title: Crystallization kinetics and molecular mobility of an amorphous active pharmaceutical ingredient: A case study with Biclotymol.
abstract: The present case study focuses on the crystallization kinetics and molecular mobility of an amorphous mouth and throat drug namely Biclotymol, through differential scanning calorimetry (DSC), temperature resolved X-ray powder diffraction (TR-XRPD) and hot stage microscopy (HSM). Kinetics of crystallization above the glass transition through isothermal and non-isothermal cold crystallization were considered. Avrami model was used for isothermal crystallization process. Non-isothermal cold crystallization was investigated through Augis and Bennett model. Differences between crystallization processes have been ascribed to a site-saturated nucleation mechanism of the metastable form, confirmed by optical microscopy images. Regarding molecular mobility, a feature of molecular dynamics in glass-forming liquids as thermodynamic fragility index m was determined through calorimetric measurements. It turned out to be around m=100, describing Biclotymol as a fragile glass-former for Angell's classification. Relatively long-term stability of amorphous Biclotymol above Tg was analyzed indirectly by calorimetric monitoring to evaluate thermodynamic parameters and crystallization behavior of glassy Biclotymol. Within eight months of storage above Tg (T=Tg+2°C), amorphous Biclotymol does not show a strong inclination to crystallize and forms a relatively stable glass. This case study, involving a multidisciplinary approach, points out the importance of continuing looking for stability predictors.
authors.affiliation: Crystal Genesis Unit, EA 3233 SMS, Normandie Université, Université de Rouen, 76821 Mont-Saint-Aignan Cedex, France; AMME-LECAP, EA 4528 International Lab, Av. de l'Université, BP12, Normandie, Université and INSA Rouen, 76801 Saint-Étienne-du-Rouvray, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schammé
authors.affiliation: Crystal Genesis Unit, EA 3233 SMS, Normandie Université, Université de Rouen, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Couvrat
authors.affiliation: Pharmasynthese (Inabata Group), Saint-Pierre-lès-Elbeuf 76320, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Malpeli
authors.affiliation: AMME-LECAP, EA 4528 International Lab, Av. de l'Université, BP12, Normandie, Université and INSA Rouen, 76801 Saint-Étienne-du-Rouvray, France. Electronic address: laurent.delbreilh@univ-rouen.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Delbreilh
authors.affiliation: Crystal Genesis Unit, EA 3233 SMS, Normandie Université, Université de Rouen, 76821 Mont-Saint-Aignan Cedex, France. Electronic address: valerie.dupray@univ-rouen.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Dupray
authors.affiliation: AMME-LECAP, EA 4528 International Lab, Av. de l'Université, BP12, Normandie, Université and INSA Rouen, 76801 Saint-Étienne-du-Rouvray, France.
authors.forename: Éric
authors.initials: É
authors.lastname: Dargent
authors.affiliation: Crystal Genesis Unit, EA 3233 SMS, Normandie Université, Université de Rouen, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Coquerel
mesh_terms: D002152:Calorimetry, Differential Scanning / Q000379:methods; D003080:Cold Temperature; D003460:Crystallization; D005898:Glass / Q000737:chemistry; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010636:Phenols / Q000737:chemistry*; D011208:Powders / Q000737:chemistry; D013816:Thermodynamics; D044366:Transition Temperature; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D004364:Pharmaceutical Preparations; D010636:Phenols; D011208:Powders; C533149:2,2-methylenebis(4-chloro-3-methyl-isopropylphenol)
keywords: Amorphous; Biclotymol; Biclotymol (PubChem CID: 71878); Crystallization; Molecular mobility; Nucleation; Stability