Category: Formulation and Quality
Purpose: To evaluate the impact of wet granulation process parameters on granule properties and compression characteristics of an immediate release tablet of poorly soluble drug.
Methods: Wet granulation for this study was performed at 3.5 kg scale using a high shear wet granulator and fluid bed dryer. Amount of water, spray time, and impeller speed were identified as process parameters and studied as independent variables. Impact of the wet granulation process parameters were studied to evaluate on the granules properties (granule flow properties and particle size distribution), compression characteristics (tablet hardness, tablet friability, tablet disintegration time) and bulk product quality (content uniformity and dissolution). Total of 6 batches including a centre-point were manufactured as specified in attachment 1. Amount of water and spray time were studied at 2 levels (low and high) and impeller speed was studied at one level (high). For compression study, impact of compression force (10 kN, 13kN and 16 kN) on compression characteristic (hardness, friability and disintegration time) was evaluated as specified in attachment 2.
Results: The final blend showed % fine (below 177 micron) 62.4, 48.1 and 47.8 when water amount used for granulation were 24%, 30% and 36%, respectively. Also Hausner Ratio was 1.613, 1.25 and 1.22 and Carr’s index was 38, 21 and 18 when water amount used for granulation were 24%, 30% and 36%, respectively. These results indicated that lower amount of water produced more fine and exhibit poor flow characteristic. However, 24%, 30% and 36% of water amount had no impact on compression characteristics and core tablet dissolution. The % fine in final blend was 58%, 48.1% and 47.8% when spray time was 221 seconds, 285 seconds and 360 seconds, respectively. However, spray time had no impact on compression characteristics and core tablet dissolution. The % fine in final blend was 51.9% and 48.1% when it was granulated at 544 rpm and 272 rpm impeller speed, respectively. Tablets compressed with granules manufactured at higher impeller speed has higher disintegration time (~14 minutes) compare to tablet compressed with granules manufactured at target impeller speed (~5 min). This was also supported by dissolution data that the % dissolved in first 15 minutes was lower with tablets manufactured with higher impeller speed granules.
Conclusion: In a studied range of process parameters (amount of water, spray time and impeller speed) indicated that wet granulation process parameters have impact on granule property and compression characteristic. Though compression defects (sticking/edge erosion) was not observed as a results of higher % fine in final blend, it may appears during scale-up. This study indicated that disintegration time was impacted by higher impeller speed though core tablets dissolution was within range. These results suggested that amount of water, impeller speed and spray time ranges have to optimize using full factorial design of experiments, prior to scale-up study.