Pharmaceutical Research

, Volume 25, Issue 1, pp 147–157 | Cite as

Predicting the Solubility of the Anti-Cancer Agent Docetaxel in Small Molecule Excipients using Computational Methods

  • Loan Huynh
  • Justin Grant
  • Jean-Christophe Leroux
  • Pascal Delmas
  • Christine Allen
Research Paper



To develop an in silico model that provides an accurate prediction of the relative solubility of the lipophilic anticancer agent docetaxel in various excipients.

Materials and Methods

The in silico solubility of docetaxel in the excipients was estimated by means of the solubility (δ) and Flory-Huggins interaction (χ FH) parameters. The δ values of docetaxel and excipients were calculated using semi-empirical methods and molecular dynamics (MD) simulations. Cerius2 software and COMPASS force-field were employed for the MD simulations. The χ FH values for the binary mixtures of docetaxel and excipient were also estimated by MD simulations.


The values obtained from the MD simulations for the solubility of docetaxel in the various excipients were in good agreement with the experimentally determined values. The simulated values for solubility of docetaxel in tributyrin, tricaproin and vitamin E were within 2 to 6% of the experimental values. MD simulations predicted docetaxel to be insoluble in β-caryophyllene and this result correlated well with experimental studies.


The MD model proved to be a reliable tool for selecting suitable excipients for the solubilization of docetaxel.

Key words

docetaxel excipients Flory-Huggins interaction parameter molecular dynamics simulations solubility parameters 



The authors are grateful to Natural Sciences and Engineering Research Council (NSERC) for funding this research.

Supplementary material

11095_2007_9412_MOESM1_ESM.doc (78 kb)
ESM 1 (DOC 78.0 KB)


