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Pharmaceutical Research

, Volume 23, Issue 10, pp 2375–2380 | Cite as

Additive-Induced Metastable Single Crystal of Mefenamic Acid

  • Eun Hee Lee
  • Stephen R. Byrn
  • M. Teresa Carvajal
Research Paper

Purpose

To utilize additives to develop a strategy and a method to grow single crystals that allow structure determination of a metastable form of a drug.

Materials and Methods

The metastable form of mefenamic acid (MFA) was grown in the presence of various amounts of the structurally similar additive flufenamic acid (FFA) in ethanol. Single crystal X-ray analysis was performed on the single crystals of MFA II that were formed. The solubility of MFA in the presence of FFA was measured to elucidate the mechanism of MFA II formation.

Results

A supersaturated solution of MFA in ethanol produced the metastable form using FFA as an additive. Ethanol–water mixtures and toluene were also used to investigate the relationships between form produced and solvent since these two solvent systems do not produce MFA II.

Conclusions

Additives can be used to obtain the metastable form of pharmaceutical compounds, and the relationships between molecules and solvent as well as between host and guest molecules are critical to obtaining the desired form.

Key words

flufenamic acid mefenamic acid polymorph selection single crystal XRPD 

Notes

Acknowledgments

Eun Hee Lee thanks Dr. Phillip E. Fanwick for crystal structure solution of MFA II. The financially support from the Purdue-Michigan Program on the Chemical and Physical Stability of Pharmaceutical Solids is acknowledged.

