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AAPS PharmSciTech. 2007 October; 8(4): 25–33.
Published online 2007 October 19. doi:  10.1208/pt0804084
PMCID: PMC2750670

High shear mixing granulation of ibuprofen and β-cyclodextrin: Effects of process variables on ibuprofen dissolution


The aims of the study were to evaluate the effect of high shear mixer (HSM) granulation process parameters and scale-up on wet mass consistency and granulation characteristics. A mixer torque rheometer (MTR) was employed to evaluate the granulating solvents used (water, isopropanol, and 1:1 vol/vol mixture of both) based on the wet mass consistency. Gral 25 and mini-HSM were used for the granulation. The MTR study showed that the water significantly enhanced the beta-cyclodextrin (βCD) binding tendency and the strength of liquid bridges formed between the particles, whereas the isopropanol/water mixture yielded more suitable agglomerates. Mini-HSM granulation with the isopropanol/water mixture (1:1 vol/vol) showed a reduction in the extent of torque value rise by increasing the impeller speed as a result of more breakdown of agglomerates than coalescence. In contrast, increasing the impeller speed of the Gral 25 resulted in higher torque readings, larger granule size, and consequently, slower dissolution. This was due to a remarkable rise in temperature during Gral granulation that reduced the isopropanol/water ratio in the granulating solvent as a result of evaporation and consequently increased the βCD binding strength. In general, the HSM granulation retarded ibuprofen dissolution compared with the physical mixture because of densification and agglomeration. However, a successful HSM granulation scale-up was not achieved due to the difference in the solvent mixture’s effect from 1 scale to the other.

