Relationship between inhomogeneity phenomena and granule growth mechanisms in a high-shear mixer.

A poorly understood phenomenon observed during high-shear granulation is the poor distribution of a drug in the granulate. To investigate the causes of this inhomogeneity, lactose of three different particle sizes was granulated with 0.1% micronized estradiol (5 microm) in a 10 l high-shear mixer. An aqueous solution of HPC was used as binder. Granulation with the largest lactose particles (141 microm) yielded a homogeneous granulate. However, at a prolonged process time demixing was observed. Contrary to the largest particles, granulation with the smaller lactose particles (50 and 23 microm) already leads to demixing in the first minute, although to a lesser extent. It was concluded that granulation with the largest particles resulted in breakage behavior of the granulate, thereby preventing demixing. However, once granules are strong enough (smaller particle size and prolonged process time) to survive the shear forces demixing is observed. Theoretical calculations of dynamic and static granule strength were used to explain the influence of lactose particle size and process time on breakage behavior. It was argued that once granules survive, preferential growth of the small estradiol particles in favor of the larger lactose particles causes the demixing. The extent of demixing depends on the particle size difference.