References

  1. 1.
    S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell. Solid-State Chemistry of Drugs. Second Edition. SSCI Inc. (1999).Google Scholar
  2. 2.
    U.S. Food and Drug Administration. Meeting Scientific Considerations of Polymorphism in Pharmaceutical Solids: Abbreviated New Drug Applications. http://www.fda.gov/ohrms/dockets/ac/02/briefing/3900B1_04_Polymorphism.htm (accessed 12/15/2005), part of U.S. Food and Drug Administration. http://www.fda.gov (accessed 12/15/2005).
  3. 3.
    S. R. Vippagunta, H. G. Brittain, and D. J. W. Grant. Crystalline solids. Adv. Drug Deliv. Rev. 48: 3–26 (2001).PubMedCrossRefGoogle Scholar
  4. 4.
    L. Addadi, Z. Berkovitch-Yellin, N. Domb, E. Gait, M. Lahav, and L. Leiserowitz. Resolution of conglomerates by stereoselective habit modifications. Nature. 296:21–26 (1982).CrossRefGoogle Scholar
  5. 5.
    Z. Berkovitch-Yellin, L. Addadi, M. Idelson, L. Leiserowitz, and M. Lahav. Absolute configuration of chiral polar crystals. Nature. 296:27–34 (1982).CrossRefGoogle Scholar
  6. 6.
    L. Addadi, Z. Berkovitch-Yellin, I. Weissbuch, M. Lahav, and L. Leiserowitz. The use of “Enantiopolar” directions in centrosymmetric crystals for direct assignment of absolute configuration of chiral molecules: Application to the system serine/threonine. J. Am. Chem. Soc. 104:2075–2077 (1982).CrossRefGoogle Scholar
  7. 7.
    I. Weissbuch, L. Addadi, Z. Berkovitch-Yellin, E. Gati, S. Weinstein, M. Lahav, and L. Leiserowitz. Centrosymmetric crystals for the direct assignment of the absolute configuration of chiral molecules. Application to the á-amino acid by their effect on glycine crystals. J. Am. Chem. Soc. 105:6615–6621 (1983).CrossRefGoogle Scholar
  8. 8.
    R. J. Flower. Drugs which inhibit prostaglandin biosynthesis. Pharmacol. Rev. 26:33–67 (1974).PubMedGoogle Scholar
  9. 9.
    S. L. A. Munro and D. J. Craik. NMR conformational studies of fenamate non-steroidal anti-inflammatory drugs. Magn. Reson. Chem. 32:335–342 (1994).CrossRefGoogle Scholar
  10. 10.
    J. J. Lozano, R. Pouplanar, M. Lopez, and J. Ruiz. Conformational analysis of the anti-inflammatory fenamates: a molecular mechanics and semiempirical molecular orbital study. J. Mol. Struct. (Theochem). 335:215–227 (1995).CrossRefGoogle Scholar
  11. 11.
    V. Dhanaraj and M. Vijayan. Structural studies of analgesics and their interactions. XII. Structure and interactions of anti-inflammtory fenamtes. A concerted crystallographic and theoretical conformational study. Acta Crystallogr. B. 44:406–412 (1988).PubMedCrossRefGoogle Scholar
  12. 12.
    A. J. Aguiar and J. E. Zelmer. Dissolution behavior of polymorphs of chloramphenicol palmitate and mefenamic acid. J. Pharm. Sci. 58:83–987 (1969).Google Scholar
  13. 13.
    S. Romero, B. Escalera, and P. Bustamante. Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures. Int. J. Pharm. 178:193–202 (1999).PubMedCrossRefGoogle Scholar
  14. 14.
    A. Adam, L. Schrimpl, and P. C. Schmidt. Some physicochemical properties of mefenamic acid. Drug Dev. Ind. Pharm. 26:477–487 (2000).PubMedCrossRefGoogle Scholar
  15. 15.
    A. Adam, L. Schrimpl, and P. C. Schmidt. Factors influencing capping and cracking of mefenamic acid tablets. Drug Dev. Ind. Pharm. 26:489–497 (2000).PubMedCrossRefGoogle Scholar
  16. 16.
    R. Panchagnula, P. Sundaramurthuy, O. Pillai, S. Agrawal, and Y. Ashok Raj. Solid-state characterization of mefenamic acid. J. Pharm. Sci. 93:1019–1029 (2004).PubMedCrossRefGoogle Scholar
  17. 17.
    T. Umeda, N. Ohnishi, T. Yokoyama, T. Kuroda, Y. Kita, K. Kuroda, E. Tatsumi, and Y. Matsuda. A kinetic study on the isothermal transition of polymorphic forms of tolbutamide and mefenamic acid in the solid state at high temperatures. Chem. Pharm. Bull. 33:2073–2078 (1985).PubMedGoogle Scholar
  18. 18.
    J. F. McConnell and F. Z. Company, N-(2,3-xylyl) anthranilic acid, C15H15NO2 mefenamic acid, Cryst. Struct. Commun. 5:861–864 (1976).Google Scholar
  19. 19.
    Z. Otwinowski and W. Minor. Methods Enzymol 276:307–326 (1997).CrossRefGoogle Scholar
  20. 20.
    Bruker, XPREP in SHELXTL version 6.12, Bruker AXS Inc., Madison, Wisconsin, USA. (2002).Google Scholar
  21. 21.
    M. C. Burla, R. Caliandro, M. Camali, B. Carrozzini, G. L. Cascarano, L. De Caro, D. Giacovazzo, G. Polidori, and R. Spagna. J. Appl. Crystallogr. 38:381–388 (2005).CrossRefGoogle Scholar
  22. 22.
    G. M. Sheldrick, SHELXL97. A Program for Crystal Structure Refinement. University of Gottingen, Germany, (1997).Google Scholar
  23. 23.
    Vishweshwar, P. McMahon, J. A. Oliveira, M. Peterson, M. L. and J. Zaworotko. The predictably elusive form II of aspirin. J. Am. Chem. Soc. 127:16802–16803 (2005).PubMedCrossRefGoogle Scholar
  24. 24.
    H. M. Krishna Murthy, T. N. Bhat, and M. Bijayan. Structure of a new crystal form of 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid (flufenamic acid). Acta Crystallogr., Sect.B:Struct. Crystallogr. Cryst. Chem. 38:315–317 (1982).CrossRefGoogle Scholar
  25. 25.
    H. Xiarong, J. G. Stowell Xiaorong, K. R. Morris, R. R. Pfeiffer, G. Hui Li, P. Stahly, and S. R. Byrn. Stabilization of a metastable polymorph of 4-methyl-2-nitroacetanilide by isomorphic additives. Cryst. Growth Des. 1:305–312 (2001).CrossRefGoogle Scholar
  26. 26.
    K. Y. Chow, J. Go, M. Mehdizadeh, and D. J. W. Grant. Modification of adipic acid crystals: influence of growth in the presence of fatty acid additives on crystal properties. Int. J. Pharm. 20:3–34 (1984).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Eun Hee Lee
    • 1
  • Stephen R. Byrn
    • 1
  • M. Teresa Carvajal
    • 1
  1. 1.Department of Industrial and Physical PharmacyPurdue UniversityWest LafayetteUSA

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