Laboratory of Pharmacotechnology and Biopharmacy, and Department of Metallurgy and Materials Engineering, K.U.Leuven, Leuven, Belgium.
Mol Pharm. 2010 Aug 2;7(4):1133-48. doi: 10.1021/mp100013p.
The objective of the present study was to determine the solid state solubility and miscibility of naproxen in poly(vinylpyrrolidone) (PVP) and the mutual interaction using the standard thermodynamic models and thermal analysis. Solid dispersions were prepared by spray drying several compositions of naproxen and PVP with different molecular weights, viz., PVP K 12, PVP K 25 and PVP K 90, and analyzed using modulated differential scanning calorimetry (mDSC). The kinetic miscibility limit in terms of a single mixed phase glass transition temperature was found to be relatively similar for the dispersions containing PVP with different chain lengths (>or=50% w/w drug in PVP). But the systems with different PVP followed diverse patterns of composition dependent mixed phase glass transition temperature as well as the degree of plasticization by water. The crystalline solid solubility values of naproxen in PVP estimated by using its solubility data in n-methylpyrrolidone, a low molecular weight analogue of PVP, were 6.42, 5.85 and 5.81% w/w of drug in PVP K 12, PVP K 25 and PVP K 90 respectively. The values estimated for corresponding amorphous solubility showed no marked difference. The remarkable difference between thermodynamic solubility/miscibility and kinetic miscibility implied that naproxen was highly supersaturated in the PVP solid dispersions and only stabilized kinetically. The negative value of the drug-polymer interaction parameter (-0.36) signified the systems to be favorably mixing. The melting point depression data of naproxen in PVP pointed to the composition dependence and chain length effect on the interaction. The moisture sorption by the physical mixtures not only provided the composition dependent interaction parameter but also conferred an estimate of composition dependent miscibility of naproxen in PVP in the presence of water.
本研究的目的是确定萘普生在聚乙烯吡咯烷酮（PVP）中的固溶度和混溶性，并使用标准热力学模型和热分析来研究它们之间的相互作用。通过喷雾干燥几种不同分子量的萘普生和 PVP（即 PVP K12、PVP K25 和 PVP K90）的混合物制备了固体分散体，并使用调制差示扫描量热法（mDSC）进行了分析。发现具有不同链长的 PVP 的分散体的动力学混溶性极限（以单一混合相玻璃化转变温度表示）相对相似（>或=50%w/w 药物在 PVP 中）。但是，具有不同 PVP 的系统表现出不同的混合相玻璃化转变温度以及水的增塑程度的组成依赖性模式。通过使用其在 N-甲基吡咯烷酮（PVP 的低分子量类似物）中的溶解度数据估算的萘普生在 PVP 中的结晶固溶度值分别为 PVP K12、PVP K25 和 PVP K90 中药物的 6.42、5.85 和 5.81%w/w。对应无定形溶解度的估算值没有明显差异。热力学溶解度/混溶性和动力学混溶性之间的显著差异表明，萘普生在 PVP 固体分散体中高度过饱和，仅在动力学上稳定。药物-聚合物相互作用参数的负值（-0.36）表明该系统有利于混合。萘普生在 PVP 中的熔点降低数据表明了相互作用的组成依赖性和链长效应。物理混合物的水分吸附不仅提供了组成依赖性相互作用参数，而且还估计了在存在水的情况下萘普生在 PVP 中的组成依赖性混溶性。
