Transformation of an active pharmaceutical ingredient upon high-energy milling: A process-induced disorder in Biclotymol. Schammé, B., Couvrat, N., Malpeli, P., Dudognon, E., Delbreilh, L., Dupray, V., Dargent, É., & Coquerel, G. International Journal of Pharmaceutics, 499(1–2):67–73, 2016.
Transformation of an active pharmaceutical ingredient upon high-energy milling: A process-induced disorder in Biclotymol [link]Paper  doi  abstract   bibtex   
This study investigates for the first time the thermodynamic changes of Biclotymol upon high-energy milling at various levels of temperature above and below its glass transition temperature (Tg). Investigations have been carried out by temperature modulated differential scanning calorimetry (TM-DSC) and X-ray powder diffraction (XRPD). Results indicate that Biclotymol undergoes a solid-state amorphization upon milling at Tg – 45 °C. It is shown that recrystallization of amorphous milled Biclotymol occurs below the glass transition temperature of Biclotymol (Tg = 20 °C). This displays molecular mobility differences between milled Biclotymol and quenched liquid. A systematic study at several milling temperatures is performed and the implication of Tg in the solid-state transformations generally observed upon milling is discussed. Influence of analysis temperature with respect to interpretation of results was investigated. Finally, it is shown that co-milling Biclotymol with only 20 wt% of amorphous PVP allows a stable amorphous dispersion during at least 5 months of storage.
@article{schamme_transformation_2016,
	title = {Transformation of an active pharmaceutical ingredient upon high-energy milling: {A} process-induced disorder in {Biclotymol}},
	volume = {499},
	issn = {0378-5173},
	shorttitle = {Transformation of an active pharmaceutical ingredient upon high-energy milling},
	url = {http://www.sciencedirect.com/science/article/pii/S0378517315304348},
	doi = {10.1016/j.ijpharm.2015.12.032},
	abstract = {This study investigates for the first time the thermodynamic changes of Biclotymol upon high-energy milling at various levels of temperature above and below its glass transition temperature (Tg). Investigations have been carried out by temperature modulated differential scanning calorimetry (TM-DSC) and X-ray powder diffraction (XRPD). Results indicate that Biclotymol undergoes a solid-state amorphization upon milling at Tg – 45 °C. It is shown that recrystallization of amorphous milled Biclotymol occurs below the glass transition temperature of Biclotymol (Tg = 20 °C). This displays molecular mobility differences between milled Biclotymol and quenched liquid. A systematic study at several milling temperatures is performed and the implication of Tg in the solid-state transformations generally observed upon milling is discussed. Influence of analysis temperature with respect to interpretation of results was investigated. Finally, it is shown that co-milling Biclotymol with only 20 wt\% of amorphous PVP allows a stable amorphous dispersion during at least 5 months of storage.},
	number = {1–2},
	urldate = {2016-01-14},
	journal = {International Journal of Pharmaceutics},
	author = {Schammé, Benjamin and Couvrat, Nicolas and Malpeli, Pascal and Dudognon, Emeline and Delbreilh, Laurent and Dupray, Valérie and Dargent, Éric and Coquerel, Gérard},
	year = {2016},
	keywords = {Amorphous, Biclotymol, Glass transition, Milling, Pharmaceuticals, Polyvinylpyrrolidone, Stability},
	pages = {67--73}
}

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