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
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晶体学
·
生物医学
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DOI
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2024
·
IF 4
Jian Chen,Zheng Shen,Zhuoer Cai,Jilong Ge,Xiu-Ni Hua,Kai Sun,Baiwang Sun
Paliperidone (PLPT) is a pharmaceutical compound widely used in the treatment of psychiatric disorders. However, its limited solubility poses challenges for its formulation and bioavailability.In this study, three previously unreported salt solvates of PLPT were successfully synthesized: PLPT·PCBA·H 2 O (PCBA, para-chlorobenzoic acid), PLPT·NA·2H 2 O·2MeOH (NA, niacin acid), and PLPT·GA·2EtOH (GA, gallic acid). Considering the requirement of drying in actual production, the test samples were dried in a 333.15 K overnight and then used for TGA-DSC (thermogravimetric analysis-differential scanning calorimetry) testing. The results indicate that the thermal stability of PLPT·NA·2H 2 O·2MeOH was enhanced by approximately 40 K. The salt-like nature of these compounds was confirmed through ΔpKa calculations and single-crystal structure analysis, which revealed the formation of charge-assisted hydrogen bonds (N + -H···O − ). Significant hydrogen bonding and π-π interactions were observed, as evidenced by 3D d norm Hirshfeld surfaces and 2D fingerprint plots. They were characterized by predominant H···H, O···H, and N···H interactions, contributing to their structural stability. PXRD (powder X-ray diffraction) and IR (infrared spectroscopy) characterization provided further confirmation of the solvate formation. Notably, solubility experiments demonstrated a remarkable increase in the solubility of PLPT·NA·2H 2 O·2MeOH in simulated human body environments, exhibiting solubility enhancements of approximately 883.78 times, 166.57 times, 5.18 times, and 6.37 times across the range from pure water to pH 1.2. The remaining two salt solvates exhibit a notable enhancement in solubility under different pH conditions. An anomaly is observed only at pH 4, which is associated with the degree of protonation of PLPT and the intrinsic solubility of GA and PCBA. Dissolution rates indicate a significant improvement in all three salt solvates under various simulated human physiological environments, particularly at pH 6.8.These findings highlight the potential of these solvates as promising candidates for enhanced PLPT formulations. Dissolution rate experiments also indicate that the formation of salts significantly enhances the drug's dissolution rate. This study represents the first report on salt solvates of PLPT and provides valuable insights for the improvement of PLPT and other poorly soluble drug formulations.
研究领域:
药学
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材料科学
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化学
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产品关联
DOI
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2024
·
IF 4
Gang Li,Bibo Jiang,Yanyan Huang,Jiameng Shi,Hongjuan Pan,Hanbin Shan,Fuli Zhang,Jialiang Zhong
This study successfully obtained three new crystal forms of nirmatrelvir targeting its N3H site: the nirmatrelvir isobutyl acetate solvate (Solvate II), cocrystals with triethylene diamine (Cocrystal I) and 4-dimethylaminopyridine (Cocrystal II), along with the previously reported nirmatrelvir methyl tert‑butyl ether solvate (Solvate I), and polymorph Form I. Thermal analysis, single-crystal X-ray diffraction, and Fourier-transform infrared spectroscopy characterization were performed on these solvates and cocrystals to confirm their structural correctness. Concurrently, density functional theory calculations were conducted to determine the unit cell parameters of these five crystal forms, with the predicted spectral absorption peaks aligning well with the experimental data. Molecular electrostatic potential and frontier molecular orbital analyses were also carried out to elucidate the structural features of nirmatrelvir and identify its potential binding sites. To comprehensively understand the N3H site, the interaction region indicator functions and energy decomposition analysis, based on force field methods, were used for qualitative and quantitative analysis of intermolecular interactions. The analysis revealed that weak interactions in solvates and cocrystals are primarily dominated by van der Waals forces, while subtle differences in intermolecular weak hydrogen bonds are mainly attributed to dispersion forces. The solubility of these five crystal forms was investigated, and it was found that the enhancement of solubility is closely related to the type of hydrogen bonds and the hydrophilicity of the coformers. These findings offer new insights into the design of nirmatrelvir crystal forms and the study of their properties.
