CRYSTENGCOMM
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2022
·Vol. 24
·期 17
·3217-3229
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IF 3.756
Yang Tao,Xiaoting Liu,Yunping Zhoujin,Panpan Zhou,Sean Parkin,Tonglei Li,Ju Guo,Faquan Yu,Sihui Long
To probe the effect of substitution on the benzoic acid ring on the polymorphism of phenylaminobenzoic acids, five 3-methyl-2-(phenylamino)benzoic acids (MPABAs) were synthesized. A preliminary polymorph screen led to one form for compounds 1–4 and three forms and a solvate (5-I, 5-II, 5-III, and 5-S) for compound 5. This observation is similar to that of the structurally related compounds with no substitution on the benzoic acid ring. All crystal forms were characterized by single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), and FT-IR spectroscopy. The polymorphs of compound 5 were investigated in detail experimentally and theoretically. A conformational scan provided insight into the origin of polymorphism of 5. NBO calculations confirmed the composition and nature of the sigma bond character of the two N–C bonds in 5. Hirshfeld analysis accounted for the major intermolecular interactions contributing to the overall stability of the crystals. It is clear that conformational flexibility alone doesn't lead to polymorphism, and substitution position and pattern are the real determinant of polymorphism in the investigated compounds.
研究领域:
化学
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材料科学
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药物化学
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DOI
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2022
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IF 5.518
Shiyuan Liu,Yuehua Deng,Weiqi Liu,Zhiqiang Li,Libo Li,Rui Zhang,Yanbin Jiang
The utilization of natural polymer gel to achieve drug polymorph control is usually a challenging issue, and the interplay of gelation and crystallization has been neglected in many studies. In this work, a modified chitosan (Cs) hydrogel was used to encapsulate drug Isonicotinamide (IN), where competitive crystallization and gelation was constructed for a better control of different assembly processes. It was found that the crystalline outcome of drug (cocrystals or IN Form I) depends on different crosslinking agents used. Spectral analysis and MD simulation reveal that the interplay of crosslinking effect of Cs, dimerization of crosslinking agents and aggregation of IN determines the crystalline outcome, among which the affinity to crosslinking agents of Cs chain plays the significant role. To our knowledge, it is the first time that Cs hydrogel acts as a template to regulate polymorphism of drug. This work offers a promising way for drug delivery system design.
研究领域:
药剂学
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材料科学
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DOI
高影响因子
Polymers
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2022
·Vol. 14
·期 22
·4902
·
IF 4.967
Lei Hua,Xiaodong Wang
New biodegradable aliphatic PLLA-PBA-PLLA copolymers with soft poly(butylene adipate) (PBA) and hard poly(l-lactide) (PLLA) building blocks were synthesized via ring-opening polymerization (ROP). Proton nuclear magnetic resonance (1HNMR) was utilized to confirm the volume fraction of PBA (fPBA) within PLLA-PBA-PLLA. It was found that a PBA midblock (PBA-mid) within PLLA-PBA-PLLA-s (PLLA-PBA-PLLA triblock copolymer with a short PLLA block length) might display lamellar domain structure. However, PBA-mid within PLLA-PBA-PLLA-l (PLLA-PBA-PLLA triblock copolymer with a long PLLA block length) might locate itself as a nanoscale cylindrical domain surrounded by a PLLA continuous phase. Polymorphic crystals of PBA-mid within the PLLA-PBA-PLLA copolymers were formed after melt crystallization at the given temperatures, which were studied by differential scanning calorimetry (DSC) and wide-angle X-ray diffraction (WAXD) analysis. According to the WAXD and DSC analyses, it was interesting to find that the α-type crystal of PBA-mid was favorable to develop in the lower temperature region regardless of the state (crystallization or amorphous) of the PLLA component. Additionally, when the PLLA component was held in its amorphous state, it was easier for PBA-mid within the PLLA-PBA-PLLA copolymers to transform from the metastable β-form crystal to the stable α-form crystal. Furthermore, polarized optical microscopy (POM) photos provided direct evidence of the polymorphic crystals of PBA-mid within PLLA-PBA-PLLAs.Keywords:biodegradable aliphatic;triblock copolymers;polymorphic crystal
研究领域:
材料科学
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高分子化学
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DOI
PubMed
高影响因子
CRYSTAL GROWTH & DESIGN
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2023
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IF 3.8
Yaoguo Wang,Genpei Shi,Kuo Wang,Weiwei Tang,Junbo Gong
Crystallization of chiral compounds is dictated by chiral recognition and molecular self-assembly in solution. However, their interplay remains elusive. The reason for the considerably reduced polymorphism in chiral molecules than that of nonchiral molecules remains unclear. Herein, we use a combination of experimental and computational techniques to show that excessive enantiomer functioning, as a native crystallization inhibitor, selectively suppresses the crystallization of racemic polymorphs, affording preferential crystallization of the metastable α polymorph of dl-methionine. Bulk crystallization assays show concomitant crystallization of the α and β polymorphs of racemic dl-methionine in the solution with no enantiomeric excess. However, when the solution contains excessive d-/l-methionine enantiomer, only the metastable α form can be crystallized. Crystal growth experiments, fluoresce confocal microscopy, and atomic force microscope surface topology measurements reveal the growth inhibition of both polymorphs with preferential suppression of the β form by excess native enantiomer. Binding energy calculations and molecular dynamic simulations further demonstrate the preferential adsorption of excessive enantiomers on the (0 0 2) facet of the β form over the α form. Overall, our results uncover a unique chiral self-positioning mechanism where the excess enantiomer solutes serve as a native growth inhibitor to disrupt the kinetics of racemic polymorphic crystallization, affording selective crystallization of only one polymorph of dl-methionine. Our results highlight the important effect of excess enantiomer in a solution on the polymorph occurrence of chiral molecules.
