Pharmaceutical Engineering Group, School of Pharmacy , Queen's University Belfast , 97 Lisburn Road , Belfast BT9 7BL , United Kingdom.
Mol Pharm. 2018 Apr 2;15(4):1379-1391. doi: 10.1021/acs.molpharmaceut.7b00445. Epub 2018 Mar 22.
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.
当前用于确定 API 在聚合物中的热力学溶解度的实验方法通常涉及确定物理混合物中结晶 API 的溶解/熔融终点，或者通过使用非混合无定形固体分散体的玻璃化转变温度测量来实现。可测量的溶解度“平衡”点通常远高于体系的玻璃化转变温度，这意味着需要外推来预测药物在药学相关温度下的溶解度。在本文中，我们认为在这些体系中存在高粘性聚合物会导致实验数据相对于真实热力学溶解度出现低估或高估值。在之前的工作中，我们证明了实验条件及其对测量和预测热力学溶解度点的影响。根据目前的理解，我们开发了一种新方法来限制与粘度相关的误差，以应用于小规模热熔挤出（HME）。在这项研究中，使用 HME 生成含有结晶药物、无定形药物/聚合物富区以及药物在聚合物中分子分散的中间（多相）系统。使用扩展退火方法和高速差示扫描量热法来准确确定模型药物-聚合物系统（非洛地平与 Soluplus）的热力学溶解度的上限和下限。与我们之前发表的数据相比，当前结果证实了我们的假设，即使用结晶 API 物理混合物的溶解/熔融终点的动态测定来预测液-固曲线会导致相对于热力学溶解度点的低估。使用这种提出的方法，我们能够实验测量模型系统的液-固曲线的上限和下限。在较低的药物负载下，温度倒数与药物-聚合物溶解度参数（χ）之间的关系仍然呈线性。从新的 χ 值得出，非洛地平-Soluplus 系统的溶解度和混溶性显著提高。