  1. 1.
    S. W. Yi, Y.-H. Kim, I. C. Kwon, J. W. Chung, J. H. Park, Y. W. Choi, and S. Y. Jeong. Stable Lipiodolized emulsions for hepatoma targeting and treatment by transarterial chemoembolization. J. Control. Release 50:135–143 (1998).PubMedCrossRefGoogle Scholar
  2. 2.
    I.-H. Lee, Y. T. Park, K. Roh, H. Chung, I. C. Kwon, and S. Y. Jeong. Stable paclitaxel formulations in oily contrast medium. J. Control. Release 102:415–425 (2005).PubMedCrossRefGoogle Scholar
  3. 3.
    R. G. Strickley. Solubilizing Excipients in Oral and Injectable Formulations. Pharm. Res. 21:201–230 (2004).PubMedCrossRefGoogle Scholar
  4. 4.
    M. N. Khalid, P. Simard, D. Hoarau, A. Dragomir, and J.-C. Leroux. Long circulating poly(ethylene glycol)-decorated lipid nanocapsules deliver docetaxel to solid tumors. Pharm. Res. 23:752–758 (2006).PubMedCrossRefGoogle Scholar
  5. 5.
    P. Kan, Z.-B. Chen, C.-J. Lee, and I.-M. Chu. Development of nonionic surfactant/phospholipid o/w emulsion as a paclitaxel delivery system. J. Control. Release 58:271–278 (1999).PubMedCrossRefGoogle Scholar
  6. 6.
    J. G. Wenzel, K. S. Balaji, K. Koushik, C. Navarre, S. H. Duran, C. H. Rahe, and U. B. Kompella. Pluronic F127 gel formulations of deslorelin and GnRH reduce drug degradation and sustain drug release and effect in cattle. J. Control. Release 85:51–59 (2002).PubMedCrossRefGoogle Scholar
  7. 7.
    C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23:3–25 (1997).CrossRefGoogle Scholar
  8. 8.
    M. E. Aulton. Pharmaceutics: The Science of Dosage Form Design 2nd ed.; Elsevier Science Limited: Churchill Livingstone, 2002.Google Scholar
  9. 9.
    M. Kreilgaard. Influence of microemulsions on cutaneous drug delivery. Adv. Drug Deliv. Rev. 54:S77–S98 (2002).PubMedCrossRefGoogle Scholar
  10. 10.
    N. S. Bhattachar, L. A. Deschenes, and J. A. Wesley. Solubility: it's not just for physical chemists. Drug Discov. Today 11:1012–1018 (2006).PubMedCrossRefGoogle Scholar
  11. 11.
    B. E. Eichinger, D. Rigby, and J. Stein. Cohesive properties of Ultem and related molecules from simulations. Polymer 43:599–607 (2002).CrossRefGoogle Scholar
  12. 12.
    S. S. Patnaik, and R. Pachter. A molecular simulations study of the miscibility in binary mixtures of polymers and low molecular weight molecules. Polymer 43:415–424 (2002).CrossRefGoogle Scholar
  13. 13.
    J. Ennari, L.-O. Pietilä, V. Virkkunen, and F. Sundholm. Molecular dynamics simulation of the structure of an ion-conducting PEO-based solid polymer electrolyte. Polymer 43:5427–5438 (2002).CrossRefGoogle Scholar
  14. 14.
    T. Li, D. O. Kildsig, and K. Park. Computer simulation of molecular diffusion in amorphous polymers. J. Control. Release 48:57–66 (1997).CrossRefGoogle Scholar
  15. 15.
    J. H. Poupaert, and P. Couvreur. A computationally derived structural model of doxorubicin interacting with oligomeric polyalkylcyanoacrylate in nanoparticles. J. Control. Release 92:19–26 (2003).PubMedCrossRefGoogle Scholar
  16. 16.
    T. Spyriouni, and C. Vergelati. A molecular modeling study of binary blend compatibility of polyamide 6 and poly(vinyl acetate) with different degrees of hydrolysis: an atomistic and mesoscopic approach. Macromolecules 34:5306–5316 (2001).CrossRefGoogle Scholar
  17. 17.
    M. Zhang, P. Choi, and U. Sundararaj. Molecular dynamics and thermal analysis study of anomalous thermodynamic behavior of poly (etherimide)/polycarbonate blends. Polymer 44:1979–1986 (2003).CrossRefGoogle Scholar
  18. 18.
    S. H. Jacobson. Molecular modeling studies of polymeric transdermal adhesives: structure and transport mechanisms. Pharmaceutical Technology 23:122–130 (1999).Google Scholar
