Solvent-driven polymorphic transformation and dissolution thermodynamics study of Iguratimod

IF 2.7 3区工程技术 Q3 CHEMISTRY, PHYSICAL

Fluid Phase Equilibria Pub Date : 2026-03-01 Epub Date: 2025-11-06 DOI:10.1016/j.fluid.2025.114615

Qing Yang, Shuai Peng, Yueting Zhu, Ke Chen, Jianfang Liu

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Abstract

The dissolution behavior of drugs is critical for understanding dissolution mechanisms and optimizing pharmaceutical formulations. This study investigated the solubility of the anti-rheumatic drug Iguratimod (IGU) in 12 organic solvents between 283.15 and 323.15 K at 101.3 kPa. Notably, solvent-induced polymorphic transformation yielded two distinct crystal forms: α and β. The Apelblat, λh, Yaws, NRTL, and Wilson models were employed to correlate the solubility data, with the Apelblat equation providing the most accurate prediction. Thermodynamic analysis shows that the dissolution of both polymorphs is endothermic and enthalpy-driven. Correlation analysis and Hirshfeld surface analysis indicate that the stability and solubility of crystal form α are mainly influenced by solvent polarity and hydrogen bond acidity. The crystal structure may be stabilized through an intrinsic hydrogen bonding network, and solubility is achieved in solvents that exhibit high polarity and low hydrogen bonding self-association tendency. The formation and solubility of crystal form β are determined by its unique crystal stacking mode, the formation of crystal structure is determined by the steric hindrance and weak hydrogen bonding donor ability of the solvent through dynamic pathway selection, and its solubility is mainly guided by the thermodynamic equilibrium between the lower lattice energy (HH and HO interactions) of the crystal itself and the high polarity solvation ability of the solvent. This work provides fundamental insights into solvent-induced polymorphic transformation, offering a theoretical basis for rational polymorph control and solvent selection in pharmaceutical processing.

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Iguratimod溶剂驱动的多晶转变及溶解热力学研究

药物的溶出行为对于了解药物的溶出机制和优化药物配方至关重要。本研究考察了抗风湿药物Iguratimod （IGU）在283.15 ~ 323.15 K、101.3 kPa的12种有机溶剂中的溶解度。值得注意的是，溶剂诱导的多晶转变产生了两种不同的晶体形式：α和β。采用Apelblat、λh、Yaws、NRTL和Wilson模型来关联溶解度数据，其中Apelblat方程提供了最准确的预测。热力学分析表明，这两种晶型的溶解都是吸热和焓驱动的。相关分析和Hirshfeld表面分析表明，α晶型的稳定性和溶解度主要受溶剂极性和氢键酸度的影响。晶体结构可以通过内在的氢键网络稳定，并且在具有高极性和低氢键自缔合倾向的溶剂中实现溶解度。β晶型的形成和溶解度是由其独特的晶体叠层方式决定的，晶体结构的形成是由溶剂的位阻和弱氢键给体能力通过动态途径选择决定的，其溶解度主要是由晶体本身的低晶格能（HH和HO相互作用）与溶剂的高极性溶剂化能力之间的热力学平衡所引导的。这项工作为溶剂诱导的多晶转化提供了基本的见解，为药物加工中合理的多晶控制和溶剂选择提供了理论依据。

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来源期刊

Fluid Phase Equilibria 工程技术-工程：化工

CiteScore

5.30

自引率

15.40%

发文量

223

审稿时长

53 days

期刊介绍： Fluid Phase Equilibria publishes high-quality papers dealing with experimental, theoretical, and applied research related to equilibrium and transport properties of fluids, solids, and interfaces. Subjects of interest include physical/phase and chemical equilibria; equilibrium and nonequilibrium thermophysical properties; fundamental thermodynamic relations; and stability. The systems central to the journal include pure substances and mixtures of organic and inorganic materials, including polymers, biochemicals, and surfactants with sufficient characterization of composition and purity for the results to be reproduced. Alloys are of interest only when thermodynamic studies are included, purely material studies will not be considered. In all cases, authors are expected to provide physical or chemical interpretations of the results. Experimental research can include measurements under all conditions of temperature, pressure, and composition, including critical and supercritical. Measurements are to be associated with systems and conditions of fundamental or applied interest, and may not be only a collection of routine data, such as physical property or solubility measurements at limited pressures and temperatures close to ambient, or surfactant studies focussed strictly on micellisation or micelle structure. Papers reporting common data must be accompanied by new physical insights and/or contemporary or new theory or techniques.