Improving powder flow properties of a direct compression formulation using a two-step glidant mixing process.

To improve powder flow of a high-dose direct compression formulation (drug content 30%), we compared a two-step operation for mixing glidants with a conventional one-step glidant mixing process. This two-step mixing operation was studied with two kinds of mixtures; an active pharmaceutical ingredient (API)-glidant combination and a direct compression excipient-glidant combination. The two-step operation permitted the selection of the optimum glidant type and concentration in each glidant-mixing procedure even though the formulation had different powder properties such as micronized API and enlarged direct compression vehicles, whereas the conventional approaches forced the selection of a certain glidant type and concentration at one-step mixing. The addition of 0.5% nonporous silica markedly improved API flow. In contrast, 1.0% porous silica was the appropriate glidant to enhance excipient flow at direct compression excipient-glidant mixing. The two-step operation dominantly enhanced powder flow when the appropriate API-glidant mixture and the suitable direct compression excipients-glidant mixture were blended compared to the one-step operation with its optimum glidant concentration. The results showed that the angle of repose was 43 degrees and the critical orifice diameter was 10 mm in the two-step operation, whereas it was 47 degrees and 16 mm in the one-step operation. The two-step operation of glidant mixing enhanced powder flow of the high-dose direct compression formulation compared with the one-step operation. The two-step operation eliminates the bottleneck of powder flow and allows direct compression to be more worth applying for formulation and process development trials.

Rheological analysis and quantitative evaluation of wet kneaded wax matrix.

The properties of the wet kneaded wax matrix were evaluated using a compression tester, whereby a newly proposed sigma index for the plastic deformation was assessed in the pressure transmission diagram. The sigma index was indicative of a characteristic of the plastic yield point in the rheological behavior, and presented an initial and abrupt deformation of wet kneaded mass when the wet kneaded mass was subjected to the pressure. The value of sigma index was confirmed to decrease along with an increase in the plasticity of wet kneaded mass. The wet mass of wax matrix was prepared under various kneading time, and then extruded. The properties of the extruded granules such as pore volume, strength and dissolution were investigated. As a result, it was found that the sigma index decreased with an increase in kneading time. The granules with small value of sigma index showed few porosities, large strength and slow dissolution. It was demonstrated that the sigma index linked the characteristics of wet kneaded mass to the dissolution and the other granule properties. Existence of this link was revealed by sigma index evaluation relevant to the plasticity. The sigma index could be a decisive criterion to permit an in-process evaluation of the kneading progress quantitatively, and also useful for anticipating the dissolution of the final granules roughly.