Stabilization of a Supersaturated Solution of Mefenamic Acid from a Solid Dispersion with EUDRAGIT® EPO
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The stabilization mechanism of a supersaturated solution of mefenamic acid (MFA) from a solid dispersion with EUDRAGIT® EPO (EPO) was investigated.
The solid dispersions were prepared by cryogenic grinding method. Powder X-ray diffractometry, in vitro dissolution test, in vivo oral absorption study, infrared spectroscopy, and solid- and solution-state NMR spectroscopies were used to characterize the solid dispersions.
Dissolution tests in acetate buffer (pH 5.5) revealed that solid dispersion showed > 200-fold higher concentration of MFA. Supersaturated solution was stable over 1 month and exhibited improved oral bioavailability of MFA in rats, with a 7.8-fold higher area under the plasma concentration-versus-time curve. Solid-state 1H spin–lattice relaxation time (T1) measurement showed that MFA was almost monomolecularly dispersed in the EPO polymer matrix. Intermolecular interaction between MFA and EPO was indicated by solid-state infrared and 13C-T1 measurements. Solution-state 1H-NMR measurement demonstrated that MFA existed in monomolecular state in supersaturated solution. 1H-T1 and difference nuclear Overhauser effect measurements indicated that cross relaxation occurred between MFA and EPO due to the small distance between them.
The formation and high stability of the supersaturated solution were attributable to the specifically formed intermolecular interactions between MFA and EPO.
Key wordssolid dispersion supersaturation NMR oral bioavailability EUDRAGIT® EPO
- 11.Chokshi RJ, Sandhu HK, Iyer RM, Shah NH, Malick AW, Zia H. Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/solution. J Pharm Sci. 2005;94(11):2463–74.PubMedCrossRefGoogle Scholar
- 30.Torchia DA. The measurement of proton-enhanced carbon-13 T1 values by a method which suppresses artifacts. J Magn Reson. (1969). 1978;30(3):613-616.Google Scholar
- 38.Dokorou V, Ciunik Z, Russo U, Kovala-Demertzi D. Synthesis, crystal structures and spectroscopic studies of diorganotin derivatives with mefenamic acid. Crystal and molecular structures of 1,2:3,4-di-[mu]2-2-[(2,3-dimethylphenyl)amino]-benzoato-O,O-1,3-bis-2-[(-[(2,3-dimethylphenyl)amino]benzoato-O-1,2,4:2,3,4-di-[mu]3-oxo-tetrakis[di-methyltin(IV)] and 1,2:3,4-di-[mu]2-2-[(-[(-[(2,3-dimethylphenyl)amino]-benzoato-O,O-1,3-bis-2-[(-[(-[(2,3-dimethylphenyl)amino]benzoato-O-1,2,4:2,3,4-di-[mu]3-oxo-tetrakis[di-n-butyltin(IV)]. J Organomet Chem. 2001;630(2):205–14.CrossRefGoogle Scholar
- 43.Heald CR, Stolnik S, Kujawinski KS, De Matteis C, Garnett MC, Illum L, Davis SS, Purkiss SC, Barlow RJ, Gellert PR. Poly(lactic acid)−Poly(ethylene oxide) (PLA−PEG) Nanoparticles: NMR Studies of the Central Solidlike PLA Core and the Liquid PEG Corona. Langmuir. 2002;18(9):3669–75.CrossRefGoogle Scholar
- 44.Breitmaier E, Voelter W. Carbon-13 NMR spectroscopy: high resolution methods and applications in organic chemistry and biochemistry. Verlag Chemie: Weinheim; 1986.Google Scholar
- 45.Kalk A, Berendsen HJC. Proton magnetic relaxation and spin diffusion in proteins. J Magn Reson. 1976;24(3):343–66.Google Scholar