A NEW ATTEMPT TO SOLVE THE SCALE-UP PROBLEM FOR GRANULATION USING RESPONSE-SURFACE METHODOLOGY

Scale-up from lab to production is always problematic for the developm ent of pharmaceuticals. In granulation, an optimal formulation of bind er solution determined in a lab scale is often different than that in a production scale. A new mathematical procedure to solve this scale-u p problem is assessed. Granules were prepared in the two manufacturing scales (2- and 5-kg scale) by using a highspeed mixer granulator. In the manufacturing process, the binder solution plays an essential role in the formation of granules with desired physical properties, in clo se conformity with the manufacturing scare. A computerized optimizing technique based on a response surface methodology was developed to stu dy the scale-up problem in the manufacturing of granules. For this pur pose, a new mathematical function was introduced for the first time, w hich is namely an integrated optimization function. A universal optima l formulation unaffected by manufacturing scale could be obtained by m inimizing the integrated optimization function. Predicted values such as yield, mean granule size, and uniformity of granule size agreed wel l with experimental ones on both scales. Furthermore, the optimized ch aracteristics measured at the production scale coincided well with tho se obtained at laboratory scale, suggesting that this approach could b e very useful in minimizing scale-up problems.