Journal of Pharmaceutical Innovation

, Volume 8, Issue 1, pp 11–27 | Cite as

Computer-Aided Flowsheet Simulation of a Pharmaceutical Tablet Manufacturing Process Incorporating Wet Granulation

  • Fani Boukouvala
  • Anwesha Chaudhury
  • Maitraye Sen
  • Ruijie Zhou
  • Lukasz Mioduszewski
  • Marianthi G. Ierapetritou
  • Rohit Ramachandran
Research Article

Abstract

In this work, a dynamic flowsheet model for the production of pharmaceutical tablets through a continuous wet granulation process is developed. The unit operation models which are integrated to compose the process line form a hybrid configuration which is comprised of a combination of mechanistic models, population balance models, and empirical correlations, based on the currently available process knowledge for each individual component. The main objective of this study is to provide guidance in terms of the necessary steps which are required in order to move from the unit operation level to the simulation of an integrated continuous plant operation. Through this approach, not only significant process conditions for each individual process are identified but also crucial interconnecting parameters which affect critical material properties of the processed powder stream are distinguished. Through the integration of the dynamic flowsheet with a final component of tablet dissolution, the connection of the processing history of a set of powders which undergo wet granulation and are contained in each produced tablet to the release rate of the pharmaceutical ingredient is enabled. The developed flowsheet is used for the simulation of different operating scenarios and disturbances which are often encountered during operation for the assessment of their effects towards critical material attributes, product properties, and the operation of further downstream processes. Simulation results demonstrate that granulation and milling which control the particle size distribution of the processed powder mixture highly affect the hardness and dissolution of the produced tablets.

Keywords

Pharmaceutical manufacturing Wet granulation Flowsheet simulation Population balance modeling 

