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The free energy perturbation method is employed to study the free energy of solvation of a drug molecule in its pure drug melt, which is supposed to be considered the second step in predicting the solubility of drugs in water. The analysis reveals contradictory results, revealing that the Coulomb interactions are much weaker in pure drug systems, whereas the van der Waals interactions are extremely important and highly influence the interaction.

The study uses the free energy of the perturbation method and the optimized potential for the liquid simulations to take the first step for the computational prediction of drug solubility by measuring the free energy of hydration. The analysis provides an accurate demonstration of the macroscopic surface tension of water, which is not in agreement with the surface tension for water around a spherical cavity that normally is supposed to be dependent on the size of the cavity.

A computational method of predicting the effects of the metastability of drug solutions is sought. A simple extension of our in silicio approach to thermodynamic drug solubility is tested on the drug bicalutamide for which we performed vapor pressure measurements complementing earlier measurements of aqueous solubility and crystal-water interfacial tension. The free energy of formation of an N-cluster of the drug molecule is estimated semiempirically by use of an Einstein model of the crystal in which experiment supplies the crystal structure, enthalpy of sublimation, and Einstein frequency of vibration. The rigid drug clusters with N from 2 to 14 are extracted from the bulk crystal by minimization of either cluster energy or radius of gyration. The free energy of hydration is estimated by Monte Carlo simulation combined with simplified response theory based on the OPLS-AA/COMPASS force field for the drug-water interaction and the TIP4P water model. The results have been interpreted in terms of an apparent crystal-water interfacial tension according to classical nucleation theory. The energy-minimal and radius of gyration-minimal clusters seem to give very similar crystal-water interfacial tensions for both the monoclinic and the triclinic polymorph. The interfacial tension of the monoclinic polymorph is significantly higher (by around 20%) than that of the triclinic polymorph in accordance with experiment. For the triclinic polymorph a substantial overestimation of the interfacial tension compared to estimates from crystal nucleation experiments is found, mitigated somewhat by an empirical scaling of the simulated binding energies and free energies of hydration.

The solubility of drugs in water is investigated in a series of papers. In this work, we address the process of bringing a drug molecule from the vapor into a pure drug amorphous phase. This step enables us to actually calculate the solubility of amorphous drugs in water. In our general approach, we, on one hand, perform rigorous free energy simulations using a combination of the free energy perturbation and thermodynamic integration methods. On the other hand, we develop an approximate theory containing parameters that are easily accessible from conventional Monte Carlo simulations, thereby reducing the computation time significantly. In the theory for solvation, we assume that DeltaG* = DeltaGcav + ELJ + EC/2, where the free energy of cavity formation, DeltaGcav, in pure drug systems is obtained using a theory for hard-oblate spheroids, and ELJ and EC are the Lennard-Jones and Coulomb interaction energies between the chosen molecule and the others in the fluid. The theoretical predictions for the free energy of solvation in pure amorphous matter are in good agreement with free energy simulation data for 46 different drug molecules. These results together with our previous studies support our theoretical approach. By using our previous data for the free energy of hydration, we compute the total free energy change of bringing a molecule from the amorphous phase into water. We obtain good agreement between the theory and simulations. It should be noted that to obtain accurate results for the total process, high precision data are needed for the individual subprocesses. Finally, for eight different substances, we compare the experimental amorphous and crystalline solubility in water with the results obtained by the proposed theory with reasonable success.

As a first step in the computational prediction of drug solubility the free energy of hydration, DeltaG*(vw) in TIP4P water has been computed for a data set of 48 drug molecules using the free energy of perturbation method and the optimized potential for liquid simulations all-atom force field. The simulations were performed in two steps, where first the Coulomb and then the Lennard-Jones interactions between the solute and the water molecules were scaled down from full to zero strength to provide physical understanding and simpler predictive models. The results have been interpreted using a theory assuming DeltaG*(vw) = A(MS)gamma + E(LJ) + E(C)/2 where A(MS) is the molecular surface area, gamma is the water-vapor surface tension, and E(LJ) and E(C) are the solute-water Lennard-Jones and Coulomb interaction energies, respectively. It was found that by a proper definition of the molecular surface area our results as well as several results from the literature were found to be in quantitative agreement using the macroscopic surface tension of TIP4P water. This is in contrast to the surface tension for water around a spherical cavity that previously has been shown to be dependent on the size of the cavity up to a radius of approximately 1 nm. The step of scaling down the electrostatic interaction can be represented by linear response theory.