Experimental analysis of inter- and intra-batch variation of granule porosity, stiffness and dissolution rate

Abstract Using a pharmaceutical formulation, granule batches were produced at a range of granulator volumes from 0.5 L to 400 L and process conditions, characterised by the Froude number in the range from Fr = 0.26 to Fr = 1.63. The mean values and the standard deviations of granule porosity, granule stiffness and granule dissolution rate evaluated from each batch using the 400–1000 μm sieve fraction were compared in order to establish structure–property correlations. Both granule stiffness and granule dissolution rate were found linearly correlated with the Froude number. A significant intra-batch variability of all investigated granule properties was observed. The relative standard deviation of granule stiffness also increased linearly with the Froude number. Coupled experiments relating the microstructure of granules with their individual compression and dissolution curves were carried out for the first time. A surprising diversity of intra-batch granule structures and their associated dissolution rates was found in batches produced at both low and high Froude numbers, highlighting the importance of avoiding granule segregation in downstream unit operations in order to maintain consistent drug release profiles from the investigated formulation.