Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)


Pharmaceutical Sciences

First Advisor

Joan M. Lausier


The effects of process and formulation variables on pharmaceutical wet granulation processes using various mixer-processors were studied. The first investigation utilized RSM methods with a central-composite experimental design to study two process variables using a double-paddle planetary mixer. Systematic numerical grid search procedures were used to locate an optimum combination of mixing speeds and granulating fluid levels which simultaneously satisfied all imposed constraints using multiple response variables. This optimum defined a granulation end-point which was an intermediate between a direct compression blend and a fully granulated product. Mixing speed played only a minor role in the process, which depended chiefly on the amount of fluid added. In a second investigation, a factorial design approach was used to discriminate between alternative high-shear mixer designs and two comparable pregelatinized starches by using high mixing speeds as a process variable. One mixer, the Ross PowerMix™, was found to have a significantly more intense mixing action than the TK Fielder™ which resulted in enhanced material and tableting properties. It was found that Starch 1500™ slightly outperformed Starch 1551 ™ in flow and compactability into tablets for a 90% acetaminophen-starch powder. A subsequent investigation used the PowerMix™ to study two additional process factors using the same acetaminophen-starch formulation. The interactions between mixing speeds, granulating fluid levels and starch types revealed that mixing speed was the critical variable in the process, followed closely by the amount of granulating fluid added. Differences between the two starches were substantiated. The effects of drying granulations by fluidized-bed techniques or by static oven drying were negligible. A fourth investigation tested the spheronization potential of three grades of microcrystalline cellulose with three grades of theophylline in a novel fluidized-bed rotary granulation technique. The coarsest grade of theophylline was amenable to processing using all three Avicels at drug loading levels of up to 90%. The finest grade (micronized) formed acceptable spheres only at drug loading levels below 50%. Larger grades of Avicel performed lightly better than the finest grade. Shape analyses revealed that sphere quality always deteriorated when drug loading levels exceeded 70%.