(T1330-08-43) Interaction Effects of Wet Granulation Process Parameters on Granule Size and Dissolution Performance of a High Drug Load Product Manufactured in a High-Shear Mixer

Purpose: High Shear wet granulation, fluid bed processing and subsequent milling variables that can influence final granule characteristics of lactose-based formulation for a high drug load formulation (Compound A) were evaluated using a fractional factorial experimental design. Factors evaluated were water quantity, granulation time, wet massing time, inlet temperature, inlet air volume and milling speed. The objective of this study is to evaluate the interaction effects of the above listed factors and their impact on the response variables: dissolution and particle size.

Methods: The API (Compound A), lactose, Colloidal silicon dioxide, crospovidone, hypromellose, and magnesium stearate (from vegetable source), were procured from established GMP vendors. The API, lactose, Crospovidone were granulated in a PMA65 high shear granulator, with purified water. The granules were sieved through a Comil to size the wet granules followed by drying in a fluid bed dryer. The dried granules were sieved through a Comil to achieve the desired particle size distribution. The dried granules were then blended with extra-granular excipients (colloidal silicon dioxide, crospovidone and magnesium stearate to form the final blend which was then encapsulated on a Bosch 700 encapsulation machine. The responses measured were dissolution time, particle size, flow properties. A total of 20 batches were executed as part of the DOE design.

Results: Water quantity was the largest significant factor impacting dissolution at 15 mins. Wet massing time was then the next most important parameter and finally a combined AC factor (water quantity/wet massing time) was next most important to dissolution performance at 15 mins. Figure 1 shows the effect of granulation water quantity on dissolution observed at 15 minutes. Approximately 95% dissolution was observed at 27% w/w granulation water whereas 87% dissolution was observed at 31% w/w granulation water. From Figure 2 wet massing was also a significant parameter; the wet massing time has a significant effect at the 31% w/w water end of the range but much less impactful at 27%. The effect of the wet massing on the 15 minute dissolution point at the 29% w/w granulation water center point is shown in Figure 2. There is a 6% decrease in dissolution rate across the 1 to 3 minute wet massing time. The model indicates this is significant. The 15 minute time point does show high variability associated with capsule opening and this should be considered in reviewing the significance of the data in Figure 2. Mill speed was examined to explore if there were any impacts on the intended operation of the mil at 675 rpm. Figure 3 shows the % (by weight) of granules 250 μm and above linked to mill speed. There was limited effect at the 27% granulation water level, but an effect was noted at the 31% water level.

Conclusion: The overall conclusions of the DoE exercise and analyses indicated some important effects, mostly due to the amount of granulating water used, on the particle size distribution of the granulation both pre- and post-dry milling. As particle size may influence the flow characteristic of the powder, the adequacy of flow, or influences of the PSD, would be borne out in the capsule filling process. Capsules from all runs showed acceptable weight variation, suggesting that the parameters evaluated had little effect on these responses in the ranges tested. In conclusion, the parameters of blend time, encapsulation time, and amount of magnesium stearate used were stretched beyond those studied in the DoE batches. The blend time was increased two-fold of proposed manufacturing process, the encapsulation time was extended to approximately 250 minutes, and the lubricant amount was increased by 0.2% from the proposed formula amount of 0.7% w/w along with two-fold increase in blend time. There was no impact to the dissolution characteristics of these batches and all would meet the proposed commercial specification of Q = 80% at 30 minutes.

Figure 1. Effect of Granulation Water Quantity and Wet Massing Time on Dissolution at 15 minute time point.



Figure 2. Effect of Wet Massing Time on Dissolution Rate at 15 minute time point with Center Point Granulation Water



Figure 3. Interaction of Mill Speed and Granulation Water Quantity on Large Granule Quantity