Additive-Induced Metastable Single Crystal of Mefenamic Acid
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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.
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.
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 wordsflufenamic acid mefenamic acid polymorph selection single crystal XRPD
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.
- 1.S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell. Solid-State Chemistry of Drugs. Second Edition. SSCI Inc. (1999).Google Scholar
- 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).
- 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.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
- 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
- 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
- 20.Bruker, XPREP in SHELXTL version 6.12, Bruker AXS Inc., Madison, Wisconsin, USA. (2002).Google Scholar
- 22.G. M. Sheldrick, SHELXL97. A Program for Crystal Structure Refinement. University of Gottingen, Germany, (1997).Google Scholar