Chemistry Reference
In-Depth Information
suggestive of phase separation with domain sizes on the order of 30 nm or greater [26]. The
PDF-analyzed PXRD data (circles) of the dispersion match well with PDF PXRD results
(black line) calculated using the separate amorphous reference materials. The agreement
between the experimental and calculated PDF PXRD patterns is therefore indicative of a
phase-separated system. In Figure 4.16b, PDFPXRDanalysis of a 50%(w/w) dispersion of
indomethacin in PVP is shown. In contrast to the dextran
PVP dispersion, this system
exhibits a single
T
g
byDSCanalysis, and the PDF PXRDanalysis of the dispersion does not
agree well with the patterns calculated from the separate amorphous reference materi-
als [26]. PDF analysis can also be applied to neutron and electron diffraction data, although
no applications of these alternative techniques to pharmaceutical amorphous solid
dispersions have yet appeared in the literature [151]. As neutrons scatter from atomic
nuclei (as opposed to X-rays, which scatter from electrons), they can offer an enhanced
view of structure in many amorphous materials, but the limited accessibility of instrumen-
tation prevents their wider usage.
Two approaches to multivariate analysis of PXRD data from amorphous dispersions
have recently been presented [158]. The
-
first approach is based on the use of a pure curve
resolution method to qualitatively assess drug
polymer miscibility. The second method,
based on alternate least squares analysis, is then used to quantify the degree of miscibility
by determining the nearest-neighbor coordination number for the dispersion, which can
provide an indication of the physical stability of the dispersion [158]. These multivariate
methods provide another opportunity for the use of PXRD in studies of amorphous solid
dispersions.
-
4.9 MICROSCOPIC AND SURFACE ANALYSIS METHODS
In addition to IR, Raman, and other molecular spectroscopy-based microscopy methods
discussed above, several additional techniques based on microscopy and surface analysis
are highly useful in the characterization of amorphous solid dispersions. Optical
polarized light microscopy (PLM) is one of the best-known and most useful methods
for detecting small amounts of crystalline materials through particle habit and
birefringence [159,160]. Most crystalline pharmaceutical substances are birefringent,
in that a single crystal will exhibit a different refractive index along each optical axis,
which allows for rapid detection using PLM. Like MDSC, PLM is extensively applied in
initial screening studies of dispersions, particularly on small evaporated
films prepared
on microscope slides. Hot-stage microscopy (HSM) can also be used to observe
crystallization within dispersions at higher temperatures [159,160].
Scanning electron microscopy (SEM) is also widely used in the characterization of
amorphous solid dispersions. SEM makes use of a monochromatic electron beam to
probe the surface and near-surface areas of materials [160,161]. SEM analysis of
amorphous solid dispersions can be used to probe particle morphology after dispersion
formation by techniques such as spray drying, electrospinning, or milling of hot melt
extrusion fragments. Images can be formed using both secondary electron (SE) and
backscattered electron (BSE) detection, although the latter is often preferred for
morphology studies because of its superior sensitivity to sample topology. In typical
