Sugar Spheres 3

Home , Excipient

® 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. There were suitable pellet solutions for nearly all requirements, pellet contains the active substance. E-MAIL: [email protected] · WWW.PHARM-A-SPHERES.COM with a rapid increase in the market share of corresponding products. There are numerous applications for both alternatives on the market, so it is still not possible to ascertain any clear preference of one over pharmaceutical quality is verifi ed. But they should not replace the a Particle size Together with the different possibilities available for test sieve procedu- the other. Each solution offers its own pros and cons, depending on fore said main ingredients. One important requirement is for the closest possible distribution of res (vibration sieving, airjet sieving, RoTap sieving), laser diffraction the specifi c product. The following points outline certain aspects where The tests for identity, purity and content stated in the mentioned mono- the sugar sphere‘s particle size. This is a vital prerequisite for uniform and image analysis have also become established methods in recent 21-23 the two concepts differ, to make it easier for the user to decide which graphs contain no special aspects worth mentioning. Only defi nition application of the active substance in subsequent coating. Calcula- years. Although these instruments have a far higher purchase price one to choose: of the sucrose content by polarimetry means that no other optically ting the surface-per-input quantity also depends on a uniform particle than test sieve machines, they do offer the advantage of automatic • The use of sugar spheres means that the drug producer can out- active excipient can be used as an ingredient. When other sugars or size, as well as a spherical shape. sieving, and of measuring a far larger quantity of samples. Image source pelletization to a specialist and concentrate on processing starch hydrolysates are used, alternative methods are required (e.g., The particle size is defi ned according to the international sieve series, analysis also provides other important parameters, for example, the API. This will produce sugar spheres as a spherical excipient specifi c enzymatic methods) to obtain correct results. whereby the partly uneven numbers of the nominal mesh widths come particle roundness. But even when using these modern procedures, of uniform size. By containing corn starch, the sugar spheres also contain water. On from conversion from the still common ASTM standard sieves. Table 1 precise calibration and matching of the procedures is necessary to • The shaping process involved in pelletization entails thermal load the condition that this is not surplus water from the production process, shows the µm limits and corresponding ASTM mesh values. ensure that supplier and customer obtain coinciding results. and contact with a solvent (usually water). This can cause stability it should be noted that this water is not available in free state, and Usually a specifi cation defi nes an upper and lower limit within which The results supplied by all methods consist either in the defi ned par- problems, depending on the susceptibility of the active substance. our experience shows that it cannot interfere with active substances at least 90% of the particles must lie. This type of close particle size ticle size range as a percentage or the calculated mean diameter • Pelletization and classifi cation produces fractions (attrition or ag- susceptible to hydrolysis. This water is permanently bound to the starch spectrum is normally produced using sieves. The corresponding sieve derived from the primary data. The width of the distribution curve is glomerates): recycling these in the production process often causes molecules and required for their technological properties. An attempt fabrics must comply with the international standard.19 Table 2 shows crucial for estimating the risk of segregation or nonuniform behaviour quality, batch homogeneity and traceability problems. lf active to remove this water from the sugar spheres would result in very com- the requirements of this standard, clearly indicating how far the effec- during coating. substances are already involved in the pelletization process, fraction plicated drying procedures; the sugar spheres would become hygro- tive and nominal mesh width can differ in specifi c cases. disposal is often not possible for cost reasons, whereas in the scopic and absorb moisture again from the air. This means that the The sieve fabrics consist of a large number of woven wire meshes Mechanical stability case of sugar spheres, only low-cost excipients are affected. success of this procedure would be in doubt. It is only important that whose size is distributed in statistical terms in both the warp and weft Robustness against mechanical stress is an important parameter for • Pellets produced by direct pelletization often only show moderate the water activity (the aW value) as a measure for water bonding re- direction so that it is possible for the sieve results to differ considerably further