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 by H 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 = -0.83) with rDiff, where SE and rDiff 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.

Intermolecular Interactions between Drugs and Aminoalkyl Methacrylate Copolymer in Solution to Enhance the Concentration of Poorly Water-Soluble Drugs

“…[45][46][47][48] Our group has investigated drug-EUD-E interactions in detail using various 1 H-NMR techniques. 33,49) Kojima et al prepared a solid dispersion of mefenamic acid (MFA) and EUD-E at a weight ratio of 24 : 76 by cryogenic cogrinding. 33) The MFA/EUD-E solution was obtained by dispersing the solid dispersion into 0.1 M acetate buffer at pH 5.5.…”

“…The high-resolution magic-angle spinning (HR-MAS) technique was applied to determine the interaction sites in the MFA-EUD-E solution. 49) In HR-MAS experiments, viscous solutions and gels were placed into a glass rotor and spun at a rate of several kHz at a magic-angle of 54.74° with respect to the direction of the magnetic field. According to MAS, a highly-resolved spectrum was obtained by averaging out anisotropic interactions, such as chemical shift anisotropy and internuclear dipolar couplings.…”

On demand manufacturing of patient-specific liquid capsules via co-ordinated 3D printing and liquid dispensing

“…It has been used as a taste-masking agent (Taki et al, 2017) and provides a glossy and slippery easy-to-swallow finishing. Its use is well established for pharmaceutical purposes as a solubility enhancer (Higashi et al, 2016;Saal et al, 2017Saal et al, , 2018, stability enhancer (Ochi et al, 2016) and in the manufacturing of immediate release dosage forms (Qiao et al, 2010;Sadia et al, 2016;Yang et al, 2015). Its compatibility with hot melt extrusion has also been previously demonstrated (Ashour et al, 2016;Li et al, 2016a;Li et al, 2016b).…”

Influence of gel preparation concentration on statistical mechanics of poly(dialkylaminoethyl methacrylate) gels on the basis of scaling concept: Toward tunable elasticity and thermomechanical parameters

“…Depending on the properties of the virgin monomer, the chemical structure of crosslinker as well as the density of the crosslink points, polymeric gels as two‐component or multicomponent systems in the thermodynamic equilibrium state may contain various amounts of diluent and exhibit resistance to dissolution arising from the crosslinks. These properties should be balanced through the optimal design to regulate the properties of polymeric gels for specific applications . It is now believed that the responsive behavior of smart materials is complex functions of the initial monomer and crosslinker concentration, the extent of the polymerization reaction, the effective density distribution in the polymer matrix, pH, and the ionic strength of the swelling media.…”

“…These properties should be balanced through the optimal design to regulate the properties of polymeric gels for specific applications. 3,4 It is now believed that the responsive behavior of smart materials is complex functions of the initial monomer and crosslinker concentration, the extent of the polymerization reaction, the effective density distribution in the polymer matrix, pH, and the ionic strength of the swelling media. To establish the relationship between the thermodynamic network parameters of a crosslinked polymer (swelling ratio and effective crosslinking density) and the initial monomer concentration at the synthesis conditions, it is vital to understand the effect of network defects and heterogeneities in determining the structural properties of real polymer networks not only because it would allow preparation of smart materials with intended characteristics, but also it provide some fundamental formalism based on the statistical mechanics which guides in the task of calculating various parameters.…”