  19. 19.
    Y.-M. Lam, G. Goldbeck-Wood, and C. Boothroyd. Mesoscale Simulation and cryo-TEM of Nanoscale Drug Delivery Systems. Molecular Simulation 30:239–247 (2004).CrossRefGoogle Scholar
  20. 20.
    G. Srinivas, D. E. Discher, and M. L. Klein. Self-assembly and properties of diblock copolymers by coarse grain molecular dynamics. Nature Materials 3:638–644 (2004).PubMedCrossRefGoogle Scholar
  21. 21.
    G. Srinivas, and M. L. Klein. Coarse-grain molecular dynamics simulations of diblock copolymer surfactants interacting with a lipid bilayer. Molec. Phys. 102:883–889 (2004).CrossRefGoogle Scholar
  22. 22.
    D. Pavel, and J. Lagowski. Computationally designed monomers and polymers for molecular imprinting of theophylline and its derivatives. Polymer 46:7528–7542 (2005).CrossRefGoogle Scholar
  23. 23.
    O. Pradier, M. Rave-Fränk, J. Lehmann, E. Lücke, O. Boghun, C.-F. Hess, and H. Schmidberger. Effects of docetaxel in combination with radiation on human head and neck cancer cells (ZMK-1) and cervical squamous cell carcinoma cells (CASKI). Int. J. Cancer 91:840–845 (2001).PubMedCrossRefGoogle Scholar
  24. 24.
    J. E. Cortes, and R. Pazdur. Docetaxel. J. Clin. Oncol. 13:2643–2655 (1995).PubMedGoogle Scholar
  25. 25.
    E. K. Rowinsky, and R. C. Donehower. Drug therapy: paclitaxel (Taxol). N. Engl. J. Med. 332:1004–1014 (1995).PubMedCrossRefGoogle Scholar
  26. 26.
    U.S. Food and Drug Administration, date of access: May 2007,
  27. 27.
    U.S. Food and Drug Administration, date of access: May 2007,
  28. 28.
    U.S. Food and Drug Administration, date of access: May 2007,
  29. 29.
    U.S. Food and Drug Administration, date of access: May 2007,
  30. 30.
    U.S. Food and Drug Administration, date of access: May 2007,
  31. 31.
    J. H. Hildebrand, and R. L. Scott. The Solubility of Nonelectrolytes, 3rd ed., Reinhold Publishing Corporation, New York, 1950.Google Scholar
  32. 32.
    W. Blokzij, and J. B. F. N. Engberts. Hydrophobic effects. Opinions and facts. Angew. Chem. Int. Ed. Engl. 32:1545–1579 (1993).CrossRefGoogle Scholar
  33. 33.
    M. H. Abraham. Scales of solute hydrogen-bonding: their construction and application to physicochemical and biochemical processes. Chem. Soc. Rev. 22:73–83 (1993).CrossRefGoogle Scholar
  34. 34.
    R. F. Fedors. A method for estimating both the solubility parameters and molar volumes of liquids. Polym. Eng. Sci. 14:147–154 (1974).CrossRefGoogle Scholar
  35. 35.
    E. Ruckenstein, and I. Shulgin. Solubility of drugs in aqueous solutions. Part 1. Ideal mixed solvent approximation. Int. J. Pharm. 258:193–201 (2003).PubMedCrossRefGoogle Scholar
  36. 36.
    Accelrys Software Inc., Cerius2 Simulation & Prediction, Release 4.6, San Diego: Accelrys Software Inc., 2001.Google Scholar
  37. 37.
    T. Higuchi, and K. A. Connors. Phase-solubility techniques. Advan. Anal. Chem. Instr. 4:117–212 (1965).Google Scholar
  38. 38.
    H. van der Waterbeemd, H. Lennernäs, P. Artursson. Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability. Wiley VCH Verlag GmbH & Co. KGaA, Weinheim, 2003, Chapters 1 and 6.Google Scholar
  39. 39.
    M. M. A. Omari, M. B. Zughul, J. E. D. Davies, and A. A. Badwan. Thermodynamic enthalpy–entropy compensation effects observed in the complexation of basic drug substrates with β-cyclodextrin. J. Incl. Phenom. Macrocycl. Chem. 57:379–384 (2007).CrossRefGoogle Scholar
  40. 40.
    K. G. H. Desain, and H. J. Park. Solubility studies on valdecoxib in the presence of carriers, cosolvents, and surfactants. Drug Dev. Res. 62:41–48 (2004).CrossRefGoogle Scholar