processing of the sugar spheres. Sugar spheres must have ade- mechanical stability. But subsequent coating procedures demand mains below 0.65 so that any microbial growth is reliably prevented. from the nominal value. This explains the technological diffi culty of quate mechanical stability to withstand the loads during subsequent adequate abrasion and crushing resistance. These interpretations are based on the water vapour absorption iso- producing very narrow particle size ranges. When agreeing on a coating, including contact with solvents. Interesting parameters here The use of sugar spheres results in a layered structure of the subsequent therms, which are available for sugar spheres, and which should also specifi cation, it is, therefore, important to check in advance exactly are friability and crushing strength. 13, 14 sustained release pellets, as shown in Figure 2. be ascertained on the same basis for active substance pellets. which requirements are really necessary for later product quality. The Roche friabilator developed for tablets is not suitable for asses- The technological properties of the sugar spheres are particularly The problems involved in the precision of sieve fabrics are also involved sing the friability of sugar spheres; even if the test time is prolonged, Qualitative characteristics important for the user; their main details are discussed below. in the analytical determination of particle size. lt is often possible for no measurable attrition is obtained because of the high resistance. The qualitative requirements for sugar spheres are meanwhile described different laboratories to produce different results for the particle size There have been numerous attempts to develop methods specially 24 in monographs in the major pharmacopoeias. Here it is worth giving Flow properties for one and the same sample. There can, therefore, be considerable suited to pellets. ln all these instructions, there is doubt as to whether a special mention to the longstanding monograph „Sugar Spheres“of Sugar spheres are normally purchased in bulk, therefore, the rheo- differences in the fi gures particularly for near-mesh grains, which is the mechanical stress corresponds to the actual loads involved in later the National Formulary and the more recent monograph „Sugar logical properties are important for handling and also for fi lling in always the case for narrow particle size specifi cations. processing. For example, methods recommending the use of steel or 15 Spheres”of the European Pharmacopoeia (EP), both of which have the capsules later on. There are a number of suitable methods for Prerequisite for a uniform appraisal is, therefore, close consultation in glass beads are dubious because the crushing of pellets caused by 11, 12 already been extensively harmonized. obtaining reproducible values here. terms of testing systems and the fabrics being used.20 the impact of steel balls is in no way comparable with the forces Sugar spheres characteristically consist of sucrose and corn starch, Flowability is analysed using the EP method, which is identical with involved, for example, in a fl uidized bed procedure, where friction 16 25 which are pharmacologically indifferent, digestible excipients fre- international standards. Thanks to the frequently obtained ideal Table 1 Common sieve series. between the particles or tangential friction on the unit wall is typical. quently occurring in the normal diet. These are also described in spherical form of the sugar together with a smooth surface, the fl ow- In our opinion, an instrument that has proven effective in detecting item-no. mesh ASTM diameter in µm the pharmacopoeias (for example the United States Pharmacopeia ability is so high that there is no need to defi ne the angle of response differences in the mechanical properties between different pellets or 08001 1 7 0 - 1 00 9 0 - 1 5 0 26 and EP). Other auxiliary substances are not explicitly ruled out and after being poured in bulk. 08013 1 0 0 - 8 0 1 5 0 - 1 8 0 batches is the Born Friabimat. Here, load is created by reproducibly can be used to achieve certain desirable properties, as long as their Valuable information is also provided by the parameters obtained 08023 8 0 - 7 0 1 8 0 - 2 1 2 shaking the pellets in a glass vessel, whereby the fi rst pellets in every after measuring the bulk and tap density using the stamping volumeter.17 08025 8 0 - 6 0 1 8 0 - 2 5 0 cycle do impact on the glass or lid surface, but this is followed essen- It is then possible to calculate the Hausner factor and Carr index as 08033 7 0 - 6 0 2 1 2 - 2 5 0 tially by friction or impact between the pellets. 08035 7 0 - 5 0 2 1 2 - 3 0 0 18 Figure 1 Pelletization of active substances and sugar sphere a measure of compressibility. Top quality sugar spheres show low 08043 6 0 - 5 0 2 50 - 3 0 0 Another interesting development is a unit simulating the conditions in a coatings. compressibility and, therefore, scarcely cause any problems in the 08050 5 0 - 4 5 3 00 - 3 5 5 fl uidized bed.27 But the mechanical forces in this test are so low, even handling and dosing stages, for example from so-called bridging. 