Indomethacin: Effect of Diffusionless Crystal Growth on Thermal Stability during Long-Term Storage
Abstract
:1. Introduction
2. Experimental
3. Results
3.1. Differential Scanning Calorimetry
3.2. Raman Spectroscopy
3.3. X-ray Diffraction Analysis and Optical Microscopy
4. Discussion
4.1. Quantification of Thermal Behavior
4.2. Crystallization Kinetics
4.3. Kinetic Predictions
5. Conclusions
- The preferential formation/dominance of particular polymorphs is consistent and well reproducible, with the increased formation of the α-IMC phase being associated with high T (and mobility in general), the presence of mechanical defects, and long-term nucleation at the free surface.
- Whereas the nonisothermal crystallization proceeds uniformly (in an apparent single process), isothermal DSC crystallization data show that below ~80 °C, the significantly faster crystal growth from the mechanical defects proceeds independently from the growth at the free surface of the IMC grains.
- At 10 °C and zero humidity, the GC growth proceeds during long-term storage in accordance with the literature reports on crystal growth rate (~100 µm of the γ-IMC phase in 100 days).
- At 25 °C (still well below Tg) and laboratory humidity, the freely stored fine powder samples (with daver ≤ 250–300 µm) exhibited practically no traces of the crystalline phase during the first 14 days of storage; after 100 days, the same was still true for powders with daver ≤ 125–180 µm. This indicates marked suppression of the GC growth by the presence of mechanical defects at these conditions. This finding may open a revolutionary route to the long-term storage of amorphous APIs.
- The freely stored bulk material with no mechanical damage and a smooth surface exhibited zero traces of GC growth (as confirmed by microscopy) after >150 days of storage.
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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daver/µm | 50–125 | 250–300 | ||
q+/°C·min−1 | 0.5 | 20 | 0.5 | 20 |
Ec/kJ·mol−1 | 98 | 98 | 68 | 68 |
log(A/s) | 12.1551 | 11.6612 | 7.6702 | 7.3840 |
MAC | 0.8235 | 0.4249 | 0.7781 | 0.5538 |
NAC | 0.4209 | 0.9941 | 0.8679 | 0.8719 |
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Svoboda, R.; Koutná, N.; Košťálová, D.; Krbal, M.; Komersová, A. Indomethacin: Effect of Diffusionless Crystal Growth on Thermal Stability during Long-Term Storage. Molecules 2023, 28, 1568. https://doi.org/10.3390/molecules28041568
Svoboda R, Koutná N, Košťálová D, Krbal M, Komersová A. Indomethacin: Effect of Diffusionless Crystal Growth on Thermal Stability during Long-Term Storage. Molecules. 2023; 28(4):1568. https://doi.org/10.3390/molecules28041568
Chicago/Turabian StyleSvoboda, Roman, Nicola Koutná, Daniela Košťálová, Miloš Krbal, and Alena Komersová. 2023. "Indomethacin: Effect of Diffusionless Crystal Growth on Thermal Stability during Long-Term Storage" Molecules 28, no. 4: 1568. https://doi.org/10.3390/molecules28041568