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The purpose of this research was to evaluate the use of a rotating fluidized-bed granulator to produce acetaminophen granules with sufficient binding force between particles and good plasticity in tablets. Ethenzamide and ascorbic acid were used to compare the relationship between granulation and the sample wetness. It was revealed that a blade rotation rate of 300 rpm, inlet air flow rate of 42 m3/hr, and spraying pressure of 1.5 kg/cm3 produced tablets with the best properties. The granule and tablet properties of ethenzamide and ascorbic acid were compared to those of acetaminophen. These compounds showed different wetting behaviors with water and different compression behaviors. With an increase in medicament content, tablet hardness increased except for the ascorbic acid formulation. Capping and sticking were observed in acetaminophen and in ascorbic acid, respectively, and acetaminophen and ethenzamide showed prolonged disintegration time.

1431Recently the importance of QbD (Quality by design) in International Conference on Harmonisation (ICH) Q8 has been highlighted, 1) and scientific levels of formulation designing and manufacturing designing are more and more emphasized. In addition, there is pressure on the pharmaceutical industry in shortening the development time of new products. Further, considering current situation that there are cases where levels of formulation study and scale-up study, prerequisites of validation, are not sufficient, it is tended to be interpreted that conventional validation is not final verification of validity of acceptable manufacturing conditions, but one of processes of the cycle oriented to Continuous Improvement of quality through Product Life Cycle. 1,2) From the viewpoint of QbD, in the unit operations of formulation manufacturing, granulation process is a process which has a significant impact on quality of final products, and should be considered mostly to be studied. Therefore scale-up of high shear granulation has been approached in several ways.3-7) But in wet granulation, for example, there are numerous combinations of process parameters such as agitation speed, irrigation speed of binder solution, etc. and current situation is that generalized solution, covering from a small production scale to a commercial production scale, is not obtained.The concept of Design Space introduced in ICH Q8 defines the appropriate operation space of respective operation parameter in a commercial production scale, and vast experiments should be needed to establish multidimensional operation space of these variation factors. In the case of investigational drugs, however, there is a situation that ample drug substance can not be available, and this situation being considered, it is a critical requisite to establish experiment system of a small scale where by using small quantity of drug substance extrapolation to commercial production is intended as a means of realizing the concept of ICH Q8. But few studies report scale-up from a mini-scale to pilot scale. 5)In this study, experiments and analyses were performed by using a newly developed 0.2 L mini-scale high shear mixer where extremely small amount of drug substance is used, in order to seek possibilities to establish Design Space which can extrapolate manufacturing conditions from a small scale to pilot scale (investigational new drug production scale), finally to a commercial scale. ExperimentalMaterials Anhydrous caffeine (Shiratori Seiyaku Co., Ltd.) was used as model drug. The following inactive ingredients were purchased from commercial sources: D-mannitol (Toa Kaseikogyo Co., Ltd.) and dibasic calcium phosphate (Kyowa Kagaku Co., Ltd.) as fillers, pregelatinized starch (Matsutani Kagakukogyo Co., Ltd.) as a binder, corn starch (Nihonshokuhin-Kako Co., Ltd.) as a disintegrant, magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.) as a lubricant for the preparation of the tablets. Purified water was used as the granulation liquid.Preparation of Granules All materials ...