Definitive screening design (DSD) is a new class of small three-level experimental design that is attracting much attention as a technical tool of a quality by design (QbD) approach. The purpose of this study is to examine the usefulness of DSD for QbD through a pharmaceutical study on the preparation of ethenzamidecontaining orally disintegrating tablet. Model tablets were prepared by directly compressing the mixture of the active pharmaceutical ingredient (API) and excipients. The five evaluated factors assigned to DSD were: the contents of API (X1) and lubricant (X2), and the compression force (X3) of the tableting process, the mixing time (X4), and the filling ratio of powder in the V-type mixer (X5). After tablet preparation, hardness and disintegration time were measured. The same experiments were performed by using the conventional design of experiments [i.e., L8 and L16 orthogonal array designs and central composite design (CCD)]. Results showed that DSD successfully clarified how various factors contribute to tablet properties. Moreover, the analysis result from DSD agreed well with those from the L8 and L16 experiments. In additional experiments, response surfaces for tablet properties were created by DSD. Compared with the response surfaces created by CCD, DSD could produce reliable response surfaces for its smaller number of experiments. We conclude that DSD is a powerful tool for implementing pharmaceutical studies including the QbD approach.

The different states of water incorporated in wet granules were studied by a low-field benchtop 1 H-NMR time-domain NMR (TD-NMR) instrument. Wet granules consisting different fillers [cornstarch (CS), microcrystalline cellulose (MCC), and D-mannitol (MAN)] with different water contents were prepared using a high-speed granulator, and then their spin-spin relaxation time (T 2 ) was measured using the NMR relaxation technique. The experimental T 2 relaxation curves were analyzed by the two-component curve fitting, and then the individual T 2 relaxation behaviors of solid and water in wet granules were identified. According to the observed T 2 values, it was confirmed that the molecular mobility of water in CS and MCC granules was more restricted than that in the MAN granule. The state of water appeared to be associated with the drying efficiency and moisture absorption capacity of wet granules. Thus, it was confirmed that the state of water significantly affected the wet granulation process and the characteristics of the resultant granules. In the final phase of this study, the effects of binders on the molecular mobility of water in granulation fluids and wet granules were examined. The state of water in granulation fluids was substantially changed by changing the binders. The difference was still detected in wet granules prepared by addition of these fluids to the fillers. In conclusion, TD-NMR can offer valuable knowledge on wet granulation from the viewpoint of molecular mobility of water.

The purpose of the present study is to demonstrate the applicability of magnetic resonance imaging, especially T relaxation time mapping, for nondestructive monitoring of the dispersion state of nanoparticles (NPs) in concentrated suspensions. TiO 15-nm-diameter NPs, for use in sunscreen lotion products, were examined as a test NP. First, this study investigated whether T is sensitive to the NP concentration. In experiments with pulsed nuclear magnetic resonance on TiO NP suspensions with different organic solvents (ethanol, acetone, and decamethylcyclopentasiloxane), the T of each solvent varied in the suspensions according to the NP concentration. This study also confirmed that T mapping was effective for visualizing differences in NP concentration. Subsequently, gravitational sedimentation of the test suspensions was investigated. T mapping exhibited better detection sensitivity to sedimentation occurring in concentrated suspensions than visual observation, as it enabled the detection of changes in NP distributions that could not be visible to the naked eye. In addition, measurements of backscattered light enabled the full understanding of the dispersion stability of the TiO NPs in each solvent. Finally, the present study evaluated the centrifuge sedimentation of a commercial TiO NP suspension. T mapping clearly showed the complicated sedimentation behavior induced by the centrifugation treatment. The simulated fluid flow was consistent with the particle distribution in the centrifuged sample; thus, the sedimentation was believed to have developed in accordance with the vorticity generated by the centrifugation.

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