Liquid-Liquid Phase Separation in Highly Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs: Implications for Solubility Enhancing Formulations
Liquid-Liquid Phase Separation in Highly Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs: Implications for Solubility Enhancing Formulations
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DOI：
10.1021/cg301679h
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发表时间：
2013-04-01
影响因子：
3.8
通讯作者：
Taylor, Lynne S.
中科院分区：
文献类型：
--
作者：
Ilevbare, Grace A.;Taylor, Lynne S.
高度过饱和的药物水溶液通常在药物测试期间和递送给患者时产生。这种溶液的相行为似乎很复杂，而且人们对它的了解很少，经常有关于胶体药物聚集体形成的报道。在这项研究中，八个疏水性差的水溶性药物分子在高度过饱和的水溶液中的相行为进行了检查，并解释了胶体形成的液液相分离（LLPS）。发现LLPS被观察到的浓度和理论上预测的无定形“溶解度”值之间的关系，其中后者是基于结晶固体/过冷液体和溶液活度系数的热力学性质预测的。利托那韦-水系统的相图作为温度的函数用于证明LLPS发生在相图的亚稳区，因此LLPS是结晶的前体。使用利托那韦和聚（乙烯基吡咯烷酮）的无定形固体分散体，表明通过过饱和剂型可实现的过饱和程度存在上限，并且该极限由LLPS相变浓度决定。在这项研究中概述的方法提供了一种替代方法来评估过饱和系统的性能，包括无定形溶解度的测定。
Highly supersaturated aqueous drug solutions are often generated during drug testing and upon delivery to the patient. The phase behavior of such solutions appears complex and poorly understood, with the formation of colloidal drug aggregates often being reported. In this study, the phase behavior of eight hydrophobic poorly water-soluble drug molecules in highly supersaturated aqueous solutions was examined, and colloid formation was explained in terms of liquid liquid phase separation (LLPS). A relationship was found between the concentration at which LLPS was observed and the theoretically predicted amorphous "solubility" value, where the latter was predicted based on the thermodynamic properties of the crystalline solid/supercooled liquid and solution activity coefficients. A phase diagram for the ritonavir-water system as a function of temperature was used to demonstrate that LLPS occurs in the metastable region of the phase diagram, and thus LLPS is a precursor to crystallization. Using an amorphous solid dispersion of ritonavir and poly(vinylpyrrolidone), it was shown that there is an upper limit to the extent of supersaturation achievable by a supersaturating dosage form and that this limit is dictated by the LLPS phase transition concentration. The approaches outlined in this study provide an alternative way to assess the properties of supersaturating systems, including the determination of the amorphous solubility.