Figure 3 shows how, at a constant water content of 15% and a fixed screw speed of 600 rpm, the BFE of granules produced for the DCP formulation substantially increases as the dry powder feed rate to the granulator is reduced. Additional data show that granules with the same BFE can be made at lower water contents by reducing the feed rate. For example, granules with 15% water content produced at a feed rate of about 18kg/hr have similar properties to granules containing 25% water made at a feed rate of 25kg/hr. As with the studies on the APAP blend, these results show how granules that are identical in terms of a specific powder property can be produced from multiple combinations of processing conditions.
Table 1 shows the different process parameters used to manufacture two pairs of granules with different properties. Conditions 1 and 2 generated BFE values for the wet mass of approximately 2200mJ, while conditions 3 and 4 resulted in BFE values of around 3200mJ. The BFE of the granules was also measured after each of the following process steps. These include drying, milling and lubrication to improve processability, where the flow additive in this study was magnesium stearate. Throughout these stages, the relative BFE values remain consistently grouped, with the BFE values of 3 and 4 consistently higher than 1 and 2.
Figure 4 plots the flow properties of the granules at each stage of the manufacturing process. Conditions 3 and 4 show an increase in BFE following drying, due to the granules’ large relative size, higher density and higher mechanical strength, compared to those manufactured under conditions 1 and 2. Following milling, particle sizes are more similar, although differences in granule density, shape and stiffness still exist and rationalize the observed differences in BFE. These differences are retained following lubrication with noticeable distinctions between conditions 1-2 and 3-4.
These results clearly show that it is possible to produce granules with specific flow properties, as measured by BFE, using a range of different process conditions. Such work demonstrates how BFE values can be employed for product and process development of wet granulation operations. However, they also invite the question as to whether BFE values can be further utilized to predict in-press behavior and, importantly, whether BFE can be related directly to a tablet critical quality attribute?
The four batches of wet granules were subject to drying, milling and lubrication before being run under identical settings on the tablet press. The hardness of the resulting tablets was then measured. Figure 5 shows how tablet hardness correlates with the flow properties of the granules at each stage.
The results show that BFE and tablet hardness are strongly correlated, with particularly good differentiation for the wet mass and dried granules. Correlations for the wet mass and lubricated granules are reasonable, although slightly weaker than those of the dried and milled granules. The poorer differentiation and correlation observed for the lubricated granules is attributed to the overwhelming effect of the magnesium stearate.
This data has shown that there is a direct relationship between the flow properties of the granules at each stage of manufacture — as characterized by BFE — and a critical quality attribute of the final tablet, in this case hardness. This means that once a specific BFE has been linked to optimal tablet hardness, it can be used to drive the optimization of a wet granulation process. These results suggest that, providing the wet granules attain the target BFE, the quality of the end tablet, as measured by hardness will be assured. This offers opportunities to streamline product and process development as well as providing a route to better process control during either batch or continuous granulation.
Today, the traditional batch process approach to manufacturing remains dominant, however, in the coming years many within the industry anticipate that continuous manufacture will be adopted for a substantial share of products.