Chemistry Reference
In-Depth Information
an increase in the nucleation rate. However, even though the polymer increased the
hygroscopicity of the system, it still exerted an overall protective effect against crystallization
by decreasing the nucleation rate relative to a systemwith no polymer, stored at a comparable
RH. Such studies provide a quantitative comparison of the impact of polymers on one aspect
of the crystallization process, namely, nucleation. Similar quantitative measurements have
beenmade on crystal growth rates [6,10,57,89]. In one such study [10], the effect of 1 and 2%
PVPonthelineargrowthrateofthe
β
-polymorph of nifedipine as a function of temperature
was measured. The polymer was able to decrease the crystal growth rate of nifedipine, with
the inhibitory effect becoming more pronounced at lower temperatures, even though the
polymer had no in
uence on
T
g
at these low concentrations. Using a similar method, the
ability of different polymers to inhibit the crystal growth of felodipine as a function of
temperature, at temperatures above
T
g
[90], was measured. It was found that PVP was a more
ef
cient inhibitor of crystal growth than hydroxypropylmethyl cellulose acetate succinate
(HPMCAS) for felodipine. Furthermore, the impact of different molecular weight grades of
PVP on the growth rate was investigated whereby a small MWdependency of the inhibitory
effect of PVP was observed, with higher MW grades being more effective inhibitors [91].
Crystal growth rate measurements provide a quantitative measurement of linear growth rates
and enable polymer effectiveness to be directly compared, at least at low polymer
concentrations where growth rates can be measured over experimentally accessible time-
scales. However, in many instances it is of interest to determine the kinetics of the overall
crystallization process and/or the amount of crystallized material.
5.5.2 X-Ray Diffraction
X-ray powder diffraction (XRPD) is one of the most common approaches used to detect
and quantitate the presence of crystallinity in amorphous systems, and has been used for
many years for this purpose [92]. Detection of crystallinity in amorphous solid disper-
sions is based on the appearance of diffraction peaks superimposed on the amorphous
halo that are greater than the signal-to-noise ratio. With laboratory-based diffractometers,
limits of detection are typically in the range of 1
95].
With synchrotron-based systems, much lower detection limits, as low as 0.2%, have been
reported [96]. When attempting to quantitate the extent of crystallinity in amorphous
solid dispersions, it is important to prepare calibration samples that are as representative
of the dispersions as possible. The best approach appears to be preparing the amorphous
solid dispersion, and spiking this material with known amounts of crystalline mate-
rial [94,97], rather than making a blend of amorphous and crystalline drug with the
polymer. This is because interactions between the drug and the polymer in the dispersion
impact the shape of the amorphous halo. Thus, a physical mixture of amorphous drug and
polymer does not yield the same scattering pattern as the drug mixed at a molecular level
with the polymer. Based on these differences, X-ray scattering has also been used to
evaluate miscibility, sometimes in combination with pairwise distribution func-
tions [63,66]. In addition, application of multivariate analysis has been found to be
useful in improving the quantitative ability of X-ray methods [94,98].
There are a number of literature reports describing the use of XRPD to evaluate
amorphous solid dispersions [98
-
5% crystallinity by weight [93
-
-
101] and a few examples will be discussed. The
