What is the true solubility advantage for amorphous pharmaceuticals?

Purpose, To evaluate the magnitude of the solubility advantage for amorphou s pharmaceutical materials when compared to their crystalline counterparts. Methods. The thermal properties of several drugs in their amorphous and cry stalline states were determined using differential scanning calorimetry. Fr om these properties the solubility advantage for the amorphous form was pre dicted as a function of temperature using a simple thermodynamic analysis. These predictions were compared to the results of experimental measurements of the aqueous solubilities of the amorphous and crystalline forms of the drugs at several temperatures. Results. By treating each amorphous drug as either an equilibrium supercool ed liquid or a pseudo-equilibrium glass, the solubility advantage compared to the most stable crystalline form was predicted to be between 10 and 1600 fold. The measured solubility advantage was usually considerably less than this, and for one compound studied in detail its temperature dependence wa s also less than predicted. It was calculated that even for partially amorp hous materials the apparent solubility enhancement (theoretical or measured ) is likely to influence in-vitro and in-vivo dissolution behavior. Conclusions. Amorphous pharmaceuticals are markedly more soluble than their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simple thermodynamic considerat ions. This appears to be the result of difficulties in determining the solu bility of amorphous materials under true equilibrium conditions. Simple the rmodynamic predictions can provide a useful indication of the theoretical m aximum solubility advantage for amorphous pharmaceuticals, which directly r eflects the driving force for their initial dissolution.