Nuances in the Calculation of Amorphous Solubility Enhancement Ratio.

The theoretical amorphous solubility enhancement ratio (Rs) can be calculated based on the free energy difference between amorphous and crystalline forms (ΔGx→a), using several experimentally determined input parameters. This work compares the various approaches for the calculation of Rs and explores the nuances associated with its calculation. The uncertainty of Rs 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 Rs was most influenced by the measurement of heat of fusion. The range in values of Rs using the various equations in the literature was within the calculated uncertainty of the theoretical Rs value. Still, all equations appear to overpredict the experimental value of Rs, sometimes by more than a factor of 5, when an experimental value is attainable. Methods for the calculation of ΔGx→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 Rs were also considered. These additional corrections improved agreement between theoretical and experimental Rs.