title: 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.
abstract: 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 alpha-form indomethacin were mixed with 500 mg of sodium bicarbonate. The mixture was kept at 40 degrees C and at several relative humidities. The reaction was monitored by IR spectroscopy, X-ray powder diffraction, and solid-state NMR. At 40 degrees C and 80% RH, the reaction is nearly complete after 300 h. As observed by IR spectroscopy, the characteristic peaks of alpha-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 alpha-indomethacin is observed when the mixtures are stored at different relative humidities. At 40 degrees C and 66% RH, the reaction of sodium bicarbonate with alpha-indomethacin is about 86% complete after 500 h. No detectable reaction was observed for sodium bicarbonate with the alpha form of indomethacin at 40 degrees 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.
authors.affiliation: Department of Industrial and Physical Pharmacy, School of Pharmacy and Pharmacal Sciences, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47906-2051, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Chen
authors.forename: Ulrich J
authors.initials: UJ
authors.lastname: Griesser
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Te
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Pfeiffer
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Morris
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Stowell
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Byrn
mesh_terms: D002138:Calibration; D006813:Humidity; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D033362:Powder Diffraction; D017693:Sodium Bicarbonate / Q000737:chemistry*; D013055:Spectrophotometry, Infrared; D014961:X-Ray Diffraction
chemical_list: D017693:Sodium Bicarbonate; D007213:Indomethacin