08051 6 0 - 4 5 2 5 0 - 3 5 5 with a drastic increase in the fl ow of compressed air, that there is scarcely 08052 5 0 - 4 0 3 0 0 - 4 2 5 08053 6 0 - 4 0 2 5 0 - 4 2 5 any abrasion of sugar spheres produced in the coating method. Both 08062 4 5 - 3 5 3 5 5 - 5 0 0 tests are decribed in the European pharmacopoeia now.28 Excipients API and excipents 08063 4 5 - 4 0 3 5 5 - 4 2 5 In companies where sugar spheres are processed in a production 08065 5 0 - 3 5 3 0 0 - 5 0 0 08073 4 0 - 3 5 4 2 5 - 5 0 0 machine, and which also have an identically designed, but smaller 3 5 - 3 0 5 0 0 - 6 0 0 unit for test purposes, it is possible for the batches to be tested in this Figure 2 Diagram to show the structure of a sustained release 08130 08150 3 5 - 2 5 5 0 0 - 7 1 0 miniature version. These test conditions are then identical to the later pellet with sugar sphere care (grey), active substance layer (red) 08230 3 0 - 2 5 6 0 0 - 7 1 0 conditions and scaling-up of the results is feasible. and fi lm coating (blue). 10 08250 3 0 - 2 0 6 0 0 - 8 5 0 08330 2 5 - 2 0 7 1 0 - 8 5 0 Similarly, the instruments normally used to measure the crushing re- Pelletization 08350 2 5 - 1 8 7 1 0 - 1 , 0 0 0 sistance (or pressure resistance) of tablets, such as the established 08430 2 0 - 1 8 8 5 0 - 1 , 0 0 0 Schleuniger tester, are usually not suitable for the far smaller pellets. 08450 2 0 - 1 6 8 5 0 - 1 , 1 8 0 08530 1 8 - 1 6 1,0 0 0 - 1 , 1 8 0 As a substitute, an apparatus developed for testing the texture of Sugar 08630 1 6 - 1 4 1, 1 8 0 - 1 , 4 0 0 food products equipped with a suitably formed transducer tool has 29 sphere API Pelletization 08643 1 6 - 1 2 1, 1 8 0 - 1 , 7 0 0 proven effective. The analysis of individual pellets gives a force-over- 08653 1 4 - 1 2 1,4 0 0 - 1 , 7 0 0 08663 1 2 - 1 0 1,7 0 0 - 2, 0 0 0 distance curve that can be evaluated according to the maximum or area under the curve (AUC) to obtain a detailed statement about the mechanical properties. Table 2 Requirements for test sieves as per ISO Coating 3310/1:2000, illustrated for mesh width of 850 µm. Surface W=850 µm The properties of the surface are interesting in biopharmaceutical terms. lt is important to know these properties to calculate the subsequent X=127 µm Tolerance range for the individual mesh Active Active coating procedure, as well as the release kinetics. Ideally, the surface- pellet pellet 723–977 µm per-pellet mass can be calculated as sphere surface from the mean Y=29 µm Tolerance range for the mean mesh width 821–879 µm diameter. ln sugar spheres produced using a modifi ed sugar-coating so it is still not possible to ascertain any clear preference of one over pharmaceutical quality is verifi ed. But they should not replace the a Particle size Together with the different possibilities available for test sieve procedu- the other. Each solution offers its own pros and cons, depending on fore said main ingredients. One important requirement is for the closest possible distribution of res (vibration sieving, airjet sieving, RoTap sieving), laser diffraction the specifi c product. The following points outline certain aspects where The tests for identity, purity and content stated in the mentioned mono- the sugar sphere‘s particle size. This is a vital prerequisite for uniform and image analysis have also become established methods in recent 21-23 the two concepts differ, to make it easier for the user to decide which graphs contain no special aspects worth mentioning. Only defi nition application of the active substance in subsequent coating. Calcula- years. Although these instruments have a far higher purchase price one to choose: of the sucrose content by polarimetry means that no other optically ting the surface-per-input quantity also depends on a uniform particle than test sieve machines, they do offer the advantage of automatic • The use of sugar spheres means that the drug producer can out- active excipient can be used as an ingredient. When other sugars or size, as well as a spherical shape. sieving, and of measuring a far larger quantity of samples. Image source pelletization to a specialist and concentrate on processing starch hydrolysates are used, alternative methods are required (e.g., The particle size is defi ned according to the international sieve series, analysis also provides other important parameters, for example, the API. This will produce sugar spheres as a spherical excipient specifi c enzymatic methods) to obtain correct results. whereby the partly uneven numbers of the nominal mesh widths come particle roundness. But even when using these modern procedures, of uniform size. By containing corn starch, the sugar spheres also contain water. On from conversion from the still common ASTM standard sieves. Table 1 precise calibration and matching of the procedures is necessary to • The shaping process involved in pelletization entails thermal load the condition that this is not surplus water from the production process, shows the µm limits and corresponding ASTM mesh values. ensure that supplier and customer obtain coinciding results. and