研究领域:
化学
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材料科学
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计算化学
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DOI
高影响因子
JOURNAL OF MOLECULAR LIQUIDS
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2023
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IF 6
Jinqiu Fu,Fan Wang,Yuzhong Shi,Chiyi Wang,Jingjing Zhao,Yihang Hou,Wei Zhuang,Hanjie Ying,Pengpeng Yang,Keke Zhang
Glutathione (GSH) is a bioactive oligopeptide which was widely used in sports, pharmaceutical and food industry. This paper compared the properties of two crystalline forms of GSH (Form α and Form β) in thermodynamics and explored the transformation of corresponding polymorph. The solubility data of GSH were determined by using the dynamic method in binary mixed solvents (methanol + water, ethanol + water, isopropanol + water, ethylene glycol + water) at temperatures ranging from 278.15 to 313.15 K. The solubilities of the two forms both increased with the increasing of mole fraction of water and temperature. The modified Apelblat equation, the CNIBS/R-K model and the Jouyban-Acree model were used to correlate the experimental solubility. The mixing thermodynamic properties of GSH in the binary mixed solvents were calculated by Van’t Hoff equation. Form β was supposed to be the stable crystalline form based on the thermodynamics analysis, which corresponded to the solvent-mediated transformation from Form α to Form β.
研究领域:
药学
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化学
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生物化学
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DOI
高影响因子
CRYSTAL GROWTH & DESIGN
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2023
·
IF 3.8
Hongji Liu,H. C. Stephen Chan,Xinyi Yu,Jianting Li,Jiaquan Li,Zhengzheng Zhou
In this study, the crystal structures of 1:1 theophylline–ferulic acid cocrystal polymorphs are reported for the first time. Interestingly, both forms crystallize in the same space group but with a different number of molecules in the asymmetric unit (form I = 2; form II = 4). The two polymorphs show distinct crystal morphology, demonstrating prism and rod single crystals, respectively. Theoretical calculations are performed to predict their morphology and thermodynamic stability (form I > form II). The prediction result agrees well with the measured pharmaceutical properties. Form I presents better hygroscopic stability (RH < 95%), slower dissolution, and lower solubility (1.06 ± 0.03, 1.63 ± 0.01, 1.30 ± 0.08 and 4.09 ± 0.05 mg/mL in water, pH = 1.2, pH = 4.5 and pH = 6.8 buffered solutions) over form II (8.45 ± 0.33, 2.41 ± 0.17, 3.46 ± 0.26 and 28.71 ± 0.87 mg/mL in water, pH = 1.2, pH = 4.5 and pH = 6.8 buffered solutions). In summary, this work elucidates the experimental findings with relevant predictions systematically and enriches our understanding of the structure–property relationship of the theophylline cocrystal system.
