Experimental Study of Wet Granulation in Fluidized Bed:Impact of the Binder Properties on the Granule Morphology

摘要

In this work, the effect of the physicochemical properties of aqueous hydroxypropylcellulose(HPC) binder solutions and different pharmaceutical excipients (mannitol andanhydrous CaHPO4) on the agglomeration kinetics and granule properties wereinvestigated. First, a particle size distribution (PSD) analysis together with a detailedanalysis of morphological properties of the excipient particles were performed [1].Second, the viscosity, density, surface tension and size of the spray droplets of bindersolutions with different HPC concentrations were determined and wetting characteristicsof the binders on the excipients were measured. Third, several fluid bed wet granulationexperiments were conducted for pure excipients and their blends with binder solution ofdifferent HPC concentrations in a pilot plant Wurster granulator. The observed granulegrowth for different binder concentrations was a strong function of the binderconcentration and the excipient solubility. For mannitol, a significant "coating" periodfollowed by a slow granule growth was observed for the case with the diluted 5% binder.The "coating" period was significantly shorter for the 10% HPC binder and did not existfor the 15% HPC for which immediate and fast granule growth was observed. ForCaHPO4 (trademark A-TAB), no growth was observed for the 10% HPC binder and along coating period followed by fast granule growth was observed for the 15% HPC.Simple physically-based criteria [2] were also evaluated, which employ themorphological properties of excipients (size and surface roughness) together withphysical properties of the used binder for prediction of the coating vs. agglomerationregime at given flow conditions (collision velocity). As expected, a preferentialcoalescence and growth of the mannitol granules from the blend of mannitol + A-TABwas observed. Finally, the mechanical and morphological properties of the producedgranules were measured and correlated to the HPC concentration of the binder used in theexperiments. A clear correlation between the granule porosity (evaluated by X-raytomography) and the binder concentration was found for the mannitol granules.