Physicochemical Stability - Lipid Nanoparticles: Production, Characterization and Stability - page 82

For genuinely solid SLNs, polymorphism remains an aspect that can cause
physical degradation of solid dosage forms. Polymorphism is the ability of a solid
material to exist in different unit structures in crystals, arising from a combina-
tion of different molecular conformations and packing. Despite the fact that the
polymorphs have a similar chemical nature, their physical properties such as the
melting points and the enthalpies are distinguishable (Bunjes and Unruh 2007 ), as
exemplified above, and discussed below, for the α , β ′ and β forms of glycerides.
Glycerides commonly used in the production of lipid nanoparticles exist in
three polymorphic forms, in increasing order of stability: α , β ′ and β . The most
unstable α -form has a tendency to transform into a metastable β ′-form that has
better chain packing. The β -form is the most stable form of glyceride available.
Conformational transition from the α to the β ′ and consequent transition to the
β -form is the preferred path for optimal packing of glycerides (Lawler and Dimick
2002 ). The unstable polymorph gradually transforms into the more stable poly-
morph during storage at elevated temperatures. During the process, the particles
lose the initial spherical shape and form crystalline aggregates. For this reason
alone, drug laden SLNs should be stored at low temperatures.
Lipid polymorphism influences the drug content and can result in drug expul-
sion on storage. Lipid molecules have a greater mobility in thermodynamically
unstable morphic forms, making them more capable of incorporating drug mol-
ecules. This can be used to advantage with the inclusion of oils in the formulation
of NLCs increasing mobility in the lipid system and thus the drug loading capacity
(Bunjes et al. 1996 ; Jenning et al. 2000c ). The crystallization of glyceryl behenate
lipid nanoparticles can be delayed by inclusion of liquid medium chain triglycer-
ides, consequently increasing the long term stability. The release of drug, which
normally depends on the polymorphic transformation, was also delayed showing
both improved emulsion stability and improved drug retention. Another example is
that of the drug, Baicalein, which was able to be incorporated into an SLC through
the addition of Vitamin E. The inclusion of Vitamin E, a liquid, in the formulation
increases the number of imperfections and consequently reduces the partitioning
of drug between the aqueous and lipid phases. Baicalein, which is prone to oxida-
tion in aqueous environments was not expelled on storage, thus also protecting it
from chemical integrity (Tsai et al. 2012 ).
Crystals with ordered lattices have high melting enthalpies and more energy is
required to disturb that ordered arrangement. Lipid nanoparticles with increased
melting enthalpies have been reported to exhibit a higher degree of drug expulsion
(Tan and Billa 2014 ). The crystals rearrange themselves towards a higher ther-
modynamically stable configuration during storage, and this often leads to drug
expulsion (Jenning et al. 2000b ). As discussion, the polymorphic transition from β ′
to β form reduces the amorphous regions in the crystal lattice which causes drug
expulsion (Jenning et al. 2000a ).
The mechanism of drug release has been linked to crystal structure by a
number of researchers (Lukowski et al. 2000 ). An increased release of drug has
been observed with polymorphic transitions in SLNs. The metastable polymor-
phic form is responsible for sustained release of drug. Changes in crystallinity