  41. 41.
    R. Singh, M. Ajagbe, S. Bhamidipati, Z. Ahmad, and I. Ahmad. A rapid isocratic high-performance liquid chromatography method for determination of cholesterol and 1,2-dioleoyl-sn-glycero-3-phosphocholine in liposome-based drug formulations. J. Chromatogr. A 1073:347–353 (2005).CrossRefGoogle Scholar
  42. 42.
    B. Vaisman, A. Shikanov, A. J. Domb. Normal phase high performance liquid chromatography for determination of paclitaxel incorporated in a lipophilic polymer matrix. J. Chromatogr. A 1064:85–95 (2005).PubMedCrossRefGoogle Scholar
  43. 43.
    S. K. Tahir, M. A. Nukkala, N. A. Z. Mozny, R. B. Credo, R. B. Warner, Q. Li, K. W. Woods, A. Claiborne, S. L. Gwaltney, D. J. Frost, H. L. Sham, S. H. Rosenberg, and S.-C. Ng. Biological activity of A-289099: an orally active tubulin-binding indolyloxazoline derivative. Mol. Cancer Ther. 2:227–233 (2003).PubMedGoogle Scholar
  44. 44.
    D. W. van Krevelen. Properties of Polymers. 3rd ed.; Elsevier Scientific Pub. Co.: New York, 1990.Google Scholar
  45. 45.
    M. Waldman, and A. T. Hagler. New combining rules for rare gas van der waals parameters. J. Comput. Chem. 14:1077–1084 (1993).CrossRefGoogle Scholar
  46. 46.
    P. Gestoso, and J. Brisson. Towards the simulation of poly(vinyl phenol)/poly(vinyl methyl ether) blends by atomistic molecular modelling. Polymer 44:2321–2329 (2003).CrossRefGoogle Scholar
  47. 47.
    J. A. Mason, and L. H. Sperling. Polymer Blends and Composites; Plenum Press: New York, 1976.Google Scholar
  48. 48.
    J. A. McCammon. Dynamics of Proteins and Nucleic Acids; Press Syndicated of the University of Cambridge: New York, 1989; pp. 60–65.Google Scholar
  49. 49.
    M. P. Allen, and D. J. Tildesley. Computer Simulation of Liquids; Claredon Press Oxford, 1987.Google Scholar
  50. 50.
    H. Sun. COMPASS: An ab Initio Force Field optimized for condensed-phase applications-overview with details on alkane and benzene compounds. J. Phys. Chem. B 102:7338–7364 (1998).CrossRefGoogle Scholar
  51. 51.
    D. Rigby, H. Sun, and B. E. Eichinger. Computer simulations of poly(ethylene oxide): force field, PVT diagram and cyclization behavior. Polym. Inter. 44:311–330 (1997).CrossRefGoogle Scholar
  52. 52.
    M. J. Hwang, T. P. Stockfisch, and A. T. Hagler. Derivation of class II force fields. 2. Derivation and characterization of a class II force field, CFF93, for the alkyl functional group and alkane molecules. J. Am. Chem. Soc. 116:2515–2525 (1994).CrossRefGoogle Scholar
  53. 53.
    J. M. G. Cowie. Polymers: Chemistry and Physics of Modern Materials, 2nd ed.; Nelson Thornes Ltd.: Cheltenham, 1991, Chapter 8.Google Scholar
  54. 54.
    C. F. Fan, B. D. Olafson, and M. Blanco. Application of molecular simulation to derive phase diagrams of binary mixtures. Macromolecules 25:3667–3676 (1992).CrossRefGoogle Scholar
  55. 55.
    F. H. Case, and J. D. Honeycutt. Will my polymers mix? - Applications for modeling to study miscibility, compatibility and formulation. TRIP 2:256 (1994).Google Scholar
  56. 56.
    P. J. Flory. Principles of Polymer Chemistry; Cornell University Press: Ithaca, New York, 1953.Google Scholar
  57. 57.
    D. Merino-Garcia, and S. Correra. A shortcut application of a Flory-like model to asphaltene precipitation. J. Dispersion Sci. Technol. 28:339–347 (2007).CrossRefGoogle Scholar
  58. 58.
    P. Bahadur, and N. V. Sastry. Principles of Polymer Science, 2nd ed.; Alpha Science International Ltd.: Oxford, UK, 2005, Chapter 8.Google Scholar
  59. 59.
