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A Systematic Study of Molecular Interactions of Anionic Drugs with a Dimethylaminoethyl Methacrylate Copolymer Regarding Solubility Enhancement
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-03-21 00:00:00 , DOI: 10.1021/acs.molpharmaceut.6b01116 Wiebke Saal 1, 2 , Alfred Ross 3 , Nicole Wyttenbach 3 , Jochem Alsenz 3 , Martin Kuentz 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-03-21 00:00:00 , DOI: 10.1021/acs.molpharmaceut.6b01116 Wiebke Saal 1, 2 , Alfred Ross 3 , Nicole Wyttenbach 3 , Jochem Alsenz 3 , Martin Kuentz 1
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The methacrylate-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 EPO for a panel of seven acidic crystalline drugs. Diffusion data (determined by 1H 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 (rSpearman = −0.83) with rDiffAPI, where SE and rDiffAPI 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, piroxicam, 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.
中文翻译：
阴离子药物与甲基丙烯酸二甲氨基乙酯共聚物关于增溶剂的分子相互作用的系统研究
甲基丙烯酸酯共聚物Eudragit EPO（EPO）引起了人们对提高阴离子药物溶解度的兴趣。尽管它们对口服剂型的溶解和稀释很重要，但在相当低的聚合物浓度下对药物水溶液的溶解度的影响却鲜为人知。我们提供了证据，证明由七种酸性结晶药物组成的低EPO浓度（0.1-5％（w / w））引起的水溶性差的阴离子药物的水溶性显着提高（因子4-230）。扩散数据（由1确定）1 H核磁共振光谱法表明，通过定量超高效液相色谱监测的溶解度增加效果主要是由本体液相中的分子API聚合物相互作用引起的。通过X射线粉末衍射测试，残留的固体API保持不变。溶解度增强（SE）显示与rDiff API显着的等级相关性（r Spearman = -0.83），其中SE和rDiff API是在有和没有EPO的情况下定义的溶解度和扩散系数的比率。SE降低的顺序为消炎痛，甲芬那酸，华法林，吡罗昔康，呋塞米，苯扎贝特和甲苯磺丁酰胺。增溶作用归因于药物与EPO之间的离子和疏水相互作用。EPO优异的增溶性能对于药物开发非常有前途，并且该数据集提供了迈向了解药物-赋形剂相互作用机理的第一步。
更新日期：2017-03-21
中文翻译：
阴离子药物与甲基丙烯酸二甲氨基乙酯共聚物关于增溶剂的分子相互作用的系统研究
甲基丙烯酸酯共聚物Eudragit EPO（EPO）引起了人们对提高阴离子药物溶解度的兴趣。尽管它们对口服剂型的溶解和稀释很重要，但在相当低的聚合物浓度下对药物水溶液的溶解度的影响却鲜为人知。我们提供了证据，证明由七种酸性结晶药物组成的低EPO浓度（0.1-5％（w / w））引起的水溶性差的阴离子药物的水溶性显着提高（因子4-230）。扩散数据（由1确定）1 H核磁共振光谱法表明，通过定量超高效液相色谱监测的溶解度增加效果主要是由本体液相中的分子API聚合物相互作用引起的。通过X射线粉末衍射测试，残留的固体API保持不变。溶解度增强（SE）显示与rDiff API显着的等级相关性（r Spearman = -0.83），其中SE和rDiff API是在有和没有EPO的情况下定义的溶解度和扩散系数的比率。SE降低的顺序为消炎痛，甲芬那酸，华法林，吡罗昔康，呋塞米，苯扎贝特和甲苯磺丁酰胺。增溶作用归因于药物与EPO之间的离子和疏水相互作用。EPO优异的增溶性能对于药物开发非常有前途，并且该数据集提供了迈向了解药物-赋形剂相互作用机理的第一步。
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