Thermodynamic consideration of dissolution and distribution behavior of carvedilol in pharmaceutical significant media

Abstract

The key physico-chemical properties for pharmaceutical design as solubility and distribution coefficients of cardiovascular carvedilol (CVD) in modeling solvents and biphasic systems were determined using the classic shake flask method in the temperature range (293.15–313.15) K. The drug solubility in 1-octanol and hexane was measured at first time. The equilibrium mole fraction solubility of CVD at reference temperature was changed in following order: 1-octanol (2.79∙10^-3) > hexane (4.56∙10^-6) > buffer pH 2.0 (3.39∙10^-6) > buffer pH 7.4 (1.53∙10^-7). Solubility pH-profile was characterized a weak solubility in acidic media and very poor solubility in neutral. The experimental lipophilic values logD_O/B (1.83 and 2.36 at buffer solution pH 2.0 and 7.4, respectively) were shown the excellent penetration power into both the circulatory system and the entire intestinal tract. The temperature dependences of the CVD distribution coefficients in 1-octanol/buffer and hexane/buffer two-phase systems at pH two values (2.0 and 7.4) were considered from the thermodynamic view point. Thermodynamic functions of solubility and transfer processes were calculated and analyzed. Thermophysical parameters of the compound were used for estimation of the ideal solubility and activity coefficients. Moreover partial excess thermodynamic functions of CVD dissolution in saturated solutions, demonstrating the positive deviation real solvents from ideality, are also evaluated in detail. The data obtained will be in demand both for the creation of conceptually new dosage forms of carvedilol with improved bioavailability, and for constructing structure–property correlations in a number of structure-like compounds.