Pharmaceutical Research

, Volume 25, Issue 12, pp 2853–2858 | Cite as

Evidence for a New Crystalline Phase of Racemic Ibuprofen

  • Emeline Dudognon
  • Florence Danède
  • Marc Descamps
  • Natália T. Correia
Research Paper



The aim of this work is to search for the existence of crystalline polymorphism for racemic Ibuprofen.


The pharmaceutical material was studied by X-ray diffraction to identify crystalline phases, and by Differential Scanning Calorimetry to follow the thermodynamic evolution of these forms versus temperature.


Results presented here show that, in addition to the already known conventional crystalline phase, whose nucleation domain extends between 233 K and 263 K and which melts at 349 K, racemic Ibuprofen can crystallize in another polymorphic phase. The nucleation of this new polymorphic variety is triggered by a stay at least 60 degrees below the glass transition temperature Tg of Ibuprofen (Tg = 228 K). This nucleation is probably of heterogeneous type. The new phase melts well below the conventional one, i.e. at 290 K. A schematic free energy diagram is provided allowing establishing the relative thermodynamic stability of the two polymorphs.


These results establish, for the first time, that Ibuprofen can exist under two different crystalline phases which constitute a monotropic system, the new form being metastable.


glass transition ibuprofen nucleation polymorphism 



This work is supported by the Hubert Curien partnership PESSOA grant. Region Nord/Pas de Calais and an INTERREG (FEDER) grant helped in providing X-ray equipment.


