Chemistry Reference
In-Depth Information
separation [60,102]. This would clearly be undesirable since the polymer concentration
in the drug phase would be reduced, and thus it would be anticipated that the system
would be much more susceptible to crystallization.
There are some new IR-based methodologies under development that are of potential
interest for the characterization of amorphous solid dispersions. In photothermal induced
resonance spectroscopy, an atomic force probe is used to measure the local thermal
expansion following irradiation by IR light produced froma tunable laser [125]. Because an
AFM probe is used to detect the signal, the spatial resolution is much improved compared
with conventional IR imaging, and it is possible to obtain spectra from submicrometer
domains aswell as chemical images with submicrometer resolution. In a study of felodipine
and polyacrylic acid dispersions, theAFMtopographical image showed the presence of the
domains, but could not provide any chemical information about their chemical composi-
tion. However, nano-IR imaging showed that the discrete domains were drug rich, and
these domains were embedded in a polymer-rich continuous phase [126]. This methodol-
ogy thus appears to be an emerging technique that offers the potential for improved
understanding of the microstructure of amorphous solid dispersions.
5.5.6 Second-Order Nonlinear Optical Imaging of Chiral Crystals
As discussed previously, detection of small amounts of crystalline material in solid
dispersions can be challenging, in particular when the drug loading is low and the
dispersion is predominantly comprised of a polymer. A promising technique for extending
the limits of detection is second-order nonlinear optical imaging of chiral crystals
(SONICC) that has recently been reported to show very high sensitivity for detecting
tiny amounts of crystalline material present in an otherwise amorphous sample [127]. The
detection limits for crystalline griseofulvin and chlorpropamide in predominantly amor-
phous sample of pure drugwere estimated to be a factor of 10
5
better thanwith conventional
methods such as labXRPD. SONICC is dependent on second harmonic generation (SHG),
which is a nonlinear optical effect that is possible only with noncentrosymmetrically
ordered materials, and hence can usually only detect crystals with chiral space groups.
Thus, this technique is not universally applicable to all APIs, for example, compounds that
are racemic or achiral. However, it holds promise for detecting small amounts of crystalline
material of SHG-active compounds in a solid dispersion since the carrier polymers
employed typically will have low-to-zero SHG activity, potentially allowing the detection
of nanoscopic domains (on the order of 100 nm) of crystalline material. In a study with
naproxen
HPMCAS dispersions, the ability to detect crystalline material with Raman
spectroscopy, XRPD, and SONICC was compared [128]. Crystalline material could be
detected in the amorphous solid dispersion immediately after production using the
SONICC technique, but could not be detected based on the XRPD patterns or the Raman
spectra. A comparison of the images obtained from the SONICC studies and the XRPD are
shown in Figure 5.4. The bright areas in the SONICC images depict crystalline material,
while the dark areas arise from amorphous sample. It is clear that crystallinity can be
sensitively detected with the SONICC imaging method. Based on these results, it is
certainly of interest to further explore the application of SONICC for the detection of the
early stages of crystallization in amorphous solid dispersions.
-
