Liu Chang, Xu Yue, Yuan Haikuan, Tian Guangxin, Qin Xiaolan, Lou Boxuan, Liu Xijian, Zhang Lijuan, Lu Jie
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science Shanghai 201620 China
RSC Adv. 2023 Jul 27;13(32):22172-22184. doi: 10.1039/d3ra02521g. eCollection 2023 Jul 19.
In this work, the solubility of resmetirom (form A) was initially measured in heptane and seven alcohol solvents by gravimetric methods. Then, the transformation temperature between form A and ethanol solvate was determined at 333.76 K. Subsequently, some commonly used models were applied to fit the solubility data, and it was found that the modified Apelblat equation and the Jouyban-Acree-van't Hoff (J-A-V) model achieved the highest correlation accuracy for those in mono-solvents and heptane + propanol, respectively. And the average relative deviation (ARD) values of models were less than 0.5%, indicating a good agreement with the experimental results. Additionally, through density functional theory calculation and the analysis of solvent parameters, it was observed that hydrogen-bonding played primary roles in the dissolution process of resmetirom. The multiple factors such as the polarity of solvent, active site interaction, the molecular size and free volume all affect the solubility of resmetirom. Furthermore, by comparing the experimental and simulated infrared spectra of form A and two alcohol solvates, five characteristic bands were selected for quantification. Partial least squares regression (PLSR), a multivariate statistical analysis method, was used to extract quantitative information. The quantitative analysis model was established based on specific wavelength intervals, which were associated with inter-molecular interactions. Combined with PLSR, a new high-precision quantitative method was established to study the solid transformation process between form A and solvates. From 303.15 to 323.15 K, the rate of transformation from form A to methanol solvate or ethanol solvate was decreased with increasing temperature, revealing that the transformation process was driven by the solubility difference between form A and solvates under the studied conditions. This research will definitely afford necessary solubility data and solvent selection for the design of the crystallization process of resmetirom (form A) in industry, and provide basic data for the production of resmetirom (form A) in the pharmaceutical industry.
在本研究中，首先采用重量法测定了瑞美替隆（晶型A）在庚烷和七种醇类溶剂中的溶解度。然后，确定了晶型A与乙醇溶剂化物之间的转变温度为333.76K。随后，应用一些常用模型对溶解度数据进行拟合，发现修正的Apelblat方程和Jouyban-Acree-van't Hoff（J-A-V）模型分别对单溶剂体系以及庚烷+丙醇体系中的溶解度数据具有最高的关联精度。模型的平均相对偏差（ARD）值均小于0.5%，表明与实验结果吻合良好。此外，通过密度泛函理论计算和溶剂参数分析，发现氢键在瑞美替隆的溶解过程中起主要作用。溶剂极性、活性位点相互作用、分子大小和自由体积等多种因素均影响瑞美替隆的溶解度。此外，通过比较晶型A和两种醇溶剂化物的实验红外光谱和模拟红外光谱，选择了五个特征谱带进行定量分析。采用多元统计分析方法偏最小二乘回归（PLSR）提取定量信息。基于与分子间相互作用相关的特定波长区间建立了定量分析模型。结合PLSR，建立了一种新的高精度定量方法来研究晶型A与溶剂化物之间的固相转变过程。在303.15至323.15K范围内，晶型A向甲醇溶剂化物或乙醇溶剂化物的转变速率随温度升高而降低，表明在所研究的条件下，转变过程是由晶型A与溶剂化物之间的溶解度差异驱动的。本研究无疑将为工业上瑞美替隆（晶型A）结晶过程的设计提供必要的溶解度数据和溶剂选择依据，并为制药工业中瑞美替隆（晶型A）的生产提供基础数据。
