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 hydroxypropylcellulosern(HPC) binder solutions and different pharmaceutical excipients (mannitol andrnanhydrous CaHPO4) on the agglomeration kinetics and granule properties wererninvestigated. First, a particle size distribution (PSD) analysis together with a detailedrnanalysis of morphological properties of the excipient particles were performed [1].rnSecond, the viscosity, density, surface tension and size of the spray droplets of binderrnsolutions with different HPC concentrations were determined and wetting characteristicsrnof the binders on the excipients were measured. Third, several fluid bed wet granulationrnexperiments were conducted for pure excipients and their blends with binder solution ofrndifferent HPC concentrations in a pilot plant Wurster granulator. The observed granulerngrowth for different binder concentrations was a strong function of the binderrnconcentration and the excipient solubility. For mannitol, a significant "coating" periodrnfollowed by a slow granule growth was observed for the case with the diluted 5% binder.rnThe "coating" period was significantly shorter for the 10% HPC binder and did not existrnfor the 15% HPC for which immediate and fast granule growth was observed. ForrnCaHPO4 (trademark A-TAB), no growth was observed for the 10% HPC binder and arnlong coating period followed by fast granule growth was observed for the 15% HPC.rnSimple physically-based criteria [2] were also evaluated, which employ thernmorphological properties of excipients (size and surface roughness) together withrnphysical properties of the used binder for prediction of the coating vs. agglomerationrnregime at given flow conditions (collision velocity). As expected, a preferentialrncoalescence and growth of the mannitol granules from the blend of mannitol + A-TABrnwas observed. Finally, the mechanical and morphological properties of the producedrngranules were measured and correlated to the HPC concentration of the binder used in thernexperiments. A clear correlation between the granule porosity (evaluated by X-rayrntomography) and the binder concentration was found for the mannitol granules.