In the pharmaceutical industry, the three most common granulation processes for solid dosage form production are wet granulation, dry granulation (i.e., roller compaction), and direct blending. In spite of their popularity, each of the processes raise concerns as they are currently practiced.
The obligatory use of a granulating liquid during wet granulation generates large granules during the wet massing and kneading stages. The typical amount of water used in the formulation is 20–50% of the weight of the dry powder mixture. After granulation, most of the added water usually is removed by drying, followed by a granule-sizing step. In a way, the drying process cancels the water-addition step, and the sizing step shrinks the large granules formed during the process. One vexing, but thankfully infrequent, problem with the wet-granulation process is that it produces a bimodal particle-size distribution of the final granulation that may result in unsatisfactory granulation flow and compactability.
In the dry-granulation process, the powder mixture is roller compacted into ribbons that are milled into granules. Unlike the wet-granulation process, the roller-compaction process commonly obtains a final granulation with a bimodal particle-size distribution. Roller-compaction processes have the added problem of yielding material with low compactability during ribbon formation, thus resulting in soft and friable tablets.The direct-blending process, followed by tablet compression or other downstream actions, often depends on the batch-to-batch and vendor-to-vendor consistency of drugs and excipients. The potential for segregation and inadequate material flow are risks often associated with this process.
In what is arguably the seminal paper on the moisture-activated dry-granulation (MADG) process, the authors proposed a simple, economical, and novel granulation process that uses a small amount (1–4%) of water to cause agglomeration without subsequently requiring a drying step (1). Few studies of this process appear in the literature (2–3). Given its simplicity and cost-saving potential, the authors expected that the MADG process would have been widely adopted in the pharmaceutical industry by this time. The MADG process has not caught on, however, perhaps because of its unusual simplicity coupled with uncertainty about equipment specifications and ambiguity about the manufacturing process.
This paper will explain the MADG process further and provide guidance for the selection of the excipients and equipment necessary for its successful implementation. The authors will also give instructions for the development of MADG-based formulations.
The MADG process
As its name implies, MADG is a process in which moisture is used to activate granule formation (i.e., agglomeration) without the need for applying heat to dry the granules. The formation of the moist agglomerates is followed by the stepwise addition and blending of common pharmaceutical ingredients that absorb and distribute the moisture, thereby resulting in a uniform, free-flowing, and compactible granulation. This process enables the drug to bind with the excipients after the agglomeration phase, thus resulting in small, almost spherical granules with low potential for segregation of the drug in the formulation. The intent of the MADG process is not to make large particles, but rather to agglomerate the fines and bind the drug with excipients to create free flowing, compactible, and nonaggregating granules.
The essence of the MADG process is to add enough water to achieve agglomeration without adding excess water that would require a drying step. It is equally important that only enough particle-size enlargement be achieved to ensure satisfactory granulation flow and compactability without segregation. The MADG process has the advantages of not generally requiring further size reduction and avoiding the regeneration of fines as a result of milling. And, unlike the conventional wet- and dry-granulation processes, MADG does not overdo and then undo what has been overdone.