This article is based on a two-part series of reports published in Pharmaceutical Technology in November and December 2009, respectively.
The MADG process
MADG is a process in which moisture is used to activate granule formation, without the need to apply heat to dry the granules. During this process, the generation of moist agglomerates is followed by the stepwise addition and blending of common pharmaceutical ingredients that absorb and distribute the moisture, which results in a uniform, free-flowing and compactable granulation.
There are two major stages in MADG: agglomeration and moisture distribution/absorption.
In moisture distribution/absorption, moisture absorbents, such as microcrystalline cellulose or silicon dioxide, are added while mixing continues. When they come into contact, the moisture absorbents pick up moisture from the moist agglomerates, resulting in moisture redistribution within the mixture. When this happens, the entire mixture becomes relatively dry. While some of the moisture is removed from the wet agglomerates, some of these agglomerates remain almost intact and some — usually the larger particles — may break up. This process results in granulation with more uniform particle size distribution.
The process continues with the addition of a disintegrant, such as crospovidone, to the mixture followed by blending for a few minutes. Then, while mixing, lubricant(s), such as magnesium stearate are added and blended for sufficient time to achieve adequate lubricity.
This completes the MADG granulation process.
The granule formation mechanism in MADG is the same as 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 the two are the amount of granulating liquid used and the level of agglomeration achieved. In conventional wet granulation, substantially more water is utilised to create larger and wetter granules. This is then followed by heat drying to remove the excess water and milling to reduce the granule size.
In MADG, only a small amount of water is used to create agglomeration, followed by moisture distribution and absorption. Neither heat drying nor milling is required. Because the amount of water used in MADG is small (usually only 1–4% of the entire formulation), it is important that the water is delivered accurately and distributed uniformly during the agglomeration stage — this makes the selection of a spray system that provides accurate delivery and a well-defined spray pattern very important.
In terms of equipment, a high-shear granulator is more suitable for the MADG process, and an ideal machine should have efficient impellers/blades and choppers to allow good mass movement and proper mixing. It should also allow water to be sprayed only on the powder bed and not on the blades, choppers or granulator wall. Also, the blades and bowl configuration should be such that it does not allow "wet pockets" or "dead spots" to remain after the moisture distribution or absorption stage, which would then necessitate additional sizing and shifting of the granulation.