  1. 1.
    J. Bernstein. Polymorphism in molecular crystals. Oxford Science, Oxford, 2002.Google Scholar
  2. 2.
    S. S. Adams, P. Bresloff, and C. G. Manson. Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of ibuprofen. J. Pharm. Pharmacol. 28:256–257 (1976).PubMedGoogle Scholar
  3. 3.
    N. Rasenack, and B. B. W. Müller. Properties of Ibuprofen crystallized under various conditiond: a comparative study. Drug. Dev. Ind. Pharm. 28:1077–1089 (2002). doi: 10.1081/DDC-120014575.PubMedCrossRefGoogle Scholar
  4. 4.
    N. Rasenack, and B. B. W. Müller. Crystal habit and tableting behavior. Int. J. Pharm. 244:45–57 (2002). doi: 10.1016/S0378-5173(02)00296-X.PubMedCrossRefGoogle Scholar
  5. 5.
    A. H. Nada, S. M. Al-Saidan, and B. W. Mueller. Crystal modification for improving physical and chemical properties of ibuprofen. Pharm. Technol. 29:90–101 (2005). (Nov).Google Scholar
  6. 6.
    T. Lee, C. S. Kuo, and Y. H. Chen. Solubility, polymorphism, crystallinity, and crystal habit of acetaminophen and ibuprofen. Pharm. Technol. 30:72–92 (2006). (Oct.).Google Scholar
  7. 7.
    J. F. McConnell. 2-(4-Isobuthylphenyl) propionic acid. C13 H18 O2 ibuprofen or prufen. Cryst. Struct. Comm. 3:73–75 (1974).Google Scholar
  8. 8.
    N. Shankland, C. C. Wilson, A. J. Florence, and P. J. Cox. Refinement of ibuprofen at 100 K by single-crystal pulsed neutron diffraction. Acta Cryst. C53:951–954 (1997). doi: 10.1107/S0108270197003193.Google Scholar
  9. 9.
    S. Lerdkanchanaporn, and D. Dollimore. A thermal analysis study of ibuprofen. J. Therm. Anal. 49:879–886 (1997). doi: 10.1007/BF01996773.CrossRefGoogle Scholar
  10. 10.
    A. J. Romero, L. Savastano, and C. T. Rhodes. Monitoring crystal modifications in systems containing ibuprofen. Int. J. Pharm. 99:125–134 (1993). doi: 10.1016/0378-5173(93)90354-I.CrossRefGoogle Scholar
  11. 11.
    F. Xu, L. X. Sun, Z. C. Tan, J. G. Liang, and R. L. Li. Thermodynamic study of ibuprofen by adiabatic calorimetry and thermal analysis. Thermochim. Acta. 412:33–37 (2004). doi: 10.1016/j.tca.2003.08.021.CrossRefGoogle Scholar
  12. 12.
    A. R. Brás, M. Dionisio, and N. T. Correia. Molecular motions in amorphous pharmaceuticals. In Proceedings of IWCS 2007, AIP CP 982:91–97 (2008).Google Scholar
  13. 13.
    G. P. Johari, S. Kim, and R. M. Shanker. Dielectric relaxation and crystallization of ultraviscous melt and glassy states of Aspirin, Ibuprofen, Progesterone, and Quinidine. J. Pharm. Sci. 96:1159–1175 (2007). doi: 10.1002/jps.20921.PubMedCrossRefGoogle Scholar
  14. 14.
    K. F. Kelton. Crystal nucleation in liquids and glasses. In H. Ehrenreich, and D. Turnbull (eds.), Solid State Physics, Academic, San Diego, 1991, pp. 75–177.Google Scholar
  15. 15.
    J. E. Shelby. Introduction to glassy science and applications. Royal Society of Chemistry, Cambridge, United Kingdom, 2002.Google Scholar
  16. 16.
    N. V. Phadnis, and R. Suryanarayanan. Simultaneous quantification of an enantiomer and the racemic compound of ibuprofen by X-ray powder diffarctometry. Pharm. Res. 14:1176–1180 (1997). doi: 10.1023/A:1012198605891.PubMedCrossRefGoogle Scholar
  17. 17.
    A. Guinier. X-ray crystallographic technology. Hilgerand Watts, Hilger Division, London, 1952.Google Scholar
  18. 18.
    A. Burger, and R. Ramberger. On the polymorphism of pharmaceuticals and other molecular crystals. I. Theory of thermodynamic rules. Mikrochimica Acta. II:259–271 (1971).Google Scholar
  19. 19.
    A. Burger, and R. Ramberger. On the polymorphism of pharmaceuticals and other molecular crystals. I. Applicability of thermodynamic rules. Mikrochimica Acta. II:273–316 (1971).Google Scholar
  20. 20.
    F. Paladi, and M. Oguni. Generation and extinction of crystal nuclei in an extremely non-equilibrium glassy state of salol. J. Phys. Condens. Mater. Surf. Interfaces Biophys. 15:3909–3917 (2003). doi: 10.1088/0953-8984/15/23/306.Google Scholar
  21. 21.
    F. Paladi, and M. Oguni. Anomalous generation and extinction of crystal nuclei in nonequilibrium supercooled liquid o-benzylphenol. Phys. Rev. B. 65:144202 (2002). doi: 10.1103/PhysRevB.65.144202.CrossRefGoogle Scholar
  22. 22.
    V. Legrand, M. Descamps, and C. Alba-Simionesco. Glass-forming meta-toluidine: a thermal and structural analysis of its crystalline polymorphism and devitrification. Thermochim. Acta. 307:77–83 (1997). doi: 10.1016/S0040-6031(97)00271-2.CrossRefGoogle Scholar
  23. 23.
    R. Becker, and W. Döring. Kinetische Behandlung der Keimbildung in übersätttigten Dämpfen. Annalen der Physik. 24:719–752 (1935). doi: 10.1002/andp.19354160806.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Emeline Dudognon
    • 1
  • Florence Danède
    • 1
  • Marc Descamps
    • 1
  • Natália T. Correia
    • 2
  1. 1.Laboratoire de Dynamique et Structure des Matériaux Moléculaires, UMR CNRS 8024, ERT 1066Université des Sciences et Technologies de LilleVilleneuve d’Ascq CedexFrance
  2. 2.REQUIMTE, Departamento de QuímicaFaculdade de Ciências e Tecnologia da Universidade Nova de LisboaCaparicaPortugal

Personalised recommendations