In Part I of this article, which appeared in the November 2009 issue of Pharmaceutical Technology, the authors explained a process for moisture-activated dry granulation (MADG) in detail and provided guidance for the selection of excipients and equipment. 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. The authors also compared how quality-by-design concepts could be applied to the MADG process, the wet- granulation process, and the drygranulation process.
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 ingrethents 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 ingrethent (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 microcrystalline 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 formulation development.
Materials
Active pharmaceutical ingrethents. Acetaminophen USP (Rhodia, Cranbury, NJ) and Compounds A, B, C, D (Bristol-Myers Squibb, BMS, New York) were used. At room temperature, the ingrethents' 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 Ingrethents, 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 granulatore commonly used in the pharmaceutical industry were selected for the MADG process based on the experimental scale. Diosna Pl/6 2 L (DIOSNA Dierks und Söhne, Germany) and AeromaticFielder PMA 150 L (Hampshire, England) were used for 400-g and 30-kg batch sizes, respectively. The water- del i ver y system used for the granulation process was a digital gear …
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 ingrethents 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 ingrethent (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 microcrystalline 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 formulation development.
Materials
Active pharmaceutical ingrethents. Acetaminophen USP (Rhodia, Cranbury, NJ) and Compounds A, B, C, D (Bristol-Myers Squibb, BMS, New York) were used. At room temperature, the ingrethents' 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 Ingrethents, 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 granulatore commonly used in the pharmaceutical industry were selected for the MADG process based on the experimental scale. Diosna Pl/6 2 L (DIOSNA Dierks und Söhne, Germany) and AeromaticFielder PMA 150 L (Hampshire, England) were used for 400-g and 30-kg batch sizes, respectively. The water- del i ver y system used for the granulation process was a digital gear …
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