Del Barrio, M.; Huguet, J.; Rietveld, I.; Robert, B.; Céolin, R.; Tamarit, J. Ll. Journal of pharmaceutical sciences Vol. 106, num. 6, p. 1538-1544 DOI: 10.1016/j.xphs.2017.02.003 Data de publicació: 2017-06-01 Article en revista
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.
Robert, B.; Perrin, M.; Del Barrio, M.; Tamarit, J. Ll.; Coquerel, G.; Céolin, R.; Rietveld, I. Journal of pharmaceutical sciences Vol. 105, num. 1, p. 64-70 DOI: 10.1016/j.xphs.2015.10.015 Data de publicació: 2016-01 Article en revista
Two polymorphs of the 1:1 fumarate salt of 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromophenyl ester, developed for the treatment of cognitive symptoms of schizophrenia and Alzheimer disease, have been characterized. The 2 crystal structures have been solved, and their phase relationships have been established. The space group of form I is P21/c with a unit-cell volume of 1811.6 (5) Å3 with Z = 4. The crystals of form I were 2-component nonmerohedral twins. The space group of form II is P21/n with a unit-cell volume of 1818.6 (3) Å3 with Z = 4. Relative stabilities have been inferred from experimental and topological P-T diagrams exhibiting an overall enantiotropic relationship between forms I and II although the solid–solid transition has never been observed. The slope of the I-II equilibrium in the P-T diagram is negative, form II is the stable phase below the solid–solid transition temperature of 371 K, and form I exhibits a stable melting equilibrium. The I-II transition temperature has been obtained from the intersection of the sublimation curves of the 2 solid forms.
Perrin, M.; Bauer, M.; Del Barrio, M.; Tamarit, J. Ll.; Céolin, R.; Rietveld, I. Journal of pharmaceutical sciences Vol. 102, num. 7, p. 2311-2321 DOI: 10.1002/jps.23612 Data de publicació: 2013-05-20 Article en revista
Crystalline polymorphism occurs frequently in the solid state of active pharmaceutical
ingredients, and this is problematic for the development of a suitable dose form. Rimonabant,
an active pharmaceutical ingredient developed by Sanofi and discontinued because
of side effects, exhibits dimorphism; both solid forms have nearly the same melting temperatures,
melting enthalpies, and specific volumes. Although the problem may well be academic
from an industrial point of view, the present case demonstrates the usefulness of constructing
pressure–temperature phase diagrams by direct measurement as well as by topological
approach. The system is overall monotropic and form II is the more stable solid form. Interestingly,
the more stable form does not possess any hydrogen bonds, whereas the less stable one
Del Barrio, M.; Maccaroni, E.; Rietveld, I.; Macpezzi, L.; Masciocchi, N.; Céolin, R.; Tamarit, J. Ll. Journal of pharmaceutical sciences Vol. 101, num. 3, p. 1072-1078 DOI: 10.1002/jps.22821 Data de publicació: 2012-03 Article en revista
The active pharmaceutical ingredient racemic benfluorex hydrochloride (benfluorex–HCl) has an interesting phase behavior due to an elusive solid–solid phase transition. The stability hierarchy between different phases is often determined based on heat-related experiments only or slurry interconversion. It is shown that if pressure and volume are taken into account, not only the phase equilibria are correctly positioned in the pressure–temperature phase diagram, but the experimental data also improves. Thus, it has been found that the racemic benfluorex–HCl is enantiotropic under “ordinary conditions” with polymorph II and polymorph I, respectively, being the low- and the high-temperature phases. Above ∼151 MPa, the system becomes monotropic and polymorph II is the single stable phase.
Rietveld, I.; Del Barrio, M.; Tamarit, J. Ll.; Nicolaï, B.; Van de Streek, J.; Mahé, N.; Céolin, R.; Do, B. Journal of pharmaceutical sciences Vol. 100, num. 11, p. 4774-4782 DOI: 10.1002/jps.22672 Data de publicació: 2011-06-22 Article en revista
Mahé, N.; Perrin, M.; Del Barrio, M.; Nicolaï, B.; Rietveld, I.; Tamarit, J. Ll.; Céolin, R. Journal of pharmaceutical sciences Vol. 100, num. 6, p. 2258-2266 DOI: 10.1002/jps Data de publicació: 2011-05-01 Article en revista
The pressure–temperature (P–T) melting curve of lidocaine was determined
(dP/dT¼3.56MPaK 1), and the lidocaine–water system was investigated as a function of
temperature and pressure. The lidocaine–water system exhibits a monotectic equilibrium at
321K (ordinary pressure) whose temperature increases as the pressure increases until the two
liquids become miscible. A hydrate, unstable at ordinary pressure, was shown to form, on
increasing the pressure, from about 70MPa at low temperatures (200–300 K). The thermodynamic
conditions of its stability were inferred from the location of the three-phase equilibria
involving the hydrate in the lidocaine–water pressure–temperature–mole fraction (P–T–x) diagram.
Del Barrio, M.; Espeau, P.; Tamarit, J. Ll.; Perrin, M.; Veglio, N.; Céolin, R. Journal of pharmaceutical sciences Vol. 98, num. 5, p. 1657-1670 DOI: 10.1002/jps.21541 Data de publicació: 2009-05 Article en revista
Céolin, R.; Tamarit, J. Ll.; Del Barrio, M.; Lopez, D.; Nicolaï, B.; Perrin, M.; Espeau, P.; Veglio, N. Journal of pharmaceutical sciences Vol. 97, p. 3927-3941 Data de publicació: 2008-08 Article en revista