研究领域:
药物化学
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晶体学
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计算化学
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产品关联
DOI
高影响因子
JOURNAL OF MOLECULAR LIQUIDS
·
2022
·
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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产品关联
DOI
高影响因子
RSC Advances
·
2021
·Vol. 11
·期 40
·24836-24842
·
IF 3.361
Yunping Zhoujin,Mingtao Zhang,Sean Parkin,Tonglei Li,Faquan Yu,Sihui Long
A new solvate of clonixin (CLX), a dimethylacetamide (DMA) solvate, has been obtained by crystal growth in DMA. The new form was characterized by NMR, single-crystal X-ray diffraction, and PXRD. The crystal structure is stabilized by a strong hydrogen bond between the carboxylic acid OH of CLX and the DMA carbonyl, the strength of which is on par with those of the four solvent-free forms of CLX and the DMF solvate. These previously known forms are based on either the acid–acid homosynthon or the acid–pyridine heterosynthon, depending on the dihedral angle between the two aromatic rings of CLX, or the heterodimer between CLX and DMF. The new solvate loses DMA to convert into form I of CLX, as confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), similar to how the DMF solvate does. A comparison of the two solvates was carried out and theoretical studies were performed to shed light on the conformational difference between the two CLX molecules in the two solvates and the packing differences between them. The insight gained on this solvatomorphic system could aid the design of new solvates and cocrystals of CLX.
研究领域:
药物化学
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晶体学
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材料科学
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DOI
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2025
·
IF 4.7
Gang Li,Wenxia Sun,Jingming Yang,Hanbin Shan,Hongjuan Pan,Fuli Zhang,Lingjing Zuo,Jialiang Zhong
This study reports the successful preparation and detailed characterization of the isostructural ethanol (N-EA) and isopropanol (N-IPA) solvates of nirmatrelvir. Single-crystal X-ray diffraction reveals that both crystallize in the monoclinic P 2₁ space group, exhibiting nearly identical molecular conformations, packing modes, and hydrogen-bond networks. PXRD, TGA/DSC, and hot-stage microscopy confirmed stepwise solvent release, while dynamic vapor sorption demonstrated that the desolvation–resolvation cycle is rapid and strongly affects crystallite integrity. Compared with the solvent-free form N-I, incorporation of ethanol or isopropanol reduces crystal stability, resulting in marked increases in equilibrium solubility (2.6 - 2.9 mg·mL⁻¹ at pH 1.2 and 6.8) and intrinsic dissolution rate (up to 33-fold). These findings demonstrate that isostructural ethanol and isopropanol solvates enable precise modulation of nirmatrelvir’s physicochemical properties and offer a practical strategy for crystal-form engineering.
研究领域:
药物晶体工程
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药剂学
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结构化学
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分子药理学
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固态化学
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产品关联
DOI
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2019
·Vol. 44
·期 3
·852-860
·
IF 3.069
Juan Xu,Rongkai Du,Lvying Wu,Xianrui Zhang,Su Guan,Lei Zhang,Lifeng Ning,Shan Li
Two azilsartan–piperazine salt solvates with methanol (Az–Pz·MeOH) and ethanol (Az–Pz·EtOH) and a hydrate (Az–Pz·H2O) have been prepared and exhaustively characterized by physicochemical methods. The crystal structures suggest that one azilsartan transfers one proton from the carboxylic group to piperazine to form 2-D corrugation-like structures in Az–Pz·MeOH and Az–Pz·EtOH, and transfers two protons from carboxylic and oxadiazolyl groups to piperazine to form a 1-D chain structure in Az–Pz·H2O. The salt solvates and hydrate are very stable after 24 h slurry experiments in distilled water at 37 °C, and improve the azilsartan solubility with approximately a 322-fold increase for Az–Pz·H2O and a 140-fold increase for Az–Pz·MeOH and Az–Pz·EtOH over that of the free Az form. The pharmacokinetic experiments show that Az–Pz·EtOH and Az–Pz·H2O improve the plasma azilsartan concentration Cmax and AUC (P < 0.05) over the free Az form in Sprague-Dawley rats. The most incredible result is that Az–Pz·H2O features bioequivalence to an azilsartan tablet (Azilva®, P > 0.05). The research demonstrates that the pharmaceutical salt is a promising approach in increasing the solubility and enhancing the oral bioavailability of low-solubility azilsartan.
