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

J Pharm Biomed Anal. 2005 Jul 15;38(4):670-7. doi: 10.1016/j.jpba.2005.02.017. Epub 2005 Mar 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calibration
  • Humidity
  • Hydrogen-Ion Concentration
  • Indomethacin / chemistry*
  • Magnetic Resonance Spectroscopy
  • Powder Diffraction
  • Sodium Bicarbonate / chemistry*
  • Spectrophotometry, Infrared
  • X-Ray Diffraction

Substances

  • Sodium Bicarbonate
  • Indomethacin