CRYSTAL GROWTH & DESIGN
·
2022
·
IF 4.01
Shuqi Lu,Kaxi Yu,Shuping Wang,Jiyong Liu,Shuna Liu,Xiurong Hu,Guping Tang
Lenvatinib is a cancer treatment drug approved by the U.S. Food and Drug Administration, which is a multitarget tyrosinase inhibitor. The commercially available form is its mesylate. In this work, five lenvatinib mesylate (LEM) solid-state forms, including two polymorphs (LEM-A, LEM-C) and three pseudopolymorphs (a hydrate (LEM-H) and two iso-structural solvates (LEM-H-EA and LEM-H-THF)), were prepared and characterized using various methods. Powder diffractions of LEM-A and LEM-C have been reported, but their crystal structures were reported for the first time by us. Hydrate and two iso-structural solvates were also first prepared and characterized by thermal analysis, X-ray diffraction, and so forth. The mutual transformation of different forms was studied. Two solvates easily lost their solvent and turned into LEM-B, which provided the possibility for the preparation of LEM-B. In addition, thermal stability and solubility of LEM-A, LEM-C, and LEM-H were determined, along with the respective molecular conformation, their inter- and intramolecular interactions, and packing arrangements.
研究领域:
药物化学
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晶体学
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药剂学
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产品关联
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Shuting Li,Binbin Liu,Ziqiao Chen,Xiao Ou,Haowei Rong,Ming Lu
Identification of a thermodynamically stable polymorph is an important step in the early stage of drug development. Ritonavir (RIT) is a well-known case where the most stable polymorph II emerged after being marketed, leading to a loss of $250 million. Herein, we report the findings that routine melt crystallization can reveal the late-appearing polymorph II of RIT at small supercooling, but the probability of nucleation is very low. The addition of 30–50% polyethylene glycol (PEG) promotes the crystallization of Form II as the only phase at low supercooling, making it easier to detect in polymorphism screening. During the course of our research, a new polymorph, denoted Form III, was unexpectedly discovered, crystallizing as the major phase from neat RIT melts. Single crystals of Form III were grown from melt microdroplets. Benefiting from the ability of synchrotron radiation to detect weak diffraction signals that cannot be accessible by a laboratory diffractometer, a reasonable structure of Form III was solved with slight disorder relative to thiazole groups (P1 space group and Z′ = 4). The thermodynamic stability ranking of the three true polymorphs is Form II > Form I > Form III, as opposed to the order of solubility. The capacity to efficiently reveal rich polymorphs, especially the kinetically hindered polymorph, and rapidly grow single crystals of a new phase for structure determination together highlights the necessity of incorporating melt crystallization into routine methods for pharmaceutical polymorphism screening.
研究领域:
药学
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材料科学
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晶体学
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产品关联
DOI
PubMed
高影响因子
AICHE JOURNAL
·
2023
·
IF 3.7
Tuo Yao,Jian Liu,Xuxing Wan,Beibei Li,Sohrab Rohani,Zhenguo Gao,Junbo Gong
In situ monitoring and closed-loop control of the solution crystallization process are the modern trends for pharmaceutical development, in which the critical process parameters (CPPs) as well as the product critical quality attributes (CQAs) can be regulated and guaranteed during the manufacturing process. In this study, an in situ image monitoring methodology based on a state-of-the-art deep-learning model was developed to track the CQAs such as polymorph ratio, two-dimensional crystal size, and crystal shape in a solvent-mediated polymorphic transformation (SMPT) process. Coupled with the multidimensional process information, a 2D population balance model (PBM) was developed and validated using the results of the in situ image-based CQAs analysis. The 2D-PBM was solved using a high-resolution finite volume method (HR-FVM) which could provide a high dimensional particle-size distribution. Through the validation between the process image analysis and the 2D-PBM, the accuracy of image analysis was discussed, and the potential and challenges of in situ image analysis were proposed. This work aims to integrate the crystal polymorphism and two-dimensional crystal size distribution (2D-CSD) information in the SMPT process using intelligent microscopic image analysis and then to validate the results of neural network processing by solving the numerical solution of the multidimensional PBM.
研究领域:
制药工程
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化学工程
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人工智能应用
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产品关联
DOI
高影响因子
CRYSTAL GROWTH & DESIGN
·
2024
·
IF 3.2
Ronghua Peng,Xueyou Qin,Jiawei Lin,Lingyu Wang,Songgu Wu,Junbo Gong
We designed a solvent mixture composed of carboxylic acid solvents and water as the crystallization medium for the selective preparation of three distinct γ-aminobutyric acid (GABA) conformational polymorphs (Form-I, Form-II, and the newly discovered Form-IV). By adjusting the carbon chain length and content of carboxylic acid solvents, we were able to finely tune the solvation environment, leading to the formation of the desired polymorphs. Crash-cooling crystallization experiments demonstrated that with the carbon chain length (C1–C6) and content (0–30%) of carboxylic acid increasing, the polymorphic outcomes gradually change from Form-I to Form-II and ultimately to Form-IV. Interestingly, four different conformations were observed within these three polymorphs. DFT calculation indicated that the stability order of these conformations is conformer-IVβ > conformer-IVα > conformer-II > conformer-I. Based on solution FTIR analysis and solvation free energy calculation, the solvation effect on GABA molecules diminishes with an increasing carbon chain length and content of carboxylic acid solvents. A lower solvation effect makes the desolvation process of GABA molecules much easier so that GABA molecules can undergo sufficient conformational rearrangement during the nucleation stage, thereby adopting a more stable conformation during the molecular assembly process. In this crystallization conditions, Form-IV with a more stable conformation in its crystal structure has the potential to replace Form-II and Form-I through preferential crystallization.
