title: Transformation of an active pharmaceutical ingredient upon high-energy milling: A process-induced disorder in Biclotymol.
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.
authors.affiliation: Normandie Univ, Laboratoire SMS-EA3233, Univ Rouen, F-76821 Mont Saint Aignan, France; Normandie Univ, AMME-LECAP EA 4528 International Lab, Univ Rouen, Avenue de l'Université, BP12, F-76801 Saint Etienne du Rouvray, France. Electronic address: benjamin.schamme1@univ-rouen.fr.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schammé
authors.affiliation: Normandie Univ, Laboratoire SMS-EA3233, Univ Rouen, F-76821 Mont Saint Aignan, France. Electronic address: nicolas.couvrat@univ-rouen.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Couvrat
authors.affiliation: Pharmasynthese (Inabata Group), F-76320 Saint Pierre les Elbeuf, France. Electronic address: pascal.malpeli@inabata.com.
authors.forename: Pascal
authors.initials: P
authors.lastname: Malpeli
authors.affiliation: UMET (Unité Matériaux et Transformations) UMR CNRS 8207, Bat P5, Université Lille 1, F-59655 Villeneuve d'Ascq, France. Electronic address: emeline.dudognon@univ-lille1.fr.
authors.forename: Emeline
authors.initials: E
authors.lastname: Dudognon
authors.affiliation: Normandie Univ, AMME-LECAP EA 4528 International Lab, Univ Rouen, Avenue de l'Université, BP12, F-76801 Saint Etienne du Rouvray, France. Electronic address: laurent.delbreilh@univ-rouen.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Delbreilh
authors.affiliation: Normandie Univ, Laboratoire SMS-EA3233, Univ Rouen, F-76821 Mont Saint Aignan, France. Electronic address: valerie.dupray@univ-rouen.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Dupray
authors.affiliation: Normandie Univ, AMME-LECAP EA 4528 International Lab, Univ Rouen, Avenue de l'Université, BP12, F-76801 Saint Etienne du Rouvray, France. Electronic address: eric.dargent@univ-rouen.fr.
authors.forename: Éric
authors.initials: É
authors.lastname: Dargent
authors.affiliation: Normandie Univ, Laboratoire SMS-EA3233, Univ Rouen, F-76821 Mont Saint Aignan, France. Electronic address: Gerard.Coquerel@univ-rouen.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Coquerel
mesh_terms: D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004355:Drug Stability; D004356:Drug Storage; D010636:Phenols / Q000008:administration & dosage / Q000737:chemistry*; D013696:Temperature; D013816:Thermodynamics; D044366:Transition Temperature; D014961:X-Ray Diffraction
chemical_list: D010636:Phenols; C533149:2,2-methylenebis(4-chloro-3-methyl-isopropylphenol)
keywords: Amorphous; Biclotymol; Biclotymol (PubChem CID71878); Glass transition; Milling; Pharmaceuticals; Polyvinylpyrrolidone; Polyvinylpyrrolidone (PubChem CID6917); Stability