® References: 11. United States Pharmacopoeial Con- Pharm. Dev. Technol. 9(4), 359-367 33. A.M. Juppo et al., Eur. J. Pharm. pharm-a-spheres 1. D. Werner, Pharma International, 2, vention, National Formulary, 23rd (2004). Biopharm. 44(2), 205-214 (1997). 70-77 (1984). edition, Rockville, MD, USA (2005). 24. C. Christiansen and B.W. Müller, 34. F. El Saleh and P Kleinebudde, 2. U. Hofer, in W. Fahrig and U. Hofer, 12. Council of Europe: European Phar- Pharm. Ind. 64(4), 390-397 (2002). Pharm. Technol. Int. 10(11), 18-26 Eds, Die Kapsel (Wissenschaftliche macopoeia, 5th edition, Brussels, 25. L.S.C. Wan and T. Jeyabalan, Acta (1998). Verlagsgesellschaft mbH, Stuttgart, Belgium (2005). Pharm. Technol. 32 (4), 197-199 35. W.A. Ritschel and A. Bauer-Brandl, Germany, 1983) pp 83-111. 13. D. Werner, Pharm. Technol. int. 8(9), (1986). Die Tablette: Handbuch der Entwick- Sugar spheres 3. W.A. Ritschel, Angewandte 30-36 (1996). 26. U. Körber and T. Moest, Acta Pharm. lung, Herstellung und Qualitätssi- Biopharmazie (Wissenschaftliche 14. Anonymous, Pharm. Ind. 61(5), 483 Technol. 36(1), 33-35 (1990). cherung, Aufl age 2nd edition (Editio Verlagsgesellschaft mbH, Stuttgart, (1999). 27. P. Schultz and P. Kleinebudde, Cantor Verlag, Aulendorf Germany, Germany,1973) pp 396-423. 15. R. Chopra et al., Eur. J. Pharm. Pharm. Ind. 57(4), 323-328 (1995). 2002) pp 28. 4. P. Langguth and G. Fricker, Wunderli- Biopharm. 53(3), 327-333 (2002). 28. Bundesministerium für Gesundheit 36. W.G. Schmidt, „KontrolIierte Wirk- Allenspach, Biopharmazie (Wiley- 16. European Pharmacopoeia, Method und soziale Sicherung: ”Deutsches stoff-Freisetzung aus Matrixpellets” VCH Verlag, Weinheim, Germany, 2.9.16 ”Flowability“ 5th edition, Arzneibuch“, Entwurf für eine Ph.D thesis, Freie Universität Berlin, 2004) pp 367 ff. Brussel, Belgium (2005). Monographie 2.9.N2: ”Abrieb von Germany (1992). 5. I. Ghebre-Sellassie, Pharmaceutical 17. DIN Deutsches Institut für Normung: Pellets und Granulaten“, Methode I 37. M.P. Flament et al., Pharm. Technol. Pelletization Technology (Marcel DIN ISO 787 Teil 11 Bestimmung (Wirbelschichtapparatur) und Metho- Int. 6(2), 19-25 (1994). Dekker Inc., New York, NY, USA, des Stampfvolumens und der de II (Schwingapparatur); Deutscher 38. T. Beckert, „Verpressen von magen- Sugar spheres: a versatile excipient for oral pellet 1989). Stampfdichte, Beuth Verlag, Berlin, Apotheker Verlag, Stuttgart (not saftresistent überzogenen Pellets zu 6. K.H Bauer et al., Überzogene Germany (1983). published yet). zerfallenden Tabletten“, Ph.D thesis, Arzneiformen (Wissenschaftliche 18. L. Hellen et al., Pharm. Technol. Int. 29. Anonymous, ”Texture Analysis Appli- Eberhard-Karls- Universität,Tiibingen, medications with modifi ed release kinetics Verlagsgesellschaft mbH, Stuttgart, 5(2), 38-48 (1993). cation Overview-Tablets, Granules (1995). Germany, 1988) pp 40-49. 19. International Organization for and Pellets“, (Stable Micro Systems, 39. R. Bodmeier, Eun J. Pharm. Biopharm. 7. K. Knop and B.C. Lippold, Pharm. Standardization, Standard ISO Godalmlng, UK, 2005). 43(1), 1-8 (1997). Ind. 51(3), 302-309 (1989). 3310-1:2000, Test Sieves, Technical 30. F. Balszuweit, T. Wagner and P. 40. M. Türkoglu, H.Varol and M. Celi- 8. M. Niskanen et al., Pharm. Technol. Requirements and Testing, Part 1: Kleinebudde, Pharm. Ind. 62(12), kok, Eur. J. Pharm. Biopharm. 57(2), Int. 2(1O), 22-28 (1990) and Pharm. Test Sieves of Metal Wire Cloth, 4th 985-991 (2000). 279-286 (2004). Technol. Int. 2(11), 32-36 (1990). edition, Geneva (2000). 31. A.R. Gupte, Acta Pharm. Technol. 41. J.M. Newton, Pharm. Technol. Int. 9. E. Nürnberg and J. Wunderlich, 20. D. Werner, Laborpraxis 23(1), 42-47 22(3), 153-168 (1976). 12(5), 40 (2000) and D. Werner, Pharm. Technol. Int. 11(2), 41-47 (1999). 32. P.A. Webb, An Introduction to the Letter to the Editor, Pharm. Technol. (1999) and Pharm. Technol. Int. 21. H. Kanerva, Pharm. ind. 55(8), 775- Physical Characterization of Materi- Int. 12(9), 10 (2000). 11(3), 30-34 (1999). 779 (1993). als by Mercury Intrusion Porosimetry 10. PC. Schmidt and K. Weyhing, Dtsch. 22. H. Lindner and P. Kleinebudde, with Emphasis on Reduction and Detlef Werner, Ph. D. Apoth. Zig. 144(18), 2082-2086 Pharm. ind. 55(7), 694-701 (1993). Presentation of Experimental Data is quality manager at Hanns G. Werner (2004). 23. G. Heinicke and J.B. Schwartz, (Micromeritics, Norcross, UK 2001). GmbH + Co. KG, Germany. 