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A Novel CFD Model of SMX Static Mixer Used in Advanced Continuous Manufacturing of Active Pharmaceutical Ingredients (API)

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Abstract

Purpose

The growing demand for effective pharmaceutical treatments, notably amidst health challenges like COVID, highlights the urgency for improved drug production techniques. This study examines the simulation of the Sulzer SMX static mixer in laminar conditions for the continuous pharmaceutical manufacturing of significant pharmaceuticals, notably imatinib.

Methods

Computational fluid dynamics (CFD) were employed to assess the SMX static mixer’s hydrodynamics and mixing performance. Emphasis was on mixing efficiency and residence time distributions (RTD) in a mixer with SMX elements. We refined the model’s reliability and explored the correlation between friction factor and Reynolds number. The Definitive Screening Design (DSD) was used to determine major factors impacting mixer dynamics.

Results

We established a novel correlation between friction factor and Reynolds number. The study reveal that lower flowrates significantly impact mixing efficiency, with different solvents inducing mixing delays. The RTD study identified the total inlet flowrate’s influence on distribution, with higher flowrates leading to more distinct RTD profiles and decreased axial mixing. The screening analysis highlighted flowrate’s dominance over other factors in determining mixing efficiency and residence time.

Conclusions

Through precise computational fluid dynamics (CFD) simulations, the study affirms the robustness of the developed model and underscores the novel correlation between the friction factor and Reynolds number. Insights into flow rate’s pivotal role in dictating mixer efficiency and residence time distribution are discerned, culminating in a comprehensive guide for refining static mixer operations for optimized drug manufacturing.

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References

  1. Babnik S, Erklavec Zajec V, Oblak B, Likozar B, Pohar A. A Review of Computational Fluid Dynamics (CFD) Simulations of Mixing in the Pharmaceutical Industry. Biomed J Sci Tech Res. 2020;27(3):20732–6.

    Google Scholar 

  2. Lavanya NL, Bhattacharyya S. Computational fluid dynamics-the futuristic innovation in pharmaceutical industry. Indian JPharmEducRes. 2021;55(4):930–8.

    Google Scholar 

  3. Jovanović A, Pezo M, Pezo L, Lević L. DEM/CFD analysis of granular flow in static mixers. Powder Technol. 2014;266:240–8.

    Article  Google Scholar 

  4. Núñez-Flores A, Sandoval A, Mancilla E, Hidalgo-Millán A, Ascanio G. Enhancement of photocatalytic degradation of ibuprofen contained in water using a static mixer. Chem Eng Res Des. 2020;156:54–63.

    Article  Google Scholar 

  5. Brechtelsbauer C, Ricard F. Reaction engineering evaluation and utilization of static mixer technology for the synthesis of pharmaceuticals. Org Process Res Dev. 2001;5(6):646–51.

    Article  CAS  Google Scholar 

  6. Douroumis D, Fahr A. Enhanced dissolution of oxcarbazepine microcrystals using a static mixer process. Colloids Surf B Biointerfaces. 2007;59(2):208–14.

    Article  CAS  PubMed  Google Scholar 

  7. Chen W, Chen X, Gandhi RB, Mantri RV, Sadineni V, Saluja A. Application of mechanistic models for process design and development of biologic drug products. J Pharm Innov. 2016;11:200–13.

    Article  Google Scholar 

  8. Hörmann TJ, Suzzi D, Adam S, Khinast JG. DOE-based CFD optimization of pharmaceutical mixing processes. J Pharm Innov. 2012;7:181–94.

    Article  Google Scholar 

  9. Zeberli A, Casola G, Badr S, Siegmund C, Mattern M, Sugiyama H. Approach for multicriteria equipment redesign in sterile manufacturing of biopharmaceuticals. J Pharm Innov. 2018;15:15–25.

    Article  Google Scholar 

  10. Kresta SM, Etchells AW III, Dickey DS, Atiemo-Obeng VA, editors. Advances in Industrial Mixing: A Companion to the Handbook of Industrial Mixing. Hoboken, NJ: John Wiley & Sons; 2015.

  11. Liu Y, Rao A, Ma F, Li X, Wang J, Xiao Q. Investigation on mixing characteristics of hydrogen and natural gas fuel based on SMX static mixer. Chem Eng Res Des. 2023;197:738–49.

    Article  CAS  Google Scholar 

  12. Thakur RK, Vial C, Nigam KDP, Nauman EB, Djelveh G. Static mixers in the process industries—a review. Chem Eng Res Des. 2003;81(7):787–826.

