AAPS PharmSciTech

, Volume 11, Issue 2, pp 720–728 | Cite as

Physical Characterization of 1,3-dipropyl-8-cyclopentylxanthine (CPX)

  • Timothy McPherson
  • Rahul V. Manek
  • William Kolling
  • Sihui Long
  • Tonglei Li
Research Article


1,3-dipropyl-8-cyclopentylxanthine (CPX) has been shown to stimulate in vitro CFTR activity in ∆F508 cells. Data from a phase I study demonstrated erratic bioavailability and no measurable clinical response to oral CPX. One cause for its poor bioavailability may have been dissolution rate limited absorption, but there is little published physicochemical data on which to base an analysis. The objective of this study was to determine the solubility and solid-state characteristics of CPX. CPX is a weak acid with pKa of 9.83 and water solubility at pH 7.0 of 15.6 μM. Both laureth-23 and poloxamer 407 increased the apparent water solubility linearly with increasing concentrations. CPX exists in two crystal forms, one of which (form II) has been solved. Form II is a triclinic crystal with space group P1 and calculated density of 1.278 g/cm3. X-ray powder diffraction and differential scanning calorimetry studies (DSC) indicated that CPX crystals prepared at room temperature were mixtures of forms I and II. DSC results indicated a melting point of approximately 195°C for form I and 198°C for form II. Thermogravimetric analysis indicated no solvent loss upon heating. Dynamic water vapor sorption data indicated no significant water uptake by CPX up to 90% RH. Analysis of the data indicates that CPX may not be amenable to traditional formulation approaches for oral delivery.

Key words

CPX pH solubility profile physico-chemical characterization thermal analysis X-ray crystal structure 



The authors acknowledge SciClone Pharmaceuticals, Inc. for providing CPX for solubility experiments and Dr. A. Michael Crider for assistance with CPX synthesis. We acknowledge support via National Science Foundation grants DMR-0449633 (TL) and DUE-0410642 (SIUE).


