POLYMORPHISM IN ORGANIC MATERIALS
Prof. J.Ll. Tamarit
Coordinator of the Group of Characterization of Materials
Department of Physics and Nuclear Engineering
联系方式：jose.luis.tamarit@upc.edu
Although sometimes neglected by drug marketers, polymorphism is nowadays brought into the limelight, and polymorph screening has become an inescapable requirement for both regulatory and moral considerations. In fact, hunting for the stable polymorph has nowadays become an important part in drug early development. Polymorphism in pharmaceutical solids, considered as molecular materials, has become a significant part of the solid-state chemistry of drugs for practical and regulatory considerations. Nevertheless, this is a phenomenon for which real occurrence (whether naturally or experimentally induced) remains far from being predicted or monitored, and even coherently described, despite being recognized more than two centuries ago as an intriguing question of science. Two scientific fundamental fields are clearly involved in the study of polymorphism, crystallography and thermodynamics. The field of crystallography has progressed rapidly, and new methods, along with improved data collection techniques, operate effectually in crystal structure determination. However, thermodynamic conditions under which any ‘‘experimental’’ polymorph is (or remains) the stable one are hardly inferred from crystal structures alone, even if they permit energy calculations through theoretical (computational) chemistry. The ‘‘Ostwald rule’’
(issued from the two principles of thermodynamics), according to which the more stable polymorph exhibits the smaller vapor pressure, should help finding an answer, but vapor pressure measurements are hardly ever performed. As the Ostwald rule does not even imply calculating inequalities from measured vapor pressure values, the rule should work effectually providing sublimation curves are qualitatively located with respect to each other in some convenient pressure-temperature (p-T) phase diagram. If vapor pressure inequalities can be read on a ‘‘topological’’ p-T graph, the question is whether a simple and reliable method can be found for drawing P-T graphs, from which inequality in vapor pressures can then be inferred at any temperature. It then means that experimental pressure-temperature phase diagrams (and, when possible, pressurevolume-temperature diagrams) can be used as irrefutable proofs for a complete description of polymorphism. The present post-doctoral position will be devoted to the determination of p-T and p-v-T phase diagrams for organic compounds, among them, drugs as materials. References listed below can highlight the studies developed during the last years by the group of Characterization of Materials at the Universitat Politècnica de Catalunya (Barcelona Tech). Detailed information concerning the group can be found in http://gcm.upc.edu/.

References: Polymorphism in drugs
M. Barrio, E. Maccaroni, I. B. Rietveld, L. Malpezzi, N.Masciocchi, R. Céolin, J.Ll. Tamarit
Pressure-Temperature State Diagram forthe Phase Relationships between Benfluorex Hydrochloride
Forms I and II: A Case of Enantiotropic Behavior
Journal of Pharmaceutical Science, in press, DOI: 10.1002/jps.22821 (2012)
N. Mahé, B. Do, B. Nicolaï, I. B. Rietveld, M. Barrio, J.Ll. Tamarit, R. Céolin, Ch. Guéchot, J.M. Teulon
Crystal Structure and Solid-State studies of aged samples ofTienoxolol, an API Designed against
Hypertension
International Journal of Pharmaceutics, 422, 47– 51 (2012)
I. B. Rietveld, M. Barrio, J.Ll. Tamarit, B. Do, R. Céolin
Enantiomer Resolution by pressure increase: inferences from experimental and topological results for the
binary enantiomer system (R)- and (S)-mandelic acid
Journal of Physical Chemistry B, 115 (49), 14698–14703 (2011)
I. B. Rietveld, M. Barrio, J.Ll. Tamarit, B. Nicolaï, J. van de Streek, N. Mahé, R.Ceolin, B. Do.
Dimorphism of the Prodrug L-Tyrosine Ethyl Ester: The Pressure-Temperature State Diagram and the
Crystal Structure of Phase II.
