A combined calorimetric and semiempirical quantum chemical approach to describe the solution thermodynamics of drugs.

A combined calorimetric-semiempirical quantum chemical approach is presented to calculate the energy changes for the solution process of drugs. The aim of the presented approach is to understand the elementary steps of the solution process and to propose strategies for an improvement of solubility of drugs. On the basis of the Hess theorem, an alternative route for the solution process via sublimation of the solute, creation of a cavity for the solute in the solvent, transfer into this cavity, and the reorganization of the dipoles of the solute and the solvent can be taken. This approach allows the calculation of all energies describing the direct solution process as well as the alternative route. The approach was tested on 11 substances of different molecular structure by calculating the standard free energy of the specific phase transition. A general way to calculate the energy changes of all phase transitions is given. The complete cycle with DeltaG, DeltaH, and DeltaS was calculated exemplary for the nonsteroidal analgesic ibuprofen. The low solubility of ibuprofen was shown to be due to its high standard free energy of sublimation. Therefore the preparation of solid dispersions could be considered.