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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