Analysis of the acid-base reaction between solid indomethacin and sodium bicarbonate using infrared spectroscopy, X-ray powder diffraction, and solid-state nuclear magnetic resonance spectroscopy

Indomethacin was used as a model compound to investigate acid-base reactions of solid materials, a common type of drug-excipient interaction. In a typical experiment, 500 mg of pure α-form indomethacin were mixed with 500 mg of sodium bicarbonate. The mixture was kept at 40 °C and at several relative humidities. The reaction was monitored by IR spectroscopy, X-ray powder diffraction, and solid-state NMR. At 40 °C and 80% RH, the reaction is nearly complete after 300 h. As observed by IR spectroscopy, the characteristic peaks of α-indomethacin disappear during the course of the reaction with the appearance of the characteristic peaks of the salt product, sodium indomethacin trihydrate. Solid-state NMR spectra and X-ray powder diffraction patterns of the reaction mixtures confirm the transformation of the mixtures to sodium indomethacin trihydrate; the reduced peak intensities in the diffraction patterns of the product relative to the initial mixtures indicate the formation of a microcrystalline product. A change in the reaction rate of sodium bicarbonate with α-indomethacin is observed when the mixtures are stored at different relative humidities. At 40 °C and 66% RH, the reaction of sodium bicarbonate with α-indomethacin is about 86% complete after 500 h. No detectable reaction was observed for sodium bicarbonate with the α form of indomethacin at 40 °C and 11% RH after 15 months. The combination of these solid-state characterization techniques is demonstrated to be essential to detect and monitor acid-base reactions in solid materials, which are impossible to monitor using solution-chemistry methods. The reaction kinetics at 66% RH fits the Jander equation very well, which is consistent with a diffusion-controlled mechanism.