References

  1. 1.
    Basu P, Joglekar G, Rai S, Suresh P, Vernon J. Analysis of manufacturing costs in pharmaceutical companies. J Pharm Innov 2008;3:30–40.CrossRefGoogle Scholar
  2. 2.
    Betz G, Junker-Purgin P, Leuenberger H. Batch and continuous procesing in the production of pharmaceutical granules. Pharm Dev Technol 2003;8:289–97.PubMedCrossRefGoogle Scholar
  3. 3.
    Borgquist P, Krner A, Piculell L, Larsson A, Axelsson A. A model for the drug release from a polymer matrix tablet—effects of swelling and dissolution. J Control Release 2006;113(3):216–25.PubMedCrossRefGoogle Scholar
  4. 4.
    Boukouvala F, Niotis V, Ramachandran R, Muzzio FJ, Ierapetritou MG. An integrated approach for dynamic flowsheet modeling and sensitivity analysis of a continuous tablet manufacturing process. Comput Chem Eng 2012a;42(0):30–47.CrossRefGoogle Scholar
  5. 5.
    Boukouvala F, Ramachandran R, Vanarase A, Muzzio FJ, Ierapetritou MG. Computer aided design and analysis of continuous pharmaceutical manufacturing processes. Comput aided Chem Eng 2011;29:216–20.CrossRefGoogle Scholar
  6. 6.
    Boukouvala F, Vanarase A, Dubey A, Ramachandran R, Muzzio F, Ierapetritou M. Computational approaches for studying the granular dynamics of continuous blending processes ii: Population balance and data-based methods. Macromol Mater Eng 2012b;297:9–19.CrossRefGoogle Scholar
  7. 7.
    Burgschweiger J, Tsotsas E. Experimental investigation and modelling of continuous fluidized bed drying under steady-state and dynamic conditions. Chem Eng Sci 2002;57(24):5021–38.CrossRefGoogle Scholar
  8. 8.
    Costa P, Lobo JMS. Modeling and comparison of dissolution profiles. Eur J Pharm Sci 2001;13(2):123–33.PubMedCrossRefGoogle Scholar
  9. 9.
    Crowe CT. Multiphase flow handbook. Boca Raton: Taylor & Francis; 2006.Google Scholar
  10. 10.
    Dosta M, Heinrich S, Werther J. Fluidized bed spray granulation: analysis of the system behaviour by means of dynamic flowsheet simulation. Powder Technol 2010;204:71–82.CrossRefGoogle Scholar
  11. 11.
    Engisch W, Ierapetritou M, Muzzio FJ. 2010. Hopper refill of loss-in-weight feeding equipment. In : Proceedings of the AIChE Annual Meeting 2010. Salt Lake City, UT, USA.Google Scholar
  12. 12.
    Ennis BJ. Particle technology: the legacy of neglect in the US. Chem Eng Prog 1990;90:32–6.Google Scholar
  13. 13.
    Ennis BJ, Tardos G, Pfeffer R. A microlevel-based characterization of granulation phenomena. Powder Technol 1991;65(1–3):257–72.CrossRefGoogle Scholar
  14. 14.
    Fung KY, Ng KM. Product-centered processing: pharmaceutical tablets and capsules. AIChE J 2003;49(5):1193–215.CrossRefGoogle Scholar
  15. 15.
    Glaser T, Sanders CFW, Wang FY, Cameron IT, Ramachandran R, Litster JD, Poon JMH, Immanuel CD, Doyle III FJ. 987 Model predictive control of drum granulation. J Process Contr 2009;19:615–22.CrossRefGoogle Scholar
  16. 16.
    Gluba T, Obraniak A, Gawot-Młynarczyk E. The effect of granulation conditions on bulk density. Physicochem Probl MI 2004;38:177–86.Google Scholar
  17. 17.
    Goldschmidt M. Hydrodynamic modeling of fluidized bed spray granulation. Ph.D. Thesis. Netherlands: University of Twente; 2001.Google Scholar
  18. 18.
    Gorsek A, Glavic P. Design of batch versus continuous processes: part 1: single-purpose equipment. Chem Eng Res Des 1997;75:709–17.CrossRefGoogle Scholar
  19. 19.
    Grunh G, Werther J, Schmidt J. Flowsheeting of solids processes for energy saving and pollution reduction. J Clean Prod 2004;12:147–51.CrossRefGoogle Scholar
  20. 20.
    Hapgood KP, Litster JD, Smith R. Nucleation regime map for liquid bound granules. AIChE J 2003;49(2):350–61.CrossRefGoogle Scholar
  21. 21.
    Hartge EU, Pogodda M, Reimers C, Schwier D, Gruhn G, Werther J. Flowsheet simulation of solids processes. KONA 2006;24:146–56.Google Scholar
  22. 22.
    Hounslow M. The population balance as a tool for understanding particle rate processes. KONA 1998;16:179–93.Google Scholar
