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


Table I: A general moisture-activated dry granulation formulation, Formulation G.
Batch manufacturing. Table I shows a typical MADG formulation, designated as Formulation G. In this formulation, lactose monohydrate, representing 65.0% (w/w) of the formula, is a surrogate for the API. The amount of lactose monohydrate maybe reduced to accommodate the drug load. Iron oxide (red) is used to demonstrate the mixing uniformity of the formulation. PVP K-12 is the granulating binder, and water is the granulating liquid. Micro crystalline cellulose (Avicel PH200 LM) and silicon dioxide (Aeroperl 300) are used as fillers and moisture absorbents, respectively. Crospovidone and magnesium stearate are added as a disintegrant and a lubricant, respectively.


Table II: Compositions of Formulations G, G7, and G9.
The ingredients for Formulation G,in the amounts listed in Table I were used to manufacture a 400-g batch using a Diosna 2 L granulator. Lactose monohydrate, PVP K-12, and iron oxide were premixed in the granulator for 1 min. at an impeller speed of 400 rpm (tip speed 3.7 m/s) and a chopper speed of 1200 rpm. Keeping the same mixing conditions, 5.6 g of water was sprayed onto the powder bed at a rate of 10 g/min using a Schlick spray nozzle with a 0.15-mm diameter orifice. Water-droplet size (d90) was ~110 μm during the spraying. Mixing was continued at the same conditions for an additional 3 min to form the moist agglomerates. With continual mixing, microcrystalline cellulose was added into the granulator and mixed for 3 min. Silicon dioxide was next added and mixed for 3 min, followed by crospovidone for an additional mixing of 2 min. Then, with the impeller speed reduced to 200 rpm and the chopper turned off, magnesium stearate was added into the granulator and mixed for 30 s. This final blend was compressed into pellets (500-mg weights), using a Carver press with a set of 7/16-in. round, flat-faced tooling. The compression force was 4000 lb with dwell time of no more than 1 s. The pellet-ejection force was measured using an in-house device. The average pellet-ejection force and hardness of three replicate measurements were reported.


Table III: Compositions of Formulations G, G200, and G60.
Additional batches based on Formulation G were manufactured at a 400-g batch size to evaluate the effects of critical formulation and process variables in the MADG process. Table II lists Formulations G, G7, and G9 made with the granulating binder, PVP K-12, at levels of 5.0%, 7.0%, and 9.0%, respectively. Table III lists Formulations G, G200, and G60 made with water-droplet sizes (d90) of 110 μm, 200 μm, and 60 μm, respectively, while maintaining PVP K-12 level the same at 5.0%. Table IV lists Formulations G, GH, GC, and GM made with different granulating binders (i.e., PVP K-12, HPC EXF, copovidone, and Maltrin 180, respectively).


Table IV: Compositions of Formulations G, GH, GC, and GM.
Formulation G7 was manufactured three times at the 400-g batch scale to evaluate the reproducibility of the MADG process. Formulation G was also manufactured at a 30-kg batch size to evaluate the process scalability using an Aeromatic-Fielder PMA 150 L high-shear granulator (see Table I). While keeping all other manufacturing process parameters the same as those used for the 400-g batch, premixing and agglomeration were carried out with impeller and chopper speeds of 95 rpm (3.7 m/s) and 1700 rpm, respectively. Water was sprayed onto the powder bed at a rate of 120 g/min using a Schlick spray nozzle with a 0.4-mm diameter orifice.


Table V: Compositions of Formulations G, M, and A.
The wide applicability of the MADG process was evaluated by replacing lactose monohydrate in Formulation G with other materials. Table V lists Formulations G, M, and A, in which the main ingredient is lactose monohydrate, mannitol, or acetaminophen. Each product was manufactured following the same procedure as that used for Formulation G at the 400-g scale.


Table VI: Compositions of Formulations CA, CB, CC, and CD.
MADG process-based tablet formulations were also developed for compounds A, B, C, and D. Table VI lists Formulations CA, CB, CC, and CD made with compounds A, B, C, and D, respectively. Each product was manufactured using the same procedure as that used for the Formulation G at the 400 g scale.


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