Thermodynamics Research Center / ThermoML | Journal of Chemical and Engineering Data

ABSTRACT

Physicochemical characterization of 10-hydroxy-camptothecin (10-HC) was carried out to fully characterize the poor aqueous solubility and hydrolytic instability that severely limit its efficient delivery and pharmacological activity. Molecular and system properties were determined from titration, partition, and solubility studies using UV and fluorescence spectroscopy, while solid state characterization of the 10-HC was carried out with X-ray, DSC, and TGA. The enthalpies of solution of the unionized and ionized forms of 10-HC, as deduced from isothermal and iso-pH equilibrium solubility measurements, were 45.4 kJ*mol-1 and 22.7 kJ*mol-1, respectively. The pKa of 10-HC was determined to be 1.42 at 25 deg C, while the basicity of the quinoline group of 10-HC was shown to decrease with increasing temperature due to a positive enthalpy of deprotonation of 23.6 kJ*mol-1. The intrinsic partition coefficient of 10-HC was determined to be 6.49, which is significantly smaller than that of the parent camptothecin. Evidently, the hydroxyl substitution on the A ring of camptothecin renders the molecule considerably more polar, though still hydrophobic and sparingly soluble in aqueous media. Dissolution studies supported by X-ray and thermal analysis revealed polymorphism and serious metastability of the 10-HC anhydrous form in aqueous solutions. The aqueous solubility of 10-HC-lactone monohydrate was found to be pH and temperature dependent with an estimated intrinsic solubility of (1.81 +- 0.2) ?M. Contrary to the low intrinsic solubility, the solubility of 10-HC in extremely acidic media increased by more than 3 orders of magnitude. This feature can be used to facilitate fabrication of highly efficient drug delivery systems for 10-HC systemic administration.