Pharmaceutical Research

, Volume 20, Issue 8, pp 1317–1322 | Cite as

Water-Oil Partition Profiling of Ionized Drug Molecules Using Cyclic Voltammetry and a 96-Well Microfilter Plate System

  • Sorina M. Ulmeanu
  • Henrik Jensen
  • Géraldine Bouchard
  • Pierre-Alain Carrupt
  • Hubert H. Girault


Purpose. A new experimental set-up for studying partitioning of ionizable drugs at the interface between two immiscible electrolyte solutions (ITIES) by amperometry is presented. The method is quite general, as it can be applied to any charged drug molecule.

Methods. The procedure is based on 96-well microfilter plates with microporous filters to support 96 organic liquid membranes. The new methodology is first validated using a series of tetra-alkylammonium ions and subsequently used to construct the ion partition diagrams of 3,5-N,N-tetramethylaniline and 2,4-dinitrophenol. The lipophilicity of these drugs was examined by potentiometry and cyclic voltammetry in the NPOE/water system.

Results. Cyclic voltammetry resulted in potential-pH profiles of the studied drugs. When the aqueous phase pKa is already known, the logPNPOEof lipophilic drugs could be determined using a very little amount of solvents and drugs. The values of the partition coefficients for the neutral forms agree well with those obtained by potentiometry.

Conclusions. The procedure based on commercially available 96-well microfilter plates is shown to be useful for determining logP of ionized drugs in a rapid and efficient way.

