Hancock B C, Parks M
Pfizer Inc., Groton, Connecticut 66340, USA.
Pharm Res. 2000 Apr;17(4):397-404. doi: 10.1023/a:1007516718048.
To evaluate the magnitude of the solubility advantage for amorphous pharmaceutical materials when compared to their crystalline counterparts.
The thermal properties of several drugs in their amorphous and crystalline states were determined using differential scanning calorimetry. From these properties the solubility advantage for the amorphous form was predicted 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.
By treating each amorphous drug as either an equilibrium supercooled liquid or a pseudo-equilibrium glass, the solubility advantage compared to the most stable crystalline form was predicted to be between 10 and 1,600 fold. The measured solubility advantage was usually considerably less than this, and for one compound studied in detail its temperature dependence was also less than predicted. It was calculated that even for partially amorphous materials the apparent solubility enhancement (theoretical or measured) is likely to influence in-vitro and in-vivo dissolution behavior.
Amorphous pharmaceuticals are markedly more soluble than their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simple thermodynamic considerations. This appears to be the result of difficulties in determining the solubility of amorphous materials under true equilibrium conditions. Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage for amorphous pharmaceuticals, which directly reflects the driving force for their initial dissolution.
评估无定形药物材料与其结晶对应物相比时的溶解优势程度。
使用差示扫描量热法测定几种药物无定形和结晶态的热性质。根据这些性质，通过简单的热力学分析预测无定形形式的溶解优势随温度的变化函数。将这些预测结果与在几个温度下对药物无定形和结晶态水溶解度的实验测量结果进行比较。
将每种无定形药物视为平衡过冷液体或准平衡玻璃态时，与最稳定的结晶形式相比，预测的溶解优势在10至1600倍之间。测量得到的溶解优势通常远低于此，并且对于一种详细研究的化合物，其对温度的依赖性也低于预测值。据计算，即使对于部分无定形材料，表观溶解度增强（理论或测量值）也可能影响体外和体内的溶解行为。
无定形药物的溶解度明显高于其结晶对应物，然而，它们的实验溶解优势通常小于简单热力学考虑所预测的。这似乎是由于在真实平衡条件下测定无定形材料溶解度存在困难所致。简单的热力学预测可为无定形药物理论上的最大溶解优势提供有用的指示，这直接反映了其初始溶解的驱动力。
