Moisture Activated Dry Granulation (MADG) was developed in response to the difficulties experienced with wet granulation,
in terms of endpoint, drying and milling. Wet granulation process endpoint is very sensitive to granulation time and shear.
The wet granules need to be dried to a narrow range of moisture contents, which is difficult. The dried granules need to be
milled, but the milled granules often have either too many fines or too many coarse particles (or both) — an undesirable bimodal
MADG is a very simple and innovative process where granules are created with water and a granulating binder, as in wet granulation,
but are not heat dried or milled. This process helps to minimise endpoint sensitivity.
The MADG process
MADG has two stages: agglomeration and moisture distribution. Success depends on the selection and order in which the formulation
ingredients are added, as well as how the process is carried out.
During agglomeration, a major portion of the formulation containing the drug is agglomerated. The drug is blended with filler
and binder in the powder form, and this blend constitutes approximately 50–80% of the formula weight. In the second stage,
a small amount (1–4%) of water is sprayed as small droplets onto the blend (while blending). Water moistens the blend and
causes the binder to become tacky, which causes particles, particularly fines, to form moist agglomerates. The process does
not create large granules, which would need milling, and because very little water is used in the process, the endpoint is
not sensitive to blending.
The remaining formula ingredients are then added (while blending), which results in dry and free flowing granulation. Most
tablet granulations contain dry binders, such as microcrystalline cellulose, a disintegrant, a lubricant and, quite often,
some colloidal silica. These common ingredients are also used in MADG formulations, but are added in a specific order. Following
agglomeration, while blending, microcrystalline cellulose is added, which absorbs most of the excess water. Colloidal silica
is then added, further absorbing any remaining moisture. If adequate amounts of microcrystalline and silica are used, the
granulation at this stage will be dry and free flowing. After this, a disintegrant can be added and blended, followed by the
The process only takes about 10–15 min and the final granulation looks like a direct blend formulation with fine particle
size distribution. In this process, the drug is bound with the ingredients, as in wet granulation, which minimises the potential
In short, MADG has the best attributes of dry blending and wet granulation. However, it must be noted that MADG is not a formula;
it is just a simpler process to create granules without heat drying and milling. Granulation and resulting tablet and capsule
characteristics will depend on the formula composition. Every formula may not need all of the typical excipients used in the
MADG process based formulation; excipients should be selected based on the nature and amount of API and the desired formulation
Some of the advantages of MADG include:
applicable to more than 90% of the granulation needs for pharmaceutical, food and nutritional industry
- short processing time
- very few variables, resulting in less need for expensive PAT technology
- applicable to a number of formulations, including high and lowdrug load formulations, polymer matrix type controlled release
formulations, and soluble and insoluble drug formulations
- suitable for continuous processing
- it uses very little energy, so it is a green process.
In essence, MADG is just a creative form of wet granulation: granules are created with water with the help of granulating
material, but no more water is added than necessary. Additionally, because the necessary excipients are already commonly used
by the pharma industry there is no conceivable regulatory concern.
There are, however, some drawbacks to MADG:
- not applicable to moisture-sensitive drugs or high drug load moisture absorbing APIs
- could be other issues with the API, with high-drug load formulations being particularly difficult to develop
- less familiarity with the process and some apprehension towards adoption.