title: Solid state stability and solubility of triethylenetetramine dihydrochloride.
abstract: The API triethylenetetramine dihydrochloride used as an alternative treatment of Wilson's disease is sensitive to water and it exhibits polymorphism. As this may become an issue for the drug formulation, the physical stability has been studied by differential scanning calorimetry, high-pressure thermal analysis, dynamic vapor sorption, and X-ray diffraction as a function of temperature. In addition, high-pressure liquid chromatography and mass spectrometry have been used to study the purity and chemical stability of the API. A pressure-temperature phase diagram of the pure compound has been constructed and it can be concluded that form II is monotropic in relation to form I, which is the only stable solid. The solubilities of the different solid forms have been determined with the help of a temperature - composition phase diagram. The API is very soluble, at 20° C about 10% of the saturated solution with respect to the dihydrate consists of API and the solubility of the pure form I is twice as high. Moreover, it has been shown that at 20°C, a relative humidity above 40% induces the formation of the dihydrate and at 70% a saturated solution appears. At higher temperatures, the formation of the dihydrate appears at lower relative humidity values. A clear link has been established between the API's chemical stability, its physical stability and the relative humidity in the air. Humidity levels above 40% are detrimental to the quality of the API.
authors.affiliation: Matériaux et Santé (EA 401), Faculté de Pharmacie, Université Paris Sud, 5, Rue Jean-Baptiste Clément, 92296, Chatenay-Malabry, France.
authors.forename: Théo
authors.initials: T
authors.lastname: Henriet
authors.affiliation: Laboratoire de chimie analytique, Faculté de Pharmacie, Université de Monastir, rue Ibn Sina, 5000 Monastir, Tunisie, Tunisia.
authors.forename: Inès
authors.initials: I
authors.lastname: Gana
authors.affiliation: Etablissement Pharmaceutique de l'Assistance Publique-Hôpitaux de Paris, Agence Générale des Equipements et Produits de Santé, 7, rue du Fer à Moulin, 75005 Paris, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Ghaddar
authors.affiliation: Grup de Caracterització de Materials (GCM), Departament de Física, Universitat Politècnica de Catalunya, ETSEIB, Diagonal 647, 08028 Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Barrio
authors.affiliation: Normandie Université, Laboratoire SMS ⿿ EA 3233, Université Rouen, F-76821 Mont Saint Aignan Cedex, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Cartigny
authors.affiliation: Matériaux et Santé (EA 401), Faculté de Pharmacie, Université Paris Sud, 5, Rue Jean-Baptiste Clément, 92296, Chatenay-Malabry, France.
authors.forename: Najet
authors.initials: N
authors.lastname: Yagoubi
authors.affiliation: Matériaux et Santé (EA 401), Faculté de Pharmacie, Université Paris Sud, 5, Rue Jean-Baptiste Clément, 92296, Chatenay-Malabry, France; Etablissement Pharmaceutique de l'Assistance Publique-Hôpitaux de Paris, Agence Générale des Equipements et Produits de Santé, 7, rue du Fer à Moulin, 75005 Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Do
authors.affiliation: Grup de Caracterització de Materials (GCM), Departament de Física, Universitat Politècnica de Catalunya, ETSEIB, Diagonal 647, 08028 Barcelona, Spain.
authors.forename: Josep-Lluis
authors.initials: JL
authors.lastname: Tamarit
authors.affiliation: Caractérisation des Matériaux Moléculaires à Activité Thérapeutique (CAMMAT), Faculté de Pharmacie, Université Paris Descartes, 4, avenue de l⿿Observatoire, 75270 Paris cedex 06, France. Electronic address: ivo.rietveld@parisdescartes.fr.
authors.forename: Ivo B
authors.initials: IB
authors.lastname: Rietveld
mesh_terms: D002152:Calorimetry, Differential Scanning / Q000379:methods; D004355:Drug Stability; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D012995:Solubility; D014266:Trientine / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D014266:Trientine
keywords: Chemical stability; Phase behavior; Phase diagram; Phase equilibrium; Physical stability; Thermodynamics; Water vapor