研究领域:
药物化学
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晶体学
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制药工程
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DOI
高影响因子
CRYSTAL GROWTH & DESIGN
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2024
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IF 3.2
Jiyong Liu,Chunguang Dai,Dier Shi,Kaxi Yu,Shuna Liu,Linshen Chen,Zhiguo Zheng,Xiurong Hu
Avatrombopag maleate (AVAT), a second-generation oral thrombopoietin (TPO) receptor agonist, is currently in development for the therapeutic management of thrombocytopenia. The present study introduces a novel comparative analysis that elucidates the intricate relationship between the crystallographic structures and the diverse physicochemical properties inherent to the complex polymorphic forms of the Avatrombopag (AVA) maleic salt. Seven solid-state forms, including two polymorphic forms (AVAT-B, AVAT-C), a new trihydrate (AVAT-3H), and four solvates (AVAT-A, AVAT-dimethyl sulfoxide (AVAT-DMSO), AVAT-dimethylformamide (AVAT-DMF), and AVAT-tetrahydrofuran (AVAT-THF)), were synthesized and analyzed in detail. Although the powder diffraction patterns for polymorphs AVAT-A, AVAT-B, and AVAT-C have been previously reported, our study marks the inaugural report of their crystallographic structures. Trihydrate and three new solvates were initially identified and subjected to a comprehensive characterization through thermal analysis, X-ray diffraction, etc. Thermal stability and transformation in aqueous solutions for different forms were conducted. Surprisingly, it was found that all five other solid forms except AVAT-B would be transformed to AVAT-3H when suspended in aqueous solution. All solvates retained their original framework structure after the removal of part of the solvent and could not lose all solvents until decomposition. AVAT trihydrate did not lose water upon storage under ambient conditions. Furthermore, the solubility profiles of AVAT-B, AVAT-C, and AVAT-3H were meticulously determined. By integrating the distinct molecular conformations with the respective intermolecular and intramolecular interactions as well as the packing arrangements, we were able to elucidate the underlying factors influencing their phase behavior. The insights gained from this analysis were instrumental in simulating crystal growth, thereby facilitating a comprehensive understanding of the specific interactions that govern the phase behavior of these compounds.
研究领域:
药学
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材料科学
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生物化学
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DOI
高影响因子
VIBRATIONAL SPECTROSCOPY
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2023
·
IF 2.5
Xinyu Cheng,Xiuzhi Chen,Chengfeng Liang,Hongjun Jin,Shizhao Ren,Rongrong Xue,Fenghua Chen
Bicalutamide (BIC) is one fluorine-containing drug with poor aqueous solubility, and it is essential to study the polymorphism of BIC, especially the metastable polymorphs and amorphous phase, to improve the oral effect. Selective crystallizations of BIC amorphous phases and solutions were studied and further explained and predicted by using mid-frequency Raman difference spectra (MFRDS) here. The relationships among various polymorphs and solutions of BIC were established by calculating the values of average deviation (a. d., the average value of absolute value of the intensity of MFRDS) and standard deviation (s. d.) of the MFRDS. And the possible routes to obtain metastable Form II and amorphous BIC were proposed based on the MFRDS results. Metastable Form II can be obtained by recrystallization of the amorphous BIC prepared through melt-quenching method. Amorphous BIC without additives can be prepared through a quicky evaporation process of acetone and ethyl acetate solutions, which was reported for the first time. The MFRDS results confirmed the presence of residual acetone and ethyl acetate in amorphous BIC obtained by evaporation, and the residual solvents changed the recrystallization products of amorphous BIC. MFRDS analysis can be a useful tool to guide the preparation and selective crystallization of metastable polymorphs and amorphous phase.
研究领域:
药学
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材料科学
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产品关联
DOI
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2023
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IF 5
Xiangjun Shi,Yu Deng,Zijuan Wang,Xinyue Liu,Qifeng Chen,Junjie Peng,Xiaoyi Xing,Weike Su
Nilotinib , a tyrosine kinase inhibitor of Bcr-Abl, is classified as a BCS IV drug with low solubility. Therefore, it is necessary to screen polymorphs with solubility advantages to enhance nilotinib bioavailability. In this study, two new polymorphs (form X and form Y) of nilotinib were prepared by melt crystallization . Notably, in the phosphate buffer saline (pH 6.8), the solubility and dissolution rate of form X were increased up to 4.00 and 7.04 fold than form A, and the solubility and dissolution rate of form Y were increased up to 1.07 fold and 1.52 fold than form A, which could provide more options for formulation development of nilotinib. Form X was induced by polymers, and the impact of polymers on polymorphism selectivity and nucleation induction time was investigated, which could be related to the effect of carbonyl groups and steric conformation of polymers. Form Y was prepared by two-time melt crystallization. Moreover, the formation of form Y was influenced by the thermal history, which displayed complex behavior concerning the parent melting state. Generally speaking, this study developed two nilotinib polymorphs with advanced solubility and discussed the mechanism of nilotinib melting crystallization, which could be guidance for melt crystallization screening.
