A priori performance prediction in pharmaceutical wet granulation: testing the applicability of the nucleation regime map to a formulation with a broad size distribution and dry binder addition.

In this study, Hapgood's nucleation regime map (Hapgood et al., 2003) was tested for a formulation that consists of an active pharmaceutical ingredient (API) of broad size distribution and a fine dry binder. Gabapentin was used as the API and hydroxypropyl cellulose (HPC) as the dry binder with deionized water as the liquid binder. The formulation was granulated in a 6l Diosna high shear granulator. The effect of liquid addition method (spray, dripping), liquid addition rate (29-245 g/min), total liquid content (2, 4 and 10%), and impeller speed (250 and 500 rpm) on the granule size distribution and lump formation were investigated. Standard methods were successfully used to characterize the process parameters (spray drop size, spray geometry and powder surface velocity) for calculating the dimensionless spray flux. However, the addition of dry binder had a very strong effect on drop penetration time that could not be predicted from simple capillary flow considerations. This is most likely due to preferential liquid penetration into the fine pores related to the dry binder particles and subsequent partial softening and dissolution of the binder. For systems containing a dry binder or other amorphous powders, it is recommended that drop penetration time be measured directly for the blended formulation and then scaled to the drop size during spraying. Using these approaches to characterize the key dimensionless groups (dimensionless spray flux and drop penetration time), Hapgood's nucleation regime map was successfully used to predict a priori the effect of process conditions on the quality of the granule size distribution as measured by lump formation and the span of the size distribution, both before and after wet massing for range of conditions studied. Wider granule size distributions and higher amount of lumps were obtained moving from intermediate to mechanical dispersion regime. Addition of the liquid in the dripping mode gave the broadest size distribution with ungranulated fines and highest percentage of lumps compared to spraying mode. Addition of the liquid by spraying in the intermediate regime gave the narrowest size distribution with the lowest amount of lumps. The effects of impeller speed and wet massing time on granule size distribution were complex. At 2% liquid content, increasing the impeller speed and adding wet massing time caused some breakage of lumps and the production of fines. At higher liquid contents, the effects were less clear, likely due to a balance between increased breakage and increased granule consolidation and growth. Nevertheless, this work has demonstrated that for complex formulations with dry binder addition, the final granule size distribution still depends strongly on the homogeneity of the initial liquid distribution which is well predicted by the nucleation regime map analysis.