The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy
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 ob...
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MDPI AG
2022-10-01
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| Online Access: | https://www.mdpi.com/1999-4923/14/11/2276 |
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| author | Konstantin V. Belov Luís A. E. Batista de Carvalho Alexey A. Dyshin Sergey V. Efimov Ilya A. Khodov |
| author_facet | Konstantin V. Belov Luís A. E. Batista de Carvalho Alexey A. Dyshin Sergey V. Efimov Ilya A. Khodov |
| author_sort | Konstantin V. Belov |
| collection | DOAJ |
| description | 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-d<sub>6</sub> (at 25 °C and 0.1 MPa) and in a mixed solvent supercritical carbon dioxide + dimethyl sulfoxide-d<sub>6</sub> (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. |
| first_indexed | 2024-03-09T18:45:35Z |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T18:45:35Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-f60d757bccb942e79e55b5d2ebd2dcd92023-11-24T06:19:30ZengMDPI AGPharmaceutics1999-49232022-10-011411227610.3390/pharmaceutics14112276The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY SpectroscopyKonstantin V. Belov0Luís A. E. Batista de Carvalho1Alexey A. Dyshin2Sergey V. Efimov3Ilya A. Khodov4Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, RussiaMolecular Physical-Chemistry R&D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, PortugalKrestov Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, RussiaInstitute of Physics, Kazan Federal University, 420008 Kazan, RussiaKrestov Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, RussiaMefenamic 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-d<sub>6</sub> (at 25 °C and 0.1 MPa) and in a mixed solvent supercritical carbon dioxide + dimethyl sulfoxide-d<sub>6</sub> (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.https://www.mdpi.com/1999-4923/14/11/2276supercritical fluidfenamatesspatial structurehigh-pressure NMR |
| spellingShingle | Konstantin V. Belov Luís A. E. Batista de Carvalho Alexey A. Dyshin Sergey V. Efimov Ilya A. Khodov The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy Pharmaceutics supercritical fluid fenamates spatial structure high-pressure NMR |
| title | The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy |
| title_full | The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy |
| title_fullStr | The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy |
| title_full_unstemmed | The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy |
| title_short | The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy |
| title_sort | role of hidden conformers in determination of conformational preferences of mefenamic acid by noesy spectroscopy |
| topic | supercritical fluid fenamates spatial structure high-pressure NMR |
| url | https://www.mdpi.com/1999-4923/14/11/2276 |
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