研究领域:
药学
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药物化学
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制剂开发
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DOI
高影响因子
Crystals
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2022
·Vol. 12
·期 4
·550
·
IF 2.67
Xinbo Zhou,Kaxi Yu,Jiyong Liu,Zhiping Jin,Xiurong Hu
Baloxavir marboxil (BXM) is a new blockbuster FDA-approved anti-influenza virus agent. However, its poor solubility has limited its oral bioavailability. In this study, BXM was crystallized from several organic solvents, obtaining three polymorphs, and their dissolution behaviors were studied. Detailed crystallographic examination revealed that Form I is monoclinic, space groupP21, with unit cell parameters a = 7.1159 (3) Å, b = 20.1967 (8) Å, c = 9.4878 (4) Å, β = 109.033 (1)°,V= 1289.02 (9) Å3, andZ= 2, and Form II is monoclinic, space groupP21, with unit cell parameters a = 7.1002 (14) Å, b = 39.310 (7) Å, c = 9.7808 (18) Å, β = 110.966 (5)°,V= 2549.2 (8) Å3, andZ= 4. Form I has a rectangular three-dimensional energy frameworks net, while Form II has a two-dimensional net. On the other hand, Form II has a much larger percentage of its surface area of exposed hydrogen bond acceptors than Form I. These crystallographic features offered increased solubility and dissolution rate to Form II. The results of stability and solubility experiments suggest that Form II may be preferred in the solid form used for the industrial preparation of BXM medicinal products.Keywords:baloxavir marboxil;crystallization;polymorphism;crystal structure;energy framework;solubility
研究领域:
药学
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化学
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DOI
高影响因子
CRYSTAL GROWTH & DESIGN
·
2022
·
IF 4.01
Chunhao Liu,Yongli Wang,Yihan Zhao,Xin Li,Na Wang,Xin Huang,Ting Wang,Hongxun Hao
In an attempt to understand the relationship between solution chemistry and polymorphic nucleation, the flexible molecule chlorpropamide is used as a model compound to study its cooling crystallization behavior in four solvent systems. Online ATR-FTIR spectra proved the existence of dimers and solvated monomers in the solution. 2D nuclear overhauser effect spectroscopy and molecular dynamics simulations further revealed the molecular preassembled species in the solution. The results show that, in ethanol, ethanol/n-heptane, and ethyl acetate/n-heptane solvents, the solute molecules exist in the form of solvated monomers in multiple conformations. The stable formation of metastable form γ in ethyl acetate/n-heptane shows that, compared to conformational flexibility, the desolvation process plays a crucial role in overall self-assembly during the nucleation process. While in ethyl acetate, the solute molecules mainly exist as dimers and the rearrangement of the “wrong conformation” dimers becomes a key step to the nucleation rate and leads to the formation of stable form α. As a result, the self-association mode and conformational distribution of chlorpropamide in the solution work together to affect the nucleation process and polymorphic outcome.
研究领域:
化学
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材料科学
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DOI
高影响因子
Energetic Materials Frontiers
·
2022
·
IF 0
Zhi-qiang Wang,Zhen-qi Zhang,Shan-hu Sun,Mi Yan,Shi-liang Huang,Shuang-qi Hu,Jin-jiang Xu,Li-shuang Hu
Polymorphs of energetic materials generally exhibit distinct features, such as density, thermal stability, sensitivity, and detonation performance. These features are important in determining the appropriate applications of a given polymorph. To understand the thermal stability of new high explosive 4,4′,5,5′-tetranitro-1H,1′H- [2,2′-biimidazole]-1,1′-diamine (DATNBI), we systematically investigated its polymorphic transition (PT) under thermal stimulation and discovered a novel stable γ form of DATNBI. The results showed that the solid-solid PT path was β → α → γ . In this study, the three polymorphs of DATNBI were prepared through solvent recrystallization, and their PT processes in solution were explored. Crystal structure analysis of γ -DATNBI suggested that its special cross-cross grid crystal packing may be the main reason for its stable existence at room temperature and its lack of PT process before chemical decomposition, which starts at 240 °C. To further explore the PT process of DATNBI, the solid phase transition mechanism of DATNBI was analyzed using non-isothermal kinetics. The results demonstrated that the two high-temperature PT processes— β → α and α → γ —were not single-step reactions but complex multi-step reactions. The PT activation energy of the β → α process was slightly higher than that of the α → γ process. In addition, the influences of different polymorphs on the performance of DATNBI were explored. The results revealed that safety and detonation performance should decrease as a result of the incorporation of γ -DATNBI. This study contributes to understanding the PT behavior and the crystal structure evolutionary mechanism of DATNBI. This study provides practical support for formula design, process condition selection, and thermal stability evaluation of DATNBI explosives.
研究领域:
材料科学
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化学
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DOI
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