Pharmaceutical Research

, Volume 27, Issue 2, pp 246–258 | Cite as

Hydrodynamic and Species Transfer Simulations in the USP 4 Dissolution Apparatus: Considerations for Dissolution in a Low Velocity Pulsing Flow

  • Deirdre M. D’Arcy
  • Bo Liu
  • Geoff Bradley
  • Anne Marie Healy
  • Owen I. Corrigan
Research Paper



To simulate the hydrodynamics in the flow-through (USP 4) dissolution apparatus and investigate the effects of hydrodynamics on mass transfer in a low velocity pulsing flow.


Computational fluid dynamics (CFD) was used to simulate the hydrodynamics and mass transfer in pulsing flow. Experimental flow visualisation was used to qualitatively confirm simulated hydrodynamic and mass transfer features. The experimental dissolution rate at 8 ml min−1 (22.6 mm flow-through cell) was compared to the experimental dissolution rate in a free convection system.


Simulations revealed periods of low velocity at all flow rates, evidence of boundary layer separation, and, at higher flow rates, residual fluid motion during zero inlet velocity periods. The simulated diffusion boundary layer thickness varied in certain regions over the course of the pulse. The experimental dissolution rate in the free convection system was faster than that at 8 ml min−1 in the flow-through apparatus.


A low velocity pulsing flow running counter to gravity inhibited the experimental dissolution rate compared to that in a free convection system. From the CFD simulations generated, simulation of both hydrodynamics and species transfer is recommended to characterise the influence of hydrodynamics on dissolution in a low velocity pulsing flow.

Key Words

computational fluid dynamics (CFD) dissolution flow-through dissolution apparatus (USP apparatus 4) flow visualisation hydrodynamics 



Computational Fluid Dynamics




sodium hydroxide


parts per million


revolutions per minute




United States Pharmacopeia

Supplementary material

11095_2009_10_MOESM1_ESM.mpeg (4.5 mb)
Animation 1Animation of CFD simulation of pulsing flow, at 17 ml min−1, through the 12 mm diameter cell. The model consists of one quarter of the cell and one quarter of a disk of the same dimensions as the compact used in the flow visualisation studies. Residual fluid movement near the top of the compact during the “zero inflow velocity” period is clearly evident. The animation is not presented in real time. Vectors are coloured by velocity magnitude. (MPEG 4654 kb)
11095_2009_10_MOESM2_ESM.gif (4.4 mb)
Animation 2Animation of contours coloured by mass fraction of species (representing salicylic acid proportional concentration) in the 12 mm diameter cell at 17 ml min−1 over the course of two pulses. (GIF 4488 kb)
Flow visualisation video

Video of pulsing flow in the 12 mm diameter cell at 17 ml min−1 flow rate. Flow is visualised by the pink colour of the phenolphthalein contained in the salicylic acid/phenolphathalein tablet when released into the alkaline medium (0.02 M NaOH ) as the tablet dissolves. (MPEG 2232 kb)