研究领域:
药学
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晶体学
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药物化学
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产品关联
DOI
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 17
·6320
·
IF 4.6
Fuying Li,Shiying Chen,Haoxin Hu,Chengfeng Liang,Shiyu Sun,Can Jin,Fenghua Chen
Crystallization selectivity is an important principle in polymorph control. Ribavirin Form I, Form II, DMSO solvate, and amorphous ribavirin are prepared, and the short-range order similarities between these solid forms and ribavirin aqueous solution and DMSO solution are compared via mid-frequency Raman difference spectra (MFRDS). The crystallization process from amorphous ribavirin to Form I and from solution to amorphous phase is explained. Reasons for the difficulty in preparing the DMSO solvate are proposed. The rationale provided for the crystallization selectivity provides a foundation for the synthesis of metastable phases with a robust and convenient method.Keywords:ribavirin;crystallization selectivity;solution;amorphous phase;solvate;mid-frequency Raman difference spectra
研究领域:
药学
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材料科学
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产品关联
DOI
PubMed
高影响因子
CRYSTENGCOMM
·
2021
·Vol. 23
·期 22
·3995-4004
·
IF 3.545
Pingping Cui,Qiuxiang Yin,Shihao Zhang,Wenchao Yang,Lihong Jia,Jiayu Dai,Ling Zhou,Zhao Wang
Amoxicillin sodium heterosolvates, including SM–M (methanol–methyl acetate solvate), SE–M (ethanol–methyl acetate solvate), and SM–E (methanol–ethyl acetate solvate), were obtained for the first time in this work. The single crystal of non-solvated crystal form (form I) was successful obtained via the phase transformation of amoxicillin sodium heterosolvate. The crystallographic data of amoxicillin sodium form I and heterosolvate were obtained via single crystal X-ray diffraction. Amoxicillin sodium molecules in form I and SM–M exhibited a similar conformation. In comparison with SM–M, the relative positions of the benzene ring and Na+ ion in form I was changed, thus facilitating the formation of a new coordinate bond between Na+ ion and phenolic hydroxyl group during the desolvation of SM–M. Methanol and methyl acetate molecules played different roles in the formation of SM–M. Methanol molecules formed strong coordinate bonds with amoxicillin sodium molecules, while methyl acetate molecules helped in improving the packing efficiency. The phase transformation behavior was explored via thermal analyses. The two-step desolvation mechanism of the heterosolvates was proposed and further verified via density functional theory computational analysis. Finally, the accelerated stability tests showed high relative humidity break the desolvation of heterosolvates and form I exhibited higher physical stability than the three heterosolvates.
