Physical Characterization of 1,3-dipropyl-8-cyclopentylxanthine (CPX) |
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Authors: | Timothy McPherson Rahul V Manek William Kolling Sihui Long Tonglei Li |
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Institution: | (1) Department of Pharmaceutical Sciences, Southern Illinois University Edwardsville School of Pharmacy, Edwardsville, Illinois 62026, USA;(2) Exelixis Inc., South San Francisco, California, USA;(3) Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, Kentucky, USA |
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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 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. |
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