  1. 1.
    Butler WCG, Bateman SR. A flow-through dissolution method for a two component drug formulation where the actives have markedly differing solubility properties. Int J Pharm. 1998;173:211–9.CrossRefGoogle Scholar
  2. 2.
    Phillips JG, Chen Y, Wakeling IN. A flow-through dissolution approach to in vivo/in vitro correlation of adinazolam release from sustained release formulations. Drug Dev Ind Pharm. 1989;15:2177–95.CrossRefGoogle Scholar
  3. 3.
    Wu Y, Ghaly ES. Effect of hydrodynamic environment on tablet dissolution using flow-through dissolution apparatus. Puerto Rico Health Sciences Journal. 2006;25:75–83.PubMedGoogle Scholar
  4. 4.
    Sunesen VH, Pedersen BL, Kristensen HG, Müllertz A. In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media. Eur J Pharm Sci. 2005;24:305–13.CrossRefPubMedGoogle Scholar
  5. 5.
    Stevens LE, Missel PJ. Impact of density gradients on flow-through dissolution in a cylindrical flow cell. Pharm Dev Technol. 2006;11:529–34.CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang GH, Vadino WA, Yang TT, Cho WP, Chaudry IA. Evaluation of the flow-through cell dissolution apparatus: effects of flow rate, glass beads and tablet position on drug release from different type of tablets. Drug Dev Ind Pharm. 1994;20:2063–78.CrossRefGoogle Scholar
  7. 7.
    Graffner C, Särkelä M, Gjellan K, Nork G. Use of statistical experimental design in the further development of a discriminating in vitro release test for ethyl cellulose ER-coated spheres of remoxipride. Eur J Pharm Sci. 1996;4:73–83.CrossRefGoogle Scholar
  8. 8.
    Cammarn SR, Sakr A. Predicting dissolution via hydrodynamics: salicylic acid tablets in flow through cell dissolution. Int J Pharm. 2000;201:199–209.CrossRefPubMedGoogle Scholar
  9. 9.
    Bhattachar SN, Wesley JA, Fioritto A, Martin PJ, Babu SR. Dissolution testing of a poorly soluble compound using the flow-through cell dissolution apparatus. Int J Pharm. 2002;236:135–43.CrossRefPubMedGoogle Scholar
  10. 10.
    Hurtado y de la Peña M, Vargas Alvarado Y, Domínguez-Ramírez AM, Cortés Arroyo AR. Comparison of dissolution profiles for albendazole tablets using USP apparatus 2 and 4. Drug Dev Ind Pharm. 2003;29:777–84.CrossRefPubMedGoogle Scholar
  11. 11.
    United States Pharmacopeia 32, United States Pharmacopeial Convention, Rockwell, MD, USA; 2009.Google Scholar
  12. 12.
    Guidance for industry: Dissolution testing of immediate release solid oral dosage forms, Centre for Drug Evaluation and Reseach, Food and Drug Administration,U.S. Department of Health and Human Services; 1997.Google Scholar
  13. 13.
    Guidance for Industry: Bioavailability and bioequivalence studies for orally administered drug products—General considerations, Center for Drug Evaluation and Research, Food and Drug Administration, U.S. Department of Health and Human Services; 2003.Google Scholar
  14. 14.
    McCarthy LG, Kosiol C, Healy AM, Bradley G, Sexton JC, Corrigan OI. Simulating the hydrodynamic conditions in the United States Pharmacopeia paddle dissolution apparatus. AAPS PharmSciTech 2003; Vol. 4 Article 22.Google Scholar
  15. 15.
    McCarthy LG, Bradley G, Sexton JC, Corrigan OI, Healy AM. Computational fluid dynamics modeling of the paddle dissolution apparatus: agitation rate, mixing patterns and fluid velocities. AAPS PharmSciTech 2004; Vol. 5 Article 31.Google Scholar
  16. 16.
    Kukura J, Arratia PE, Szalai ES, Muzzio FJ. Engineering tools for understanding the hydrodynamics of dissolution tests. Drug Dev Ind Pharm. 2003;29:231–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Kukura J, Baxter JL, Muzzio FJ. Shear distribution and variability in the USP apparatus 2 under turbulent conditions. Int J Pharm. 2004;279:9–17.CrossRefPubMedGoogle Scholar
  18. 18.
    D’Arcy DM, Corrigan OI, Healy AM. Evaluation of hydrodynamics in the basket dissolution apparatus using computational fluid dynamics—dissolution rate implications. Eur J Pharm Sci. 2006;27:259–67.CrossRefPubMedGoogle Scholar
  19. 19.
    Bai G, Armenante P. Hydrodynamic, mass transfer, and dissolution effects induced by tablet location during dissolution testing. J Pharm Sci 2009;98:1511–31Google Scholar
  20. 20.
