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Putting pressure on resolving phase relationships between polymorphs of pharmaceuticals To cite this article: Ivo B. Rietveld et al 2017 J. Phys.: Conf. Ser. 950 032009
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AIRAPT IOP Conf. Series: Journal of Physics: Conf. Series 1234567890 950 (2017) 032009
IOP Publishing doi:10.1088/1742-6596/950/3/032009
Putting pressure on resolving phase relationships between polymorphs of pharmaceuticals Ivo B. Rietveld a,*, Maria Barrio b, René Céolin a, Josep-Lluìs Tamarit b a
b
Faculté de Pharmacie, Université Paris Descartes, Paris, France Departament de Fisica I Enginyeria Nuclear, Universitat Politècnica de Catalunya, Barcelona, Spain
Although Bridgman studied crystalline polymorphism as a function of pressure for many small organic molecules, in the pharmaceutical industry, pressure as a variable of the Gibbs energy to determine polymorph stability is rarely used. For a long time, even crystalline polymorphism has been neglected by the pharmaceutical industry, even though they were not unaware of its existence (see chloramphenicol palmitate in 1967).1 Ever since the notorious case of ritonavir and following the adage “better safe than sorry”, the EMEA and the FDA require crystalline polymorph screening and stability testing for new drug molecules. Whereas polymorph screening can be a difficult task, as it depends in part on trial and error, the stability of observed polymorphs is in principle strictly described by thermodynamics. The minimum of the Gibbs energy determines the most stable state and the two characteristic variables of the Gibbs energy are temperature and pressure. Whereas temperature is obviously important for a drug formulation, pressure is considered negligible even if the French name for a tablet is “comprimé” (= compressed). Thus pressure may actually be important in industrial processes such as grinding and compression, but it can also be used as a tool to obtain a complete description of the polymorph behavior, a so-called pressure - temperature phase diagram. Our group uses two approaches to obtain the behavior of a system as a function of pressure. The first method is by direct measurement in a high-pressure differential thermal analyzer and by X-ray under pressure (synchrotron). The second approach is by using standard laboratory measurements such as differential scanning calorimetry and X-ray diffraction as a function of temperature, which in combination with the Clapeyron equation (eq. 1) can lead to pressuretemperature phase diagrams of the polymorphism of drug molecules. dP ΔS ΔH = = dT ΔV T ΔV
(1)
With dP/dT the slope of a phase equilibrium in a pressure - temperature phase diagram, ΔS the entropy associated to the phase change, ΔV the volume change, ΔH the enthalpy change, and T the temperature at which the previous quantities have been obtained. As an example case, the phase diagram of the two polymorphs of ritonavir will be constructed, which surprisingly has never been published before.2 Other examples to demonstrate the topological method (using the Clapeyron equation) and the construction of phase diagrams by direct measurements will be provided in the presentation. It will be shown that although direct measurement may be better, making use of the topological method will lead to the same overall conclusions in the phase behavior of crystalline polymorphs and may be a good alternative, when high-pressure measurements are inaccessible or not feasible. References [1] A.J. Aguiar, J. Jr. Krc, A.W. Kinkel, J.C. Samyn, J. Pharm. Sci. 56, 847 (1967). [2] R. Céolin, I.B. Rietveld, Ann. Pharm. Fr. 73, 22 (2015) *
[email protected] Keywords: ritonavir, topological method, phase diagram, physical stability
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