Novel identification of pseudopolymorphic changes of theophylline during wet granulation using near infrared spectroscopy.

The purpose of this study was to demonstrate the efficiency of near infrared (NIR) spectroscopy in studying the pseudopolymorphic changes and the state of water during the wet granulation process. Anhydrous theophylline was granulated in a planetary mixer using water as granulation liquid. NIR spectra and differential scanning calorimetric (DSC) and wide-angle X-ray scattering (WAXS) patterns of theophylline granules, anhydrous theophylline, and theophylline monohydrate were measured. At a low level of granulation liquid (0.3 mol of water per mole of anhydrous theophylline), water absorption maxima in the NIR region occurred first at around 1475 and 1970 nm. These absorption maxima were identical to those of theophylline monohydrate. At higher levels of granulation liquid (1.3-2.7 mol of water per mole of anhydrous theophylline), the increasing absorption maxima occurred at 1410 and 1905 nm due to OH vibrations of free water molecules. X-ray diffraction patterns confirmed the transformation of anhydrous theophylline to theophylline monohydrate during wet granulation. NIR spectroscopy was able to detect different states of water molecules during the wet granulation process faster and in a more flexible manner than conventional methods.