1. Evaluation of the Critical Process Parameters in Optimization of Formulation Composition Involving Wet Granulation Feiqian Yu 1, Yusheng Fang 1, Lei Chen 2, Jim Fang 2 1. Product Development, TAI HENG Industry Co.,Ltd, No.18 Cao Xi Road(North), Shanghai, P.R.China 2. Product Development, Stason Pharmaceuticals Inc., 11 Morgan, Irvine, CA 92618, USA Experiment12345 DesignX1=-1 X2=-1 0 1 0 1 Experiment6789 DesignX1=1 X2=1 0101 0000 0 Factorial design approach has been approved to be effective but also time consuming and expensive. Effort of trying to increasing the efficiency of this approach was presented here through the granulation study during product development process of a high drug load (~84%) generic product. The target is to find out a formulation/process which has equivalent dissolution profile compared to that of RLD. Wet granulation approach was chosen due to the physical property of API and high drug load of this product. Since this is a IR product, so the binder level in the formulation is critical to the in-vitro dissolution profile. A 3 2 full factorial design (See Table 1) was used to optimize the binder (HPMC) amount in the formulation. In the subsequent study, critical wet granulation process parameters were evaluated through single factor DOE on the optimized formulation to determine their impact on the product dissolution profile. METHODS Table 1 Variables in 3 2 full factorial design Independent variable,factor Levels used Low (-1)(%) Middle (0) (%) High (1) (%) X1: HPMC concentration in the granulation fluid 024 X2: Total HPMC level in the final formulation 12.54 Dependent variable,responseY=In Vitro Dissolution Release RESULTS The results shown in figure 1 suggests that the amount of HPMC in pre-blend is critical to the dissolution profile of final product. If HPMC is added thought granulation fluid, the concentration of HPMC or amount of HPMC in the final formulation does not affect the dissolution profile. Thus water was chosen as granulation fluid. The effect of the amount of water used for granulation was also evaluated and results are shown in figure 2. Similar study was performed to evaluate the effect of granulation time on product dissolution (figure 3). Based on all the studies listed above, an optimized wet granulation process was designed and product in-vitro dissolution profile was equivalent to RLD (figure 4). CONCLUSION Selectively choosing formulation/process parameters for factorial design will significantly improve efficiency of product development process. Critical parameters can be evaluated to create enough design space for target product while less critical parameters can be fixed at reasonable level to simplify the situation. Fig 2 Effect of Granulation Fluid Amount on Product Dissolution Fig 3 Effect of Granulation Time on Product Dissolution Fig 4 RLD and TH tablet dissolution profiles Other Process Parameters Copyright ® 2009 Taiheng Industry Co.,Ltd INTRODUCTION Fig 1 HPMC Level Evaluation Study Results HPMC was added into the formulation through blending process only in Exp, 1, 2 and 3 (when X1=-1). For all other experiments, HPMC was added into the formulation through different concentration of granulation fluid (2% when X1=0 and 4% when X1=1).