Makarova Veronika, Mandrik Mark, Antonov Sergey
A.V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, Leninsky pr. 29, 119991 Moscow, Russia.
Department of Pharmaceutical Technology, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Ministry of Health of the Russian Federation, 8-2 Trubetskaya str., 119991 Moscow, Russia.
Pharmaceutics. 2025 Jul 3;17(7):875. doi: 10.3390/pharmaceutics17070875.
The solubility and phase behavior of APIs are crucial for the development of medicines and ensuring their stability. However, conventional experimental approaches often do not allow for the precise determination of phase transitions and solubility limits, especially for poorly soluble compounds. The aim of this study was to demonstrate the possibility of using the laser microinterferometry method, traditionally used to define the phase equilibria of polymer systems, to determine the thermodynamic solubility of the APIs. Using laser microinterferometry, the thermodynamic solubility and phase behavior of amorphous darunavir were determined in various pharmaceutical solvents, including vaseline and olive oils, water, glycerol, alcohols (methanol, ethanol, isopropanol), glycols (propylene glycol, polyethylene glycol 400, polypropylene glycol 425, polyethylene glycol 4000), and ethoxylated polyethylene glycol ether obtained from castor oil in the temperature range of 25-130 °C. Dissolution kinetics was estimated at 25 °C. Hansen solubility parameter calculations were also performed for comparison. Darunavir is practically insoluble in olive and vaseline oils. In water and glycerol, an amorphous equilibrium with an upper critical solution temperature was observed, and phase diagrams were constructed for the first time. In alcohols, glycols, and ethoxylated polyethylene glycol ether obtained from castor oil, darunavir showed high solubility, accompanied by the formation of crystalline solvates. Kinetic evaluation showed that the dissolution rate of darunavir in methanol is four times faster than in ethanol and thirty times faster than in isopropanol. Comparison of the obtained data with previously published and calculated values of solubility parameters demonstrates a good correlation. Laser microinterferometry has been demonstrated as a potential tool for determining the thermodynamic solubility of APIs. This method allows for directly observing the dissolution process, determining the solubility limits, and detecting phase transitions. These studies are necessary for selecting appropriate excipients, preventing the formation of undesirable solvates and predicting formulation stability, which are all critical factors in early-stage drug development and pharmaceutical formulation design.
药物活性成分（APIs）的溶解度和相行为对于药物研发及确保其稳定性至关重要。然而，传统的实验方法往往无法精确测定相变和溶解度极限，尤其是对于难溶性化合物。本研究的目的是证明使用传统上用于定义聚合物体系相平衡的激光微干涉法来测定APIs热力学溶解度的可能性。利用激光微干涉法，在25 - 130°C的温度范围内，测定了无定形达芦那韦在各种药用溶剂中的热力学溶解度和相行为，这些溶剂包括凡士林和橄榄油、水、甘油、醇类（甲醇、乙醇、异丙醇）、二醇类（丙二醇、聚乙二醇400、聚丙二醇425、聚乙二醇4000）以及由蓖麻油制得的乙氧基化聚乙二醇醚。在25°C下估计了溶解动力学。还进行了汉森溶解度参数计算以作比较。达芦那韦实际上不溶于橄榄油和凡士林油。在水和甘油中，观察到具有上临界溶液温度的无定形平衡，并首次构建了相图。在醇类、二醇类以及由蓖麻油制得的乙氧基化聚乙二醇醚中，达芦那韦显示出高溶解度，并伴有结晶溶剂化物的形成。动力学评估表明，达芦那韦在甲醇中的溶解速率比在乙醇中快四倍，比在异丙醇中快三十倍。将所得数据与先前发表的以及计算得到的溶解度参数值进行比较，显示出良好的相关性。激光微干涉法已被证明是一种测定APIs热力学溶解度的潜在工具。该方法能够直接观察溶解过程、确定溶解度极限并检测相变。这些研究对于选择合适的辅料、防止形成不良溶剂化物以及预测制剂稳定性是必要的，而这些都是早期药物研发和药物制剂设计中的关键因素。
