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.

The search for new forms of already known drug compounds is an urgent problem of high relevance as more potent drugs with fewer side effects are needed. The trifluoromethyl group in flufenamic acid renders its chemical structure differently from other fenamates. This modification is responsible for a large number of conformational polymorphs. Therefore, flufenamic acid is a promising structural modification of well-known drug molecules. An effective approach in this field is micronization, employing “green” supercritical fluid technologies. This research raises some key questions to be answered on how to control polymorphic forms during the micronization of drug compounds. The results presented in this work demonstrate the ability of two-dimensional nuclear Overhauser effect spectroscopy to determine conformational preferences of small molecular weight drug compounds in solutions and fluids, which can be used to predict the polymorphic form during the micronization. Quantitative analysis was carried out to identify the conformational preferences of flufenamic acid molecules in dimethyl sulfoxide-d6 medium at 25 °C and 0.1 MPa, and in mixed solvent medium containing supercritical carbon dioxide at 45 °C and 9 MPa. The data presented allows predictions of the flufenamic acid conformational preferences of poorly soluble drug compounds to obtain new micronized forms.

This study examines the influence of mefenamic acid on the physical and chemical properties of silica aerogels, as well as its effect on the sorption characteristics of the composite material. Solid state magic angle spinning nuclear magnetic resonance (MAS NMR) and high-pressure ¹³C NMR kinetic studies were conducted to identify the presence of mefenamic acid and measure the kinetic rates of CO₂ sorption. Additionally, a high-pressure T₁–T₂ relaxation-relaxation correlation spectroscopy (RRCOSY) study was conducted to estimate the relative amount of mefenamic acid in the aerogel’s pores, and a high-pressure nuclear Overhauser effect spectoscopy (NOESY) study was conducted to investigate the conformational preference of mefenamic acid released from the aerogel. The results indicate that mefenamic acid is affected by the chemical environment of the aerogel, altering the ratio of mefenamic acid conformers from 75% to 25% in its absence to 22% to 78% in the presence of aerogel.