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As seen in Figure 4.25, the amorphous samples did not show any substantial crystallization (i.e. no detectable mass loss) following 3 hours at 50% or 3 hours at 70% ethanol in the total gas flow (separate experiments were performed and each experiment was carried out at the specified percentage of ethanol for 3 hours). It must be explained though that, minor crystallization could be starting to take place but that the loss in weight caused by crystallization was less than that gained due to sorption of ethanol into the amorphous terfenadine sample. Visual inspection of the amorphous terfenadine samples after exposure to ethanol vapour in a percentage from 50 - 70% showed that the samples were identical in appearance to slow cooled amorphous terfenadine beads (transparent glass beads). Figure 4.25 also shows that the amorphous terfenadine sample
started to crystallize in the DVS at 85% ethanol (indicated by the loss in weight seen in the DVS profile). Samples removed from the DVS following exposure to 85% ethanol were run on the DSC from 25 - 180 °C at 10 °C/ min in hermetically sealed aluminium pans in a nitrogen atmosphere. The samples had both a glass transition temperature at 51.6 °C (n = 4, S.D. = 1.4) and a melting endotherm at 153.9 (n = 4, S.D. = 1.9)) with an average enthalpy of fusion (AHf) of 81.5 J/g. (n = 4, S.D. = 6.9). A typical DSC trace of amorphous terfenadine samples following exposure to 85% ethanol in the DVS for three hours is seen in Figure 4.26.
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Figure 4.26 DSC trace of amorphous terfenadine showing a Tg and a melt after being exposed to 85% ethanolfor three hours in the DVS at 25
The Tg value of the amorphous regions in the terfenadine sample after exposure to 85 % ethanol in the DVS (51.6 °C) was higher than expected from a sample that had gained sufficient molecular mobility whereby Tg was expected to drop below T (25 °C) thus giving the sample a chance to start to crystallize. This might be explained as being due to partial evaporation of ethanol during handling and transfer of the samples from the DVS apparatus to the DSC pans. Thus reducing the amount of ethanol available to impart mobility to the amorphous regions of the terfenadine sample resulting in a higher Tg value on the DSC than would be expected. Another possible explanation is that ethanol was not equally distributed in the amorphous regions of terfenadine and thus some amorphous regions were more plasticized than others in the same amorphous
sample resulting in a net Tg value that was higher than ambient conditions (25 ®C) contrary to what was expected from a crystallizing sample.
The enthalpy of fusion of the crystalline part of terfenadine after exposure to 85% ethanol for three hours in the D V S (average value of 81.5 J/g) was lower than that of the completely crystalline sample (ca.l02 J/g as seen in Table 3.1). Percentage crystallinity however cannot be calculated from the D S C results based on the enthalpy of fusion since loss of ethanol on the TGA was seen at the region of the melt and this is possibly the cause of the relatively high standard deviation (S .D . = 6.9) in the AHf values. Testing of the samples on the TGA from ambient temperature to 180 at 10°C / min in open aluminium pans after exposure to 85% ethanol in the D V S showed a weight loss in a temperature range from ca. 90 to the end of the run (180 ®C). The weight loss had an average value of 0.88% (n = 2, S.D . = 0.02). A typical TGA trace of terfenadine beads subsequent to exposure to 85% ethanol on the D V S is shown in Figure 4.27.
100.2 0.6 100.0- 0.1189 % C0.01394 mg) -0.4 99.8- —0. 2 99.4- - 0. 0 99.0- -0.2 20 40 Temperature (*C)
Figure 4.27 TGA trace of amorphous terfenadine after being exposed to 85% ethanol
for three hours in the DVS at 25 "C.
Scanning electron microscopy (SEM) carried out on sliced and un-sliced crystallized beads showed incomplete crystallization of the beads with crystallization starting on the surface of the beads by nucléation while the inner parts of the beads stayed amorphous (indicated by the smooth appearance) (Figures 4.28 - 4.31). This can be explained as being due to ethanol vapour accessing the amorphous beads through pores and cracks available on the surface of the beads (seen previously in Figure 4.14) triggering crystallization to start at these surface sites. At the same time, the large bead size (ca. 3 mm in diameter) and the relatively low uptake of ethanol vapour was only sufficient to
absorb into and plasticize some local surface regions without being sufficient to diffuse into the inner parts of the beads and trigger complete crystallization of the sample within the time scale of the DVS experiment (3 hours). The absorption of ethanol had a plasticising effect giving increasing molecular mobility at the surface relative to the bulk. Increased molecular mobility at the surface relative to the bulk can result in surface initiated crystallization (Andronis et al., 1997).
In Figure 4.28, crystallization around a crack on the surface of the sliced bead can be noticed with the core staying amorphous (smooth appearance). It can also be noted from Figures 4.29 - 4.31 that larger pores form due to surface crystallization of the terfenadine beads (compare with pores of the original, fresh amorphous terfenadine bead seen in Figure 4.23a) but that due to insufficient percentage of ethanol or insufficient exposure time in the DVS at 85% ethanol, further diffusion of ethanol vapours through these larger pores into the inner parts of the beads was limited and thus could not trigger complete crystallization of the amorphous terfenadine beads.
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