Skip to main content
SpringerLink
Log in

Hydrotropic Solubilization of Paclitaxel: Analysis of Chemical Structures for Hydrotropic Property

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. To identify hydrotropic agents that can increase aqueous paclitaxel (PTX) solubility and to study the chemical structures necessary for hydrotropic properties so that polymeric hydrotropic agents can be synthesized.

Methods. More than 60 candidate hydrotropic agents (or hydro- tropes) were tested for their ability to increase the aqueous PTX solubility. A number of nicotinamide analogues were synthesized based on the observation that nicotinamide showed a favorable hydrotropic property. The identified hydrotropes for PTX were used to examine the structure-activity relationship.

Results. N,N-Diethylnicotinamide (NNDENA) was found to be the most effective hydrotropic agent for PTX. The aqueous PTX solubility was 39 mg/ml and 512 mg/ml at NNDENA concentrations of 3.5 M and 5.95 M, respectively. These values are 5-6 orders of magnitude greater than the intrinsic solubility of 0.30 ± 0.02 μg/ml. N-Picolylnicotinamide, N-allylnicotinamide, and sodium salicylate were also excellent hydrotropes for PTX. Solubility data showed that an effective hydrotropic agent should be highly water soluble while maintaining a hydrophobic segment.

Conclusions. The present study identified several hydrotropic agents effective for increasing aqueous solubility of PTX and analyzed the structural requirements for this hydrotropic property. This information can be used to find other hydrotropic compounds and to synthesize polymeric hydrotropes that are effective for PTX and other poorly water-soluble drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. S. H. Yalkowsky. Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington, D.C., 1999.

    Google Scholar 

  2. R. Löbenberg, G. L. Amidon, and M. Vierira. Solubility as a limiting factor to drug absorption. In J. B. Dressman and H. Lennernäs (eds.), Oral Drug Absorption. Prediction and Assessment, Marcel Dekker, New York, 2000, pp. 137–153.

    Google Scholar 

  3. R. H. Müller and B. Böhm. Nanosuspensions. In R. H. Müller, S. Benita, and B. Böhm (eds.), Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs, Medpharm Scientific Publishers, Stuttgart, 1998, pp. 149–174.

    Google Scholar 

  4. B. R. Goldspiel. Clinical overview of the taxanes. Pharmacotherapy 17:110S-125S (1997).

    Google Scholar 

  5. R. Paradis and M. Page. New active paclitaxel amino acids derivatives with improved water solubility. Anticancer Res. 18:2711–2716 (1998).

    Google Scholar 

  6. S. Y. Leung, J. Jackson, H. Miyake, H. Burt, and M. E. Gleave. Polymeric micellar paclitaxel phosphorylates Bcl-2 and induces apoptotic regression of androgen-independent LNCaP prostate tumors. Prostate 44:156–163 (2000).

    Google Scholar 

  7. A. G. Floyd and S. Jain. Injectable emulsions and suspensions. In H. A. Lieberman, M. M. Rieger, and G. S. Banker (eds.), Pharmaceutical Dosage Forms: Disperse Systems, Vol. 2, Marcel Dekker, New York, 1998, pp. 261–318.

    Google Scholar 

  8. H. Alkan-Onyuksel, S. Ramakrishnan, H. B. Chai, and J. M. Pezzuto. A mixed micellar formulation suitable for the parenteral administration of taxol. Pharm. Res. 11:206–212 (1994).

    Google Scholar 

  9. J. L. Ford. The current status of solid dispersions. Pharm. Acta Helv. 61:69–88 (1986).

    Google Scholar 

  10. A. T. M. Serajuddin. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 88:1058–1066 (1999).

    Google Scholar 

  11. J. Rubino and S. Yalkowsky. Cosolvency and cosolvent polarity. Pharm. Res. 4:220–230 (1987).

    Google Scholar 

  12. R. E. Coffman and D. O. Kildsig. Hydrotropic solubilization-mechanistic studies. Pharm. Res. 13:1460–1463 (1996).

    Google Scholar 

  13. B. W. Müller and E. Albers. Effect of hydrotropic substances on the complexation of sparingly soluble drugs with cyclodextrin derivatives and the influence of cyclodextrin complexation on the pharmacokinetics of the drugs. J. Pharm. Sci. 80:599–604 (1991).

    Google Scholar 

  14. S. C. Lee, G. Acharya, J. Lee, and K. Park. Hydrotropic polymers: Synthesis and characterization of polymers containing picolylnicotinamide moieties. Macromolecules 36:2248–2255 (2003).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Pharmaceutics and Biomedical Engineering, Purdue University, West Lafayette, Indiana, 47907

    Jaehwi Lee, Sang Cheon Lee, Ghanashyam Acharya, Ching-jer Chang & Kinam Park

Authors
  1. Jaehwi Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sang Cheon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ghanashyam Acharya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ching-jer Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kinam Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kinam Park.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, J., Lee, S.C., Acharya, G. et al. Hydrotropic Solubilization of Paclitaxel: Analysis of Chemical Structures for Hydrotropic Property. Pharm Res 20, 1022–1030 (2003). https://doi.org/10.1023/A:1024458206032

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1024458206032

Search

Navigation