What is the true solubility advantage for amorphous pharmaceuticals?
What is the true solubility advantage for amorphous pharmaceuticals?
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DOI：
10.1023/a:1007516718048
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发表时间：
2000-04-01
影响因子：
3.7
通讯作者：
Parks, M
中科院分区：
文献类型：
--
作者：
Hancock, BC;Parks, M
目的：评价非晶态药物与晶态药物相比的溶解度优势的大小。用差示扫描量热法测定了几种药物的非晶态和结晶态的热性质。根据这些性质，使用简单的热力学分析，预测了非晶态的溶解度优势作为温度的函数。将这些预测与不同温度下药物的非晶态和晶态的水溶解度的实验测量结果进行了比较。通过将每一种非晶态药物视为平衡过冷液体或伪平衡玻璃，与最稳定的晶型相比，溶解度优势预计在10至1600倍之间。测得的溶解度优势通常比这要小得多，对于一种详细研究的化合物，其温度依赖性也比预测的要小。计算表明，即使对于部分非晶态材料，表观溶解度的增加(理论或测量)也可能影响体外和体内的溶出行为。非晶态药物明显比晶态药物更易溶，然而，它们的实验溶解度优势通常比从简单热力学考虑预测的要小。这似乎是由于难以确定非晶态物质在真实平衡条件下的溶解度所致。简单的热力学预测可以为无定形药物的理论最大溶解度优势提供有用的指示，这直接反映了它们最初溶解的驱动力。
Purpose, To evaluate the magnitude of the solubility advantage for amorphous pharmaceutical materials when compared to their crystalline counterparts.Methods. 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.Results. 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 1600 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.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 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.