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 non-steroidal 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 1H resonances of MFA in one-dimensional 1H NMR spectrum of the supersaturated solution are well resolved, thus enabling the complete assignment of MFA 1H resonances in the aqueous solution. Two-dimensional (2D) 1H/1H 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 1H/1H 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 1H/1H RFDR demonstrates that the molecular MFA-EPO interaction is quite flexible and dynamic.

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

“…Recently, 1 H-NMR spectroscopy was used to observe interactions between drugs and EUD-E in solution. [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.…”

Mechanistic insight into the dramatic improvement of probucol dissolution in neutral solutions by solid dispersion in Eudragit E PO with saccharin

“…Solid dispersion with EPO also improved the dissolution of indomethacin and piroxicam in weakly acidic solutions. Recently, we characterized MFA/EPO supersaturated solutions using high‐resolution magic‐angle spinning NMR, and the intermolecular interactions between MFA and EPO were clearly demonstrated using two‐dimensional NMR techniques such as nuclear Overhauser effect spectroscopy and radio frequency‐driven recoupling spectroscopy [22]. We also observed that the formation of ionic bonds and hydrogen bonds in addition to hydrophobic interactions between MFA and EPO could increase the stability of the supersaturated solution.…”

Novel Chronotherapeutic Multiparticulate Drug Delivery System of Felodipine: an Effective Treatment for Cardiac Arrhythmia

“…The same can be attributed to the flexible chains present in the polymer which accommodate themselves to form a clear matrix at a temperature as low as 40-45°C. This property, in particular, has been imparted by the low glass transition temperature (Tg of around 45°C) of Eudragit EPO (Higashi et al, 2014). As only Eudragit EPO was able to form a transparent film, the same was selected for further optimization employing DoE.…”

“…Further, Eudrgait EPO prevents the recrystallization by stabilizing the drug substance through hydrogen bonding, vander Waal and ionic interactions (Higashi et al, 2014). Povidone, on the other hand, provided a synergistic effect in drug release.…”