Journal of Pharmaceutical Science, 100, 4774-4782 (2011)
N. Mahé, M.-A. Perrin, M. Barrio, B. Nicolaï, I. B. Rietveld, J.Ll. Tamarit, R. Céolin
Solid-state studies of the triclinic (Z’=2) antiprotozoal drug Ternidazole
Journal of Pharmaceutical Science, 100, 2258-2266 (2011)
I. B. Rietveld, M. Barrio, Ph. Espeau, J. Ll. Tamarit, R. Céolin
Topological and experimental approach to the pressure-temperature-composition phase diagram of the
binary enantiomer system d- and l-camphor
Journal of Physical Chemistry B, 115, 1672–1678 (2011)
B. Nicolaï, N. Mahé, R. Céolin, I. B. Rietveld, M. Barrio, N.Veglio, J. Ll. Tamarit
Tyrosine Alkyl Esters as Prodrug: The Structure and Intermolecular Interactions of L-Tyrosine Methyl
Ester Compared to L-Tyrosine and its Ethyl and n-Butyl Esters
Structural Chemistry, 22, 649-659 (2011)
R Céolin, M. Barrio, J.Ll. Tamarit, N. Veglio, M.A. Perrin, P. Espeau
Liquid-Liquid Miscibility Gaps and Hydrate Formation in Drug-Water Binary Systems: Pressure-
Temperature phase diagram of lidocaine and pressure-temperature-composition phase diagram of the
lidocaine –water system.
Journal of Pharmaceutical Science, 99, 2756-2765 (2010).
M. Barrio, P. Espeau, J. Ll. Tamarit, N. Veglio, R. Céolin
Polymorphism of Progesterone: Relative Stabilities of the Orthorhombic Phases I and II Inferred from
Topological and Experimental Pressure-Temperature Phase Diagrams.
Journal of Pharmaceutical Science, 98, 1657-1670 (2009)
R. Céolin, J. Ll. Tamarit, M. Barrio, D. O. López, B. Nicolaï, M.A. Perrin, P. Espeau, N. Veglio
Overall Monotropic Behavior of a Metastable Phase of Biclotymol, 2,2’-Methylenebis (4-Chloro-3-
Methyl-Isopropylphenol), Inferred from Experimental and Topological Construction of the Related p-
T State Diagram.
Journal of Pharmaceutical Science, 97, 3927-3941 (2008)
References: Polymorphism in organic materials and high-pressure studies
Ll. Mañosa, D. González-Alonso, A. Planes, M. Barrio, J.Ll. Tamarit, I. S. Titov, M. Acet, S. Mahumdar
Inverse barocaloric effect in La-Fe-Si-Co
Nature Communications, 2, 595 (2011)
M. Barrio, Ph. Negrier, J. Ll. Tamarit, D. Mondieig
From high-temperature orientationally disordered mixed crystals to low-temperature complexes
formation in the two-component system (CH3)3CBr+ Cl3CBr
Journal of Physical Chemistry B, 115, 1679–1688 (2011)
Ph. Negrier, M. Barrio, J. Ll. Tamarit, N. Veglio, D. Mondieig
Structure of Phase III and Polymorphism of (CH3)3CBr
Crystal Growth and Design, 10, 2793-2800 (2010)
Ll. Manosa, D. Gonzalez-Alonso, A. Planes, E. Bonnot, M. Barrio, J.Ll. Tamarit, S. Aksoy, M. Acet
Giant solid-state barocaloric effect in the Ni-Mn-In magnetic shape-memory alloy.
Nature Materials Letters, 9,478-481 (2010)
M. Barrio, J. Ll. Tamarit, R. Céolin, L. C. Pardo, Ph. Negrier and D. Mondieig
Connecting the normal pressure equilibria of the two-component system CCl(CH3)3+CBrCl3 to the
pressure-temperature phase diagrams of pure components
Chemical Physics, 358, 156-160 (2009)
R. Levit, M. Barrio, N. Veglio, J. Ll. Tamarit, Ph. Negrier, L.C. Pardo, J. Sanchez-Marcos, and D.
Mondieig.
