Advertisement

Journal of Pharmaceutical Innovation

, Volume 3, Issue 3, pp 161–174 | Cite as

Using Compartment Modeling to Investigate Mixing Behavior of a Continuous Mixer

  • Patricia M. Portillo
  • Fernando J. Muzzio
  • Marianthi G. IerapetritouEmail author
Research Article

Abstract

In this paper, the development of a compartment model to simulate mixing within a continuous blender is reported. The main benefit of the method is that it can generate extensive modeling predictions in very short computational time. The model can also be used to explore the effect of sampling parameters on estimated mixing performance, a topic that has been central to pharmaceutical manufacturing for the past 15 years and that remains a central issue in the PAT initiative. However, this method requires more input than conventional particle dynamics methods. Thus, we investigate the effects of modeling parameters on mixing performance to develop general guidance needed to adapt this modeling framework to any continuous process. An experimental technique based on longitudinal sampling is used to examine the content uniformity of the blend along the continuous mixer. The model compares favorably with continuous mixing experiments, capture the effects of feeding rate variability, active product ingredient concentration, and blender processing angle, while effectively capturing and making explicit the effect of sampling parameters such as number of samples and sample size. The modeling approach provides a convenient tool for process design.

Keywords

Compartment modeling Continuous powder mixing 

Notes

Acknowledgment

The authors would like to thank the National Science Foundation for their financial support through grants NSF-0504497 and NSF-ECC 0540855 both to Fernando J. Muzzio as well as the Nanopharmaceutical IGERT Fellowship to Patricia M. Portillo.