  23. 23.
    Kawakita K, Ldde K-H. Some considerations on powder compression equations. Powder Technol 1971;4(2):61–8.CrossRefGoogle Scholar
  24. 24.
    Kimber JA, Kazarian SG, Stephanek F. Microstructure-based mathematical modelling and spectroscopic imaging of tablet dissolution. Comput Chem Eng 2011;35(7):1328–39.CrossRefGoogle Scholar
  25. 25.
    Kuentz M, Leuenberger H. A new model for the hardness of a compacted particle system, applied to tablets of pharmaceutical polymers. Powder Technol 2000;111(12):145–53.CrossRefGoogle Scholar
  26. 26.
    Leuenberger H. New trends in the production of pharmaceutical granules: batch versus continuous processing. Eur J Pharm Biopharm 2001;52:289–98.PubMedCrossRefGoogle Scholar
  27. 27.
    Leuenberger H. Scale-up in the 4th dimension in the field of granulation and drying or how to avoid classical scale-up. Powder Technol 2003;130:225–30.CrossRefGoogle Scholar
  28. 28.
    Leuenberger H, Betz G. Chapter 15 granulation process control—production of pharmaceutical granules: the classical batch concept and the problem of scale-up. In: Salman AD, Seville J, Hounslow M, editors. Handbook of powder technology: granulation, vol 11; 2007, pp. 705–33.Google Scholar
  29. 29.
    Liu LX, Litster JD, Iveson SM, Ennis BJ. Coalescence of deformable granules in wet granulation processes. AIChE J 2000;46(3):529–39.CrossRefGoogle Scholar
  30. 30.
    Madec L, Falk L, Plasari E. Modelling of the agglomeration in suspension process with multidimensional kernels. Powder Technol 2003;130(1–3):147–53.CrossRefGoogle Scholar
  31. 31.
    Marshall Jr CL, Rajniak P. Multi-component population balance modeling of granulation with continuous addition of binder. Powder Technol 2012. doi:10.1016/j.powtec.2012.01.027.Google Scholar
  32. 32.
    Matsoukas T, Marshall Jr CL. Bicomponent aggregation in finite systems. EPL 2010;92(4):46007.CrossRefGoogle Scholar
  33. 33.
    Muschert S, Siepmann F, Leclercq B, Carlin B, Siepmann J. Prediction of drug release from ethylcellulose coated pellets. J Control Release 2009;135(1):71–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Ng KM. Design and development of solids processes: a process systems engineering perspective. Powder Technol 2002;126:205–10.CrossRefGoogle Scholar
  35. 35.
    Pantelides CC, Oh M. Process modelling tools and their application to particulate processes. Powder Technol 1996;87:13–20.CrossRefGoogle Scholar
  36. 36.
    Papavasileiou V, Koulouris A, Siletti C, Petrides D. Optimize manufacture of pharmaceutical products with process simulation and production tools. Chem Eng Res Des 2007;85:1086–97.CrossRefGoogle Scholar
  37. 37.
    Pinto MA, Immanuel CD, Doyle III FJ. A feasible solution technique for higher-dimensional population balance models. Comput Chem Eng 2007;31(10):1242–56.CrossRefGoogle Scholar
  38. 38.
    Plumb K. Continous processing in the pharmaceutical industry: changing the mindset. Chem Eng Res Des 2005;83:730–8.CrossRefGoogle Scholar
  39. 39.
    Radford R. A model of particulate drying in pneumatic conveying systems. Powder Technol 1997;93(2):109–26.CrossRefGoogle Scholar
  40. 40.
    Rajniak P, Mancinelli C, Chern R, Stepanek F, Farber L, Hill B. Experimental study of wet granulation in fluidized bed: impact of the binder properties on the granule morphology. Int J Pharm 2007;334(1–2):92–102.PubMedCrossRefGoogle Scholar
  41. 41.
    Rajniak P, Stepanek F, Dhanasekharan K, Fan R, Mancinelli C, Chern R. A combined experimental and computational study of wet granulation in a wurster fluid bed granulator. Powder Technol 2009;189(2):190–201.CrossRefGoogle Scholar
  42. 42.
    Ramachandran R, Ansari MA, Chaudhury A, Kapadia A, Prakash AV, Stepanek F. A quantitative assessment of the influence of primary particle size polydispersity on granule inhomogeneity. Chem Eng Sci 2012;71:104–10.CrossRefGoogle Scholar
  43. 43.
