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

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 degrees C and 0.1 MPa, and in mixed solvent medium containing supercritical carbon dioxide at 45 degrees 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.

Automated summary

The search for new forms of known drug compounds is important for developing more potent and less side effect drugs. The trifluoromethyl group in flufenamic acid leads to different conformational polymorphs, making it a promising modification of well-known drug molecules. Micronization using green supercritical fluid technologies is an effective approach, and this research focuses on controlling polymorphic forms during the micronization process of drug compounds. The results show that two-dimensional nuclear Overhauser effect spectroscopy can determine the conformational preferences of small drug compounds, aiding in the prediction of polymorphic forms during micronization.