Effect of the structure, solid state and lipophilicity on the solubility of novel bicyclic derivatives

• The solubility in buffer pH 7.4 of novel bicyclo-derivatives of amine were measured.
• The influence of melting parameters and lipophilicity on the solubility was studied.
• The thermodynamic parameters of the solubility process were calculated.

Novel bicyclic derivatives have been synthesized. The solubility of drug-like substances in phosphate buffer рН 7.4 has been measured within the range of (9.02 · 10−5 to 1.05 · 10−4) mol/l. The relationship between the chemical nature and the structure of the aryl substituents and the solubility parameter was investigated. The fusion temperatures, enthalpies and entropies have been determined experimentally. The influence of thermophysical characteristics and lipophilicity on the solubility was studied using regression analysis. The calculations by the solubility/lipophilicity equation showed an overall improvement of the predictions equal to 0.5 log units. It was concluded that the solvation has a considerable influence on the solubility of the compounds under consideration. It was also determined that the alkyl- and halogen-derivatives solubility values correlate with HYBOT descriptors characterizing the (donor + acceptor) properties of the substances. The thermodynamic parameters of the solubility process were calculated using the temperature dependences. The study also revealed that the solubility of the bicyclic compounds is characterized by high endothermicity of the processes and negative entropies.