Practical Estimation of Amorphous Solubility Enhancement Using Thermoanalytical Data: Determination of the Amorphous/Crystalline Solubility Ratio for Pure Indomethacin and Felodipine

Abstract

Use of amorphous phases can mitigate the low in vivo exposures of poorly soluble, crystalline active pharmaceutical ingredients. However, it remains challenging to accurately predict the solubility enhancement offered even by a pure amorphous phase relative to the crystalline form. In this work, a methodology is presented that allows estimation of the amorphous:crystalline solubility ratio, α, using only measured thermodynamic quantities for each of the pure phases. With this approach, α values of 7.6 and 4.7 were calculated for indomethacin and felodipine, respectively, correlating more closely than previous predictions with the experimentally measured values of 4.9 and 4.7 reported in the literature. There are 3 key benefits to this approach. First, it uses simple mathematical functions to more precisely relate the temperature variations in the heat capacity (Cp) to allow a more accurate estimation of the configurational energy difference between the 2 phases, whereas traditional models typically assume that Cp of both phases are constant(s). Second, the Hoffman equation is leveraged in translating the free energy of crystal lattice formation to the actual temperature of interest (selected to be 25°C/298K in this work), again, for better accuracy. Finally, as only 2 modulated differential scanning calorimetry scans are required (one for each phase), it is attractive from an experimental simplicity standpoint.