Evaluation of Accuracy of Amorphous Solubility Advantage Calculation by Comparison with Experimental Solubility Measurement in Buffer and Biorelevant Media

The accuracy of amorphous solubility advantage calculation was evaluated by experimental solubility measurement. Ten structurally diverse compounds were studied to test the generlity of the theoretical calculation. Three reported methods of calculating Gibbs free energy difference between amorphous and crystalline solids were evaluated. Experimental solubility advantage was measured by direct dissolution of amorphous solid in buffer. When necessary, hydroxypropyl methylcellulose acetate succinate (HPMCAS) was predissolved in buffer to inhibit desupersaturation. By direct dissolution, the effect of different preparation methods on amorphous solubility was also studied. Finally, solubility measurement was performed in fasted state simulated intestinal fluid (FaSSIF) to assess the effect of bile salt on the concentration-based amorphous solubility advantage. The results showed that the assumption of constant heat capacity differences between crystal and supercooled liquid or amorphous solid is sufficient for accurate theoretical calculation, which is attributed to the fact that the heat capacity of crystal is nearly parallel to that of supercooled liquid or amorphous solid. Different preparation methods do not have significant impact on amorphous solubility advantage. Experimental measurement agrees with the theoretical calculation within a factor of 0.7 to 1.8. The concentration-based amorphous solubility advantage in FaSSIF agrees well with theoretical calculation. This work demonstrates that theoretical calculation of amorphous solubility advantage is robust and can be applied in early drug development for assessing the utility of the amorphous phase.