期刊
MOLECULAR PHARMACEUTICS
卷 14, 期 4, 页码 1243-1250出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.6b01116
关键词
nuclear magnetic resonance (NMR) spectroscopy; polymer-drug interaction; acidic drugs; solubility enhancement
The methacrylatet-copolymer Eudragit EPO (EPO) has raised interest in solubility enhancement of anionic drugs. Effects :on aqueous drug solubility at rather low polymer concentrations are barely known despite their importance upon dissolution and dilution of oral dosage forms. We provide evidence for substantial enhancement (factor 4-230) of aqueous solubility of poorly water-soluble anionic drugs induced by low (0.1-5% (w/w)) concentration of :PTO for a panel of seven acidic crystalline drugs. Diffusion data (determined by H-1 nuclear magnetic resonance spectroscopy) indicate that the solubility increasing effect monitored by quantitative ultraperformance liquid chromatography was caused primarily by molecular API polymer interactions in the bulk liquid phase. Residual solid API remained unaltered as tested by X-ray powder diffraction. The solubility enhancement (SE) revealed a significant rank correlation (r(Spearman) = -0.83) with rDiff(APD), where SE and rDiff(API) are defined ratios of solubility and diffusion coefficient in the presence and absence of EPO. SE decreased in the order of indomethacin,. mefenamic acid, warfarin, piroxicain, furosemide, bezafibrate, and tolbutamide. The solubilizing, effect was attributed to both ionic and hydrophobic interactions between drugs and EPO. The excellent solubilizing properties of EPO are highly promising for pharmaceutical development, and the data set provides first steps toward an understanding of drug-excipient interaction mechanisms.
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