Journal of Thermal Analysis and Calorimetry

, Volume 102, Issue 1, pp 211–216 | Cite as

Polymorphism and solvation of indomethacin

Characterization of an indomethacin–tetrahydrofuran solvate leading to phase I
  • Béatrice Nicolaï
  • René Céolin
  • Ivo B. Rietveld


Indomethacin crystallizes from solutions in tetrahydrofuran as a solvate exhibiting the mole ratio 1 indomethacin:2 tetrahydrofuran. Upon heating, desolvation into indomethacin phase I occurs through partial amorphization and transitory formation of a phase, which is different from the crystallographically known polymorphs. The X-ray powder diffraction pattern of the solvate was tentatively indexed on a triclinic lattice (a = 31.454(5) Å, b = 17.883(3) Å, c = 10.551(2) Å, α = 70.55(2)°, β = 105.31(2)°, γ = 136.70(1)°). Assuming Z = 6 (1 indomethacin + 2 tetrahydrofuran) formula units per unit cell, the solvate’s specific volume is similar to the value calculated using additivity.


Indomethacin Polymorphism Solvation Indomethacin–tetrahydrofuran solvate 




  1. 1.
    Yamamoto H. 1-Acyl-indoles. II. A new syntheses of 1-(ion-chlorobenzoyl)-5-methoxy-3-indolylacetic acid and its polymorphism. Chem Pharm Bull (Tokyo). 1968;16:17–9.Google Scholar
  2. 2.
    Borka L. Polymorphism of indomethacine. New modifications, their melting behavior, and solubility. Acta Pharm Suec. 1974;11:295–303.Google Scholar
  3. 3.
    Crowley KJ, Zografi G. Cryogenic grinding of indomethacin polymorphs and solvates: assessment of amorphous phase formation and amorphous phase physical stability. J Pharm Sci. 2002;91:492–507.CrossRefGoogle Scholar
  4. 4.
    Spychala S, Butkiewicz K, Pakula R, Pichnej L. Polymorphism of indomethacin. Part II. Identification and rapid determination of polymorphic forms of indomethacin by IR spectrometry. Pol J Pharmacol Pharm. 1977;29:157–60.Google Scholar
  5. 5.
    Kaneniwa N, Otsuka M, Hayashi T. Physicochemical characterization of indomethacin polymorphs and the transformation kinetics in ethanol. Chem Pharm Bull. 1985;33:3447–55.Google Scholar
  6. 6.
    Yoshioka M, Hancock BC, Zografi G. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J Pharm Sci. 1994;83:1700–5.CrossRefGoogle Scholar
  7. 7.
    Legendre B, Feutelais Y. Polymorphic and thermodynamic study of indomethacin. J Therm Anal Calorim. 2004;76:255–64.CrossRefGoogle Scholar
  8. 8.
    Hamdi N, Feutelais Y, Yagoubi N, de Girolamo D, Legendre B. Solvates of indomethacin. J Therm Anal Calorim. 2004;76:985–1001.CrossRefGoogle Scholar
  9. 9.
    Pan X, Julian T, Augsburger L. Quantitative measurement of indomethacin crystallinity in indomethacin-silica gel binary system using differential scanning calorimetry and X-ray powder diffractometry. AAPS PharmSciTech. 2006;7:E11.CrossRefGoogle Scholar
  10. 10.
    Kistenmacher TJ, Marsh RE. Crystal and molecular structure of an antiinflammatory agent, indomethacin, 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid. J Am Chem Soc. 1972;94:1340–5.CrossRefGoogle Scholar
  11. 11.
    Galdecki Z, Glowka ML. Crystal and molecular structure of the gamma-form of 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid. A comparison of results based on photographic data with previous results obtained by means of a single crystal diffractometer. Rocz Chem. 1976;50:1139–48.Google Scholar
  12. 12.
    Cox PJ, Manson PL. γ-Indomethacin at 120 K. Acta Crystallogr Sect E Struct Rep Online. 2003;E59:o986–8.CrossRefGoogle Scholar
  13. 13.
    Chen X, Morris KR, Griesser UJ, Byrn SR, Stowell JG. Reactivity differences of indomethacin solid forms with ammonia gas. J Am Chem Soc. 2002;124:15012–9.CrossRefGoogle Scholar
  14. 14.
    Cox PJ, Manson PL. Indomethacin tert-butanol solvate at 120 K. Acta Crystallogr Sect E Struct Rep Online. 2003;E59:o1189–91.CrossRefGoogle Scholar
  15. 15.
    Slavin PA, Sheen DB, Shepherd EEA, Sherwood JN, Feeder N, Docherty R, et al. Morphological evaluation of the gamma-polymorph of indomethacin. J Cryst Growth. 2002;237–239:300–5.CrossRefGoogle Scholar
  16. 16.
    Rodriguez-Carvajal J. Recent advances in magnetic structure determination by neutron powder diffraction. Physica B (Amsterdam). 1993;192:55–69.Google Scholar
  17. 17.
    Rodriguez-Carvajal J. Commission on powder diffraction (IUCr). Newsletter. 2001;26:12.Google Scholar
  18. 18.
    Boultif A, Louer D. Powder pattern indexing with the dichotomy method. J Appl Crystallogr. 2004;37:724–31.CrossRefGoogle Scholar
  19. 19.
    Luger P, Buschmann J. Twist conformation of tetrahydrofuran in the crystal form. Angew Chem Int Ed. 1983;22:410–1.Google Scholar
  20. 20.
    Steininger R, Bilgram JH, Gramlich V, Petter W. Crystal growth, crystal optics, and crystal structure of the phase IV of tertiary-butyl alcohol. Z Kristallogr. 1989;187:1–13.CrossRefGoogle Scholar
  21. 21.
    McGregor PA, Allan DR, Parsons S, Clark SJ. Hexamer formation in tertiary butyl alcohol (2-methyl-2-propanol, C4H10O). Acta Crystallogr Sect B Struct Sci. 2006;B62:599–605.CrossRefGoogle Scholar

Copyright information

© Akadémiai Kiadó, Budapest, Hungary 2009

Authors and Affiliations

  • Béatrice Nicolaï
    • 1
  • René Céolin
    • 1
  • Ivo B. Rietveld
    • 1
  1. 1.Laboratoire de Chimie Physique, EA4066, Faculté des Sciences Pharmaceutiques et BiologiquesUniversité Paris DescartesParisFrance

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