Scale-up feasibility in high-shear mixers: determination through statistical procedures.

The wet granulation scale-up of a formulation exhibiting plastic deformation behavior under compression was examined. Through experimental factorial design, the effect of solution level, mixing time, and mixer speed on granulation properties was investigated. Measurements of mean particle size, tapped density, bulk density, Carr's index, coarse-to-fine ratio, cumulative percentage, and flow rate were taken and compared among granulations. In addition, comparisons were done on the hardness of tablets made from the formulations. It was shown that the characteristics of the granulations made under different conditions were highly reproducible. The excipient system of microcrystalline cellulose and pregel starch was shown to be a very robust formulation that is resistant to changes in the scaling-up process in high-shear mixers.

Statistical comparison of high-shear versus low-shear granulation using a common formulation.

Experimental combinations from the ranges assigned to the independent factors were studied using both a low-shear (planetary) mixer and a high-shear mixer for granulation. The independent factors studied were X1 calcium phosphate/mannitol ratio, X2 pregelatinized starch, X3 magnesium stearate, X4 mixer type, and X5 compression pressure. To optimize the tablet properties fully, the experimental range was varied from -2 to +2 experimental units, with the exception of X4, which was assigned -1 for the planetary mixer and +1 for the high-shear mixer. Drug dissolution did not seem to be affected by mixer type, but tablet hardness was affected by mixer type.