Agglomeration stage. In this stage, all or part of the drug is mixed with filler(s) and an agglomerating binder to obtain a uniform mixture. During mixing, a small amount of water (1–4%) is sprayed onto the powder blend, thus moistening the binder and making it tacky. The binder functions as the drug and excipients move in the circular motion caused by the mixer impellers or blades. The resulting agglomerates are small and spherical because the amount of water used in the MADG process is much lower than that in conventional wet granulation. The agglomerates therefore cannot grow into large, wet lumps. The particle size of the agglomerates generally is in the range of 150–500 μm.

It is possible, based on the drug loading technique, to add only part of the drug to the formulation during the agglomeration stage. The remaining drug can be added after the moist agglomerates have been formed. The added drug particles adhere to the wet agglomerates and become incorporated into them.

Moisture-distribution and absorption stage. In this stage, moisture absorbents such as microcrystalline cellulose or silicon dioxide are added as mixing continues. When these agents come into contact with the moist agglomerates, they pick up moisture from the agglomerates and redistribute moisture within the mixture. The entire mixture thus becomes relatively dry. Although 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 a granulation with uniform particle-size distribution. The process continues with the addition of a disintegrant to the mixture, followed by blending for a few minutes. Then, during mixing, lubricant is added and blended for sufficient time to achieve adequate lubricity. This step completes the MADG granulation process.

Excipients for the MADG process

Fillers for the MADG process during agglomeration. It is critical to select suitable excipients for a successful MADG process. Unlike the conventional wet-granulation process, which often employs microcrystalline cellulose or starch as fillers, MADG process uses nonabsorbent, easy-to-wet fillers such as lactose monohydrate and mannitol. The main reason for this selection is that microcrystalline cellulose and starch-based excipients absorb and retain a considerable amount of moisture during agglomeration. Because of this characteristic, more than the desired amount of water must be used during processing to form proper wet agglomerates. To ensure proper agglomeration, filler particles must not be too coarse or too fine. In general, coarse particles do not agglomerate easily, and fine particles require more moisture for agglomeration.

In rare cases, the drug itself could be soluble and become tacky upon moistening. Such drugs are classified as self-granulating. For these types of drugs, it is beneficial to include moisture absorbents during the agglomeration stage if a high drug-load formulation is desired in the MADG. Microcrystalline cellulose or starch products can help avoid overwetting and overgranulation of the product even when little moisture is used.

Agglomerating binders for the MADG process. The binders used in the agglomeration stage should be easily wettable and become tacky with the addition of a small amount of water. Previous studies indicate that low-viscosity polyvinylpyrrolidones (PVPs) such as PVP K-12 are ideal for this purpose. If PVP is not an acceptable choice because of formulation concerns such as chemical compatibility, binders such as hydroxypropyl cellulose (HPC), copovidone, maltodextrins, sodium carboxymethylcellulose (Na CMC), or hydroxypropyl methylcellulose (HPMC) can be used instead. The binders can be used singly or in multiple combinations to achieve the desired effects or address specific concerns.