A combined experimental and computational study of wet granulation in a Wurster fluid bed granulator

A methodology combining theoretical and experimental techniques for analyzing the growth of granules in a fluidized bed granulator was developed. The methodology combines several key features of this complicated process: (i) population balancing (PB) of growth of different granules; (ii) hydrodynamic modeling of the gas–solid mixture flow using Computational Flow Dynamics (CFD); (iii) modeling of contact mechanics and granule formation; (iv) the Stokes number analysis for calculation of successful collisions; (v) well-controlled experimental study of the wet granulation. First, a detailed CFD model of the gas–solid flow and agglomeration (Model CFD-PB) within the Wurster type granulator was developed. Second, a simplified PB model of agglomeration in a homogeneous system (Model H-PB) was developed. The quadrature method of moments (QMOM) was used for solution of PB equations in both models. The kinetic theory of granular flow (KTGF) was employed in both models for calculation of the number of collisions between solid particles of different classes. Success factors, based on the Stokes number analysis, were calculated using results of extensive mesoscale simulations of the formation of realistic three-dimensional virtual granules. Comparison of simulation results of CFD-PB vs. H-PB models allowed evaluation of the KTGF kernel functionality to be used in H-PB model. Next, fluid bed granulation experiments were conducted for typical pharmaceutical excipients (microcrystalline cellulose, mannitol and dicalcium phosphate) with 15% HPC binder solution in a pilot plant Wurster granulator. The observed granule growth was a function of the surface roughness of excipients. Finally, the H-PB model was fitted to the experimental data. The only adjustable parameter of the H-PB model was an effective agglomeration rate constant, which we expect to be mostly related to the binder wetness on the surface of colliding granules.

Graphical abstractGranulation experiments with three different pharmaceutical excipients were carried out in a fluidized bed granulator. Granule growth curves illustrate a strong dependence on the primary particle morphology. Smooth Avicel particles undergo rapid granulation, rougher mannitol grows more slowly and an initial lag without granulation exists for the roughest A-Tab particles. Observed trends are consistent with the binder distribution analysis.Figure optionsDownload full-size imageDownload as PowerPoint slide