    Article  CAS  Google Scholar 

  13. Valdés JP, Kahouadji L, Matar OK. Current advances in liquid–liquid mixing in static mixers: a review. Chem Eng Res Des. 2022;177:694–731.

    Article  Google Scholar 

  14. Soman SS, Madhuranthakam CMR. Effects of internal geometry modifications on the dispersive and distributive mixing in static mixers. Chem Eng Process. 2017;122:31–43.

    Article  CAS  Google Scholar 

  15. Klutz S, Kurt SK, Lobedann M, Kockmann N. Narrow residence time distribution in tubular reactor concept for Reynolds number range of 10–100. Chem Eng Res Des. 2015;95:22–33.

    Article  CAS  Google Scholar 

  16. Haddadi MM, Hosseini SH, Rashtchian D, Olazar M. Comparative analysis of different static mixers performance by CFD technique: an innovative mixer. Chin J Chem Eng. 2020;28(3):672–84.

    Article  CAS  Google Scholar 

  17. Vikhansky A. CFD modelling of turbulent liquid-liquid dispersion in a static mixer. Chem Eng Process Process Intensif. 2020;149:107840.

    Article  CAS  Google Scholar 

  18. Singh MK, Anderson PD, Meijer HE. Understanding and optimizing the SMX static mixer. Macromol Rapid Commun. 2009;30(4–5):362–76.

    Article  CAS  PubMed  Google Scholar 

  19. Liu S, Hrymak AN, Wood PE. Design modifications to SMX static mixer for improving mixing. AIChE J. 2006;52(1):150–7.

    Article  CAS  Google Scholar 

  20. Ghanem A, Lemenand T, Della Valle D, Peerhossaini H. Static mixers: mechanisms, applications, and characterization methods – a review. Chem Eng Res Des. 2014;92(2):205–28.

    Article  CAS  Google Scholar 

  21. Azizi F, Abou-Hweij W, Lebaz N, Sheibat-Othman N. A numerical evaluation of flows through an SMX-Plus mixer. Chem Eng Res Des. 2022;178:382–94.

    Article  CAS  Google Scholar 

  22. Rahmani RK, Ayasoufi A, Keith TG. A numerical study of the global performance of two static mixers. J Fluids Eng. 2007;129(3):338–49.

    Article  CAS  Google Scholar 

  23. Meijer HEH, Singh MK, Anderson PD. On the performance of static mixers: a quantitative comparison. Prog Polym Sci. 2012;37(10):1333–49.

    Article  CAS  Google Scholar 

  24. Kresta SM, Atiemo-Obeng VA, Paul EL, editors. Handbook of Industrial Mixing: Science and Practice. Hoboken, NJ: Wiley; 2003.

  25. Rauline D, Le Blévec JM, Bousquet J, Tanguy PA. A comparative assessment of the performance of the Kenics and SMX static mixers. Chem Eng Res Des. 2000;78(3):389–96.

    Article  CAS  Google Scholar 

  26. Rauline D, Tanguy PA, Le Blévec JM, Bousquet J. Numerical investigation of the performance of several static mixers. Can J Chem Eng. 1998;76(3):527–35.

    Article  CAS  Google Scholar 

  27. Leclaire S, Vidal D, Fradette L, Bertrand F. Validation of the pressure drop–flow rate relationship predicted by lattice Boltzmann simulations for immiscible liquid–liquid flows through SMX static mixers. Chem Eng Res Des. 2020;153:350–68.

    Article  CAS  Google Scholar 

  28. Theron F, Sauze NL. Comparison between three static mixers for emulsification in turbulent flow. Int J Multiph Flow. 2011;37(5):488–500.

    Article  CAS  Google Scholar 

  29. Chabanon E, Sheibat-Othman N, Mdere O, Valour JP, Urbaniak S, Puel F. Drop size distribution monitoring of oil-in-water emulsions in SMX+ static mixers: effect of operating and geometrical conditions. Int J Multiph Flow. 2017;92:61–9.

    Article  CAS  Google Scholar 

  30. Rafiee M. Use of Positron Emission Particle Tracking (PEPT) for Studying Laminar Mixing in Static Mixers. Ph.D. Dissertation, University of Birmingham; 2014.

  31. Christiansen RL. Establishing independence of continuous process product samples. AIChE J. 2000;46:1441–8.

    Article  CAS  Google Scholar 

  32. Fradette L, Li HZ, Choplin L, Tanguy P. 3D finite element simulation of fluid flow through a SMX static mixer. Comput Chem Eng. 1998;22:S759–61.

