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BIMODAL MOLECULAR ENCAPSULATION OF MEFENAMIC ACID ANION BY ΒCD IN SOLUTION AND SOLID STATE
M. Bogdan1, Diana Bogdan1, M.R. Caira2, S.I. Farcas1
1
National R&D Institute of Isotopic and Molecular Technologies
Department of Chemistry, University of Cape Town, Rondebosch
7701 Cape Town, South Africa
2
Inclusion complexes with cyclodextrins (CDs), formed by molecular encapsulation
of guest compounds in the cavity of macrocyclic hosts, are noncovalent associations of
current interest to the pharmaceutical industry as they could improve the solubility and
bioavailability of hydrophobic drugs1. Mefenamic acid (MF), a poorly water-soluble
nonsteroidal anti-inflammatory drug is commonly used in therapeutics because of its strong
analgesic, antipyretic and anti-inflammatory properties. A successful method used to increase
not only the water solubility, but also the stability of mefenamic acid is the complexation with
CDs.
In order to understand the biopharmaceutical functions of the mefenamic acid
molecule we need to investigate the driving forces for complexation and the structure of the
inclusion complex.
In the present study, the complexation between mefenamic acid anion and β-CD was
investigated in solution by 1H NMR. The continuous variation method was used to establish
the stoichiometry. The results obtained indicate that simultaneous inclusion of both aromatic
rings occurs, giving rise to two isomeric 1:1 complexes. The association constants for the two
1:1 complexes were calculated by non-linear least squares regression analysis, applying an
iteration procedure.
In the solid state, the crystal structure of the inclusion complex has been determined
from a combination of high-resolution synchrotron powder-diffraction data and molecularmechanics calculations. A grid search indicates two possible modes of inclusion, as in
solution, which were corroborated by molecular-mechanics calculations3. In both modes of
inclusion, MF and β-CD form a monomeric complex in a herringbone-packing scheme.
The obtained results suggest that the same modes of inclusion are effective both in
solution and in the solid state.
1. K.H. Frö m mi n g , J . S ze j tli, Cyclodextrin in Pharmacy, Kluwer Acad. Publ. Dordrecht, 1994
2. T . Hlad o n, J . P a wl ac z yk , B . S za fr a n , J. Incl. Phenom Macrocyclic Chem., 35, 497 (1999)
3. Mih ael a P o p , C. Go ub itz, G h. B o r o d i, M. B o g d an , D.J . A. De R id d er, R. P e sc h ar, H.
Sc he n k, Crystal structure of the inclusion complex of β-CD with mefenamic acid from high resolution
synchrotron powder diffraction data in combination with molecular mechanics calculations, Acta
Crystallographica B58, 1036-1043 (2002)