« XRD
50°C/95%RH for two weeks showed a line width approaching 0.08 °2θ, which is not as narrow as the non-micronized line width, 0.07 °2θ, but demonstrates significant annealing and possible increase in crystallite size in a relatively short time period. The broadening of the calculated XRPD line width was consistent with the generation of nanocrystalline content during micronization and the phase annealed with an apparent synergy of temperature and relative humidity.
Further
work is required to determine if strain is also contributing to the peak broadening and to the changes observed in the annealed samples. Additional work is ongoing to correlate these findings to changes observed between freshly micronized and aged APIs that have been stored under typical warehouse conditions.
The thermal and vapor sorption properties of the micronized samples exposed to different environmental conditions were also tested at various time points. The crystallization events attributable to high mobility surface amorphous phase and the line width sharpening due to annealing of the nanocrystalline phase occurred on different time scales. The crystallization of the amorphous content occurred at a significantly faster rate compared to the annealing of the nanocrystalline content, indicating that different components of disorder are generated during micronization. Correlations between changes in the surface area and porosity of the micronized samples and the XRPD line width analysis are being investigated to further characterize the nanocrystalline content in these systems.
NETZSCH DELTAVITA® - Enhance API Solubility and Improve Performance! Conclusions
The crystallization onset temperature of amorphous APIs is influenced by surface area and SSNMR was used to demonstrate a correlation between molecular mobility and surface available for crystallization. Based on the physical characteristics of micronized APIs, it appears that there are different components of disorder that are generated as a result of the mechanical stress incurred during processing. DSC, GVS, and SSNMR results are consistent with the formation of surface amorphous regions with enhanced molecular mobility.
XRPD line
width analyses suggest the formation of structural changes consistent with nanocrystalline content. The annealing of the nanocrystalline phase of micronized systems can be monitored using XRPD line broadening analysis. Work is ongoing to develop a comprehensive understanding of the individual components of disorder on the physicochemical properties and stability of micronized APIs.
Author Biographies
Rachel G. Forcino, Ph.D., is an investigator within Product Development at GlaxoSmithKline. Her interests include solid state analysis and process development of pharmaceutical materials. Specific focus has included the
Pharmaceutical manufacturing down to the Nanometer particle size range
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