The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy

Abstract

Mefenamic acid has been used as a non-steroidal anti-inflammatory drug for a long time. However, its practical use is quite limited due to a number of side effects on the intestinal organs. Conformational polymorphism provides mefenamic acid with unique properties regarding possible modifications obtained during the micronization process, which can improve pharmacokinetics and minimize side effects. Micronization can be performed by decompression of supercritical fluids; methods such as rapid expansion of the supercritical solution have proven their efficiency. However, this group of methods is poorly applicable for compounds with low solubility, and the modification of the method using a pharmaceutically suitable co-solvent may be useful. In our case, addition of only 2 mol % dimethyl sulfoxide increased the solubility remarkably. Information on the conformational state may be critically important for carrying out micronization. In this work, structural analysis and estimate of conformational preferences of mefenamic acid in dimethyl sulfoxide − d6 (at 25 °C and 0.1 MPa) and in a mixed solvent supercritical carbon dioxide + dimethyl sulfoxide-d6 (45 °C, 9 MPa) were performed based on nuclear Overhauser effect spectroscopy. Results show changes in the conformation fractions depending on the medium used. The importance of allowing for hidden conformers in estimating the conformational state was demonstrated in the analysis. Obtained results may be useful for improving micronization parameters.

Investigation of the Spatial Structure of Flufenamic Acid in Supercritical Carbon Dioxide Media via 2D NOESY

“…The nuclear Overhauser effect spectroscopy (2D NOESY) technique is a powerful tool for chemical structure elucidation of small drug-like molecules by NMR. In the last few years [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], this technique has been extensively used to study the structure and conformational preference of small molecules in supercritical media. The value of the cross-relax rate between proton spins in a small molecule of FFA is proportional to the sixth power of the distance between the corresponding protons.…”

Exploring the Conformational Equilibrium of Mefenamic Acid Released from Silica Aerogels via NMR Analysis

“…For example, in the case of mefenamic, when analyzing the mobility of benzene rings and the internuclear distance responsible for it, we are dealing with two groups of conformers, A + B and C + D, as described in our previous work [ 77 ]. The results of quantum chemical calculations are provided in detail in the literature.…”

Conformational Screening of Arbidol Solvates: Investigation via 2D NOESY

“…Integral NOESY cross-peak intensities as the functions of the mixing times were plotted ( Figures S8 and S9 ); cross-relaxation rates were found to be 2.48 ± 0.09 × 10 –2 and 1.10 ± 0.05 × 10 –2 s –1 and 1.41 ± 0.06 × 10 –2 ; 1.30 ± 0.08 × 10 –2 s –1 for the distances H7–H10 and H22–H25/H29 inCDCl 3 and DMSO-d 6 , respectively. In the slope of the ISPA model [ 31 , 32 ], the experimental effective distance was determined: 3.33 ± 0.05 Å for the studied system in CDCl 3 and 2.94 ± 0.05 Å in DMSO-d 6 . By comparison of this number found from the NOESY experiments with those given by X-ray analysis, the populations of the umifenovir conformer groups( x s ) in CDCl 3 and DMSO were calculated using Equation (3): where r s and r p are the interatomic distances in the conformer groups S and P, and r s is the effective distance derived from the NOESY data.…”