title: The Pressure-Temperature Phase Diagram of Metacetamol and Its Comparison to the Phase Diagram of Paracetamol.
abstract: Understanding the polymorphic behavior of active pharmaceutical ingredients is important for formulation purposes and regulatory reasons. Metacetamol is an isomer of paracetamol and it similarly exhibits polymorphism. In the present article, it has been found that one of the polymorphs of metacetamol is only stable under increased pressure, which has led to the conclusion that metacetamol like paracetamol is a monotropic system under ordinary (= laboratory) conditions and that it becomes enantiotropic under pressure with the I-II-L triple point coordinates for metacetamol TI-II-L= 535 ± 10 K and PI-II-L= 692 ± 70 MPa. However, whereas for paracetamol the enantiotropy under pressure can be foreseen, because the metastable polymorph is denser, in the case of metacetamol this is not possible, as the metastable polymorph is less dense than the stable one. The existence of the stability domain for the less dense polymorph of metacetamol can only be demonstrated by the construction of the topological phase diagram as presented in this article. It is a delicate interplay between the specific volume differences and the enthalpy differences causing the stability domain of the less dense polymorph to be sandwiched between the denser polymorph and the liquid. Metacetamol shares this behavior with bicalutamide and fluoxetine nitrate.
authors.affiliation: Grup de Caracterizació de Materials, Departament de Fisica, EEBE and Barcelona Research Center in Multiscale Science and Engineering, Universitat Politècnica de Catalunya, Eduard Maristany, 10-14, 08019 Barcelona, Catalonia, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Barrio
authors.affiliation: Grup de Caracterizació de Materials, Departament de Fisica, EEBE and Barcelona Research Center in Multiscale Science and Engineering, Universitat Politècnica de Catalunya, Eduard Maristany, 10-14, 08019 Barcelona, Catalonia, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Huguet
authors.affiliation: Laboratoire de Chimie Physique, CAMMAT, Faculté de Pharmacie, Université Paris Descartes, 4 avenue de l'Observatoire, Paris 75006, France. Electronic address: ivo.rietveld@parisdescartes.fr.
authors.forename: Ivo B
authors.initials: IB
authors.lastname: Rietveld
authors.affiliation: Sanofi R&D, Pharmaceutics Development Platform/Analytical Sciences/Solid State group, 13 quai Jules Guesde, Vitry sur Seine F-94400, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Robert
authors.affiliation: Grup de Caracterizació de Materials, Departament de Fisica, EEBE and Barcelona Research Center in Multiscale Science and Engineering, Universitat Politècnica de Catalunya, Eduard Maristany, 10-14, 08019 Barcelona, Catalonia, Spain; LETIAM, EA7357, IUT Orsay, Université Paris Sud, rue Noetzlin, Orsay Cedex 91405, France.
authors.forename: René
authors.initials: R
authors.lastname: Céolin
authors.affiliation: Grup de Caracterizació de Materials, Departament de Fisica, EEBE and Barcelona Research Center in Multiscale Science and Engineering, Universitat Politècnica de Catalunya, Eduard Maristany, 10-14, 08019 Barcelona, Catalonia, Spain.
authors.forename: Josep-Lluis
authors.initials: JL
authors.lastname: Tamarit
mesh_terms: D000082:Acetaminophen / Q000737:chemistry*; D018712:Analgesics, Non-Narcotic / Q000737:chemistry*; D003460:Crystallization; D004355:Drug Stability; D007536:Isomerism; D044367:Phase Transition; D011312:Pressure; D013696:Temperature; D013816:Thermodynamics
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen
keywords: calorimetry; crystal polymorphism; phase behavior; physical characterization; physical stability; solid state; thermal expansion; thermodynamics; topological phase diagram