Chemistry Reference
In-Depth Information
as
-relaxation processes may
be thought of as short-range reorganizations within the amorphous solid dispersion.
Theoccurrenceof
“
noncooperative
”
motional processes [9]. Conceptually,
β
or two distinct amorphous states separated
by a phase transition, is also a potential consideration [14,15]. However, the occur-
rence of true polyamorphism is rare, and can be easily confused with structural
relaxation [9].
Because amorphous forms of a drug are generally metastable with respect to
crystalline forms of a drug, crystallization can occur within dispersions if the drug is
suf
“
polyamorphism,
”
ciently concentrated to allow for crystal nucleation and growth [2]. Analytical
methods are therefore necessary to detect and quantify the presence of crystalline content
at low levels in the presence of a large amount of amorphous material. Many of the
techniques that are widely employed to detect undesired polymorphs in fully crystalline
dosage forms can be adapted for this purpose [1,16]. The most important analytical
techniques currently used for detection of crystalline content in an amorphous solid
dispersion will be discussed in this chapter.
While the analytical methods discussed here often produce data that can be directly
interpreted, for example, by measuring peak maxima in a spectrum or by analyzing the
position of a thermal event, in some cases data can be suf
ciently complex to warrant the
use of multivariate analysis (MVA) methods. MVA is commonly used to analyze
analytical data in scenarios where signi
cant overlap occurs (e.g., to extract trends from
subtle changes in a poorly resolved spectrum), or in cases where a large amount of data
must be comparatively interpreted (e.g., the results of large-scale screening experiments).
A full discussion of common MVA methods can be found elsewhere [17]. Several of the
key methods used in the analysis of amorphous solid dispersions include direct classical
least squares (DCLS), partial least squares (PLS), and principal component analysis
(PCA). These techniques are often used to analyze complex spectral data produced in
analysis of dispersions.
4.2 THERMAL ANALYSIS METHODS
The thermal analysis methods used in most reported studies of amorphous solid
dispersions include differential scanning calorimetry (DSC), thermogravimetric analysis
(TGA), and isothermal microcalorimetry (ITC) [18]. Thermal analysis methods are
uniquely suited toward the characterization of amorphous solid dispersions because of
the temperature-dependent behavior that is commonly exhibited by amorphous solids as
well as enthalpic changes that occur upon relaxation of an amorphous solid [7
9]. For
example, thermal analysis methods can probe
T
g
in amorphous solids or observe the
occurrence of multiple
T
g
values. As previously noted, in the temperature range around
T
g
, the properties of an amorphous solid gradually change from the solid-like glassy state
prevalent at lower temperatures to the supercooled liquid-like rubbery state prevalent at
higher temperatures. Since
T
g
is normally a critical parameter in the characterization of
amorphous solid dispersions, methods to observe it and other thermal or energetic
parameters are important for analytical characterization.
-
