Current experimental methodologies used to determine the thermodynamic solubility of an API within a polymer typically involves establishing the dissolution/melting end point of the crystalline API within a physical mixture or through the use of the glass transition temperature measurement of a demixed amorphous solid dispersion. The measurable “equilibrium” points for solubility are normally well above the glass transition temperature of the system, meaning extrapolation is required to predict the drug solubility at pharmaceutically relevant temperatures. In this manuscript, we argue that the presence of highly viscous polymers in these systems results in experimental data that exhibits an under or overestimated value relative to the true thermodynamic solubility. In previous work, we demonstrated the effects of experimental conditions and their impact on measured and predicted thermodynamic solubility points. In light of current understanding, we have developed a new method to limit error associated with viscosity effects for application in small-scale hot-melt extrusion (HME). In this study, HME was used to generate an intermediate (multiphase) system containing crystalline drug, amorphous drug/polymer-rich regions as well as drug that was molecularly dispersed in polymer. An extended annealing method was used together with high-speed differential scanning calorimetry to accurately determine the upper and lower boundaries of the thermodynamic solubility of a model drug–polymer system (felodipine and Soluplus). Compared to our previously published data, the current results confirmed our hypothesis that the prediction of the liquid–solid curve using dynamic determination of dissolution/melting end point of the crystalline API physical mixture presents an underestimation relative to the thermodynamic solubility point. With this proposed method, we were able to experimentally measure the upper and lower boundaries of the liquid–solid curve for the model system. The relationship between inverse temperature and drug–polymer solubility parameter (χ) remained linear at lower drug loadings. Significantly higher solubility and miscibility between the felodipine-Soluplus system were derived from the new χ values.

中文翻译：

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热熔挤出构建药物-聚合物温度-组成相图的新方法

用于确定API在聚合物中的热力学溶解度的当前实验方法通常涉及确定结晶API在物理混合物内的溶解/熔融终点，或者通过使用混合的非晶态固体分散体的玻璃化转变温度测量。溶解度的可测量“平衡”点通常远高于系统的玻璃化转变温度，这意味着需要推断才能预测药物在相关温度下的溶解度。在本手稿中，我们认为，这些系统中高粘度聚合物的存在导致实验数据相对于真实的热力学溶解度显示出偏低或偏高的值。在以前的工作中，我们证明了实验条件的影响及其对测得和预测的热力学溶解度点的影响。根据当前的理解，我们已经开发出一种新的方法来限制与粘度效应相关的误差，以用于小规模热熔挤出（HME）。在这项研究中，HME被用于生成一个中间（多相）系统，该系统包含结晶药物，无定形药物/富含聚合物的区域以及分子分散在聚合物中的药物。扩展退火方法与高速差示扫描量热法一起使用，可以准确确定模型药物-聚合物系统（非洛地平和Soluplus）的热力学溶解度的上限和下限。与我们之前发布的数据相比，目前的结果证实了我们的假设，即通过动态确定晶体API物理混合物的溶解/熔融终点来预测液固曲线，相对于热力学溶解度点存在低估。使用这种提议的方法，我们能够通过实验测量模型系统的液固曲线的上下边界。在较低的载药量下，逆温度与药物-聚合物溶解度参数（χ）之间的关系保持线性。从新的χ值得出非洛地平-Soluplus系统之间的溶解度和相溶性更高。使用这种提议的方法，我们能够通过实验测量模型系统的液固曲线的上下边界。在较低的载药量下，逆温度与药物-聚合物溶解度参数（χ）之间的关系保持线性。从新的χ值得出非洛地平-Soluplus系统之间的溶解度和相溶性更高。使用这种提议的方法，我们能够通过实验测量模型系统的液固曲线的上下边界。在较低的载药量下，逆温度与药物-聚合物溶解度参数（χ）之间的关系保持线性。从新的χ值得出非洛地平-Soluplus系统之间的溶解度和相溶性更高。