Physical Characterization of 1,3-dipropyl-8-cyclopentylxanthine (CPX)
- 153 Downloads
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 wordsCPX 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).
- 3.Registry P. Annual report. Bethesda, MD: Cystic Fibrosis Foundation; 2005. 2006.Google Scholar
- 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
- 10.US FDA: Cumulative list of all orphan designated products. www.fda.gov/orphan/designat/alldes.rtf. Accessed 24 Aug 2007.
- 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
- 13.SciFinder Scholar: Substance detail 102146-07-6. Accessed 19 Mar 2009.Google Scholar
- 18.Martin A. Physical pharmacy. 4th ed. Baltimore, MD: Williams & Wilkins; 1993.Google Scholar
- 20.Sheldrick G. Shelxl97 and Shelxs97 [Computer Software]. Germany: University of Göttingen; 1997.Google Scholar
- 21.Sheldrick G. Shelxtl/PC [Computer Software]. Madison, WI: Siemens Analytical X-ray Instruments, Inc; 1995.Google Scholar
- 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. http://www.dfa.gov/cder/guidance/index.htm Accessed 19 Mar 2009.
- 28.Rudolph A, Tuthill C, inventors. Pharmaceutical formulations comprising substituted xanthine compounds. United States patent application 2006/0052404 A1.Google Scholar
- 29.Technical data on Pluronic(R) polyols. BASF Corporation.Google Scholar
- 30.Cohen J. Theophylline. Anal Profiles Drug Subst. 1975;4:466–93.Google Scholar
- 31.McPherson TB. Characterization of the aqueous solubility of CPX. AAPS Journal. 2006;8:T2278.Google Scholar