Keywords: Granulation, ibuprofen, beta-cyclodextrin, complexation, dissolution

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Selected References

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1. Jain AC, Adeyeye MC. Hygroscopicity, phase solubility and dissolution of various substituted sulfobutylether β-cyclodextrins (SBE) and danazol-SBE inclusion complexes. Int J Pharm. 2001;212:177–186. doi: 10.1016/S0378-5173(00)00607-4. [PubMed] [Cross Ref]
2. Badawy SIF, Marshall AL, Ghorab MM, Adeyeye CM. A study of the complexation between danazol and hydrophilic cyclodextrin derivatives. Drug Dev Ind Pharm. 1996;22:959–966. doi: 10.3109/03639049609065926. [Cross Ref]
3. Badawy SIF, Ghorab MM, Adeyeye CM. Characterization and bioavailability of danazol-hydroxypropyl-β-cyclodextrin coprecipitates. Int J Pharm. 1996;128:45–54. doi: 10.1016/0378-5173(95)04214-8. [Cross Ref]
4. Chow DD, Karara AH. Characterization, dissolution and bioavailability in rats of ibuprofen-β-cyclodextrin complex system. Int J Pharm. 1986;28:95–101. doi: 10.1016/0378-5173(86)90232-2. [Cross Ref]
5. Hladon T, Pawlaczyk J, Szafran B. Stability of ibuprofen in its inclusion complex with β-cyclodextrin. J Inclusion Phenom Macro Chem. 2000;36:1–8. doi: 10.1023/A:1008046724527. [Cross Ref]
6. Munoz-Ruiz A, Paronen P. Time densification behavior of cyclodextrins. J Pharm Pharmacol. 1996;48:790–797. [PubMed]
7. Nakai Y, Yamamoto K, Terada K, Kajiyama A. Relationships between crystallinity of β-cyclodextrin and tablet characteristics. Chem Pharm Bull (Tokyo) 1985;33:5110–5112. [PubMed]
8. Fenyvesi E, Shirakura O, Szejtli J, Nagai T. Properties of cyclodextrin polymer as a tabletting aid. Chem Pharm Bull (Tokyo) 1984;32:665–669. [PubMed]
9. Giordano F, Gazzaniga A, Bettinetti GP, Manna AL. The influence of water content on the binding capacity of β-cyclodextrin. Int J Pharm. 1990;62:153–156. doi: 10.1016/0378-5173(90)90229-W. [Cross Ref]
10. Shangraw RF, Pande GS, Gala P. Characterization of the tableting properties of β-cyclodextrin and the effects of processing variables on inclusion complex formation, compactability and dissolution. Drug Dev Ind Pharm. 1992;18:1831–1851. doi: 10.3109/03639049209046334. [Cross Ref]
11. Ghorab MK, Adeyeye MC. Enhancement of ibuprofen dissolution via wet granulation with β-cyclodextrin. Pharm Dev Technol. 2001;6:305–314. doi: 10.1081/PDT-100002611. [PubMed] [Cross Ref]
12. Ghorab MK, Adeyeye MC. Enhanced bioavailability of process-induced fast-dissolving ibuprofen cogranulated with β-cyclodextrin. J Pharm Sci. 2003;92:1690–1697. doi: 10.1002/jps.10443. [PubMed] [Cross Ref]
13. Gainotti A, Bettini R, Gazzaniga A, Colombo P, Giordano F. Drug-beta-cyclodextrin containing pellets prepared with a high-shear mixer. Drug Dev Ind Pharm. 2004;30:1061–1068. doi: 10.1081/DDC-200040247. [PubMed] [Cross Ref]
14. Watano S, Takashima H, Miyanami K. Scale-up of agitation fluidized bed granulation, V: effect of moisture content on scale-up characteristics. Chem Pharm Bull (Tokyo) 1995;45:710–714.
15. Holm P. High shear mixer granulators. In: Parikh DM, editor. Handbook of Pharmaceutical Granulation Technology. vol. 81. New York, NY: Marcel Dekker; 1997. pp. 151–204.
16. Holm P, Schaefer T, Larsen C. End-point detection in a wet granulation process. Pharm Dev Technol. 2001;6:181–192. doi: 10.1081/PDT-100000739. [PubMed] [Cross Ref]
17. Knight PC. An investigation of the kinetics of granulation using a high shear mixer. Powder Technol. 1993;77:159–169. doi: 10.1016/0032-5910(93)80053-D. [Cross Ref]
18. Knight PC, Johansen A, Kristensen HG, Schaefer T, Seville JPK. An investigation of the effects on agglomeration of changing the speed of a mechanical mixer. Powder Technol. 2000;110:204–209. doi: 10.1016/S0032-5910(99)00259-4. [Cross Ref]
19. Dévay A, Mayer K, Pál S, Antal I. Investigation on drug dissolution and particle characteristics of pellets related to manufacturing process variables of high-shear granulation. J Biochem Biophys Methods. 2006;69:197–205. doi: 10.1016/j.jbbm.2006.03.006. [PubMed] [Cross Ref]
20. Badawy SIF, Menning MM, Gorko MA, Gilbert DL. Effect of process parameters on compressibility of granulation manufactured in a high shear mixer. Int J Pharm. 2000;198:51–61. doi: 10.1016/S0378-5173(99)00445-7. [PubMed] [Cross Ref]
21. Sato Y, Okamoto T, Watano S. Scale-up of high shear granulation based on agitation power. Chem Pharm Bull (Tokyo) 2005;53:1547–1550. doi: 10.1248/cpb.53.1547. [PubMed] [Cross Ref]
22. Watano S, Okamoto T, Sato Y, Osako Y. Scale-up of high shear granulation based on the internal stress measurement. Chem Pharm Bull (Tokyo) 2005;53:351–354. doi: 10.1248/cpb.53.351. [PubMed] [Cross Ref]
23. Ramaker JS, Jelgersma MA, Vonk P, Kossen NWF. Scale-down of a high-shear pelletization process: flow profile and growth kinetics. Int J Pharm. 1998;166:89–97. doi: 10.1016/S0378-5173(98)00030-1. [Cross Ref]
24. Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. A methodology for the optimization of wet granulation in a model planetary mixer. Pharm Dev Technol. 1998;3:413–422. doi: 10.3109/10837459809009869. [PubMed] [Cross Ref]
25. Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. Applicability of a scale-up methodology for wet granulation processes in Collette Gral high shear mixer-granulators. Eur J Pharm Sci. 1999;8:85–93. doi: 10.1016/S0928-0987(98)00063-3. [PubMed] [Cross Ref]
26. Ameye D, Keleb E, Vervaet C, Remon JP, Adams E, Massart DL. Scaling-up of a lactose wet granulation process in Mi-Pro high shear mixers. Eur J Pharm Sci. 2002;17:247–251. doi: 10.1016/S0928-0987(02)00218-X. [PubMed] [Cross Ref]
27. Rekhi GS, Caricofe RB, Parikh DM, Augsburger LL. A new approach to scale-up of a high-shear granulation process. Pharm Technol. 1996;20:58–67.
28. Fenyvesi E, Shirakura O, Szejtli J, Nagai T. Properties of cyclodextrin polymer as a tabletting aid. Chem Pharm Bull (Tokyo) 1984;32:665–669. [PubMed]
29. Leuenberger H. Granulation, new technique. Pharm Acta Helv. 1982;57:72–80. [PubMed]
30. Shiraishi T, Konodo S, Yuasa H, Kanaya Y. Studies on the granulation process of granules for tableting with a high speed mixer, I: physical properties of granules for tableting. Chem Pharm Bull (Tokyo) 1994;42:932–936.
31. Mackaplow MB, Rosen LA, Michael JN. Effect of primary particle size on granule growth and endpoint determination in high-shear wet granulation. Powder Technol. 2000;108:32–45. doi: 10.1016/S0032-5910(99)00203-X. [Cross Ref]
32. Badawy SIF, Hussain MA. Effect of starting material particle size on its agglomeration behavior in high shear wet granulation.AAPS PharmSciTech [serial online]. 2004;5:article 38. [PMC free article] [PubMed]
33. Eliasen H, Kristensen HG, Schaefer T. Growth mechanisms in melt agglomeration with a low viscosity binder. Int J Pharm. 1999;186:149–159. doi: 10.1016/S0378-5173(99)00158-1. [PubMed] [Cross Ref]
34. Horsthuis GJB, Laarhoven JAHV, Rooji RCBMV, Vromans H. Studies on upscaling parameters of the Gral high shear granulation process. Int J Pharm. 1993;92:143–150. doi: 10.1016/0378-5173(93)90273-I. [Cross Ref]

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