    H. Elbs, and G. Krausch. Ellipsometric determination of Flory-Huggins interaction parameters in solution. Polymer 45:7935–7942 (2004).CrossRefGoogle Scholar
  60. 60.
    Polymer Data Handbook, Oxford University Press, Inc., 1999.Google Scholar
  61. 61.
    M. R. Paillasse, C. Deraeve, P. de Medina, L. Mhamdi, G. Favre, M. Poirot, S. Silvente-Poirot. Insights into the cholecystokinin 2 receptor binding site and processes of activation. Mol. Pharmacol. 70:1935–1945 (2006).PubMedCrossRefGoogle Scholar
  62. 62.
    S. Nosé. Constant temperature molecular dynamics methods. Prog. Theoret. Phys. Supplement 103:1–46 (1991).CrossRefGoogle Scholar
  63. 63.
    S. Nosé. A molecular dynamics method for simulations in the canonical ensemble. Molec. Phys. 52:255–268 (1984).CrossRefGoogle Scholar
  64. 64.
    D. Orloff, date of access: May 2007,
  65. 65.
    U.S. Food and Drug Administration, date of access: May 2007,
  66. 66.
    U.S. Food and Drug Administration, date of access: May 2007,
  67. 67.
    U.S. Food and Drug Administration, date of access: May 2007,
  68. 68.
    U.S. Food and Drug Administration, date of access: May 2007,
  69. 69.
    U.S. Food and Drug Administration, date of access: May 2007,
  70. 70.
    D. Mastropaolo, A. Camerman, Y. Lou, G. D. Brayer, and N. Camerman. Crystal and molecular structure of paclitaxel (Taxol). Proc. Natl. Acad. Sci. 92:6920–6924 (1995).PubMedCrossRefGoogle Scholar
  71. 71.
    R. T. Liggins, W. L. Hunter, and H. M. Burt. Solid-state characterization of paclitaxel. J. Pharm. Sci. 86:1458–1463 (1997).PubMedCrossRefGoogle Scholar
  72. 72.
    L. Zhao, and S.-S. Feng. Effects of lipid chain length on molecular interactions between paclitaxel and phospholipid within model biomembranes. J. Colloid Interface Sci. 274:55–68 (2004).PubMedCrossRefGoogle Scholar
  73. 73.
    J. H. Yin, Y. Noda, N. Hazemoto, and T. Yotsuyanagi. Distribution of protease inhibitors in lipid emulsions: gabexate mesilate and camostat mesilate. Chem. Pharm. Bull. 53:893–898 (2005).PubMedCrossRefGoogle Scholar
  74. 74.
    D. J. Greenhalgh, A. C. Williams, P. Timmins, and P. York. Solubility parameters as predictor of miscibility in solid dispersions. J. Pharm. Sci. 88:1182–1190 (1999).PubMedCrossRefGoogle Scholar
  75. 75.
    T. V. M. Sreekanth, and K. S. Reddy. Analysis of solvent-solvent interactions in mixed isosteric solvents by inverse gas chromatography. Chromatographia 65:325–330 (2007).CrossRefGoogle Scholar
  76. 76.
    J. de Wit, G. A. van Ekenstein, and G. ten Brinke. Interaction between poly(vinyl pyridine) and poly(2,6-dimethyl-1,4-phenylene oxide): A copolymer blend miscibility study. Polymer 48:1606–1611 (2007).CrossRefGoogle Scholar
  77. 77.
    G. O. R. A. van Ekenstein, R. Meyboom, and G. ten Brinke. Determination of the Flory-Huggins interaction parameter of styrene and 4-vinylpyridine using copolymer blends of poly(styrene-co-4-vinylpyridine) and polystyrene. Macromolecules 33:3752–3756 (2000).CrossRefGoogle Scholar
  78. 78.
    S. M. Ali, M. Z. Hoemann, J. Aubé, L. A. Mitscher, G. I. Georg, R. McCall, and L. R. Jayasinghe. Novel cytotoxic 3'-(tert-butyl) 3'-dephenyl analogs of paclitaxel and docetaxel. J. Med. Chem. 38:3821–3828 (1995).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Loan Huynh
    • 1
  • Justin Grant
    • 1
  • Jean-Christophe Leroux
    • 2
  • Pascal Delmas
    • 3
  • Christine Allen
    • 1
  1. 1.Faculty of PharmacyUniversity of TorontoTorontoCanada
  2. 2.Canada Research Chair in Drug Delivery, Faculty of PharmacyUniversity of MontrealQuebecCanada
  3. 3.Bioxel Pharma Inc.QuebecCanada

Personalised recommendations