Moisture-Activated Dry Granulation Part II: The Effects of Formulation Ingredients and Manufacturing-Process Variables on Granulation Quality Attributes - Pharmaceutical Technology

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Moisture-Activated Dry Granulation Part II: The Effects of Formulation Ingredients and Manufacturing-Process Variables on Granulation Quality Attributes
In this article, the authors evaluated the effects of the granulating binder level, binder type, water amount, and water-droplet size on the MADG process.

Pharmaceutical Technology
Volume 33, Issue 12, pp. 42-51

Figure 4
For the final blend of the same Formulation G batch, the images of the particles retained on #60 (250-μm), #100 (150-μm), and #200 (75-μm) screens, as well as the ones that passed through the #200 screen, are shown in Figure 3. A comparison of the particle-size distribution between the physical mixture and the MADG-processed ingredients of the entire formulation is illustrated in Figure 4. As can be seen, the MADG process reduced the amount of particles smaller than 75 μm (#200 mesh) by 43% and increased the amount of particles between 75 μm (#200 mesh) and ~250 μm (#60 mesh) by 38%. The amount of particles larger than 250 μm (#60 mesh) caused by the MADG process, on the other hand, only increased by ~1%. A comparison of other properties of the physical mixture and the MADG-processed Formulation G is presented in Table VIII. The MADG process significantly improved the granulation flowability. The granulation's apparent bulk density does not change much because the MADG process results in minimal densification, which is an added advantage of the process. Other properties of the batch made with the MADG process (e.g., the final blend moisture content, pellet compaction, and pellet disintegration) were not compromised. The results show that although the MADG process does not create big granules or granule lumps that need size reduction, it reduces fine particles and creates small, uniform, free-flowing, and compactible granulation.

Figure 5
Effect of binder level. The granulating binders play a significant role in agglomeration during the MADG process. The effect of binder levels was studied by using different levels of a binder, PVP K-12, to prepare granulations of Formulation G at 400-g batch size. As shown in Table II, the amount of PVP K-12 in Formulations G, G7, and G9 is 5.0%, 7.0%, and 9.0%, respectively. The change in composition from the amount of binder and water in each formula was offset by the corresponding amount of Avicel PH200 LM. In these experiments, large amounts of binder required more water to hydrate, thus causing a proportional increase in the amount of water with binder content. As shown in Figure 5, the particle-size distribution results of these batches indicate that higher amounts of PVP K-12 and water led to coarser particles in the final blend. The number of particles larger than #30 mesh (600 μm), on the other hand, increased only slightly (i.e., from 0.6% to 1.6%). The results suggest that one can control particle-size enlargement by simply controlling the amount of binder used.

Figure 6
Effect of water-droplet size. Formulation G was used to prepare granulation batches, all at 400-g batch size, with the same amount of water, but delivered in different droplet sizes. This technique allowed the authors to study the impact of water-droplet size on the quality of the formulation. As shown in Table III, the water-droplet size (d90) for Formulations G, G200, and G60 was 110 μm, 200 μm, and 60 μm, respectively. The particle-size distribution of the final blend of each batch is shown in Figure 6 and the results indicate that the percentage of the coarse particles retained on #30 and #60 mesh screens increased when the water-droplet size was larger. However, the final blend particle-size distribution was not much different when the water-droplet size was below 110 μm. It can be deduced from these results that, although it is important to spray water onto the powder bed as uniformly as possible, the MADG process appears to allow some flexibility with respect to the range of water-droplet size that can be used.

Figure 7
Process reproducibility and scalability. The manufacture of Formulation G7 at 400-g scale was repeated three times using a Diosna 2 L high-shear granulator to evaluate the reproducibility of the MADG process (see Table II). As shown in Figure 7, the results suggest that the MADG process was consistent and reproducible for this formulation in terms of its ability to create comparable particle-size distribution in the final blend.

Figure 8
Formulation G was scaled up to a 30-kg batch size in an Aeromatic-Field PMA 150 L high-shear granulator (see Table I). Figure 8 compares the particle-size distribution of the final blend of the 30-kg batch and that obtained with the 400-g batch using a Diosna 2 L high-shear granulator. The results indicate that the scale-up batch had similar final blend and pellet physical properties to those of the smaller batch (see Table VIII). These results imply that, despite the differences in the two granulators, the MADG process is able to produce a consistent product profile even after a 75-fold scale up of the formulation.


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