From the two-component system CBrCl3+CBr4 to the high-pressure properties of CBr4
Journal of Physical Chemistry B, 112, 13916–13922 (2008)
J.Ll. Tamarit, M. Barrio, L.C. Pardo, P. Negrier, D. Mondieig
“High-pressure properties inferred from normal-pressure properties”
Journal of Physics Condensed Matter, 20, 244110 (2008)

POLYMORPHISM IN ORGANIC MATERIALS
Prof. J.Ll. Tamarit
Coordinator of the Group of Characterization of Materials
Department of Physics and Nuclear Engineering
联系方式：jose.luis.tamarit@upc.edu
Although sometimes neglected by drug marketers, polymorphism is nowadays brought into the limelight, and polymorph screening has become an inescapable requirement for both regulatory and moral considerations. In fact, hunting for the stable polymorph has nowadays become an important part in drug early development. Polymorphism in pharmaceutical solids, considered as molecular materials, has become a significant part of the solid-state chemistry of drugs for practical and regulatory considerations. Nevertheless, this is a phenomenon for which real occurrence (whether naturally or experimentally induced) remains far from being predicted or monitored, and even coherently described, despite being recognized more than two centuries ago as an intriguing question of science. Two scientific fundamental fields are clearly involved in the study of polymorphism, crystallography and thermodynamics. The field of crystallography has progressed rapidly, and new methods, along with improved data collection techniques, operate effectually in crystal structure determination. However, thermodynamic conditions under which any ‘‘experimental’’ polymorph is (or remains) the stable one are hardly inferred from crystal structures alone, even if they permit energy calculations through theoretical (computational) chemistry. The ‘‘Ostwald rule’’
(issued from the two principles of thermodynamics), according to which the more stable polymorph exhibits the smaller vapor pressure, should help finding an answer, but vapor pressure measurements are hardly ever performed. As the Ostwald rule does not even imply calculating inequalities from measured vapor pressure values, the rule should work effectually providing sublimation curves are qualitatively located with respect to each other in some convenient pressure-temperature (p-T) phase diagram. If vapor pressure inequalities can be read on a ‘‘topological’’ p-T graph, the question is whether a simple and reliable method can be found for drawing P-T graphs, from which inequality in vapor pressures can then be inferred at any temperature. It then means that experimental pressure-temperature phase diagrams (and, when possible, pressurevolume-temperature diagrams) can be used as irrefutable proofs for a complete description of polymorphism. The present post-doctoral position will be devoted to the determination of p-T and p-v-T phase diagrams for organic compounds, among them, drugs as materials. References listed below can highlight the studies developed during the last years by the group of Characterization of Materials at the Universitat Politècnica de Catalunya (Barcelona Tech). Detailed information concerning the group can be found in http://gcm.upc.edu/.

References: Polymorphism in drugs
M. Barrio, E. Maccaroni, I. B. Rietveld, L. Malpezzi, N.Masciocchi, R. Céolin, J.Ll. Tamarit
Pressure-Temperature State Diagram forthe Phase Relationships between Benfluorex Hydrochloride
Forms I and II: A Case of Enantiotropic Behavior
Journal of Pharmaceutical Science, in press, DOI: 10.1002/jps.22821 (2012)
N. Mahé, B. Do, B. Nicolaï, I. B. Rietveld, M. Barrio, J.Ll. Tamarit, R. Céolin, Ch. Guéchot, J.M. Teulon
Crystal Structure and Solid-State studies of aged samples ofTienoxolol, an API Designed against
Hypertension
International Journal of Pharmaceutics, 422, 47– 51 (2012)
I. B. Rietveld, M. Barrio, J.Ll. Tamarit, B. Do, R. Céolin
Enantiomer Resolution by pressure increase: inferences from experimental and topological results for the
binary enantiomer system (R)- and (S)-mandelic acid
Journal of Physical Chemistry B, 115 (49), 14698–14703 (2011)
I. B. Rietveld, M. Barrio, J.Ll. Tamarit, B. Nicolaï, J. van de Streek, N. Mahé, R.Ceolin, B. Do.
Dimorphism of the Prodrug L-Tyrosine Ethyl Ester: The Pressure-Temperature State Diagram and the
Crystal Structure of Phase II.