    Ramachandran R, Arjunan J, Chaudhury A, Ierapetritou M. Model-based control-loop performance of a continuous direct compaction process. J Pharm Innov 2011;6:249–63.CrossRefGoogle Scholar
  44. 44.
    Ramachandran R, Chaudhury A. Model-based design and control of a continuous drum granulation process. Chem Eng Res Des 2011;90(8):1063–73.CrossRefGoogle Scholar
  45. 45.
    Reimers C, Werther J, Grunh G. Flowsheet simulation of solids processes: data reconciliation and adjustment of model parameters. Chem Eng Process 2008;47:138–58.CrossRefGoogle Scholar
  46. 46.
    Reimers C, Werther J, Grunh G. Design specifications in the flowsheet simulation of complex solids processes. Powder Technol 2009;191:260–71.CrossRefGoogle Scholar
  47. 47.
    Rynhart PR. Mathematical modeling of granulation processes. Ph.D. thesis. New Zealand: Massey University; 2004.Google Scholar
  48. 48.
    Salman AD, Hounslow MJ, Seville JPK. Granulation. Handbook of powder technology. Amsterdam: Elsevier; 2007.Google Scholar
  49. 49.
    Schaber SD, Gerogiorgis DI, Ramachandran R, Evans JMB, Barton PI, Trout BL. Economic analysis of integrated continuous and batch pharmaceutical manufacturing: a case study. Ind Eng Chem Prod Res Dev 2011;50(17):10083–92.CrossRefGoogle Scholar
  50. 50.
    Schwier D, Hartge E, Puttman A, Grunh G, Werther J. Sensitiviy analysis in the simulation of complex solids processes. Comput aided Chem Eng 2006;21:601–6.CrossRefGoogle Scholar
  51. 51.
    Schwier D, Hartge E, Werther J, Grunh G. Global sensitivity analysis in the flowsheet simulation of solids processes. Chem Eng Process 2010;49:9–21.CrossRefGoogle Scholar
  52. 52.
    Seider WD, Seider JD, Lewin DR. Process design principles: synthesis, analysis and evaluation. Hoboken: Wiley; 1999.Google Scholar
  53. 53.
    Singh R, Gernaey KV, Gani R. ICAS-PAT: a software for design, analysis and validation of pat systems. Comput Chem Eng 1108–1136;34(7).Google Scholar
  54. 54.
    Stepanek F, Rajniak P, Mancinelli C, Chern R, Ramachandran R. Distribution and accessibility of binder in wet granules. Powder Technol 2009;189(2):376–84.CrossRefGoogle Scholar
  55. 55.
    Suresh P, Basu P. Improving pharmaceutical product development and manufacturing: Impact on cost of drug development and cost of goods sold of pharmaceuticals. J Pharm Innov 2008;3:175–87.CrossRefGoogle Scholar
  56. 56.
    Toebermann J, Rosenkranz J, Grunh G., Werther J. Block-oriented process simulation of solids processes. Comput Chem Eng 2000;23:1773–82.CrossRefGoogle Scholar
  57. 57.
    Truss Jr CL. The future of operator training. J Am Water Works Assoc 2000;92:80–1.Google Scholar
  58. 58.
    Vanarase A, Muzzio FJ. Effect of operating conditions and design parameters in a continuous powder mixer. Powder Technol 2011;208:26–36.CrossRefGoogle Scholar
  59. 59.
    Verkoeijen D, Pouw GA, Meesters GMH, Scarlett B. Population balances for particulate processes—a volume approach. Chem Eng Sci 2002;57(12):2287–303.CrossRefGoogle Scholar
  60. 60.
    Wang H, Dyakowski T, Senior P, Raghavan R, Yang W. Modelling of batch fluidised bed drying of pharmaceutical granules. Chem Eng Sci 2007;62(5):1524–35.CrossRefGoogle Scholar
  61. 61.
    Werani J, Grunberg M, Ober C, Leuenberger H. Semicontinuous granulation—the process of choice for the production of pharmaceutical granules. Powder Technol 2004;140:163–8.CrossRefGoogle Scholar
  62. 62.
    Werther J, Heinrich S, Dosta M, Hartge E-U. The ultimate goal of modeling—simulation of system and plant performance. Particuology 2011;9(4):320–9.CrossRefGoogle Scholar
  63. 63.
    Yu A, Standish N, Lu L. Coal agglomeration and its effect on bulk density. Powder Technol 1995;82(2):177–89.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Fani Boukouvala
    • 1
  • Anwesha Chaudhury
    • 1
  • Maitraye Sen
    • 1
  • Ruijie Zhou
    • 1
  • Lukasz Mioduszewski
    • 1
  • Marianthi G. Ierapetritou
    • 1
  • Rohit Ramachandran
    • 1
  1. 1.Rutgers, The State UniversityPiscatawayUSA

Personalised recommendations