What is the true solubility advantage for amorphous pharmaceuticals

无定形固体 差示扫描量热法 溶解 溶解度 过冷 热力学 玻璃化转变 溶解度参数 化学 材料科学 有机化学 聚合物 物理
作者
Bruno C. Hancock,Michael L. Parks
出处
期刊:Pharmaceutical Research [Springer Science+Business Media]
卷期号:17 (4): 397-404 被引量:1258
标识
DOI:10.1023/a:1007516718048
摘要

Purpose. To evaluate the magnitude of the solubility advantage foramorphous pharmaceutical materials when compared to their crystallinecounterparts.Methods. The thermal properties of several drugs in their amorphousand crystalline states were determined using differential scanningcalorimetry. From these properties the solubility advantage for theamorphous form was predicted as a function of temperature using a simplethermodynamic analysis. These predictions were compared to theresults of experimental measurements of the aqueous solubilities of theamorphous and crystalline forms of the drugs at several temperatures.Results. By treating each amorphous drug as either an equilibriumsupercooled liquid or a pseudo-equilibrium glass, the solubilityadvantage compared to the most stable crystalline form was predicted to bebetween 10 and 1600 fold. The measured solubility advantage wasusually considerably less than this, and for one compound studied indetail its temperature dependence was also less than predicted. It wascalculated that even for partially amorphous materials the apparentsolubility enhancement (theoretical or measured) is likely to influencein-vitro and in-vivo dissolution behavior.Conclusions. Amorphous pharmaceuticals are markedly more solublethan their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simplethermodynamic considerations. This appears to be the result of difficulties indetermining the solubility of amorphous materials under trueequilibrium conditions. Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage foramorphous pharmaceuticals, which directly reflects the driving forcefor their initial dissolution.
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