Journal of Pharmaceutical Science, 100, 4774-4782 (2011)
N. Mahé, M.-A. Perrin, M. Barrio, B. Nicolaï, I. B. Rietveld, J.Ll. Tamarit, R. Céolin
Solid-state studies of the triclinic (Z’=2) antiprotozoal drug Ternidazole
Journal of Pharmaceutical Science, 100, 2258-2266 (2011)
I. B. Rietveld, M. Barrio, Ph. Espeau, J. Ll. Tamarit, R. Céolin
Topological and experimental approach to the pressure-temperature-composition phase diagram of the
binary enantiomer system d- and l-camphor
Journal of Physical Chemistry B, 115, 1672–1678 (2011)
B. Nicolaï, N. Mahé, R. Céolin, I. B. Rietveld, M. Barrio, N.Veglio, J. Ll. Tamarit
Tyrosine Alkyl Esters as Prodrug: The Structure and Intermolecular Interactions of L-Tyrosine Methyl
Ester Compared to L-Tyrosine and its Ethyl and n-Butyl Esters
Structural Chemistry, 22, 649-659 (2011)
R Céolin, M. Barrio, J.Ll. Tamarit, N. Veglio, M.A. Perrin, P. Espeau
Liquid-Liquid Miscibility Gaps and Hydrate Formation in Drug-Water Binary Systems: Pressure-
Temperature phase diagram of lidocaine and pressure-temperature-composition phase diagram of the
lidocaine –water system.
Journal of Pharmaceutical Science, 99, 2756-2765 (2010).
M. Barrio, P. Espeau, J. Ll. Tamarit, N. Veglio, R. Céolin
Polymorphism of Progesterone: Relative Stabilities of the Orthorhombic Phases I and II Inferred from
Topological and Experimental Pressure-Temperature Phase Diagrams.
Journal of Pharmaceutical Science, 98, 1657-1670 (2009)
R. Céolin, J. Ll. Tamarit, M. Barrio, D. O. López, B. Nicolaï, M.A. Perrin, P. Espeau, N. Veglio
Overall Monotropic Behavior of a Metastable Phase of Biclotymol, 2,2’-Methylenebis (4-Chloro-3-
Methyl-Isopropylphenol), Inferred from Experimental and Topological Construction of the Related p-
T State Diagram.
Journal of Pharmaceutical Science, 97, 3927-3941 (2008)
References: Polymorphism in organic materials and high-pressure studies
Ll. Mañosa, D. González-Alonso, A. Planes, M. Barrio, J.Ll. Tamarit, I. S. Titov, M. Acet, S. Mahumdar
Inverse barocaloric effect in La-Fe-Si-Co
Nature Communications, 2, 595 (2011)
M. Barrio, Ph. Negrier, J. Ll. Tamarit, D. Mondieig
From high-temperature orientationally disordered mixed crystals to low-temperature complexes
formation in the two-component system (CH3)3CBr+ Cl3CBr
Journal of Physical Chemistry B, 115, 1679–1688 (2011)
Ph. Negrier, M. Barrio, J. Ll. Tamarit, N. Veglio, D. Mondieig
Structure of Phase III and Polymorphism of (CH3)3CBr
Crystal Growth and Design, 10, 2793-2800 (2010)
Ll. Manosa, D. Gonzalez-Alonso, A. Planes, E. Bonnot, M. Barrio, J.Ll. Tamarit, S. Aksoy, M. Acet
Giant solid-state barocaloric effect in the Ni-Mn-In magnetic shape-memory alloy.
Nature Materials Letters, 9,478-481 (2010)
M. Barrio, J. Ll. Tamarit, R. Céolin, L. C. Pardo, Ph. Negrier and D. Mondieig
Connecting the normal pressure equilibria of the two-component system CCl(CH3)3+CBrCl3 to the
pressure-temperature phase diagrams of pure components
Chemical Physics, 358, 156-160 (2009)
R. Levit, M. Barrio, N. Veglio, J. Ll. Tamarit, Ph. Negrier, L.C. Pardo, J. Sanchez-Marcos, and D.
Mondieig.
From the two-component system CBrCl3+CBr4 to the high-pressure properties of CBr4
Journal of Physical Chemistry B, 112, 13916–13922 (2008)
J.Ll. Tamarit, M. Barrio, L.C. Pardo, P. Negrier, D. Mondieig
“High-pressure properties inferred from normal-pressure properties”
Journal of Physics Condensed Matter, 20, 244110 (2008)