title: An Integrated View of the Influence of Temperature, Pressure, and Humidity on the Stability of Trimorphic Cysteamine Hydrochloride.
abstract: Understanding the phase behavior of pharmaceuticals is important for dosage form development and regulatory requirements, in particular after the incident with ritonavir. In the present paper, a comprehensive study of the solid-state phase behavior of cysteamine hydrochloride used in the treatment of nephropathic cystinosis and recently granted orphan designation by the European Commission is presented employing (high-pressure) calorimetry, water vapor sorption, and X-ray diffraction as a function of temperature. A new crystal form (I2/a, form III) has been discovered, and its structure has been solved by X-ray powder diffraction, while two other crystalline forms are already known. The relative thermodynamic stabilities of the commercial form I and of the newly discovered form III have been established; they possess an overall enantiotropic phase relationship, with form I stable at room temperature and form III stable above 37 °C. Its melting temperature was found at 67.3 ± 0.5 °C. Cysteamine hydrochloride is hygroscopic and immediately forms a concentrated saturated solution in water with a surprisingly high concentration of 47.5 mol % above a relative humidity of 35%. No hydrate has been observed. A temperature-composition phase diagram is presented that has been obtained with the unary pressure-temperature phase diagram, measurements, and calculations. For development, form I would be the best form to use in any solid dosage form, which should be thoroughly protected against humidity.
authors.affiliation: †Caractérisation des Matériaux Moléculaires à Activité Thérapeutique (CAMMAT), Faculté de Pharmacie, Université Paris Descartes, 4, Avenue de l'Observatoire, 75006 Paris, France.|‡Laboratoire de chimie analytique, Faculté de Pharmacie, Université de Monastir, rue Ibn Sina, 5000 Monastir, Tunisie.
authors.forename: Inès
authors.initials: I
authors.lastname: Gana
authors.affiliation: §Grup de Caracterització de Materials (GCM), Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, ETSEIB, Diagonal 647, 08028 Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Barrio
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: †Caractérisation des Matériaux Moléculaires à Activité Thérapeutique (CAMMAT), Faculté de Pharmacie, Université Paris Descartes, 4, Avenue de l'Observatoire, 75006 Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Nicolaï
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: Bernard
authors.initials: B
authors.lastname: Do
authors.affiliation: §Grup de Caracterització de Materials (GCM), Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, ETSEIB, Diagonal 647, 08028 Barcelona, Spain.
authors.forename: Josep-Lluís
authors.initials: JL
authors.lastname: Tamarit
authors.affiliation: ‡Laboratoire de chimie analytique, Faculté de Pharmacie, Université de Monastir, rue Ibn Sina, 5000 Monastir, Tunisie.
authors.forename: Fathi
authors.initials: F
authors.lastname: Safta
authors.affiliation: †Caractérisation des Matériaux Moléculaires à Activité Thérapeutique (CAMMAT), Faculté de Pharmacie, Université Paris Descartes, 4, Avenue de l'Observatoire, 75006 Paris, France.
authors.forename: Ivo B
authors.initials: IB
authors.lastname: Rietveld
mesh_terms: D002152:Calorimetry, Differential Scanning / Q000379:methods; D003460:Crystallization / Q000379:methods; D003543:Cysteamine / Q000737:chemistry*; D004355:Drug Stability; D006813:Humidity; D011312:Pressure; D013696:Temperature; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D014867:Water; D003543:Cysteamine
keywords: crystalline trimorphism; cysteamine hydrochloride; enantiotropic phase relationship; eutectic; hygroscopic; intermolecular interactions; phase diagram; phase stability; thermal expansion