Chemistry Reference
In-Depth Information
shelf life. In this section, different methods for physical stability assessment will be
discussed, together with their strengths and limitations.
5.5.1 Optical and Polarized Light Microscopy
Most crystalline APIs are anisotropic and therefore show the phenomenon of
birefringence. In contrast, amorphous materials are isotropic. Polarized light microscopy
(PLM) is a contrast-enhancing technique that improves the image of birefringent
materials. Typically, crystalline domains show up as colored and/or bright regions
under cross polars, whereas amorphous materials show a similar color to the background,
which is often black. Therefore, it is often easy to rapidly detect small quantities of
crystalline material in an otherwise amorphous matrix. The advantage of PLM is that
only small amounts of material are required; therefore, it is a useful screening technique.
The disadvantage is that it can often be dif
fine powders, and particles can
appear birefringent even though there is no crystallinity present due to the presence of
strain. One way to circumvent these issues is to spin coat or melt thin
cult to analyze
films of the solid
dispersion onto a glass substrate. Clear
films indicate an amorphous sample, while
colored regions under cross polarized light
indicate crystallization. From initially
transparent and colorless
films, the evolution of crystal nucleation and growth can be
readily monitored.
Microscopy has been used in a number of studies to evaluate the crystallization behavior
of amorphous systems, as well as to evaluate optimum polymers for solid dispersions. In a
small-scale screening study, the ability of seven different polymers to inhibit the crystalliza-
tion of several readily crystallizable drugs was evaluated [56]. This involved spin coating a
thin
essentially solvent
casting a solution of the drug and polymer onto a cover slip, followed by rapid evaporation
leading to an amorphous solid dispersion. The ability of the polymer to inhibit crystallization
during solvent evaporation and short-term storage under different environmental conditions
could be readily evaluated by examination of the
film of the drug and polymer onto an optically transparent substrate
-
films under a polarizing light microscope. It
was found that compounds with a higher crystallization tendency were more dif
cult to
stabilize requiring more polymer. In addition, the stabilizing ability of different polymers
varied dramatically for the different compounds suggesting that the chemistry of the drug and
the polymer are important for ensuring the formation of a stable dispersion. The small-scale
screening approach and rapid sample evaluation enabled many samples to be studied and
their relative crystallization tendency to be evaluated without providing quantitative
information. However, it is also possible to study the crystallization of amorphous materials
in a much more quantitative way using microscopic techniques. For example, optical
microscopy was used to study the nucleation rate of pure amorphous indomethacin as a
function of temperature [14]. The nucleation rate was estimated by counting the number of
crystallites as a function of time in a particular view and depth of
field. A complicated
relationship between nucleation rate and temperature was observed, which in part could be
accounted for by the formation of different polymorphs. This technique was subsequently
applied to evaluate the impact of polymers on the nucleation rate of felodipine as a function of
polymer amount and storage conditions [64,77]. It was found that the nucleation rate
decreased dramatically with increasing polymer content, but exposure to high RH resulted in