研究领域:
化学
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材料科学
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药物学
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产品关联
DOI
高影响因子
Crystals
·
2019
·Vol. 9
·期 5
·260
·
IF 2.061
Manli Zhu,Yongli Wang,Fei Li,Ying Bao,Xin Huang,Huanhuan Shi,Hongxun Hao
In this work, theophylline was selected as the model compound to study and simulate the solution-mediated polymorphic transformation. The polymorph I and polymorph II of theophylline were prepared and fully characterized. Raman and UV spectra methods were carried out to observe the phase transformation of theophylline from polymorph I to polymorph II at different temperatures. The theoretical models, including dissolution model, nucleation model, and growth model, were established to describe and simulate the transformation processes. By combination of experiments and simulations, the controlling steps of the transformation processes were discussed. The effects of temperature and/or solvent on the transformation processes were evaluated. This work can shed light on the polymorphic transformation processes.Keywords:theophylline;polymorphic transformation;temperature;solvent;mathematical model
研究领域:
药学
·
化学
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DOI
高影响因子
INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH
·
2013
·
IF 2.206
Chongjun Liu,Leping Dang,Yao Tong,Hongyuan Wei
In this paper, the influence of polymorphs on the transformation water activity that corresponds to the transformation between hydrate and anhydrate of theophylline was investigated. Theophylline is known to exist either as anhydrates or a monohydrate. The transformation water activities of theophylline form II and IV were determined respectively, and the solubility data of these two forms in methanol, ethanol, acetonitrile, and acetone was also determined. The following thermodynamic derivation indicates that the transformation water activity ratio of theophylline forms II to IV can be correlated with the solubility ratio. According to the above study, the stability and intercoversion of theophylline polymorphs is discussed. This work will be useful in understanding the transformation process and benificial for industrial process control.
研究领域:
药学
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物理化学
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DOI
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 1
·449
·
IF 4.6
Canran Wang,Shan Jiang,Wenyue Ma,Zhaoyang Liu,Leijing Liu,Yongcun Zou,Bin Xu,Wenjing Tian
Radioactive iodine-capturing materials are urgently needed for the emerging challenges in nuclear waste disposal. The various pore structures of covalent organic frameworks (COFs) render them promising candidates for efficient iodine adsorption. However, the detailed structure–property relationship of COFs in iodine adsorption remains elusive. Herein, two polymorphic COFs with significantly different crystalline structures are obtained based on the same building blocks with varied molecular ratios. The two COFs both have high crystallinity, high specific surface area, and excellent chemical and thermal stability. Compared with the [C4+C4] topology (PyT-2) with an AA stacking form, the [C4+C2] topology (PyT-1) with an AB stacking form has more twisted pore channels and complex ink-bottle pores. At ambient conditions, PyT-1 and PyT-2 both exhibit good adsorption properties for iodine capture either in a gaseous or liquid medium. Remarkably, PyT-1 presents an excellent maximum adsorption capacity (0.635 g g−1), and the adsorption limit of PyT-2 is 0.445 g g−1in ann-hexane solution with an iodine concentration of 400 mg L−1, which is highly comparable to the state-of-the-art iodine absorption performance. This study provides a guide for the future molecular design strategy toward novel iodine adsorbents.Keywords:covalent organic framework;polymorphism;iodine adsorption
研究领域:
材料科学
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化学工程
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产品关联
DOI
PubMed
高影响因子
CRYSTAL GROWTH & DESIGN
·
2024
·
IF 3.2
Peizhuo Han,Lei Wang,Shuhong Song,Changlin Yao,Xutang Tao,Guanying Xie,Huimin Li,Yaqian Qu,Hongshuai Wang,Zeliang Gao,Yanyan Sun,Huachang Wu,Weiguo Song
Molnupiravir (MPV) is a widely used oral anti-COVID-19 drug. Owing to the rotatable bonds and the large number of acceptors and donors of hydrogen bonds in the molecular structure of MPV, three pure polymorphs (forms I, II, and III) and four solvates (ethanol, isopropanol, isobutanol, and tetrahydrofuran) of MPV (MPV-EtOH, MPV-IPA, MPV-IBA, and MPV-THF) were obtained. Importantly, the crystal structures of form I and the four solvates were successfully determined by single-crystal X-ray diffraction for the first time. Interestingly, all solvates are isostructural and have very similar unit cell parameters. Meanwhile, the solvent molecules in their structures are all in the voids surrounded by MPV molecules, forming a channel structure that facilitates desolvation. The formation mechanism of the solvates was also investigated based on the molecular electrostatic potential and hydrogen-bond energy of possible synthons. Moreover, a detailed stability study of MPV was conducted by using thermal analysis and dynamic vapor sorption. Finally, the phase transformations of the different solid forms were summarized. Our study provides a comprehensive understanding of the crystal landscape of the MPV.
