Nuances in the Calculation of Amorphous Solubility Enhancement Ratio

The theoretical amorphous solubility enhancement ratio (R_s) can be calculated based on the free energy difference between amorphous and crystalline forms (ΔG_x→a), using several experimentally determined input parameters. This work compares the various approaches for the calculation of R_s and explores the nuances associated with its calculation. The uncertainty of R_s values owing to experimental conditions (differential scanning calorimetry heating rates) used to measure the input parameters was determined for 3 drugs (indomethacin, itraconazole, and spironolactone). The calculated value of R_s was most influenced by the measurement of heat of fusion. The range in values of R_s using the various equations in the literature was within the calculated uncertainty of the theoretical R_s value. Still, all equations appear to overpredict the experimental value of R_s, sometimes by more than a factor of 5, when an experimental value is attainable. Methods for the calculation of ΔG_x→a for molecules undergoing additional phase transitions (other than glass transition and melting) were developed, employing itraconazole as a model drug. In addition, the influences of enthalpy relaxation and entropy of mixing for racemic compounds on R_s were also considered. These additional corrections improved agreement between theoretical and experimental R_s.