  1. 1.
    Gadsby DC, Vergani P, Csanady L. The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature. 2006;440:477–83.CrossRefPubMedGoogle Scholar
  2. 2.
    Strasbaugh SD, Davis PB. Cystic fibrosis: a review of epidemiology and pathobiology. Clin Chest Med. 2007;28:279–88.CrossRefGoogle Scholar
  3. 3.
    Registry P. Annual report. Bethesda, MD: Cystic Fibrosis Foundation; 2005. 2006.Google Scholar
  4. 4.
    Cheng SH, Gregory RJ, Marshall J, Paul S, Souza DW, White GA et al. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell. 1990;163:827–34.CrossRefGoogle Scholar
  5. 5.
    Andersson C, Roomans G. Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX. Eur Respir J. 2000;15:937–41.CrossRefPubMedGoogle Scholar
  6. 6.
    Cohen B, Lee G, Jacobson K, Kim Y, Huang Z, Sorscher E et al. 8-cyclopentyl-1, 3-dipropylxanthine and other xanthines differentially bind to the wild-type and delta F508 first nucleotide binding fold (NBF-1) domains of the cystic fibrosis transmembrane conductance regulator. Biochem. 1997;36:6455–61.CrossRefGoogle Scholar
  7. 7.
    Eidelman O, Barnoy S, Razin M, Zhang J, Mcphie P, Lee G et al. Role for phospholipid interactions in the trafficking defect of Delta F508-CFTR. Biochem. 2002;41:11161–70.CrossRefGoogle Scholar
  8. 8.
    Eidelman O, Guay-Broder C, Van Galen PJM, Jacobson KA, Fox C, Turner RJ et al. A1 adenosine-receptor antagonists activate chloride efflux from cystic fibrosis cells. Proc Natl Acad Sci USA. 1992;89:5562–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Jacobson KA, Guay-Broder C, Van Galen PJM, Gallo-Rodriguez C, Melman N, Jacobson MA et al. Stimulation by alkylxanthines of chloride efflux in CFPAC-1 cells does not involve A1 adenosine receptors. Biochem. 1995;34:9088–94.CrossRefGoogle Scholar
  10. 10.
    US FDA: Cumulative list of all orphan designated products. Accessed 24 Aug 2007.
  11. 11.
    Pollard HB, Van Galen PJM, Jacobson KA, inventors; United States of America as represented by the Department of Health and Human Service, assignee. Method of treating cystic fibrosis using 8-cyclopenty-1,3-dipropylxanthine or xanthine amino congeners. US patent 5,366,977. 1994 Nov 22.Google Scholar
  12. 12.
    McCarty NA, Standaert TA, Teresi M, Tuthill C, Launspach J, Kelly TJ et al. A phase I randomized, multicenter trial of CPX in adult subjects with mild cystic fibrosis. Pediatr Pulmonol. 2002;33:90–8.CrossRefPubMedGoogle Scholar
  13. 13.
    SciFinder Scholar: Substance detail 102146-07-6. Accessed 19 Mar 2009.Google Scholar
  14. 14.
    Daly J, Padgett W, Shamim M, Butts-Lamb P, Waters J. 1, 3-Dialkyl-8-(p-sulfophenyl)xanthines: potent water-soluble antagonists for A1- and A2-adenosine receptors. J Med Chem. 1985;28:487–92.CrossRefPubMedGoogle Scholar
  15. 15.
    Erickson R, Hiner R, Feeney S, Blake P, Rzeszotarski W, Hicks R et al. 1, 3, 8-trisubstituted xanthines. Effects of substitution pattern upon adenosine receptor A1/A2 affinity. J Med Chem. 1991;34:1431–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Scammells P, Baker S, Belardinelli L, Olsson R. Substituted 1, 3-dipropylxanthines as irreversible antagonists of A1 adenosine receptors. J Med Chem. 1994;37:2704–12.CrossRefPubMedGoogle Scholar
  17. 17.
    Shamim MT, Ukena D, Padgett W, Hong O, Daly J. 8-Aryl-and 8-cycloalkyl-1, 3-dipropylxanthines: further potent and selective antagonists for A1-adenosine receptors. J Med Chem. 1988;31:613–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Martin A. Physical pharmacy. 4th ed. Baltimore, MD: Williams & Wilkins; 1993.Google Scholar
  19. 19.
    Otwinowski Z, Minor W. Processing of x-ray diffraction data collected in oscillation mode. In: Carter Jr CW, Sweet RM, editors. Macromolecular crystallography, Part A. New York: Academic; 1997. p. 307–26.CrossRefGoogle Scholar
  20. 20.
    Sheldrick G. Shelxl97 and Shelxs97 [Computer Software]. Germany: University of Göttingen; 1997.Google Scholar
  21. 21.
    Sheldrick G. Shelxtl/PC [Computer Software]. Madison, WI: Siemens Analytical X-ray Instruments, Inc; 1995.Google Scholar
  22. 22.
    US FDA: Guidance for Industry: Waiver of in vivo bioavailabilty and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. Accessed 19 Mar 2009.
  23. 23.
    Benet L, Amidon G, Barends D, Lennernas H, Polli J, Shah V et al. The use of BDDCS in classifying the permeability of marketed drugs. Pharm Res. 2008;25:483–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Gu CH, Li H, Levons J, Lentz K, Gandhi R, Raghavan K et al. Predicting effect of food on extent of drug absorption based on physicochemical properties. Pharm Res. 2007;24:1118–30.CrossRefPubMedGoogle Scholar
  25. 25.
    Martinez M, Amidon G. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol. 2002;42:620–43.CrossRefPubMedGoogle Scholar
  26. 26.
    Wu C, Benet L. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22:11–23.CrossRefPubMedGoogle Scholar
  27. 27.
    Yu LX. An integrated model for determining causes of poor oral drug absorption. Pharm Res. 1999;16:1883–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Rudolph A, Tuthill C, inventors. Pharmaceutical formulations comprising substituted xanthine compounds. United States patent application 2006/0052404 A1.Google Scholar
  29. 29.
    Technical data on Pluronic(R) polyols. BASF Corporation.Google Scholar
  30. 30.
    Cohen J. Theophylline. Anal Profiles Drug Subst. 1975;4:466–93.Google Scholar
  31. 31.
    McPherson TB. Characterization of the aqueous solubility of CPX. AAPS Journal. 2006;8:T2278.Google Scholar
  32. 32.
    Stephenson G. Anisotropic lattice contraction in pharmaceuticals: the influence of cryo-crystallography on calculated powder diffraction patterns. J Pharm Sci. 2006;95:821–7.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2010

Authors and Affiliations

  • Timothy McPherson
    • 1
  • Rahul V. Manek
    • 2
  • William Kolling
    • 1
  • Sihui Long
    • 3
  • Tonglei Li
    • 3
  1. 1.Department of Pharmaceutical SciencesSouthern Illinois University Edwardsville School of PharmacyEdwardsvilleUSA
  2. 2.Exelixis Inc.South San FranciscoUSA
  3. 3.Pharmaceutical SciencesUniversity of Kentucky College of PharmacyLexingtonUSA

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