AAPS PharmSci

, 1:27 | Cite as

Prediction of dissolution-absorption relationships from a continuous dissolution/Caco-2 system

  • Mark J. Ginski
  • Rajneesh Taneja
  • James E. Polli


The objectives were 1) to design a continuous dissolution Caco-2 system to predict the dissolution-absorption relationships for fast and slow dissolving formulations of piroxicam, metoprolol tartrate, and ranitidine HCl, and compare the predicted relationships with observed relationships from clinical studies; 2) to estimate the effect of croscarmellose sodium on ranitidine dissolution-absorption relationships; and 3) to estimate the effect of solubilizing agents on piroxicam dissolution-absorption relationships. A continuous dissolution/Caco-2 system was constructed from a dissolution apparatus and a diffusion cell, such that drug dissolution and permeation across a Caco-2 monolayer would occur sequentially and simultaneously. The continuous system generally matched observed dissolution-absorption relationships from clinical studies. For example, the system successfully predicted the slow metoprolol and slow ranitidiine formulations to be permeation-rate-limited. The system predicted the slow piroxicam formulation to be dissolution-rate-limited, and the fast piroxicam formulation to be permeation-rate-limited, in spite of piroxicam’s high permeability and low solubility. Additionally, the system indicated croscarmellose sodium enhanced ranitidine permeability and predicted solubilizing agents to not modulate permeability. These results suggest a dissolution/Caco-2 system to be an experimentally based tool that may predict dissolution-absorption relationships from oral solid dosage forms, and hence the relative contributions of dissolution and permeation to oral drug absorption kinetics.


Ranitidine Piroxicam Continuous System Sodium Lauryl Sulfate Solubilizing Agent 
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  1. 1.
    Ginski MJ, Polli JE. Prediction of dissolution-absorption relationships from a dissolution/Caco-2 system. Int J Pharm. 1998;177:117–125.CrossRefGoogle Scholar
  2. 2.
    Piscitelli DA, Bigora S, Propst C, et al. The impact of formulation and process changes in vitro dissolution and the bioequivalence of piroxicam capsules. Pharm Dev Technol. 1998;3:443–452.PubMedCrossRefGoogle Scholar
  3. 3.
    Rekhi GS, Eddington NE, Fossler MJ, Schwartz P, Lesko LJ, Augsburger LL. Evaluation of in vitro release rate and in vivo absorption characteristics of four metoprolol tartrate immediate-release tablet formulations. Pharm Dev Technol. 1997;2:11–24.PubMedCrossRefGoogle Scholar
  4. 4.
    Goskonda S, Propst C, Augsburger LL, Schwartz P, Lesko LJ. Investigating the influence of formulation and process variables on the performance of ranitidine HCl tablets. Pharm Res. 1994;11:S-163.Google Scholar
  5. 5.
    Piscitelli DA, McGlone Dalby J, Augsburger LL, Shah VP, Lesko LJ, Young D. The effect of formulation (FM), process (P) and batch size (BS) on the oral bioavailability of ranitidine (R) tablets. Pharm Res 1995;12:S-417.Google Scholar
  6. 6.
    United States Pharmacopeia XXIII. Rockville, MD: US Pharmacopeial Convention. 1994.Google Scholar
  7. 7.
    Dressman JB, Amidon GL, Fleisher D. Absorption potential estimating the fraction absorbed for orally administered compounds J Pharm Sci. 1985;74:588–589.PubMedCrossRefGoogle Scholar
  8. 8.
    Polli JE, Crison JR, Amidon GL. Novel approach to the analysis of in vitro-in vivo relationships. J Pharm Sci. 1996;85:753–760.PubMedCrossRefGoogle Scholar
  9. 9.
    Polli JE, Rekhi GS, Augsburger LL, Shah VP. Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets. J Pharm Sci. 1997;86:690–700.PubMedCrossRefGoogle Scholar
  10. 10.
    Polli JE, Ginski MJ. Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities. Pharm Res. 1998;15:48–53.CrossRefGoogle Scholar
  11. 11.
    Lennernas H, Palm K, Fagerholm U, Artursson P. Comparison between active and passive flux transport in human intestinal epithelial (Caco-2) cells in vitro and human jejunum in vivo. Int J Pharm. 1996;127:103–107.CrossRefGoogle Scholar
  12. 12.
    Lennernas H. Human intestinal permeability. J Pharm Sci. 1998;87:403–410.PubMedCrossRefGoogle Scholar
  13. 13.
    Takamatsu N, Welage LS, Idkaidak NM, et al. Human intestinal permeability of piroxicam, propanolol, phenylalanine, and PEG 400 determined by jejunal perfusion. Pharm Res. 1997;14:1127–1132.PubMedCrossRefGoogle Scholar
  14. 14.
    Gan LS, Hsyu PH, Pritchard JF, Thakker D. Mechanism of intestinal absorption of ranitidine and ondansetron transport across Caco-2 cell monolayers. Pharm Res. 1993;10:1722–1725.PubMedCrossRefGoogle Scholar
  15. 15.
    Anderson JM, Van Itallie CM. Tight junctions and the molecular basis for regulation of paracellular permeability. Am J Physiol. 1995;269:G467-G475.PubMedGoogle Scholar
  16. 16.
    Denker BM, Nigam SK. Molecular structure and assembly of the tight junction. Am J Physiol. 1998;274:F1-F9.PubMedGoogle Scholar
  17. 17.
    Hollenbeck RG, Mitrevej KT, Fan AC. Estimation of the extent of drug-excipient interactions involving croscarmellose sodium. J Pharm Sci. 1983;72:325–327.PubMedCrossRefGoogle Scholar
  18. 18.
    Hollenbeck RG. Bioavailability of phenylpropanolamine HCl from tablet dosage forms containing croscarmellose sodium. Int J Pharm. 1988;47:89–93.CrossRefGoogle Scholar
  19. 19.
    Newton JM, Razzo FN. The influence of additives on the presentation of a drug in hard gelatin capsules. J Pharm Pharmacol. 1977;29:294–297.PubMedCrossRefGoogle Scholar
  20. 20.
    Corrigan OI, Stanley CT. Dissolution properties of phenobarbitone-β-cyclodextrin systems. Pharm Acta Helv. 1981;56:204–208.Google Scholar
  21. 21.
    El-Arini SK, Leuenberger H. Dissolution properties of praziquantel-β-cyclodextrin systems. Pharm Dev Tech 1996;1:307–315.CrossRefGoogle Scholar
  22. 22.
    Anderberg EK, Arturrson P. Epithelial transport of drugs in cell culture. VIII: Effects of sodium dodecyl sulfate on cell membrane and tight junction permeability in human intestinal epithelial (Caco-2) cells. J Pharm Sci. 1993;82:392–398.PubMedCrossRefGoogle Scholar
  23. 23.
    Hovgaard L, Brondstad H. Drug delivery studies in Caco-2 monolayers. IV. Absorption enhancer effects of cyclodextrins. Pharm Res. 1995;12:1328–1332.PubMedCrossRefGoogle Scholar
  24. 24.
    Marttin E, Verhoef JC, Merkus FW. Efficacy, safety and mechanism of cyclodextrins as absorption enhancers in nasal delivery of peptide and protein drugs. J Drug Target. 1998;6:17–36.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 1999

Authors and Affiliations

  • Mark J. Ginski
    • 1
  • Rajneesh Taneja
    • 1
  • James E. Polli
    • 1
  1. 1.School of PharmacyUniversity of MarylandBaltimore

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