JOURNAL OF MOLECULAR LIQUIDS
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2022
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IF 6.633
Guangxin Tian,Ying Luo,Boxuan Lou,Jingjiao Sui,Xiaolan Qin,Yuhui Shen,Xueyan Zhu,Jie Lu
Resmetirom (MGL-3196) can form masses of solvates with a variety of solvents. In this study, a series of solvates, including those reported in patents and newly discovered solvates, were prepared by experimental screening. Hansen solubility parameters (HSPs) were used to investigate the formation rules of MGL-3196 solvates, and the results showed that the formation of MGL-3196 solvates was most related to the parameter Δ δ t . When the Δ δ t value between MGL-3196 and solvent was less than 14.23 MP0.5 a, MGL-3196 tended to form solvate with an accuracy of 84.09%. The precise crystal structures of six solvates and one solvent-free form (form A) were acquired by single crystal X-ray diffraction (SCXRD). After analyzing the structures of obtained solvates in-depth from the aspects of conformation, dimeric synthon, molecular packing, porosity and isostructuralism, the six solvates were classified into alcohol solvates (group 2), ester solvates (group 3) and other types of solvates (group 1). Generally, these three groups of solvates had completely different crystal structures. The solvates in group 1 and group 3 were channelized and isostructural in which solvents could be substituted without great influence on the structure, while in the alcohol solvates (group 2) solvents were fixed by strong hydrogen bonds to be a part of the crystal structure. Moreover, when solvates were desolvated, two metastable solvent-free forms (i.e., B and C) were crystallized and then transformed to form A through a structural rearrangement. The possible mechanisms for the phase transformation during different desolvation processes were finally proposed. All results shall provide an understanding and inspiration on the screening and production of polymorphic and pseudopolymorphic forms of MGL-3196 for the pharmaceutical industry.
研究领域:
药学
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化学
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DOI
高影响因子
RSC Advances
·
2023
·Vol. 13
·期 32
·22172-22184
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IF 3.9
Chang Liu,Yue Xu,Haikuan Yuan,Guangxin Tian,Xiaolan Qin,Boxuan Lou,Xijian Liu,Lijuan Zhang,Jie Lu
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.
研究领域:
药物化学
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制药工程
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2024
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IF 6.9
Sun Kai,Zhu Nan-lin,Huang Su-ling,Qu Hui,Gu Yi-pei,Qin Li,Liu Jia,Leng Ying
Excessive dietary calories lead to systemic metabolic disorders, disturb hepatic lipid metabolism, and aggravate nonalcoholic steatohepatitis (NASH). Bile acids (BAs) play key roles in regulating nutrition absorption and systemic energy homeostasis. Resmetirom is a selective thyroid hormone receptor β (THRβ) agonist and the first approved drug for NASH treatment. It is well known that the THRβ activation could promote intrahepatic lipid catabolism and improve mitochondrial function, however, its effects on intestinal lipid absorption and BA compositions remain unknown. In the present study, the choline-deficient, L -amino acid defined, high-fat diet (CDAHFD) and high-fat diet plus CCl 4 (HFD+CCl 4 )-induced NASH mice were used to evaluate the effects of resmetirom on lipid and BA composition. We showed that resmetirom administration (10 mg·kg −1 ·d −1 , i.g.) significantly altered hepatic lipid composition, especially reduced the C18:2 fatty acyl chain-containing triglyceride (TG) and phosphatidylcholine (PC) in the two NASH mouse models, suggesting that THRβ activation inhibited intestinal lipid absorption since C18:2 fatty acid could be obtained only from diet. Targeted analysis of BAs showed that resmetirom treatment markedly reduced the hepatic and intestinal 12-OH to non-12-OH BAs ratio by suppressing cytochrome P450 8B1 (CYP8B1) expression in both NASH mouse models. The direct inhibition by resmetirom on intestinal lipid absorption was further verified by the BODIPY gavage and the oral fat tolerance test. In addition, disturbance of the altered BA profiles by exogenous cholic acid (CA) supplementation abolished the inhibitory effects of resmetirom on intestinal lipid absorption in both normal and CDAHFD-fed mice, suggesting that resmetirom inhibited intestinal lipid absorption by reducing 12-OH BAs content. In conclusion, we discovered a novel mechanism of THRβ agonists on NASH treatment by inhibiting intestinal lipid absorption through remodeling BAs composition, which highlights the multiple regulation of THRβ activation on lipid metabolism and extends the current knowledge on the action mechanisms of THRβ agonists in NASH treatment.
研究领域:
代谢生物学
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肝脏病学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Chemistry
·
2026
·
IF 5.3
Jisu Qin,Qunfeng Luo,Wenyi Wu,Qin Wang,Liangliang Cai,Yonghong Zhu,Shuang Wang
Background: Resmetirom (MGL-3196), a highly selective thyroid hormone receptor β agonist, is indicated for treating adults with noncirrhotic nonalcoholic steatohepatitis (NASH) exhibiting moderate to advanced liver fibrosis. Related substances are critical factors that directly impact the safety and efficacy of the active pharmaceutical ingredient (API). Therefore, the quantitative detection of related substances in resmetirom is of particular importance. Methods: This study established a reverse-phase high-performance liquid chromatography (RP-HPLC) for the separation of resmetirom and its related substances. The analysis was performed using an Agilent 5 HC C18 (2) column (250 mm × 4.6 mm, 5 µm) at 35 ℃, with detection at 220 nm. A gradient elution method was employed, achieving effective separation of all impurities within a 45-minute runtime. The final HPLC method utilized with a mixture of H2O/ACN (90/10, v/v) containing 0.045% TFA as mobile phase A, and ACN as mobile phase B. The gradient elution proceeded as follows: 0~2 min, 10% B→ 10% B; 2~20 min, 10% B→ 50% B; 20~30 min, 50% B→ 54% B; 30~35 min, 54% B→ 54% B; 35~36 min, 54% B→ 10% B; and 36~45 min, 10% B→ 10% B. The rate of flow was 1.0 mL/min. A 10 µL volume was used for the sample injection. This is a provisional file, not the final typeset article Results: The method was validated according to International Conference on Harmonization (ICH) guidelines, and the results demonstrated that it possesses good specificity, stability, linearity, precision, repeatability, and robustness. Furthermore, a new degradation product, designated as imp-A, was generated under alkaline degradation conditions in this study. Its chemical structure was elucidated using nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS), and this compound has been reported for the first time. Conclusion: The RP-HPLC method established in this study is capable of accurately and reliably separating and detecting resmetirom and its related substances. The method is simple to operate and yields dependable results, providing a practical and efficient analytical tool for the quality control of resmetirom and its formulations. This contributes to ensuring the safety and efficacy of the drug product.
✓ 已验证
DOI
PubMed
高影响因子
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