« XRD
described above, the onset of crystallization for high surface amorphous content would be expected to be well below the glass transition of bulk amorphous.
It is noted that changes to processing parameters, such
as micronization energy, may shift the observed onset or affect the magnitude of the exotherm for the micronized samples. Regardless of the processing conditions applied, the onset for all of the micronized systems studied was observed below the glass transitions observed for bulk amorphous materials generated with a range of surface areas from various techniques. The micronized APIs were also analyzed using GVS, where the total sorption includes surface adsorption as well as absorption attributable to the presence of disordered material. Exposure to moisture may initiate crystallization, which results in the expulsion of bulk absorbed water molecules and reduction in the overall quantity sorbed at a particular relative humidity condition. The samples were exposed to two isothermal cycles up to 90%RH and for all the systems, the second sorption cycle demonstrated less moisture uptake compared to the initial cycle. Thermal analysis of the micronized samples following the GVS analysis showed significant reduction in the magnitude (compound C) or the absence (griseofulvin and compound B) of the crystallization event, consistent with rapid crystallization at the surface of the particles. Compound C demonstrates the highest crystallization onset temperature, and not surprisingly, the disordered phase is more stable compared to the other micronized materials. When compound C was processed with lower micronization energy, the crystallization exotherm was not observed following a single GVS cycle. The DSC and GVS results are consistent with the proposal that the micronized samples have high surface area and high mobility amorphous regions that require less energy to crystallize compared to bulk amorphous materials. The presence of amorphous phase in micronized compounds A and C was confirmed using SSNMR, however, it was not detected in micronized griseofulvin or compound B. The technique may not be able to detect the low levels of amorphous phase in these samples or the conditions applied during analysis may have initiated crystallization, consistent with the DSC and GVS results that showed griseofulvin and compound B require less energy to recrystallize.
In fact, crystallization of ground amorphous griseofulvin was observed during SSNMR studies.
Elevated baselines in XRPD patterns are often an indicator of the presence of amorphous content, however, the micronized systems showed no evidence of an elevated baseline. The XRPD peak widths are related to the average crystallite size in a powder sample, and can be used to study structural changes [7]. It is noted that crystallite size and particle size are different; a particle is made up of single crystals separated by fractures/grain boundaries defined as crystallites. Once the average crystallite size falls below a certain size range (typically <100 nm), line broadening of the diffraction peaks will be observed. This allows the changes to the crystallite structure induced by the micronization process to be monitored using XRPD. This is a simplified approach, since the broadening of the XRPD peaks may actually be due to a combination of size and strain components [7-9]. Additional analysis would be required to separate these contributions.
In order to obtain high quality data to use in the line width calculations, capillary samples were collected via XRPD transmission and the peak line width (FWHM) calculations were made using Rietveld refinement techniques. The calculated line widths for the micronized APIs are
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