Effects of high-shear granulation on granulate homogeneity.

This study considers the effects of particle size of the powder constituents, and of impeller speed on the homogeneity of drug distribution on granulations produced in high-speed mixers. When a micronized low-dose steroid hormone was granulated together with unmicronized lactose in a Vactron 75 high-shear granulator at 250 rpm, strong inhomogeneities of the drug distribution arose. The coarse particle size fractions of the granules were found to be superpotent up to 150% of the mean drug content, whereas the fine size fraction showed a corresponding subpotency of 50%. Both particle size and impeller speed attributed to this phenomenon. At an impeller speed of 75 rpm, a significantly better drug distribution was obtained. Results show that the inhomogeneities found are mainly a consequence of the balance between the impact pressure as exerted by the impeller on the one hand and the shear resistance of the nuclei on the other hand. At a speed of 250 rpm, the tensile strength of 3 x 10(3) N/m2 of the initially formed nuclei is too weak to resist an impact pressure of 30 x 10(3) N/m2. For that reason, particle rearrangement takes place, which results in inhomogeneity. Because an impeller speed of 75 rpm is equal to an impact pressure of 2.6 x 10(3) N/m2, significantly less demixing occurs. Similar results can be obtained when the particle size of all constituents is reduced, which increases the tensile strength of the nuclei.