Moisture-Activated Dry Granulation Part II: The Effects of Formulation Ingredients and Manufacturing-Process Variables on Granulation Quality Attributes

In this article, the authors evaluated the effects of the granulating binder level, binder type, water amount, and water-droplet size on the MADG process.
Dec 02, 2009

In 1987, Ullah et al. published a paper about a simple and novel granulation process called moisture-activated dry granulation (MADG) (1). In this granulation process, a small amount of water is used to activate the granule formation (i.e., perform agglomeration) without requiring hot air drying of the granules. After creating the moist agglomerates, this process uses stepwise addition and blending of common pharmaceutical ingredients that absorb and distribute moisture, thus resulting in a uniform, free-flowing, and compactible granulation. In 1990, Chen published a study comparing the MADG process with the conventional granulation processes for sematilide hydrochloride tablets (2). Although the active pharmaceutical ingredient (API) in the formulation was cohesive and fluffy, the granulation made with the MADG process was generally comparable with that made through the wet-granulation and roller-compaction processes. In addition, the authors found that MADG was not only a shorter process, but that the final granulation made with the MADG process showed superior flowability and better tablet-content uniformity. In 1994, Christensen employed the MADG process to successfully make pharmaceutical granulations with micro crystalline cellulose, potato starch, and both of these excipients (3).

The knowledge that the pharmaceutical industry has gained during the past several years about excipients used for solid dosage forms, the associated granulation equipment, and the manufacturing processes has fostered the acceptance of the MADG formulation process. The authors previously provided a roadmap for selecting excipients and equipment for the MADG process (4).

They also described a step-by-step procedure for MADG-based formulation development.

This article evaluates the effects of the formulation and process variables on the MADG process, provides examples of the MADG formulation-development and manufacturing processes, and introduces existing and new pharmaceutical excipients that are well-suited for the MADG process. This article also highlights the advantages and wide applicability of the MADG process in solid dosage form formulation development.

Materials

Active pharmaceutical ingredients. Acetaminophen USP (Rhodia, Cranbury, NJ) and Compounds A, B, C, D (Bristol-Myers Squibb, BMS, New York) were used. At room temperature, the ingredients' water solubility ranged from slightly soluble to practically insoluble. Their particle size (d90) ranged from <20 μm to <200 μm.

Excipients. The authors used lactose monohydrate NF (Sheffield Pharma Ingredients, New York), mannitol USP (Pearlitol 160 C, Roquette America, Keokuk, IA), povidone USP (PVP K-12, International Specialty Products, ISP, Wayne, NJ), hydroxypropyl cellulose NF (HPC EXF, Hercules, Wilmington, DE), copovidone NF (BASF Ludwigshafen, Germany), maltodextrin NF (Maltrin 180, Grain Processing, Muscatine, IA), microcrystalline cellulose NF (Avicel PH200 Low Moisture, FMC BioPolymer, Philadelphia); microcrystalline cellulose NF (Avicel PH102, FMC BioPolymer), silicon dioxide NF (Aeroperl 300, Evonik Degussa, Essen, Germany), crospovidone NF (ISP), and magnesium stearate NF (Mallinckrodt, Hazelwood, MO).

Manufacturing equipment. High-shear granulators commonly used in the pharmaceutical industry were selected for the MADG process based on the experimental scale. Diosna P1/6 2 L (DIOSNA Dierks und Söhne, Germany) and Aeromatic-Fielder PMA 150 L (Hampshire, England) were used for 400-g and 30-kg batch sizes, respectively. The water-delivery system used for the granulation process was a digital gear pump (model 75111-30, Cole-Palmer, Vernon Hills, IL) equipped with a pressure nozzle (Düsen-Schlick, Coburg, Germany), or any atomization nozzles that can provide similar hollow-cone or flat-fan spray patterns. A Carver press (Carver, Wabash, IN) was used for pellet compaction.

Experimental


Figure 1
The MADG process comprises two main stages: agglomeration and moisture absorption and distribution. The ingredients of a typical formula consist of one or more APIs, binders, fillers or water absorbents, disintegrants, lubricants, and water. Figure 1 shows a manufacturing-process flow diagram.

During the agglomeration stage, all or part of the API is mixed with fillers and a granulating binder to obtain a uniform mixture. During mixing, a small amount of water (1–4% of the weight of the entire formula) is sprayed onto the powder blend, thus enabling the water droplets to moisten the binder to make it moist and tacky. The API and excipient particles bind together as the mixer impellers or blades move them in a circular motion. The resulting agglomerates are small, spherelike granules with a typical particle size of 150–500 μm.

In the next stage of the process, moisture absorbents such as microcrystalline cellulose or silicon dioxide are added while mixing continues. The entire mixture becomes drier as some of the water in the moist agglomerates is released to the moisture absorbents. The agglomerates remain largely intact during the moisture-distribution stage, although the larger particles often break up. Disintegrant is added to the mixture at this stage and blended. Then, while mixing continues, lubricant is added and blended for sufficient time to achieve adequate lubricity. This completes the MADG granulation process, which takes about 15 min.