Purpose: The intent of this study was to evaluate the effect of wet-granulation process parameters (mixing/kneading time, amount of water added, and water addition rate) on the critical quality attributes (CQAs) of a tablet formulation of a novel oncology agent, viz. particle size distribution (PSD), bulk density/tapped density, loss on drying (LOD) and tablet compactibility. These CQAs can impact compression which in turn can affect target product attributes such as content uniformity and dissolution. Understanding how the process parameters affect these CQAs is important to have better control over the process and to ensure that the process is robust.
Methods: The granulation batches (batch size = 10 kg, drug loading of ~31%) were manufactured using a Glatt® VG-200 and were dried using Glatt® GPCG-15. For the DOE, three factors were varied at two different levels: a) water addition rate (1.5 kg/min and 2.5 kg/min), b) amount of water (3.0 kg and 4.2 kg), c) kneading time (0.5 min and 2.0 min). Additional batches were made using center-point values: 2.0 kg/min, 3.6 kg and 1 min. Bulk/Tapped density, LOD and PSD were examined as response factors. PSD was obtained using sieve analysis with screens having mesh sizes 30, 40, 60, 100, 140, and 170. All the experiments were conducted at same processing conditions. The granulated batches were compressed at different hardness values (8 kP, 11 kP, 14 kP, 17 kP) on a Manesty 700 tablet press. Porosity and tensile strengths were calculated for these tablets.
Results: From the granulation DOE analysis, it was observed that changing the three parameters didn’t have any effect on LOD values and particles of size less than 600 microns (% retained on screens with mesh sizes: 40, 60, 100, 140, 170 and Pan) for the granulated product (p > 0.05). Refer to Figure 1 for pareto chart.
However, the amount of water and kneading time did have an effect on the bulk density and tapped bulk density (p = 0.001). Increases in the amounts of water and kneading time from low to high caused increases in bulk density by ~13% and tapped density by ~7%.
Figure 2 Pareto Chart for bulk/tapped density
Of the three parameters studied, the solution addition rate did not have any effect on its own (p > 0.1). However, when combined with amount of water and kneading time, it did have effect (p = 0.028) on particles larger than 600 microns (% retained on 30 mesh screen).
For compressed tablets, a linear relation between the logarithm of tensile strength and porosity was obtained. This relation was fitted to the Ryshkewitch-Duckworth equation (lnσ = lnσ – k*ε) where σ is tensile strength, σ0 is tensile strength at zero porosity and ε is the tablet porosity (Figure 3). This equation represents exponential decay of tensile strength with increase in porosity. Using this equation, tensile strength at zero porosity was calculated, which represents the maximum compaction for a tablet. It was found that the amount of water and kneading time had a significant effect (p = 0.03) on the maximum tensile strength of the tablets.
Conclusion: The effect of granulation process parameters on the tablet formulation CQAs (LOD, bulk and tap densities, PSD and compactibility) were analyzed. The analysis identified the amount of water and kneading time as having the most significant impact on the granulated product and the compactibility of the formulation. The tensile strength showed exponential decay with tablet porosity and was accurately described by the Ryshkewitch-Duckworth equation. Additionally, granulation processing parameters that yield target CQAs have been determined. Thus, by following quality by design approach to gain process understanding, robust manufacturing control strategies can be developed.