Stabilization of a supersaturated solution of mefenamic acid from a solid dispersion with EUDRAGIT(®) EPO.
OBJECTIVE
The stabilization mechanism of a supersaturated solution of mefenamic acid (MFA) from a solid dispersion with EUDRAGIT(®) EPO (EPO) was investigated.


METHODS
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.


RESULTS
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 (1)H spin-lattice relaxation time (T(1)) 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 (13)C-T(1) measurements. Solution-state (1)H-NMR measurement demonstrated that MFA existed in monomolecular state in supersaturated solution. (1)H-T(1) and difference nuclear Overhauser effect measurements indicated that cross relaxation occurred between MFA and EPO due to the small distance between them.


CONCLUSIONS
The formation and high stability of the supersaturated solution were attributable to the specifically formed intermolecular interactions between MFA and EPO.
Chiba University, Chiba, Japan.
Taro
T
Kojima
Kenjirou
K
Higashi
Toyofumi
T
Suzuki
Kazuo
K
Tomono
Kunikazu
K
Moribe
Keiji
K
Yamamoto
D000042:Absorption; D000818:Animals; D001682:Biological Availability; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008528:Mefenamic Acid / Q000008:administration & dosage / Q000737:chemistry*; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000008:administration & dosage / Q000737:chemistry*; D011208:Powders / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D012996:Solutions / Q000737:chemistry; D013055:Spectrophotometry, Infrared / Q000379:methods; D014961:X-Ray Diffraction / Q000379:methods
D011108:Polymers; D011109:Polymethacrylic Acids; D011208:Powders; D012996:Solutions; C038300:methylmethacrylate-methacrylic acid copolymer; D008528:Mefenamic Acid