• fluid bed;
  • granulation;
  • mixing;
  • granule homogeneity;
  • content uniformity;
  • granule structure;
  • X-ray tomography;
  • Raman spectroscopy


The distribution of the drug in the granular end product is a critical quality attribute in fluidized bed spray granulation of pharmaceuticals. The evolution of drug content inhomogeneity in a case study was examined as a function of granulation time. Intragranular structure was also investigated using confocal Raman spectroscopy and computerized X-ray microtomography. A principal component analysis was conducted on the results to investigate granule structure–drug content relationships. Inhomogeneity increased at the beginning of the process but later it was found to decrease. Changes in the homogeneity were accompanied by significant changes in the intragranular structure. It was concluded that segregation of the primary components explained the observed inhomogeneity at low saturation levels when the granules grow by layering, but at elevated moisture levels, granule growth is mediated by the coalescence of agglomerates, which promotes homogeneous distribution of the drug particles. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:5254–5269, 2011