難溶藥物在立即釋放（Immediate-Released）之劑型設計上，除須考慮複雜的處方設計外，尚須使用適當的製程參數，因此為達處方設計之最適化，所需控制的變因種類則更多，本研究則利用實驗設計法（Experimental Design），從複雜的變因中逐步篩選出影響藥物溶離之主要變因，進而達到處方設計之最適化。本研究在處方設計上主要探討活性成分的顆粒大小、崩散劑的含量、結合劑的含量、錠劑硬度等4個因子，而在製程參數探討則以分散技術為主，以濕式造粒法（Wet Granulation Method）的方式來使其活性成份（Active Pharmaceutical Ingredient）分散均勻，使藥物在預定的時間內來達到完全的釋放與溶解。實驗設計的步驟分為兩個階段：1. 田口氏直交表（Orthogonal Arrays）；2. 反應曲面法（Response Surface Methodology）。第一階段採直交表L9（34）的方式，以4個因子各以3個水準來設計處方。第二階段：以曲面反應法將結合劑含量與錠劑硬度兩因子作不同的比例調整來做處方條件的最適化。經過實驗得知，影響藥物溶離最大之因子為活性成分的顆粒大小，其次為結合劑之含量與錠劑硬度，而崩散劑含量對實驗幾乎沒有影響。將實驗溶離結果與預定之溶離目標以f2值比對，得到最適化處方為：活性成分顆粒大小為10μm、崩散劑含量為9%、結合劑含量含量6%、錠劑硬度13kg，得到f2極大值73.49。 Formulation design of poorly soluble drug using is complex problem. When we designed the content of excipients, process of manufacture must to be considered, so we must to control many factors to design a formulation. This study used experimental design to find the main factor of dissolution and make dissolution profile to be similar with reference.
We find 4 factors to discuss in this study, they are: 1. particle size of API; 2. the content of disintegrant; 3. the content of binder; 4. hardness of tablet. Process of manufacture is base on dispersion technique, so we used wet granulation method (one of dispersion technique) to homogenize API and make sure drug dissolves and releases completely in the short time.
There are two steps in experimental design. First step of experimental design is pre-formulation by Taguchi Method (Orthogonal Arrays: L9)(4 factors, 3 levels). Second step is response surface methodology (RSM).
After experiment, we know particle size of API is main effect in this study, the second factor is hardness of tablet, the third factor is binder, disintegrant is the factor which to effect slightly. Next step we used RSM to find the relationship between the content of binder and hardness of tablet. Then we adjusted the formulation and made f2 value to maximum (73.49). The optimal formulation is particle size of API: 10um, disintegrant: 9%, binder: 6%, hardness of tablet: 13kg. After using experimental design, We can save time and cost and find the optimal formulation quickly.
