al. 2008 ;
Freitas and Müller 1998 ; Helgason et al. 2008 , 2009b ):
• intense contact of the aqueous dispersion with surfaces (such as needle
syringes)
• mechanical stress during sample manipulation and transport
• exposure to elevated temperatures or light or oxidising environments
• surfactants
• polymorphic transitions during storage conditions
• Ionic nature of drug
Most of these factors increase the kinetic energy of the particles, which increases
the number of collisions between the particles making the system highly unstable.
Gelling of nanodispersions is influenced by crystallinity and polymorphic transi-
tion. Surfaces that are in contact with the aqueous dispersions tend to stimulate
crystallization or lipid modification in the nanoparticle suspension. Crystallization
usually favours transition to a more stable form (i.e. β -form), thereby increasing
the surface area of the particle (formation of platelets in the β -form). Surfactants
fail to stabilize the system further and this leads to particle aggregation and/or
gelation (Awad et al. 2008 ).
The stability of aqueous suspensions of SLNs has been investigated as a func-
tion of storage temperature, light and packing material. Introduction of any form
of energy led to particle growth and consequent gelation. Particle growth was not
observed in SLN dispersions stored under cold conditions in the dark. Storage of