研究领域:
药物化学
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晶体学
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材料科学
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DOI
高影响因子
CHEMICAL ENGINEERING & TECHNOLOGY
·
2022
·Vol. 45
·期 4
·678-686
·
IF 2.215
Guijun Zhu,Jianxin Chen,Jian Han,Jihui Li,Yupeng Li,Kaili Liu
5-Sulfoisophthalic acid sodium salt (5-SSIPA) is a crucial intermediate for pharmaceuticals, pesticides, and polyesters. Several acidic groups lead to an unstable crystal structure. Two new polymorphs and three novel solvates were identified during the solvent screening. These crystals were characterized by powder X-ray diffraction, Fourier transform infrared, and scanning electron microscopy. The desolvation temperature of solvates was found to be higher than the boiling point of pure solvents, which tentatively indicated the existence of an interaction between solvents and 5-SSIPA molecules. The phenomenon that the three solvates gradually darkened with desolvation in the hot-stage microscopic images proved the occurrence of crystal desolvation. The non-isothermal desolvation kinetics of the 5-SSIPA solvates was analyzed and discussed.
研究领域:
材料化学
·
药物化学
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DOI
高影响因子
CRYSTAL GROWTH & DESIGN
·
2023
·
IF 3.8
Rui Han,Haibin Qu,Yuxin Li,Yu Liu,Tiantian Tao,Weiwei Tang,Zhonghua Li,Junbo Gong
Crystals with an acicular shape are a “nightmare” to many chemical engineers due to their poor powder properties, posing numerous challenges in purification, filtration, washing, and subsequent processing. However, these challenges may be circumvented by engineering new crystal forms with better morphology using a crystal engineering strategy. Herein, we demonstrated the validity of this strategy with the case of thiothiamine, an essential intermediate in the production of vitamin B1, which exhibits a needle-like crystal morphology in polymorph I. Another two polymorphs (forms II and III) and 14 solvates were discovered and developed using a combination of computational prediction and experimental screening with X-ray diffraction, IR spectroscopy, and thermal analysis. Crystal structures of form II and six solvates were fully determined for the first time by single crystal X-ray diffraction. First, compared to form I, form II exhibits a notably larger grain size. Furthermore, the desolvation of solvates can retain its original superior morphology. These optimization strategies targeting crystal morphology directly contribute to the enhancement of the powder performance. Specifically, the filtration time was significantly reduced by over 70%, and the flowability of the powder was also greatly improved. Crystal structure analysis reveals that inclusion of small solvent molecules in a disordered manner contributes to solvate formation, while hydrogen bonding interactions contribute to the formation of methanol solvate. This study can serve as a valuable reference for addressing filtration and flowability challenges in industry by using crystal engineering strategies to develop polymorph or solvate alternatives.
研究领域:
药学
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材料科学
·
化学工程
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产品关联
DOI
高影响因子
CRYSTENGCOMM
·
2024
·Vol. 26
·期 7
·943-950
·
IF 2.6
Jinqiu Fu,Mengyang Cai,Yuzhong Shi,Yihang Hou,Rongxi Guo,Chiyi Wang,Jingjing Zhao,Wei Zhuang,Hanjie Ying,Pengpeng Yang,Keke Zhang
L-Alanyl-L-glutamine (Ala–Gln) is a dipeptide which is widely used in medical and nutritional fields. Two new crystalline forms (form III and form IV) and a DMSO solvate form (SDMSO) of Ala–Gln were discovered in this study, which were distinguished from the known forms by Raman spectroscopy and powder X-ray diffraction (PXRD). Single crystal structures of the three new solid forms were obtained. Moreover, the crystal structure data of known forms: form II, dihydrate form (2H) and ethanol solvate form (SEtOH), which have not been reported to the best of our knowledge, were solved. The results showed that there were four kinds of molecular arrangements and frameworks in the Ala–Gln solid forms. The comparison of the molecular arrangements and cell parameters indicated that the forms III, 2H and SEtOH were isomorphic. The hydrogen bonding network of the DMSO solvate was different from those of forms II, III and IV. By comparing the bulk density, lattice energy and thermal analysis results of the three polymorphs of Ala–Gln, the order of bulk density and lattice energy was consistent with the decomposition enthalpy. Besides that, it was found that the crystal shape of the solvates can be retained after solvent removal.
研究领域:
药学
·
晶体学
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）