Moisture-Activated Dry Granulation—Part I: A Guide to Excipient and Equipment Selection and Formulation Development - Pharmaceutical Technology

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Moisture-Activated Dry Granulation—Part I: A Guide to Excipient and Equipment Selection and Formulation Development
The authors explain a process for moisture-activated dry granulation in detail and provide guidance for the selection of excipients and equipment.

Pharmaceutical Technology
Volume 33, Issue 11, pp. 62-70

If binders are available in various viscosity grades, it is desirable to use the ones with low viscosity because they tend not to retard tablet or capsule dissolution. However, binders with very low viscosity may not provide enough tackiness for agglomeration. In general, high-viscosity binders are often required in small amounts. The amount of binder needed does not depend on the viscosity alone; other factors such as binder mass must be considered. For example, if 5% of PVP K-12 is sufficient for one formulation, 2% of PVP K-30 may not be the correct proportion for the same formulation. Experiments have shown that about 3% or more of PVP K-30 would be required for proper agglomeration. This difference results from the fact that, in addition to binder viscosity and tackiness, the mass of the binder also plays an important role in covering and coating the blend particles that are to be agglomerated. The binders with small particle size and great surface area would be advantageous as well.

Generally, binders such as HPC, Na CMC, and HPMC require more water and longer hydration time compared with PVP or maltodextrin. On the other hand, binders such as Starch 1500 would not be suitable for the MADG process because this binder has a significant percentage of unhydrolyzed starch components that could absorb considerable amounts of water. As a result, the amount of water needed to effect agglomeration when using Starch 1500 would not be practical for the development of a typical MADG formulation. Completely hydrolyzed starch is not recommended because it does not have sufficient tackiness to cause agglomeration. In all cases, the binder chosen should have fine particles and sufficient tackiness upon moistening to cause adequate agglomeration.

Moisture absorbents for the MADG process. About 70–95% of any MADG formulation is agglomerated, and the remaining portion of excipients is added as is. In general, the nonagglomerated portion consists of moisture absorbents, disintegrants, and lubricants. It is desirable that nonagglomerated excipients be closer in particle-size distribution to the agglomerated portion of the formulation to minimize the potential for segregation.

Microcrystalline cellulose, which doubles as a filler and moisture absorbent, is available in the approximate particle size of 200 μm. Low moisture grades are also available. Avicel PH 200 LM (FMC, Philadelphia) is an excipient with low moisture content (< 1.5% by weight, as determined by loss on drying). Aeroperl 300, a moisture absorbent in the form of a non-lumpy, free-flowing granulated silica consisting of ~30-μm spherical particles is also available from Evonik Industries (Essen, Germany). Granular Aeroperl 300 has excellent moisture-absorbing capacity, and its surface area is much lower than that of the colloidal silica used as a glidant for granulation. The amount of Aeroperl 300 typically needed for the MADG formulation is small, which is advantageous from the standpoint of preventing tablet-ejection problems.

The disintegrant crospovidone is available in coarse particle-size grade from either ISP (Wayne, NJ) and BASF (Ludwigshafen, Germany). This material is not only a superdisintegrant, but is also compactible and acts as a moisture absorbent.

Overall, excipients such as Avicel PH 200 LM, Aeroperl 300, and the coarse grade of crospovidone for the nonagglomerated portion of the MADG process can significantly improve the quality of the formulation and facilitate the process. If the recommended excipients are not available, regular microcrystalline cellulose (e.g., Avicel PH101, PH102, and PH200), regular silicone dioxide, and crospovidone can be used as substitutes.

MADG formulation development

Assessment of API wettability. Drug solubility, particle-size distribution, and desired drug loading in the formulation are the primary factors to be considered for an MADG-based development. In general, a great amount of agglomerating binder and water are needed to create the agglomerates when a high drug load is desired for a drug with low solubility and small particle size. The converse is also true. Less agglomerating binder and water is required if the drug is water-soluble, the particle size is not small (e.g., > 10 μm), and the drug loading is low (e.g., < 25%). Self-granulating drugs sometimes do not require any binder and need less water to granulate.

Drug attributes such as wettability and agglomeration characteristics should be determined experimentally if they are not already known. Scientists can add water to the drug in a vial or in a small beaker using a syringe and stir the mixture with a small spatula. Generally, the drug is a suitable candidate for an MADG process if it can be wetted with 1–2% of water. If, on the other hand, the drug does not easily wet with 1–2% water, the formulation likely needs more binding material and water. Therefore, the higher the percentage of water needed to wet the drug, the more water or binder is needed for the agglomeration stage. As previously mentioned, it is difficult to develop an MADG process if a high amount of water or binder is required for the formulation.


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