« XRD
crystallization exotherms have been previously observed for milled griseofulvin.[1,2,4] The peak with a lower onset temperature has been explained in one study as defective crystal rearrangement.[2] In this case, the process of spray drying would not be expected to generate defective crystals, but still clearly shows the same thermal behavior. In yet another study, the explanation for the reduction in recrystallization temperature was suggested to be due to nucleated surface crystallization [1]. Based on the mechanical stress applied during the ball milling process, generation of nuclei at the surface of the material and a bimodal crystallization exotherm were anticipated; however, this thermal behavior was not observed. Additionally, melt- quenched griseofulvin was generated with a small number of intimate crystal seeds in the sample. The thermal crystallization of the melt-quenched sample with seeds showed no significant change when compared to a melt-quenched sample without seeds present. What these studies suggest is that the thermal crystallization behavior may be more closely related to the size distribution of the particles, and thus to the degree of surface available for crystallization.
To further probe the difference in thermal behavior, the melt-quenched material was gently ground to increase the surface area of the sample. The ground material demonstrated a significant reduction in crystallization onset temperature to 37°C. The sample demonstrated a broad crystallization event over a 100°C temperature range, likely due to the relatively wide particle size distribution obtained with grinding. This transition was trimodal, with a broad shoulder mode below 95°C, followed by a bimodal transition similar to the spray- dried amorphous sample. The enthalpies of crystallization obtained for both the ground and non-ground samples are comparable, at ~85 J/g. The ground material was subsequently compressed in a Carver press to revert to a lower surface area. The compressed sample demonstrates a clear glass transition around 90°C and crystallization onset of 117°C, recovering thermal properties similar to the initial low surface area melt-quenched sample (refer to Figure 1a). These results are consistent with the literature [1] and clearly demonstrate that the energy required to achieve crystallization is significantly lower for high surface area amorphous griseofulvin. The effect of surface area on the thermal behavior of amorphous materials was
further evaluated using compound A. Amorphous compound A was generated by desolvation at 200°C, forming a molten sample that was subsequently cooled to ambient temperature. The high surface area amorphous sample was obtained by trituration of the desolvated material. The glass transition for the desolvated compound A is 147°C and onset of crystallization is around 234°C, as shown in Figure 1b. The crystallization event for the desolvated ground sample is observed over the range of about 100-260°C, with onset below the glass transition
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11/09/2013 19:25 | 41
»
According to USP <232> ELEMENTAL IMPURITIES - LIMTS
<2232> ELEMENTAL CONTAMINANTS IN DIETARY SUPPLEMENTS
<735> X-RAY FLUORESCENCE SPECTROMETRY
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