AAPS PharmSciTech

, Volume 7, Issue 1, pp E125–E130 | Cite as

Improving cyclodextrin complexation of a new antihepatitis drug with glacial acetic acid

  • Jennifer L. H. Johnson
  • Yan He
  • Akash Jain
  • Samuel H. Yalkowsky


The purpose of this study was to develop and evaluate a solid nonaqueous oral dosage form for a new hepatitis C drug, PG301029, which is insoluble and unstable in water. Hydroxypropyl-β-cyclodextrin (HPβCD) and PG301029 were dissolved in glacial acetic acid. The acetic acid was removed by rotoevaporation such that the drug exists primarily in the complexed form. The stability of formulated PG301029 was determined upon dry storage and after reconstitution in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulated PG301029 was found to be stable upon storage and can be reconstituted with water to a concentration 200 times that of the intrinsic solubility. Once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours in SGF, SIF, and water. The unique use of acetic acid and HPβCD results in a solid dosage form of PG301029 that is both soluble and stable in water.


Hydroxypropyl-β-cyclodextrin acetic acid solid dose oral formulation complexation solubility stability PG301029 


  1. 1.
    He Y, Johnson JLH, Yalkowsky SH. Oral formulation of a novel antiviral agent, PG301029, in a mixture of Gelucire 44/14 and DMA (2:1, wt/wt). AAPS Pharm Sci. Tech. 2005;6:E1.CrossRefGoogle Scholar
  2. 2.
    Rossi SJ, Wright TL. New developments in the treatment of hepatitis C. Gut. 2003;52:756–757.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Thuluvath PJ, Maheshwari A, Mehdi J, et al. Randomised, double blind, placebo controlled trial of interferon, ribavirin, and amantadine versus interferon, ribavirin, and placebo in treatment naïve patients with chronic hepatitis C. Gut. 2004;53:130–135.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Centers for Disease Control web site. Available at: http://www.cdc. gov/ncidod/diseases/hepatitis. Accessed: October 28, 2004.Google Scholar
  5. 5.
    Medical Economics. Physicians’ Desk Reference. 56th ed. Florence, KY: Thomson Healthcare; 2002.Google Scholar
  6. 6.
    Proctor and Gamble Co. PG301029: A potential agent for treatment of hepatitis C infection. Unpublished company report; 1999.Google Scholar
  7. 7.
    Jia L, Wong H, Cerna C, Weitman SD. Effect of nanonization on absorption of 301029: ex vivo and in vivo pharmacokientic correlations determined by liquid chromatography/mass spectrometry. Pharm Res. 2002;19:1091–1096.CrossRefPubMedGoogle Scholar
  8. 8.
    ClogP © for Windows, Version 4 Software. Claremont, CA: BioByte Corporation; 1999.Google Scholar
  9. 9.
    Scifinder Scholar for Windows. 2004. Available at: Accessed: March 12, 2004.Google Scholar
  10. 10.
    ACD ©/Pka Software. Version 7 for Microsoft Windows. Toronto, Ontario: Advanced Chemistry Development; 2004Google Scholar
  11. 11.
    Pop E, Loftsson T, Bodor N. Solubilization and stabilization of a benzylpenicillin chemical delivery system by 2-hydroxypropyl-B-cyclodextrin. Pharm Res. 1991;8:1044–1049.CrossRefPubMedGoogle Scholar
  12. 12.
    Connors KA. The stability of cyclodextrin complexes in solution. Chem Rev. 1997;97:1325–1357.CrossRefPubMedGoogle Scholar
  13. 13.
    Tommasini S, Raneri D, Ficarra R, Calabrò ML, Stancanelli R, Ficarra P. Improvement in solubility and dissolution rate of flavonoids by complexation with β-cyclodextrin. J Pharm Biomed Anal. 2004;35:379–387.CrossRefPubMedGoogle Scholar
  14. 14.
    Ran Y, Zhao L, Xu Q, Yalkowsky SH. Solubilization of cyclosporin A. AAPS Pharm Sci Tech. 2001;2:E2.CrossRefGoogle Scholar
  15. 15.
    Nalluri BN, Chowdary KPR, Murthy KVR, Hayman AR, Becket G. Physicochemical characterization and dissolution properties of nimesulide-cyclodextrin binary systems. AAPS Pharm Sci Tech. 2003;4:E2.CrossRefGoogle Scholar
  16. 16.
    Loftsson, T, Sigurdsson HH, Masson M, Schipper N. Preparation of solid drug/cyclodextrin complexes of acidic and basic drugs. Pharmazie. 2004;59:25–29.PubMedGoogle Scholar
  17. 17.
    Kruss B, Mauz A, Ruehr K, Stassen J-M, Veit C, Wagner K, inventors. Formulation for the parenteral application of a sodium channel blocker. US patent application 20040019013. January 29, 2004.Google Scholar
  18. 18.
    Loftsson T, inventor. Non-inclusion cyclodextrin complexes. US patent application 20030109492. June 12, 2003.Google Scholar
  19. 19.
    Loftsson T, Masson M, inventors. Method to improve complexation efficacy and produce high-energy cyclodextrin complexes. US patent application 20040242538. December 2, 2004.Google Scholar
  20. 20.
    Wong H, Jia L, Camden JB, Weitman SD. Liquid chromatography-mass spectrometry assay of a thiadiazole derivative in mice: application to pharmacokientic studies. J Chromatogr B Biomed Sci Appl. 2001;765:55–62.CrossRefPubMedGoogle Scholar
  21. 21.
    Aree T, Schulz B, Reck G. Crystal structures of β-cyclodextrin complexes with formic acid and acetic acid. J Inclus Phenom Macrocycl Chem. 2003;47:39–45.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2006

Authors and Affiliations

  • Jennifer L. H. Johnson
    • 1
  • Yan He
    • 1
  • Akash Jain
    • 1
  • Samuel H. Yalkowsky
    • 1
  1. 1.University of Arizona Pharmaceutical SciencesTucson

Personalised recommendations