contact with a solvent (usually water). This can cause stability it should be noted that this water is not available in free state, and Usually a specifi cation defi nes an upper and lower limit within which The results supplied by all methods consist either in the defi ned par- problems, depending on the susceptibility of the active substance. our experience shows that it cannot interfere with active substances at least 90% of the particles must lie. This type of close particle size ticle size range as a percentage or the calculated mean diameter • Pelletization and classifi cation produces fractions (attrition or ag- susceptible to hydrolysis. This water is permanently bound to the starch spectrum is normally produced using sieves. The corresponding sieve derived from the primary data. The width of the distribution curve is glomerates): recycling these in the production process often causes molecules and required for their technological properties. An attempt fabrics must comply with the international standard.19 Table 2 shows crucial for estimating the risk of segregation or nonuniform behaviour quality, batch homogeneity and traceability problems. lf active to remove this water from the sugar spheres would result in very com- the requirements of this standard, clearly indicating how far the effec- during coating. substances are already involved in the pelletization process, fraction plicated drying procedures; the sugar spheres would become hygro- tive and nominal mesh width can differ in specifi c cases. disposal is often not possible for cost reasons, whereas in the scopic and absorb moisture again from the air. This means that the The sieve fabrics consist of a large number of woven wire meshes Mechanical stability case of sugar spheres, only low-cost excipients are affected. success of this procedure would be in doubt. It is only important that whose size is distributed in statistical terms in both the warp and weft Robustness against mechanical stress is an important parameter for • Pellets produced by direct pelletization often only show moderate the water activity (the aW value) as a measure for water bonding re- direction so that it is possible for the sieve results to differ considerably further processing of the sugar spheres. Sugar spheres must have ade- mechanical stability. But subsequent coating procedures demand mains below 0.65 so that any microbial growth is reliably prevented. from the nominal value. This explains the technological diffi culty of quate mechanical stability to withstand the loads during subsequent adequate abrasion and crushing resistance. These interpretations are based on the water vapour absorption iso- producing very narrow particle size ranges. When agreeing on a coating, including contact with solvents. Interesting parameters here The use of sugar spheres results in a layered structure of the subsequent therms, which are available for sugar spheres, and which should also specifi cation, it is, therefore, important to check in advance exactly are friability and crushing strength. 13, 14 sustained release pellets, as shown in Figure 2. be ascertained on the same basis for active substance pellets. which requirements are really necessary for later product quality. The Roche friabilator developed for tablets is not suitable for asses- The technological properties of the sugar spheres are particularly The problems involved in the precision of sieve fabrics are also involved sing the friability of sugar spheres; even if the test time is prolonged, Qualitative characteristics important for the user; their main details are discussed below. in the analytical determination of particle size. lt is often possible for no measurable attrition is obtained because of the high resistance. The qualitative requirements for sugar spheres are meanwhile described different laboratories to produce different results for the particle size There have been numerous attempts to develop methods specially 24 in monographs in the major pharmacopoeias. Here it is worth giving Flow properties for one and the same sample. There can, therefore, be considerable suited to pellets. ln all these instructions, there is doubt as to whether a special mention to the longstanding monograph „Sugar Spheres“of Sugar spheres are normally purchased in bulk, therefore, the rheo- differences in the fi gures particularly for near-mesh grains, which is the mechanical stress corresponds to the actual loads involved in later the National Formulary and the more recent monograph „Sugar logical properties are important for handling and also for fi lling in always the case for narrow particle size specifi cations. processing. For example, methods recommending the use of steel or 15 Spheres”of the European Pharmacopoeia (EP), both of which have the capsules later on. There are a number of suitable methods for Prerequisite for a uniform appraisal is, therefore, close consultation in glass beads are dubious because the crushing of pellets caused by 11, 12 already been extensively harmonized. obtaining reproducible values here. terms of testing systems and the fabrics