Prediction of Drug Solubility Using COSMO-RS

At a somewhat reduced accuracy it is also possible to circumvent the sometimes costly quantum chemical calculations and to generate o-profiles on-the-fly from fragments of precomputed COSMO files stored in a database. This approach is implemented in the software COSMOquick and is particularly useful for solubility prediction using one or several reference solvents (see also Section 9.4). 

If not stated otherwise the following results have been generated with recent COSMOt/ierm [6] and COSMOquick [21] releases and their respective COSMO-RS parameterizations, BP TZVP C30 1301.ctd (TZVP level of theory) and BP SVP AMl C30 1301.ctd (SVP level of theory). QSPR calculations have been done using the R statistics package [22], 

Because the solubility prediction capabilities of COSMO-RS have been reviewed before [14, 23], here we summarize just shortly the theoretical foundations and then focus on some recent results. 

The mole fraction solubility of the compound X in solvent S is readily obtained from the condition of equal chemical potentials at the solid-liquid equilibrium  

FIGURE 9.1 The chemical potential of paracetamol in CCl at varying concentrations (in mole fractions x) at 298 K. The intersection with the solid-state chanical potential defines the solid-liquid equilibrium (SLE) and corresponds to the solnbiUty of the dmg in this particnlar solvent. The difference between the pure liquid and the solid-state chemical potential is the free energy of fusion Also shown is the liquid-liquid equilibrium (LLE) where the virtually supercooled liquid is at equilibrium with the dissolved drug. 

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