Jennifer Wang

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 distribution. 

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. 

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 lubricant.  

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 for segregation.  

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 characteristics.  

Some of the advantages of MADG include:  

 applicable to more than 90% of the granulation needs for pharmaceutical, food and nutritional industry

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

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.

MADG only requires two pieces of equipment: an appropriate granulator and an airless spray system. 

The granulator can be a planetary or high-shear granulator, but the blades should be at the bottom (either top or bottom driven) and not exposed. This is necessary because the amount of water used is very small and added on top of the powder bed by a fine spray. If the blades were exposed, the water could hit the blades and cause loss of water, possibly creating wet lumps and nonuniform granulation. The granulator should not have dead spots or spots where material could stick. A chopper in the granulator is also useful. 

This process also requires an airless spray system that accurately delivers the desired amount of water in small (50–200 µm) droplets. The system should not have drips; peristaltic pumps, in particular, are not suitable. The gear pump or pressure vessel must also provide the right type of spray. At the developmental stage, however, an appropriate spray tip attached to a syringe is sufficient. 

One of the main issues with MADG is the capability to accurately deliver a very small amount of water in spray form (i.e., 0.2 mL). It is not always possible to start new formulation development on a large scale, but often if a process cannot be tried out on the small scale, then there is a good chance that it will never be further developed. Presently, there is no system available that can accurately deliver such a small amount of spray. Recently, however, nozzle manufacturer Orthos/Schlick (SC, USA) has developed a special spray kit for MADG applications. If development scientists have access to this, or any other technology that can accurately spray small amounts of water, they have much better chances of success at the small scale and, therefore, are more likely to follow through to largescale applications.  

The MADG process can still be improved upon and, with time, this will happen. Improvements may come from multifunctional excipients, which can make the MADG process simpler and more economical; for instance, an excipient could be developed that is both a moisture absorbent and a disintegrant, or a moisture absorbent, a disintegrant and a dry binder. The development of specialised granulators for MADG, as well as continuous processors and feeders, will also be beneficial.  

Increased uptake could also be encouraged by educating more companies about the merits of MADG. Many schools and other organisations offer courses on granulation and it would be good if these included hands-on training of MADG processes.  

Companies considering the use of MADG should not be too apprehensive. In essence, MADG is not a new process, but a creative form of wet granulation without the usual drawbacks, such as endpoint sensitivity, the need to dry and mill, and the waste of product, time and energy. Anyone interested in the process should first read MADGrelated articles to get a good grasp of the process and try out a placebo or any other simple formulation.

  To speed up the learning process, companies can also invite experts to give presentations or advice.  

 is president of Simple Pharma Solutions, LLC

 L. H. Christensen, H. E. Johansen and T. Schaefer, 

This article is part of a special feature on granulation that was published in the March issue of PTE Digital, available at 

Articles

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 distribution.