    Article  CAS  Google Scholar 

  33. Baumann A, Jeelani SAK, Holenstein B, Stössel P, Windhab EJ. Flow regimes and drop break-up in SMX and packed bed static mixers. Chem Eng Sci. 2012;73:354–65.

    Article  CAS  Google Scholar 

  34. Wünsch O, Böhme G. Numerical simulation of 3d viscous fluid flow and convective mixing in a static mixer. Arch Appl Mech. 2000;70(1):91–102.

    Google Scholar 

  35. Albertazzi J, Florit F, Busini V, Rota R. Mixing efficiency and residence time distributions of a side-injection tubular reactor equipped with Static mixers. Ind Eng Chem Res. 2021;60(29):10595–602.

    Article  CAS  Google Scholar 

  36. Valdes JP, Kahouadji L, Liang F, Shin S, Chergui J, Juric D, Matar OK. Direct numerical simulations of liquid-liquid dispersions in a SMX mixer under different inlet conditions. Chem Eng J. 2023;462:142248.

    Article  CAS  Google Scholar 

  37. Zalc J, Szalai E, Muzzio F. Mixing dynamics in the SMX static mixer as a function of injection location and flow ratio. Polym Eng Sci. 2003;43(4):875–90.

    Article  CAS  Google Scholar 

  38. Zalc J, Szalai E, Muzzio F, Jaffer S. Characterization of flow and mixing in an SMX static mixer. AIChE J. 2002;48(3):427–36.

    Article  CAS  Google Scholar 

  39. Aman J, Duijvelaar E, Botros L, Kianzad A, Schippers JR, Smeele PJ, Azhang S, Bartelink IH, Bayoumy AA, Bet PM, Boersma W, Bonta PI, Boomars KAT, Bos LDJ, van Bragt J, Braunstahl GJ, Celant LR, Eger KAB, Geelhoed JJM, van Glabbeek YLE, Grotjohan HP, Hagens LA, Happe M, Hazes BD, Heunks LMA, van den Heuvel M, Hoefsloot W, Hoek RJA, Hoekstra R, Hofstee HMA, Juffermans NP, Kemper EM, Kos R, Kunst PWA, Lammers A, van der Lee I, van der Lee EL, Maitland-van der Zee AH, Mau Asam PFM, Mieras A, Muller M, Neefjes ECW, Nossent EJ, Oswald LMA, Overbeek MJ, Pamplona CC, Paternotte N, Pronk N, de Raaf MA, van Raaij BFM, Reijrink M, Schultz MJ, Serpa Neto A, Slob EMA, Smeenk F, Smit MR, Smits AJ, Stalenhoef JE, Tuinman PR, Vanhove A, Wessels JN, van Wezenbeek JCC, Vonk Noordegraaf A, de Man FS, Bogaard HJ. Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial. Lancet Respir Med. 2021;9(9):957-68.

  40. Strobelt R, Adler J, Paran N, Yahalom-Ronen Y, Melamed S, Politi B, Shulman Z, Schmiedel D, Shaul Y. Imatinib inhibits SARS-CoV-2 infection by an off-target-mechanism. Sci Rep. 2022;12(1):5758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lim J, Collins N, Singh R, Muzzio F. A Novel Continuous API Manufacturing Process for Emergency Pandemic Response. Oral presentation at IFPAC Annual Meeting, Maryland (Washington D.C.), USA, February 28 - March 5, 2021.

  42. Singh R, Lim J, Collins N, Muzzio F. A Digital Twin for API Manufacturing Process. Oral presentation at IFPAC Annual Meeting, Maryland (Washington D.C.), USA, February 28 - March 5, 2021.

  43. Edward JT. Molecular volumes and the Stokes-Einstein Equation. J Chem Educ. 1970;47(4):261.

    Article  CAS  Google Scholar 

  44. Constantin P, Foiaş C. Navier-Stokes Equations. Chicago, IL: University of Chicago Press; 1988.

    Book  Google Scholar 

  45. Perry JH. Chemical Engineers’ Handbook. New York, NY: McGraw-Hill Book Co.; 1950.

    Book  Google Scholar 

  46. Lee MH, Kim CM, Park GY, Choi CH, Park CY. Grid independence test of computational fluid dynamics model for indoor airflow analysis. J Korean Inst Archit Sustain Environ Build Syst. 2020;14(2):183–94.

    Google Scholar 

  47. Latché J-C, Piar B, Saleh K. A discrete kinetic energy preserving convection operator for variable density flows on locally refined staggered meshes. 2019. Retrieved from HAL open science: ⟨hal-02391939⟩.

