An Investigation of the Effect of Some Formulation and Manufacturing Variables on the Wet Granulation Process

Abstract

A Hobart mixer was instrumented with a slip ring torque sensor, signals were amplified and the output was recorded using a Bascom-Turner recorder. The relative dynamic torque on the paddle was measured in millivolts as a function of granulating fluid added and time. The data generated from a formulation containing lactose, corn starch and povidone were reproducible. The maximum relative standard deviation was less than two percent at any time point on the torque curve. Formulations containing lactose, dicalcium phosphate and mannitol matrices (with four different drugs) shoed five distinct phases in the torque profile. Phases I, II, and III of the wet granulation process were studied for formulations containing five drugs (phenylpropanolamine, theophylline, hydrochlorothiazide, phenytoin and acetaminophen). Granule properties were evaluated using scanning electron microscopy, particle size measurement and determination of bulk physical properties, including flow rate as well as compressibility. A computer-interfaced instrumented tablet press was used to generate compression profiles from which the compressibility of the granules was assessed. The instrumented tablet press data substantiated a simple theory for the relationship between granulation properties and ease of compaction. The data suggest optimum flowable and compressible granulations can be obtained only from phase III of the process irrespective of the drug, drug concentration and matrix. The disintegration and hardness for some formulations (theophylline, phenylpropanolamine and hydrochlorothiazide) were sensitive to variations in the wet granulation process. However, dissolution and friability for these formulations were relatively insensitive to changes in the processing variables. A (3x2x3) factorial experimental design was used to investigate the effect of binder, binder level and granulating fluid on the wet granulation process. It was found that all these factors exerted statistically significant effects on granulations flow rate, tablet ejection force, hardness, disintegration and dissolution at fifteen and thirty minutes. A second factorial experimental design (4x5x3) was used for the study of the effect of disintegrant, disitegrant concentration and percent in intragranular disitegrant on the dissolution rate of tablets made by wet granulation process. The data indicate that these factors exerted statistically significant effects on disintegration and dissolution at fifteen and thirty minutes. This instrumentation can be used to determine the optimum amount of granulation fluid necessary for the wet granulation process. In addition, it can be a valuable tool for validation of the wet granulation process.