    D’Arcy DM, Corrigan OI, Healy AM. Hydrodynamic simulation (computational fluid dynamics) of asymmetrically positioned tablets in the paddle dissolution apparatus: impact on dissolution rate and variability. J Pharm Pharmacol. 2005;57:1243–50.CrossRefPubMedGoogle Scholar
  21. 21.
    Levich VG. Physicochemical hydrodynamics. Englewood Cliffs, N.J., U.S.A.: Prentice Hall Inc.; 1962.Google Scholar
  22. 22.
    Dokoumetzidis A, Papadopoulou V, Valsami G, Macheras P. Development of a reaction-limited model of dissolution: application to official dissolution tests experiments. Int J Pharm. 2008;355:114–25.CrossRefPubMedGoogle Scholar
  23. 23.
    Kakhi M. Classification of the flow regimes in the flow-through cell. Eur J Pharm Sci. 2009;37:531–44.CrossRefPubMedGoogle Scholar
  24. 24.
    Kakhi M. Mathematical modelling of the fluid dynamics in the flow-through cell. Int J Pharm. 2009;376:22–40.CrossRefPubMedGoogle Scholar
  25. 25.
    Stevens LE, Missel PJ, Weiner AL. Controlled flow-through dissolution methodology: a high-performance system. Pharm Dev Technol. 2008;13:135–53.CrossRefPubMedGoogle Scholar
  26. 26.
    Schiller C, Frölich C-P, Giessmann T, Siegmund W, Mönnikes H, Hosten N, et al. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2005;22:971–9.CrossRefPubMedGoogle Scholar
  27. 27.
    D’Arcy DM, Liu B, O’Dwyer R, Bradley G, Corrigan OI. Dissolution in the flow-through apparatus—use of computational fluid dynamics (CFD) to investigate hydrodynamic effects. AAPS Journal 2008;10 (S2).Google Scholar
  28. 28.
    Mauger J, Ballard J, Brockson R, De S, Gray V, Robinson D. Intrinsic dissolution performance testing of the USP dissolution apparatus 2 (rotating paddle) using modified salicylic acid calibrator tablets: proof of principle. Dissolution Technologies 2003; August:6–15.Google Scholar
  29. 29.
    Goldberg AH, Higuchi WI. Improved method for diffusion coefficient determinations employing the silver membrane filter. J Pharm Sci. 1968;57:1583–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Patrick MA, Wragg AA, Pargeter DM. Mass transfer by free convection during electrolysis at inclined electrodes. Can J Chem Eng. 1977;55:432–8.CrossRefGoogle Scholar
  31. 31.
    Jantratid E, Janssen N, Reppas C, Dressman JB. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update. Pharm Res. 2008;25:1663–76.CrossRefPubMedGoogle Scholar
  32. 32.
    D’Arcy DM, Healy AM, Corrigan OI. Towards determining appropriate hydrodynamic conditions for in vitro in vivo correlations using computational fluid dynamics. Eur J Pharm Sci. 2009;37:291–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Bradshaw LA, Irimia A, Sims JA, Gallucci MR, Palmer RL, Richards WO. Biomagnetic characterization of spactiotemporal parameters of the gastric slow wave. Neurogastroenterol Motil. 2006;18:619–31.CrossRefPubMedGoogle Scholar
  34. 34.
    Pal A, Indireshkumar K, Schwizer W, Abrahamsson B, Fried M, Brasseur JG. Gastric flow and mixing studied using computer simulation. Proc R Soc Lond, B, Biol Sci. 2004;271:2587–94.CrossRefGoogle Scholar
  35. 35.
    Garbacz G, Wedemeyer R-S, Nagel S, Giessmann T, Mönnikes H, Wilson CG, et al. Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses. Eur J Pharm Biopharm. 2008;70:421–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Perng C-Y, Kearney AS, Palepu NR, Smith BR, Azzarano LM. Assessment of oral bioavailability enhancing approaches for SB-247083 using flow-through cell dissolution testing as one of the screens. Int J Pharm. 2003;250:147–56.CrossRefPubMedGoogle Scholar
  37. 37.
    Motz SA, Schaefer UF, Balbach S, Eichinger T, Lehr C-M. Permeability assessment for solid oral drug formulations based on Caco-2 monolayer in combination with a flow through dissolution cell. Eur J Pharm Biopharm. 2007;66:286–95.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Deirdre M. D’Arcy
    • 1
  • Bo Liu
    • 1
  • Geoff Bradley
    • 2
  • Anne Marie Healy
    • 1
  • Owen I. Corrigan
    • 1
  1. 1.School of Pharmacy and Pharmaceutical SciencesTrinity College DublinDublin 2Ireland
  2. 2.Trinity Centre for High Performance ComputingTrinity College DublinDublin 2Ireland

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