Rotigotine: Unexpected Polymorphism with Predictable Overall Monotropic Behavior.
Crystallization of polymorphs still has a touch of art, as even prior observations of polymorphs do not guarantee their crystallization. However, once crystals of various polymorphs have been obtained, their relative stabilities can be established with a straightforward thermodynamic approach even if the conclusion will depend on the quality of the experimental data. Rotigotine is an active pharmaceutical ingredient, which has suffered the same setback as Ritonavir: a sudden appearance of a more stable crystalline polymorph than the one used for the formulation. Although the cause of the defect in the formulation was quickly established, the interpretation of the phase behavior of rotigotine has been lacking in clarity. In the present paper, data published in the patents resulting from the discovery of the new polymorph have been used to establish the pressure-temperature phase diagram of the two known solid forms of rotigotine. The analysis clearly demonstrates that form II is the stable solid phase and form I is metastable in the entire pressure-temperature domain: form I is overall monotropic in relation to form II. Thus, it was a sensible decision of European Medicines Agency to ask for a reformulation, as the first formulation was metastable even if crystallization appeared to be very slow.
Caractérisation des Matériaux Moléculaires à Activité Thérapeutique (CAMMAT), Faculté de Pharmacie de Paris, Université Paris Descartes, Paris 75006, France. Electronic address: ivo.rietveld@parisdescartes.fr.
Ivo B
IB
Rietveld
LETIAM, IUT d'Orsay, Université Paris Sud 11, Orsay 91400, France.
René
R
Céolin
D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D004355:Drug Stability; D011312:Pressure; D013696:Temperature; D013764:Tetrahydronaphthalenes / Q000737:chemistry*; D013816:Thermodynamics; D013876:Thiophenes / Q000737:chemistry*
D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine
phase behavior; phase diagram; phase relationship; physical stability; polymorphism; solid state; supersaturation; thermodynamics; topological approach; transition