  48. Dailey LD, Jennions IK, Orkwis PD. Simulation of laminar-turbulent transition with an explicit Navier-Stokes flow solver. J Propul Power. 1995;11:1187–94.

    Article  Google Scholar 

  49. Singh S. k–ɛ modeling using modified nodal integral method. Nucl Eng Des. 2009;239(7):1314–22.

    Article  CAS  Google Scholar 

  50. Theron F, Le Sauze N, Ricard A. Turbulent liquid−liquid dispersion in Sulzer SMX mixer. Ind Eng Chem Res. 2010;49(2):623–32.

    Article  CAS  Google Scholar 

  51. Brewster RA. A Rational Friction Factor Correlation for Laminar Fully Developed Pipe Flows of Shear-Thinning Non-Newtonian Fluids. J Fluids Eng. 2022;144(1):014502.

    Article  CAS  Google Scholar 

  52. Pimenta TA, Campos JBLM. Friction losses of Newtonian and non-Newtonian fluids flowing in laminar regime in a helical coil. Exp Thermal Fluid Sci. 2012;36:194–204.

    Article  CAS  Google Scholar 

  53. Bohnet M, Kalbitz H, Nemeth J, Pazmany J (1990) Improvement of Forced Convection Heat Transfer by Using Static Mixers. In Proceedings of the International Heat Transfer Conference Digital Library; Begel House Inc.

  54. Shah NF, Kale DD. Pressure drop for laminar flow of non-Newtonian fluids in static mixers. Chem Eng Sci. 1991;46(8).

  55. Li H, Fasol C, Choplin L. Pressure drop of Newtonian and non-Newtonian fluids across a Sulzer SMX static mixer. Chem Eng Res Des. 1997;75(8):792–6.

    Article  CAS  Google Scholar 

  56. Adrover A, Cerbelli S, Giona M. On the interplay between advection and diffusion in closed laminar chaotic flows. J Phys Chem A. 2001;105:4908–16.

    Article  CAS  Google Scholar 

  57. Nyande BW, Mathew Thomas K, Lakerveld R. CFD analysis of a kenics static mixer with a low pressure drop under laminar flow conditions. Ind Eng Chem Res. 2021;60(14):5264–77.

    Article  CAS  Google Scholar 

  58. Gong B, Zhu XJ. Experimental study of turbulence properties in a SMX mixer. Adv Mater Res. 2012;516–517:900–5.

    Article  Google Scholar 

  59. Shi W. Numerical simulation for turbulence characteristic of the SMX static mixer. Contemporary Chemical Industry. 2011.

  60. Lindenberg C, Schoell J, Vicum L, Mazzotti M, Brozio J. Experimental characterization and multi-scale modeling of mixing in static mixers. Chem Eng Sci. 2008;63:4135–49.

    Article  CAS  Google Scholar 

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Funding

U.S. Food and Drug Administration, 75F40121C00106, Ravendra Singh

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Authors and Affiliations

  1. C-SOPS, Department of Chemical & Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA

    Athanasios Kritikos, Ravendra Singh, George Tsilomelekis & Fernando J. Muzzio

Authors
  1. Athanasios Kritikos
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  2. Ravendra Singh
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  3. George Tsilomelekis
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  4. Fernando J. Muzzio
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Corresponding author

Correspondence to Ravendra Singh.

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Appendix

Appendix

Nomenclature

Abbreviations

Variable

API

CFD

CoV

Active pharmaceutical ingredient

Computational fluid dynamics

Coefficient of variation

CSTR

Continuous stirred tank reactor

DMF

Dimethylformamide

NMP

N-Methyl-2-pyrrolidone

PFR

Plugged flow reactor

RTD

THF

Residence time distribution

Tetrahydrofuran

Symbol

Variable

Units

C

Concentration

mol/m3

D

Ds

Diameter

Diffusion coefficient

m

m2/s

F(t)

f

L

Re

Vo

Cumulative distribution function

Friction factor

Length

Reynolds

Velocity

(-)

(-)

m

(-)

m/s

T

ΔP

μ

ρ

Time

Pressure drops

Viscosity

Density

s

Pa

Pa*s

Kg/m3

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Kritikos, A., Singh, R., Tsilomelekis, G. et al. A Novel CFD Model of SMX Static Mixer Used in Advanced Continuous Manufacturing of Active Pharmaceutical Ingredients (API). J Pharm Innov 19, 14 (2024). https://doi.org/10.1007/s12247-024-09813-1

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