Mechanism of the reaction between flufenamic acid and CO2 in its saturated solution in supercritical CO2

In this work, we established the occurrence of a chemical reaction between flufenamic acid (FFA) and carbon dioxide in FFA saturated solution in supercritical CO₂. Preliminary analysis of the reaction product via nuclear magnetic resonance (NMR) and attenuated total reflectance infrared spectroscopy (ATR-IR) revealed that the product aligns with a reaction pathway wherein the CO₂ molecule attacks the carboxyl group of flufenamic acid. In situ IR spectroscopy of the saturated solution phase, combined with quantum chemical calculations, indicated that flufenamic acid reacts at relatively low temperatures. However, even at the highest temperature studied, the reaction product yield did not reach 100 %, leaving unreacted flufenamic acid as an impurity in the reaction mixture. A detailed ATR-IR spectroscopy analysis of the reaction mixture demonstrated the product's high thermal stability (up to temperature of 140 °C). Conversely, in the presence of crystallization nuclei, the product decomposes under ambient conditions (for time period of about 30 min), releasing CO₂ and pure FFA. The crystallized FFA adopts a polymorphic form distinct from that of the original compound.