Table I: MADG formulation for preliminary screening.
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Formulation assessment.
Assessment of the formulation itself is the next task to be completed once the wettability of the drug has been established.
For most drugs, a preliminary formulation-development evaluation can be initiated with a small batch. Using the starting formulation
scheme provided in Table I, a 5–10-g batch can be prepared in a 20-mL scintillation vial.
For nonwettable drugs or high drug-loading formulations, additional agglomerating binder (e.g., PVP) and more water during
the agglomeration stage might be required. In addition, for drugs that are more difficult to granulate, mannitol (e.g., Perlitol
160 C, Roquette, France) or other wettable fillers can be used in place of lactose monohydrate to achieve the desired granulation.
Conversely, small amounts of binder and water are needed if the drug is easily wettable and self-granulating. The ratio of
Aeroperl 300 or other silicon-dioxide-type excipients to water should be kept to at least 1:1 by weight in the formulation.
If PVP is not desirable in a given formulation, other agglomerating binders can be used, as described above.
Final formulation and optimization.
Using the knowledge gained from the formulation-screening experiments described above, a large batch of several hundred grams
can be manufactured with a high-shear granulator. The authors' experience has shown, however, that slightly more water is
required for the experiments when a granulator is used instead of a vial. The preliminary studies enable adjustments to be
made to improve formulation characteristics such as granulation and tableting, which can be further optimized as needed. Upon
the successful completion of optimization exercises, the accelerated stability of the formulation can be evaluated. The scale-up
and design-space studies can be conducted as needed.
Mechanism of the MADG process.
The granule-formation mechanism in the MADG process is the same as that in conventional wet granulation. In both cases, it
is a process of powder particle-size enlargement, often in the presence of water and binders, through wet massing and kneading.
The main differences between these two granulation processes are the amount of granulating liquid used and the level of agglomeration
achieved. In conventional wet granulation, substantially more water is used to create large and wet granules, and heat drying
removes the excess water. This step is followed by milling to reduce the granule size. In the MADG process, only a small amount
of water is used to create agglomeration. Moisture distribution and absorption steps follow, and neither heat drying nor milling
is needed.
Additional considerations for the MADG process
Moisture in the MADG formulation.
The amount of water used in the MADG process is part of the formula composition. This amount is a fixed value in the formula
and is determined during formulation development. For example, if 2.0% (w/w) water is used, the rest of the ingredients should
make up the 98.0% (w/w) of the formula. Because the MADG process does not include a heat-drying step, the water added would
not be intentionally removed from the formulation.
Because moisture is added but not removed in the MADG process, what happens to the moisture and how it affects product quality
might be causes for concern. To answer these questions, an MADG formulation that uses 1.5% water, 20% Avicel PH 200 LM, 1.5%
Aeroperl 300, and other ingredients for a total weight of 100 g can be considered. First, 1.5 g of water is used in the agglomeration
stage. During the moisture-absorbing and -distribution stage, 20.0 g of Avicel PH200 LM (with an inherent moisture level of
1.5%) can take 0.7 g of moisture, while 1.5 g of Aeroperl 300 can absorb 2.25 g of moisture from the wet agglomerates. As
a result, the final granulation reaches its equilibrium moisture level, and neither Avicel PH200 LM nor Aeroperl 300 appears
damp or lumpy. Such a MADG formulation would not have much more free water than that produced by a typical conventional granulation
process. Even if only regular Avicel PH200 (with a moisture content of ~5%) is used without Aeroperl 300 in the same formulation,
the amount of the remaining moisture (0.8 g) would be well distributed in the other formulation excipients, thus resulting
in a free-flowing final granulation. Silicone dioxide in an MADG formulation sometimes may be preferred to minimize the risk
of granulation caking during storage, to avoid flowability problems, and to reduce the chance of moisture-induced chemical
instability. In general, unless the drug in the MADG formulation is moisture-sensitive, additional stability risks of the
finished product would not be expected.
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