Solubilities of Crystalline Drugs in Polymers: An Improved Analytical Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP, PVP/VA, and PVAc
Solubilities of Crystalline Drugs in Polymers: An Improved Analytical Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP, PVP/VA, and PVAc
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DOI：
10.1002/jps.22251
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发表时间：
2010-09-01
影响因子：
3.8
通讯作者：
Yu, Lian
中科院分区：
文献类型：
--
作者：
Sun, Ye;Tao, Jing;Yu, Lian
本文对结晶药物在聚合物中溶解度的测定方法进行了改进，使其平衡时间更长，并用于测定吲哚美辛（IMC）和硝苯地平（NIF）在两种均聚物[聚乙烯吡咯烷酮（PVP）和聚醋酸乙烯酯（PVAc）]及其共聚物（PVP/VA）中的溶解度。这些数据对于理解无定形药物聚合物分散体的稳定性是重要的，无定形药物聚合物分散体是一种积极探索的用于递送难溶性药物的策略。测量聚合物的溶解度是困难的，因为它们的高粘度阻碍了溶解度平衡的实现。在该方法中，将通过低温研磨制备的药物聚合物混合物在不同温度下退火，并通过差示扫描量热法进行分析，以确定是否存在未溶解的晶体，从而确定平衡溶液温度的上限和下限。新的退火方法得到的结果与以前的扫描方法在相对较高的温度下得到的结果一致，但在较低的温度下稍微修正了以前的结果。它还降低了测量温度，更接近玻璃化转变温度。对于n-甘露醇和IMC在PVP中的溶解度，聚合物的分子量对重量溶解度的影响很小。对于IMC和NIF，聚合物的溶解能力遵循PVP > PVP/VA > PVAc的顺序。在所研究的每种聚合物中，NIF的溶解度低于IMC。IMC和NIF溶解在各种聚合物中的活动合理地很好地拟合Flory-Huggins模型，得到相关的药物聚合物相互作用参数。新的退火方法产生更准确的数据比以前的扫描方法时，溶解度平衡是缓慢实现。在实践中，这两种方法可以结合起来提高效率。测得的溶解度是不容易预测的，这强调了准确的实验数据的重要性，用于开发预测模型。(C)2010 Wiley-Liss，Inc.和American Pharmacologist Association J Pharm Sci 99：4023-4031，2010
A previous method for measuring solubilities of crystalline drugs in polymers has been improved to enable longer equilibration and used to survey the solubilities of indomethacin (IMC) and nifedipine (NIF) in two homo-polymers [polyvinyl pyrrolidone (PVP) and polyvinyl acetate (PVAc)] and their co-polymer (PVP/VA). These data are important for understanding the stability of amorphous drug polymer dispersions, a strategy actively explored for delivering poorly soluble drugs. Measuring solubilities in polymers is difficult because their high viscosities impede the attainment of solubility equilibrium. In this method, a drug polymer mixture prepared by cryo-milling is annealed at different temperatures and analyzed by differential scanning calorimetry to determine whether undissolved crystals remain and thus the upper and lower bounds of the equilibrium solution temperature. The new annealing method yielded results consistent with those obtained with the previous scanning method at relatively high temperatures, but revised slightly the previous results at lower temperatures. It also lowered the temperature of measurement closer to the glass transition temperature. For n-mannitol and IMC dissolving in PVP, the polymer's molecular weight has little effect on the weight-based solubility. For IMC and NIF, the dissolving powers of the polymers follow the order PVP > PVP/VA > PVAc. In each polymer studied, NIF is less soluble than IMC. The activities of IMC and NIF dissolved in various polymers are reasonably well fitted to the Flory-Huggins model, yielding the relevant drug polymer interaction parameters. The new annealing method yields more accurate data than the previous scanning method when solubility equilibrium is slow to achieve. In practice, these two methods can be combined for efficiency. The measured solubilities are not readily anticipated, which underscores the importance of accurate experimental data for developing predictive models. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4023-4031, 2010