研究领域:
药物化学
·
晶体学
·
生物医学
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产品关联
DOI
高影响因子
JOURNAL OF CHEMICAL THERMODYNAMICS
·
2017
·
IF 2.726
Qiaoyin Huang,Yang Li,Fuhong Yuan,Liping Xiao,Hongxun Hao,Yongli Wang
In this work, two different polymorphs (form 1 and form 2) of glycolide were successfully prepared and characterized. The solubility of these two polymorphs in ethyl acetate, 1-propanol, ethanol, 2-propanol and 1-butanol at temperatures from 278.15 K to 328.15 K under atmospheric pressure (0.1 MPa) was experimentally measured by using the isothermal gravimetrical method and correlated by the modified Apelblat model and the van’t Hoff equation. For all the selected solvents, the solubility curve of form 1 crossed the solubility curve of form 2 at a transition temperature in the above temperature range. Combining the results of DSC, solubility curves and dissolution data of these two polymorphs, it was confirmed that form 1 and form 2 were enantiotropic. The dissolution thermodynamic properties of glycolide form 1 and form 2 were also calculated.
研究领域:
物理化学
·
药学
✓ 已验证
产品关联
DOI
高影响因子
MICROPOROUS AND MESOPOROUS MATERIALS
·
2015
·
IF 3.453
Tingting Lu,Ruren Xu,Wenfu Yan
The initial mixture containing fully hydrolysed tetraethyl orthosilicate (TEOS) and tetraethylammonium hydroxide (TEAOH) solution was treated either by heating at 80 °C or by freeze-drying. After adding an appropriate amount of concentrated hydrofluoric acid , the resulting mixture was crystallized at 150 °C. The heating treated mixture produced polymorph A-enriched zeolite beta while freeze-drying treated mixture gave only normal zeolite beta. The 13 C magic angle spinning nuclear magnetic resonance (MAS NMR) analysis and thermogravimetric analysis (TGA) indicated that a partial decomposition of TEAOH to generate triethylamine (TEA) occurred during the heating dehydration process, which was the only difference compared with the freeze-drying process. Together with the reduced TEAOH, different monoamines as a co-template directed the polymorph A-enriched zeolite beta with the freeze-drying process. Diamines as a co-template directed only the normal zeolite beta. The synthesis cost of polymorph A-enriched zeolite beta can be significantly reduced by lowering the usage of expensive TEAOH and using cheaper monoamines.
研究领域:
材料科学
·
化学工程
✓ 已验证
产品关联
DOI
高影响因子
CRYSTENGCOMM
·
2021
·Vol. 23
·期 46
·8027-8032
·
IF 3.545
Fenghua Chen,Jie Fan,Xiuzhi Chen,Yanping Li,Chengfeng Liang,Shizhao Ren,Rongrong Xue
Polymorph control of 5-fluorouracil (5-FU) was achieved by ball milling. Form II was synthesized through one-step neat grinding of raw 5-FU (RFU), and Form III (a new polymorph) was obtained by neat grinding RFU twice. Forms II and III of 5-FU were prepared separately through ball milling with different amounts of ethanol as an additive at the same period without influencing each other.
研究领域:
药物化学
·
制药工程
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产品关联
DOI
高影响因子
CRYSTAL GROWTH & DESIGN
·
2021
·
IF 4.076
Mengnan Li,Chengyu Gong,Guobin Ren,Xiaoyong Xu,Minghuang Hong,Zhong Li
Although plant virus disease is destructive for economic losses of agricultural production, few studies focus on the field of solid state of pesticides. Dufulin (DFL) is a novel plant antiviral agent with high efficiency but low solubility and is easy to agglomerate during the process of crystallization. In this paper, the polymorphism behavior of DFL was systematically studied. Five polymorphs (Forms I–IV and VI), a solvate (Form V) and an amorphous form were discovered and characterized by powder X-ray diffraction and thermal analytical methods. Single crystals of Forms I, III, IV, V, and VI were obtained and their structures were identified by single-crystal X-ray diffraction. Based on the results of stability experiments (solid-state stability and solvent-mediated transition), thermal analysis methods, solubility studies and powder dissolution experiments, Form I appeared to be the thermodynamically most stable phase with the lowest solubility under ambient conditions, closely followed by Form III. In addition, the relative stability of the different crystal forms was simulated by density functional theory. As the result, the thermodynamic order of different forms was as follows: I > III > II > IV > VI > V. It is the first time that seven crystalline forms of DFL are reported, which fills the blank of DFL in the crystal engineering field and prompts the development of the formulation.
研究领域:
农药学
·
晶体工程
·
药物化学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）