Extrusion spheronization

The manufacturing process is sometimes discussed in terms of the characteristics of the active ingredient, e.g., the need for nonaqueous granulation processes, the need for controlled humidity in the manufacturing environment. The number of different manufacturing sites requested is mentioned in the assessment reports. Special manufacturing processes such as extrusion/ spheronization are mentioned in the EPARs. 

Spherical pellets containing 5% triamcinolone acetonide were prepared by Villar-Lopez and co-workers [59] by extrusion/spheronization following formulation with microcrystalline cellulose and/or a hydrophilic excipient like lactose, sodium earbox-ymethylcellulose, or P-cyclodextrin. Their suitability for coating, with a view toward colonic drug deliveiy, was assessed in terms of their size, sphericity, and dissolution test response. The best results were afforded by a 5 90 5 composition of microcrystalline cellulose, P-cyclodextrin, and triamcinolone acetonide, prepared by complex-ation of triamcinolone acetonide with P-cyclodextrin prior to the addition of microcrystalline cellulose. 

N. Sandler, J. Rantanen, J. Heinamaki, M. Rdmer, M. Marvola and J. Yliruusi, Pellet manufacturing by extrusion-spheronization using process analytical technology, AAPS PharmSciTech, 6, E174-83 (2005). 

Extrusion-spheronization can provide highly dense, spherical pellets with a smooth surface and a narrow particle size distribution and with drug loading as high as 90%. It is also amenable to batch or continuous processing (9-11). A schematic of extrusion-spheronization and associated unit operations (12,13) are shown in Figure 1. 

Figure 1 A schematic of the extrusion-spheronization process and associated unit operations.

Evaluation of extrusion-spheronization for drug product manufacturing has focused on two main areas ... 

Table 6 Examples of End-point Metrics for Product and Process in Extrusion-Spheronization...

Shah RD, Kabadi M, Pope DG, Augsburger LL. Physico-mechanical characterization of the extrusion-spheronization process. Part II rheological determinants for successful extrusion and spheronization. Pharm Res 1995 12(4) 496-507. 

Iyer RM, Augsburger LL, Pope DG, Shah RD. Extrusion/Spheronization— Effect of moisture content and spheronization time on pellet characteristics. Pharm Dev Tech 1996 1(4) 325-331. 

Harrison PJ, Newton JM, Rowe RC. The characterization of wet powder masses suitable for extrusion/spheronization. J Pharm Pharmacol 1985 ... 

Thoma K, Zeigler I. Investigations on the influence of the type of extruder for pelletization by extrusion-spheronization. I. Extrusion behavior of formulations. Drug Dev Ind Pharm 1998 24(5) 401-411. 

Law MEL, Deasy PB. Use of hydrophilic polymers with microcrystalline cellulose to improve extrusion-spheronization. Fur J Pharm Biopharm 1998 45 57-65. 

Baert L, Remon JP. Influence of amount of granulation liquid on the drug release rate from pellets made by extrusion spheronization. Int J Pharm 1993 95 135-141. 

Newton JM, Chapman SR, Rowe RC. The assessment of the scale-up performance of the extrusion/spheronization process. Int J Pharm 1995 120 95-99. Kristensen HG. In Lindberg NO, ed. Industrial Wet Granulation. Acta Phar-maceutica Suecica. 1988 25(4-5) 187-204. 

Tho I, Kleinbudde P, Sande SA. Extrusion/Spheronization of pectin-based formulations. I. Screening of important factors. A APS Pharm Sci Tech 2001 2(4) Article 26. 

Lovgren K, Lundberg PJ. Determination of sphericity of pellets prepared by extrusion-spheronization and the impact of some process parameters. Drug Dev Ind Pharm 1989 15 2375-2392. 

Tapia C, Buckton G, Newton JM. Eactors influencing the mechanism of release from sustained release matrix pellets, produced by extrusion/spheronization. Int J Pharm 1993 92 211-218. 

Classic extrusion, spheronization, and pellitization processes typically result in pellets with irregular surfaces and of varying sizes, which are inherently more difficult to film coat. A recent report described the... 

Extrusion/spheronization (marum) Screw extruder, Marumerizer, Fluid bed coater Inexpensive raw materials Continuous process Complex multi-step process High dust during process and in product Requires highly concentrated enzyme... 

A final technique presented for the continuous production of solid dosage forms is extrusion/ spheronization—a technique producing spherical agglomerates of very uniform size. The process is based on low-pressure extrusion and shaping the moist, plastic extrudate into spheres in a spheronizer. These spheres (pellets) are, in most cases, coated after drying and filled into hard gelatin capsules or compressed into... 

Fig. 7 Flow chart of the extrusion-spheronization process showing the process variables. (From Ref. l)...

Erkoboni, D.E. Extrusion-spheronization as a granulation technique. In Handbook of Pharmaceutical Granulation Technology, Parikh, D., Ed. Marcel Dekker, Inc. New York, 1998 333-368. 

Newton, J.M. Extrusion/spheronization. In Powder Technology and Pharmaceutical Processing Ghulia, D., Delevil, M., Paercelt, Y., Eds. Elsevier Biomedical Amsterdam, 1994 391-401. 

The term moisture, usually defined as wetness conferred by an unidentified liquid, is assumed here to be due to water. Thus, the scope of this article is the characterization of and consequences due to relatively small amounts of water associated with solids of pharmaceutical interest. Chemical stability, crystal structure, powder flow, compaction, lubricity, dissolution rate, and polymer film permeability are some properties of pharmaceutical interest that have been demonstrated to be influenced by the presence of moisture. Wet granulation, extrusion, spheronization, tray drying, freeze drying, spray drying, fluid-bed drying, tableting, and aqueous film coating are some unit operations that obviously depend on the amount and state of water present. 

Extrusion-spheronization is a multistep process involving a number of unit operations and equipment. However, the most critical pieces of processing equipment that, in effect, dictate the outcome of the overall process are the extruders and the spheronizers. ... 

Although the extrusion step is a continuous process with a very high throughput, the subsequent steps (spheronization, drying, and sizing) are batch processes, and thus are rate limiting. As a result, the overall extrusion-spheronization process is a batch rather... 

In an extrusion-spheronization process, formulation components such as fillers, lubricants, and pH modifiers play a critical role in producing pellets with the desired attributes. The granulated mass must be plastic and sufficiently cohesive and self-lubricating during extrusion. During the spheronization step, it is essential that the extrudates break at appropriate length and have sufficient surface moisture to enhance formation of uniform spherical pellets. 

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