title: Physical Characterization of 1,3-dipropyl-8-cyclopentylxanthine (CPX).
abstract: 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 microM. 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/cm(3). 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 degrees C for form I and 198 degrees 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.
authors.affiliation: Department of Pharmaceutical Sciences, Southern Illinois University Edwardsville School of Pharmacy, Edwardsville, Illinois 62026, USA. tmcpher@siue.edu
authors.forename: Timothy
authors.initials: T
authors.lastname: McPherson
authors.forename: Rahul V
authors.initials: RV
authors.lastname: Manek
authors.forename: William
authors.initials: W
authors.lastname: Kolling
authors.forename: Sihui
authors.initials: S
authors.lastname: Long
authors.forename: Tonglei
authors.initials: T
authors.lastname: Li
mesh_terms: D006863:Hydrogen-Ion Concentration; D008968:Molecular Conformation; D008970:Molecular Weight; D058915:Purinergic P1 Receptor Antagonists; D012995:Solubility; D014970:Xanthines / Q000737:chemistry*
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine