title: Insights into atomic-level interaction between mefenamic acid and eudragit EPO in a supersaturated solution by high-resolution magic-angle spinning NMR spectroscopy.
abstract: The intermolecular interaction between mefenamic acid (MFA), a poorly water-soluble nonsteroidal anti-inflammatory drug, and Eudragit EPO (EPO), a water-soluble polymer, is investigated in their supersaturated solution using high-resolution magic-angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy. The stable supersaturated solution with a high MFA concentration of 3.0 mg/mL is prepared by dispersing the amorphous solid dispersion into a d-acetate buffer at pH 5.5 and 37 °C. By virtue of MAS at 2.7 kHz, the extremely broad and unresolved (1)H resonances of MFA in one-dimensional (1)H NMR spectrum of the supersaturated solution are well-resolved, thus enabling the complete assignment of MFA (1)H resonances in the aqueous solution. Two-dimensional (2D) (1)H/(1)H nuclear Overhauser effect spectroscopy (NOESY) and radio frequency-driven recoupling (RFDR) under MAS conditions reveal the interaction of MFA with EPO in the supersaturated solution at an atomic level. The strong cross-correlations observed in the 2D (1)H/(1)H NMR spectra indicate a hydrophobic interaction between the aromatic group of MFA and the backbone of EPO. Furthermore, the aminoalkyl group in the side chain of EPO forms a hydrophilic interaction, which can be either electrostatic or hydrogen bonding, with the carboxyl group of MFA. We believe these hydrophobic and hydrophilic interactions between MFA and EPO molecules play a key role in the formation of this extremely stable supersaturated solution. In addition, 2D (1)H/(1)H RFDR demonstrates that the molecular MFA-EPO interaction is quite flexible and dynamic.
authors.affiliation: Biophysics and Department of Chemistry, The University of Michigan , Ann Arbor, Michigan 48109-1055, United States.
authors.forename: Kenjirou
authors.initials: K
authors.lastname: Higashi
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Pandey
authors.forename: Kamal H
authors.initials: KH
authors.lastname: Mroue
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Moribe
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008528:Mefenamic Acid / Q000737:chemistry*; D011109:Polymethacrylic Acids / Q000737:chemistry*; D012996:Solutions
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011109:Polymethacrylic Acids; D012996:Solutions; D008528:Mefenamic Acid; C518398:Eudragit E PO