1 Figure 3 REM picture of the surface of a sugar sphere spheres with the layered structure obtained during the sugar-coating Sugar spheres are a widely used excipient for sustained-release pellet formulations. produced using the modifi ed sugar-coating procedure. process have a low interstitial surface of sucrose crystals with extreme- ly low porosity (Figure 3). This paper reviews their development in the last decades, informs about the state of the art and provides the user with the necessary information for further processing. Future development Thanks to their unique technological properties, sugar spheres are a Finally, the article focuses on the possibilities of characterization related to the key ingredient in numerous medications administered in pellet form, technological properties of the sugar spheres. and have proven their worth even when compared with alternative concepts and medication forms. New applications continue to emer- ellets are a multiparticle, solid form of medication. The individual Formulas with pellets are still a modern form of medication, which ge, such as compressing coated pellets to produce sustained release Ppellets are almost spherical with diameters usually between 100 offers an elegant solution even for new requirements. tablets (multiple unit tablets). The mechanical stability of the pellets and 2000 µm. and the elasticity of the polymer auxiliary substances in the coating Their history is related to two important development trends in pharma- Production technology 35 have an important function to play. ceutical technology: the hard gelatine capsule as an alternative to There are numerous procedures for pelletization, with two fundament- The role of the tablet is to offer the pellets in a favourable, divisible tablets, and biopharmacy and its concept of modifi ed release. ally competing concepts.5 On the one hand, the use of sugar spheres, form which is safe from manipulation and easy to use. ln the gastro- The hard gelatine capsule provided a method of oral medication, which are then coated with the active substance, and on the other, intestinal tract, it disintegrates into the partial pellets with differing sus- which made it possible to put powders or granules directly in a patient- direct pelletization of active substance/excipient mixtures. tained release rates, corresponding to the application of pellets in friendly form with specifi c dosage.2 By mixing various components Figure 1 illustrates these two alternatives. hard gelatine capsules. before fi lling the capsules or with sequential fi lling of the capsule with ln the fi rst option, sugar spheres (also called neutral pellets, nonpareil procedure, the roundness of the individual particles resulting from the There have been a large number of such developments in recent these components, it was possible to combine partial quantities that seeds, microgranules or sugar beads) are produced, preferably using 36-40 rolling motion in the production process is very high, so that this calcu- years. differ in appearance, are incompatible with each other, or have dif- a layered sugar-coating structure.6 The result is sugar spheres with suf- lation is adequately precise in a fi rst approximation. Sugar spheres can be expected to remain an important excipient fering release behaviour, in one single dose. Pellets with their almost fi cient mechanical stability for further processing. The ideally rounded On the one hand, direct optical methods are used for assessment, for solid medications in future too, with the possibility of being used ideal spherical shape offer optimum mixing and fl ow behaviour, ma- sugar spheres classed in closely graduated particle sizes are then 41 ranging from using a stereomicroscope through to automatic image successfully as a tool for new developments. king them ideal for this application. coated with the active substance and sustained release additives. The 30 analysis. At the same time, since the 1950s, biopharmacy has developed con- core of the fi nished pellet contains no active substance itself so that Indirect methods are also used for certain aspects to defi ne the spe- cepts for optimum control of active pharmaceutical ingredient (API) this solution is used for low-dose substances or substances with a 31-34 cifi c surface area or porosity and pore size (porosimetry). Sugar PHARMACEUTICAL TECHNOLOGY EUROPE release in the gastrointestinal tract, in terms of location and time.3,4 ln high effect/dose relation. But the use of small sugar spheres and particular, the sustained release from a single application over a longer corresponding procedures also makes it possible to use this method period of time (during the day) resulted in the development of mixtu- to produce pellets containing more than 75% active substance. res whose individual components were given different quantities of ln the second concept, pelletization already includes the active sub- ® a sustained release coating to ensure that the active substances are stance itself. The procedures developed here consist of fl uidized bed pharm-a-spheres released accordingly at different points in time. Pellets with their repro- granulation, rotor granulation, or extrusion followed by spheronization, ducible, smooth surface were again the solution of choice. whereby the initially cylindrical particles are then rounded out in a HANNS G. WERNER GMBH + CO. KG These two developments together resulted in numerous pellet prepara- second step.7-9 The advantage of this procedure is that the whole HAFENSTRASSE 9 · D-25436 TORNESCH · GERMANY · TEL.: +49 - (0) 41 22 - 95 76-0 · FAX: +49 - (0) 41 22 - 95 76-76 tions.