being used.20 the impact of steel balls is in no way comparable with the forces Sugar spheres characteristically consist of sucrose and corn starch, Flowability is analysed using the EP method, which is identical with involved, for example, in a fl uidized bed procedure, where friction 16 25 which are pharmacologically indifferent, digestible excipients fre- international standards. Thanks to the frequently obtained ideal Table 1 Common sieve series. between the particles or tangential friction on the unit wall is typical. quently occurring in the normal diet. These are also described in spherical form of the sugar together with a smooth surface, the fl ow- In our opinion, an instrument that has proven effective in detecting item-no. mesh ASTM diameter in µm the pharmacopoeias (for example the United States Pharmacopeia ability is so high that there is no need to defi ne the angle of response differences in the mechanical properties between different pellets or 08001 1 7 0 - 1 00 9 0 - 1 5 0 26 and EP). Other auxiliary substances are not explicitly ruled out and after being poured in bulk. 08013 1 0 0 - 8 0 1 5 0 - 1 8 0 batches is the Born Friabimat. Here, load is created by reproducibly can be used to achieve certain desirable properties, as long as their Valuable information is also provided by the parameters obtained 08023 8 0 - 7 0 1 8 0 - 2 1 2 shaking the pellets in a glass vessel, whereby the fi rst pellets in every after measuring the bulk and tap density using the stamping volumeter.17 08025 8 0 - 6 0 1 8 0 - 2 5 0 cycle do impact on the glass or lid surface, but this is followed essen- It is then possible to calculate the Hausner factor and Carr index as 08033 7 0 - 6 0 2 1 2 - 2 5 0 tially by friction or impact between the pellets. 08035 7 0 - 5 0 2 1 2 - 3 0 0 18 Figure 1 Pelletization of active substances and sugar sphere a measure of compressibility. Top quality sugar spheres show low 08043 6 0 - 5 0 2 50 - 3 0 0 Another interesting development is a unit simulating the conditions in a coatings. compressibility and, therefore, scarcely cause any problems in the 08050 5 0 - 4 5 3 00 - 3 5 5 fl uidized bed.27 But the mechanical forces in this test are so low, even handling and dosing stages, for example from so-called bridging. 08051 6 0 - 4 5 2 5 0 - 3 5 5 with a drastic increase in the fl ow of compressed air, that there is scarcely 08052 5 0 - 4 0 3 0 0 - 4 2 5 08053 6 0 - 4 0 2 5 0 - 4 2 5 any abrasion of sugar spheres produced in the coating method. Both 08062 4 5 - 3 5 3 5 5 - 5 0 0 tests are decribed in the European pharmacopoeia now.28 Excipients API and excipents 08063 4 5 - 4 0 3 5 5 - 4 2 5 In companies where sugar spheres are processed in a production 08065 5 0 - 3 5 3 0 0 - 5 0 0 08073 4 0 - 3 5 4 2 5 - 5 0 0 machine, and which also have an identically designed, but smaller 3 5 - 3 0 5 0 0 - 6 0 0 unit for test purposes, it is possible for the batches to be tested in this Figure 2 Diagram to show the structure of a sustained release 08130 08150 3 5 - 2 5 5 0 0 - 7 1 0 miniature version. These test conditions are then identical to the later pellet with sugar sphere care (grey), active substance layer (red) 08230 3 0 - 2 5 6 0 0 - 7 1 0 conditions and scaling-up of the results is feasible. and fi lm coating (blue). 10 08250 3 0 - 2 0 6 0 0 - 8 5 0 08330 2 5 - 2 0 7 1 0 - 8 5 0 Similarly, the instruments normally used to measure the crushing re- Pelletization 08350 2 5 - 1 8 7 1 0 - 1 , 0 0 0 sistance (or pressure resistance) of tablets, such as the established 08430 2 0 - 1 8 8 5 0 - 1 , 0 0 0 Schleuniger tester, are usually not suitable for the far smaller pellets. 08450 2 0 - 1 6 8 5 0 - 1 , 1 8 0 08530 1 8 - 1 6 1,0 0 0 - 1 , 1 8 0 As a substitute, an apparatus developed for testing the texture of Sugar 08630 1 6 - 1 4 1, 1 8 0 - 1 , 4 0 0 food products equipped with a suitably formed transducer tool has 29 sphere API Pelletization 08643 1 6 - 1 2 1, 1 8 0 - 1 , 7 0 0 proven effective. The analysis of individual pellets gives a force-over- 08653 1 4 - 1 2 1,4 0 0 - 1 , 7 0 0 08663 1 2 - 1 0 1,7 0 0 - 2, 0 0 0 distance curve that can be evaluated according to the maximum or area under the curve (AUC) to obtain a detailed statement about the mechanical properties. Table 2 Requirements for test sieves as per ISO Coating 3310/1:2000, illustrated for mesh width of 850 µm. Surface W=850 µm The properties of the surface are interesting in biopharmaceutical terms. lt is important to know these properties to calculate the subsequent X=127 µm Tolerance range for the individual mesh Active Active coating procedure, as well as the release kinetics. Ideally, the surface- pellet pellet 723–977 µm per-pellet mass can be calculated as sphere surface from the mean Y=29 µm Tolerance range for the mean mesh width 821–879 µm diameter. ln sugar spheres produced using a modifi ed sugar-coating ® References: 11. United States Pharmacopoeial Con- Pharm. Dev. Technol. 9(4), 359-367 33. A.M. 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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. 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