title: A Systematic Study of Molecular Interactions of Anionic Drugs with a Dimethylaminoethyl Methacrylate Copolymer Regarding Solubility Enhancement.
abstract: 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 by1H 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 rDiffAPIare 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.
authors.affiliation: Institute of Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland , Gründenstrasse 40, 4132 Muttenz, Switzerland.|Institute of Pharmaceutical Technology, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Wiebke
authors.identifier: 0000-0002-6777-8664
authors.initials: W
authors.lastname: Saal
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Alfred
authors.initials: A
authors.lastname: Ross
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wyttenbach
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Jochem
authors.initials: J
authors.lastname: Alsenz
authors.affiliation: Institute of Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland , Gründenstrasse 40, 4132 Muttenz, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Kuentz
mesh_terms: D000838:Anions / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry*; D011208:Powders / Q000737:chemistry; D012995:Solubility; D014867:Water / Q000378:metabolism; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D000838:Anions; D005079:Excipients; D004364:Pharmaceutical Preparations; D011108:Polymers; D011109:Polymethacrylic Acids; D011208:Powders; D014867:Water; C038300:methylmethacrylate-methacrylic acid copolymer
keywords: acidic drugs; nuclear magnetic resonance (NMR) spectroscopy; polymer−drug interaction; solubility enhancement