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

Image acquisition. Powder and granule images were acquired during batch manufacture using a SMZ1500 stereoscopic zoom microscope system (Nikon, Tokyo).

Water-droplet size measurement. The water-droplet size was measured with a SprayWatch imaging system (OSEIR, Tempere, Finland) (5). The system uses a charged-coupled device camera with microscope lens and a diode laser light source to measure the droplet size and velocity distribution. More than a thousand droplets were typically recorded in each image. The size distribution and its average were derived from the circumference of the enhanced droplet images.

Particle-size analysis. An ATM sonic sifter (Sepor, Wilmington, CA), equipped with #30, #60, #100, and #200 mesh sieves and pan, was used for powder particle-size analysis. The sieves were sequentially stacked with the #30 sieve on the top and the #200 sieve at the bottom on top of the pan. About 10.0 g of sample were placed on the #30 mesh screen to begin the test. The sieve-and-pan assembly was vibrated for 5 min at an amplitude level of 4–5 and a pulsing interval of 5 s. The powder or granules of various particle-size ranges was then separated and remained on each of the screens and pan. The weight of the powder or granules retained on each sieve and in the pan was used to determine the particle-size distribution of the powder.

Apparent bulk density. A Scott volumeter (Prabha Engineering Products, Delhi, India) was used to determine the apparent bulk density of powders. The weight of the powder required to fill a 1-in.3 container in a loose but reproducible manner was measured. The average of three replicate measurements was reported.

Powder flowability. An Erweka GT flow tester (Erweka USA, Flemington, NJ) was used to determine flowability of the powders. About 25–50 g of sample were placed in a 200-mL funnel and tested with the setting at agitation Level 1 for each measurement. The length of time required for the entire sample to flow through the funnel was measured. The average of three replicate measurements was reported.

Pellet hardness. A Key tablet hardness (Key International Englishtown, NJ) tester was used to determine pellet hardness. The average of three replicate measurements was reported.


Figure 2
Moisture content. A Mettler Toledo HR73 halogen moisture analyzer (Mettler-Toledo International Columbus, OH) was used to measure the loss-on-drying of the powders. Approximately 2 g of sample was kept at 85.0 C and repeatedly weighed for loss of moisture until a constant weight was achieved. The average of three replicate measurements was reported.

Results


Figure 3
Characterization of Formulation G. The granulation particle-size progression of Formulation G during the MADG process at 400-g scale is shown in Figure 2. Figure 2a is the image of the premix of lactose monohydrate, iron oxide, and PVP K-12. This dry blend has many fine particles. Figure 2b shows the image of the granules formed during the agglomeration stage as a result of the addition and mixing with water. The fine particles in the premix have bound together to form spherelike agglomerates with a particle-size range of 150–500 μm. These agglomerates are moist at this stage. The granule particle-size enlargement progression was obvious from the premix (Figure 2a) stage to the end of agglomeration (Figure 2b). Figure 2c shows the image of the granules after mixing with microcrystalline cellulose (Avicel PH200 LM). As can be seen, some agglomerates in Figure 2b have broken up into smaller granules because of the drying effect of Avicel PH200 LM. Some of the moisture in the moist agglomerates is taken up by the drier Avicel PH200 LM, and this moisture redistribution results in the drying of the moist agglomerates. Some breakage of the larger agglomerates also occurs as a result of the drying of the moist agglomerates. As a consequence of some of the larger agglomerates breaking, the granulation particle-size distribution became fairly uniform with few fines. Figure 2d shows the image of the final blend of Formulation G. Unlike in Figure 2c, the smaller particles in Figure 2d essentially came from the crospovidone and magnesium stearate. The silicon-dioxide particles can barely be seen because they are transparent under the light used for microscopic observation.


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