lipophilicity liquid membranes cyclic voltammetry 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    F. Reymond, G. Steyaert, P. A. Carrupt, B. Testa, and H. H. Girault. Ionic partition diagram: a potential-pH representation. J. Am. Chem. Soc. 118:11951-11957 (1996).Google Scholar
  2. 2.
    K. Arai. Electrochemical-behavior of drugs at immiscible oil-water interfaces. Bunseki Kugaku 451:41-53 (1996).Google Scholar
  3. 3.
    A. Avdeef, K. J. Box, J. E. A. Comer, C. Hibbert, and K. Y. Tam. pH-metric logP 10. Determination of liposomal membrane-water partition coefficients of ionizable drugs. Pharm. Res. 152:209-215 (1998).Google Scholar
  4. 4.
    D. A. Smith and H. van de Waterbeemd. Pharmacokinetics and metabolism in early drug discovery. Curr. Opin. Chem. Biol. 34:373-378 (1999).Google Scholar
  5. 5.
    A. Berthod, A. I. Allet, and M. Bully. Measurement of partition coefficients in waterless biphasic liquid systems by countercurrent chromatograpby. Anal. Chem. 683:431-436 (1996).Google Scholar
  6. 6.
    G. Caron, G. Steyaert, A. Pagliara, F. Reymond, P. Crivori, P. Gaillard, P. A. Carrupt, A. Avdeef, J. Comer, K. J. Box, H. H. Girault, and B. Testa. Structure-lipophilicity relationships of neutral and protonated #x0392-blockers Part I Intra-and intermolecular effects in isotropic solvent systems. Helv. Chim. Acta 828:1211-1222 (1999).Google Scholar
  7. 7.
    H. H. Girault. Charge transfer across liquid-liquid interfaces. Mod. Aspects Electrochem. 25:1-62 (1993).Google Scholar
  8. 8.
    F. Reymond, G. Steyaert, A. Pagliara, P. A. Carrupt, B. Testa, and H. H. Girault. Transfer Mechanism of Ionic Drugs: Piroxicam as a Agent Facilitating Proton Transfer. Helv. Chim. Acta 79:1651-1669 (1996).Google Scholar
  9. 9.
    F. Reymond, P. A. Carrupt, B. Testa, and H. H. Girault. Charge and delocalisation effects on the lipophilicity of protonable drugs. Chem. Eur. J. 51:39-47 (1999).Google Scholar
  10. 10.
    F. Reymond. Transfer mechanisms and lipophilicity of ionizable drugs. In Marcel Dekker (ed), Liquid Interfaces in Chemical, Biological, and Pharmaceutical Applications, New York, 2001, pp. 729-774.Google Scholar
  11. 11.
    M. Pourbaix. Atlas d'Equilibres Electrochimiques. Gautier-Villars, Paris, 1963.Google Scholar
  12. 12.
    M. H. Abraham, C. E. Green, and W. E. Acree. Correlation and prediction of the solubility of Buckminster-fullerene in organic solvents; estimation of some physicochemical properties. J. Chem. Soc.-Perkin Trans. 2:281-286 (2000).Google Scholar
  13. 13.
    A. Avdeef, J. E. A. Comer, and S. J. Thomson. Ph-Metric Log.3. Glass-electrode calibration in methanol water, applied to pK a determination of water-insoluble substances. Anal. Chem. 651:42-49 (1993).Google Scholar
  14. 14.
    K. Valko, C. M. Du, C. Bevan, D. P. Reynolds, and M. H. Abraham. Rapid method for the estimation of octanol/water partition coefficient (log P-oct) from gradient RP-HPLC retention and a hydrogen bond acidity term (Sigma alpha(H)(2)). Curr. Med. Chem. 89:1137-1146 (2001).Google Scholar
  15. 15.
    F. Wohnsland and B. Faller. High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes. J. Med. Chem. 446:923-930 (2001).Google Scholar
  16. 16.
    V. Gobry, S. Ulmeanu, F. Reymond, G. Bouchard, P. A. Carrupt, B. Testa, and H. H. Girault. Generalization of ionic partition diagrams to lipophilic compounds and to biphasic systems with variable phase volume ratios. J. Am. Chem. Soc. 123:10684-10690 (2001).Google Scholar
  17. 17.
    Z. Samec, J. Langmaier, and A. Trojanek. Polarization phenomena at the water/O-Nitrophenyl octyl ether interface. 1. Evaluation of the standard Gibbs energies of ion transfer from the solubility and voltammetric measurements. J. Electroanal. Chem. 4091-2:1-7 (1996).Google Scholar
  18. 18.
    M. H. Abraham, C. M. Du, and J. A. Platts. Lipophilicity of the nitrophenols. J. Org. Chem. 6521:7114-7118 (2000).Google Scholar
  19. 19.
    V. Chopineaux-Courtois, F. Reymond, G. Bouchard, P. A. Carrupt, B. Testa, and H. H. Girault. Effects of charge and intermolecular structure on the lipophilicity of nitrophenols. J. Am. Chem. Soc. 121:1743-1747 (1999).Google Scholar
  20. 20.
    S. Wilke and T. Zerihun. Standard Gibbs energies of ion transfer across the water vertical bar 2-nitrophenyl octyl ether interface. J. Electroanal. Chem. 5151-2:52-60 (2001).Google Scholar
  21. 21.
    S. M. Ulmeanu, H. Jensen, Z. Samec, G. Bouchard, P. A. Carrupt, and H. H. Girault. Cyclic voltammetry of highly hydrophilic ions at a supported liquid membrane. J. Electroanal. Chem. 530:10-15 (2002).Google Scholar
  22. 22.
    G. Bouchard, P. A. Carrupt, B. Testa, V. Gobry, and H. H. Girault. Lipophilicity and solvation of anionic drugs. Chem. 815:3478-3484 (2002).Google Scholar
  23. 23.
    H. H. Girault and D. J. Schiffrin. Electrochemistry of liquid/liquid interfaces. Electroanal. Chem. 15:1-141 (1989).Google Scholar
  24. 24.
    H. Matsuda, Y. Yamada, K. Kanamori, Y. Kudo, and Y. Takeda. On the facilitation effect of neutral macrocyclic ligands on the ion transfer across the interface between aqueous and organic solutions.1. theoretical equation of ion-transfer-polarographic current-potential curves and its experimental-verification. Bull. Chem. Soc. Jpn. 645:1497-1508 (1991).Google Scholar
  25. 25.
    M. Senda, Y. Kubota, and H. Katano. Voltammetric Study of Drugs at Liquid-Liquid Interfaces. Marcel Dekker, New York, 2001.Google Scholar
  26. 26.
    T. Ohkouchi, T. Kakutani, and M. Senda. Electrochemical Study of the Transfer of Uncouplers across the Organic Aqueous Interface. Bioelectrochem. Bioenergetics 251:71-80 (1991).Google Scholar
  27. 27.
    T. B. Stolwijk, E. J. R. Sudholter, and D. N. Reinhoudt. Effect of crown ether lipophilicity on the facilitated transport of guanidinium thiocyanate through an immobilized liquid membrane. J. Am. Chem. Soc. 11116:6321-6329 (1989).Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Sorina M. Ulmeanu
    • 1
  • Henrik Jensen
    • 1
  • Géraldine Bouchard
    • 2
  • Pierre-Alain Carrupt
    • 2
  • Hubert H. Girault
    • 1
  1. 1.Laboratoire d'Electrochimie Physique et AnalytiqueEcole Polytechnique Fédérale de LausanneLausanneSwitzerland
  2. 2.Institut de Chimie ThérapeutiqueUniversité de LausanneLausanneSwitzerland

Personalised recommendations