References

  1. 1.
    Alexander AW, Chaudhuri B, Faqih AM, Muzzio FJ, Davies C, Tomassone MS. Avalanching flow of cohesive powders. Powder Technol. 2006;164(1):13–21.CrossRefGoogle Scholar
  2. 2.
    Andersson M, Svensson O, Folestad S, Josefson M, Wahlund K-G. NIR spectroscopy on moving solids using a scanning grating spectrometer—impact on multivariate process analysis. Chemometr Intell Lab Syst. 2005;75:1–11.CrossRefGoogle Scholar
  3. 3.
    Beaudry JP. Blender efficiency. Chem Eng. 1948;55:112–3.Google Scholar
  4. 4.
    Beddow JK, Meloy T. Testing and characterization of powders and fine particles. London: Heyden and Son; 1980.Google Scholar
  5. 5.
    Berthiaux H, Marikh K, Mizonov V, Ponomarev D, Barantzeva E. Modeling continuous powder mixing by means of the theory of Markov chains. Part Sci Technol. 2004;22:379–89.CrossRefGoogle Scholar
  6. 6.
    Berthiaux H, Mosorov V, Tomczak L, Gatumel C, Demeyre JF. Principal component analysis for characterising homogeneity in powder mixing using image processing techniques. Chem Eng Process. 2006;45(5):397–403.CrossRefGoogle Scholar
  7. 7.
    Bertrand F, Leclaire L-A, Levecque G. DEM-based models for the mixing of granular materials. Chem Eng Sci. 2005;60:2517–31.CrossRefGoogle Scholar
  8. 8.
    Bhattachar SN, Hedden DB, Olsofsky AM, Qu X, Hsieh W-Y, Canter KG. Evaluation of the vibratory feeder method for assessment of powder flow properties. Int J Pharm. 2004;269:385–92.PubMedCrossRefGoogle Scholar
  9. 9.
    Bridson RH, Robbins PT, Chen Y, Westerman D, Gillham CR, Roche TC, Seville JPK. The effects of high shear blending on α-lactose monohydrate. Int J Pharm. 2007;339:84–90.PubMedCrossRefGoogle Scholar
  10. 10.
    Brone D, Alexander A, Muzzio FJ. Quantitative characterization of mixing of dry powders in V-blenders. AICHE. 1998;44(2):271–8.CrossRefGoogle Scholar
  11. 11.
    Chaudhuri B, Mehrotra A, Muzzio FJ, Tomassone MS. Cohesive effects in powder mixing in a tumbling blender. Powder Technol. 2006;165(2):105–14.CrossRefGoogle Scholar
  12. 12.
    Chowhan ZT, Chi LH. Drug-excipient interactions resulting from powder mixing. IV: Role of lubricants and their effect on in vitro dissolution. J Pharm Sci. 1986;75(6):542–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Cleary PW, Metcalfe G, Liffman K. How well do discrete element granular flow models capture the essentials of mixing processes? Appl Math Model. 1998;22(12):995–1008.CrossRefGoogle Scholar
  14. 14.
    Cleary PW, Sawley ML. DEM modelling of industrial granular flows: 3D case studies and the effect of particle shape on hopper discharge. Appl Math Model. 2002;26:89–111.CrossRefGoogle Scholar
  15. 15.
    Fan LT, Chen SJ, Watson CA. Solids mixing. Ind Eng Chem. 1970;62(7):53.CrossRefGoogle Scholar
  16. 16.
    Faqih AM, Chaudhuri B, Alexander AW, Davies C, Muzzio FJ, Tomassone MS. An experimental/computational approach for examining unconfined cohesive powder flow. Int J Pharm. 2006;324(2):116–27.PubMedCrossRefGoogle Scholar
  17. 17.
    FDA. Powder blends and finished dosage units—stratified in-process dosage unit sampling and assessment, Pharmaceutical CGMP’s, Guidance for Industry; 2003.Google Scholar
  18. 18.
    Gilbertson MA, Eames I. The influence of particle size on the flow of fluidised powders. Powder Technol. 2003;131(2–3):197–205.CrossRefGoogle Scholar
  19. 19.
    Johansen A, Schaefer T. Effects of interactions between powder particle size and binder viscosity on agglomerate growth mechanisms in a high shear mixer. Eur J Pharm Sci. 2001;12(3):297–309.PubMedCrossRefGoogle Scholar
  20. 20.
    Johanson K, Eckert C, Ghose D, Djomlija M, Hubert M. Quantitative measurement of particle segregation mechanisms. Powder Technol. 2005;159:1–12.CrossRefGoogle Scholar
  21. 21.
    Kaneko Y, Shiojima T, Horio M. Numerical analysis of particle mixing characteristics in a single helical ribbon agitator using DEM simulation. Powder Technol. 2000;108:55–64.CrossRefGoogle Scholar
  22. 22.
    Kehlenbeck V, Sommer K. Possibilities to improve the short-term dosing constancy of volumetric feeders. Powder Technol. 2003;138:51–6.CrossRefGoogle Scholar
  23. 23.
    Laurent BFC. Scaling factors in granular flow—analysis of experimental and simulations results. Chem Eng Sci. 2006;61:4138–46.CrossRefGoogle Scholar
  24. 24.
    Lemieux M, Léonard G, Doucet J, Leclaire L-A, Viens F, Chaouki J, Bertrand F. Large-scale numerical investigation of solids mixing in a V-blender using the discrete element method. Powder Technol. 2007;181:205–15.CrossRefGoogle Scholar
  25. 25.
    Ramkrishna D, Mahoney AW. Population balance modeling. Promise for the future. Chem Eng Sci. 2002;57:595–606.CrossRefGoogle Scholar
  26. 26.
    Marikh K, Berthiaux H, Mizonov V, Barantseva E. Experimental study of the stirring conditions taking place in a pilot plant continuous mixer of particulate solids. Powder Technol. 2005;157:138–43.CrossRefGoogle Scholar
  27. 27.
    Massol-Chaudeur S, Berthiaux H, Dodds JA. Experimental study of the mixing kinetics of binary pharmaceutical powder mixtures in a laboratory hoop mixer. Chem Eng Sci. 2002;57(19, 13):4053–65.Google Scholar
  28. 28.
    Mehrotra A, Muzzio FJ, Shinbrot T. Spontaneous separation of charged grains. Phys Rev Lett. 2007;99:058001.PubMedCrossRefGoogle Scholar
  29. 29.
    Moakher M, Shinbrot T, Muzzio FJ. Experimentally validated computations of flow, mixing and segregation of non-cohesive grains in 3D tumbling blenders. Powder Technol. 2000;109:58–71.CrossRefGoogle Scholar
  30. 30.
    Muerza S, Berthiaux H, Massol-Chaudeur S, Thomas G. A dynamic study of static mixing using on-line image analysis. Powder Technol. 2002;128:195–204.CrossRefGoogle Scholar
  31. 31.
    Muzzio FJ, Goodridge CL, Alexander A, Arratia P, Yang H, Sudah O, Mergen G. Sampling and characterization of pharmaceutical powders and granular blends. Sampling and characterization of pharmaceutical powders and granular blends. Int J Pharm. 2003;250:51–64.PubMedCrossRefGoogle Scholar
  32. 32.
    Portillo PM, Ierapetritou MG, Muzzio FJ. Characterization of continuous convective powder mixing processes. Powder Technol. 2008;182:368–79.CrossRefGoogle Scholar
  33. 33.
    Portillo PM, Muzzio FJ, Ierapetritou MG. Characterizing powder mixing processes utilizing compartment models. Int J Pharm. 2006;320:14–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Ristow GH. Flow properties of granular materials in 3D Geometries, Ph.D. Thesis, Philipps-Universitat Marburg; 1998.Google Scholar
  35. 35.
    Ross S. A first course in probability, 6th edn. Upper Saddle River, NJ: Prentice Hall; 2002.Google Scholar
  36. 36.
    Szépvölgyi J. Handbook of conveying and handling of particulate solids. Amsterdam: Elsevier Science B.V.; 2001. pp. 665–671.Google Scholar
  37. 37.
    Stewart RL, Bridgwater J, Zhou YC, Yu AB. Simulated and measured flow of granules in a bladed mixer, a detailed comparison. Chem Eng Sci. 2001;56:5457–71.CrossRefGoogle Scholar
  38. 38.
    Wightman C, Muzzio FJ, Wilder J. A quantitative image analysis method for characterizing mixtures of granular materials. Powder Technol. 1996;89:165–76.CrossRefGoogle Scholar
  39. 39.
    Williams J, Rahman M. Prediction of the performance of continuous mixers for particulate solids using residence time distributions. Part I. Theoretical. Powder Technol. 1971;5:87–92.CrossRefGoogle Scholar
  40. 40.
    Zhu HP, Yu AB, Wu YH. Numerical investigation of steady and unsteady state hopper flows. Powder Technol. 2006;170(3):125–34.CrossRefGoogle Scholar
  41. 41.
    Zuurman K, Riepma KA, Bolhuis GK, Vromans H, Lerk CF. The relationship between bulk density and compactibility of lactose granulations. Int J Pharm. 1994;102:1–9.CrossRefGoogle Scholar
  42. 42.
    Zuurman K, Bolhuis GK, Vromans H. Effect of binder on the relationship between bulk density and compactibility of lactose granulations. Int J Pharm. 1995;119(1):65–69.CrossRefGoogle Scholar

Copyright information

© International Society for Pharmaceutical Engineering 2008

Authors and Affiliations

  • Patricia M. Portillo
    • 1
  • Fernando J. Muzzio
    • 1
  • Marianthi G. Ierapetritou
    • 1
    Email author
  1. 1.Department of Chemical and Biochemical EngineeringRutgers UniversityPiscatawayUSA

Personalised recommendations