NEW JOURNAL OF CHEMISTRY
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2021
·Vol. 45
·期 42
·19704-19713
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IF 3.591
Yunan Zhang,Yu Duan,Jin Su,Lixin Liu,Yanru Feng,Lili Wu,Lei Zhang,Yunjie Zhang,Dongyu Zou,Yingli Liu
In order to improve the solubility of pipemidic acid (PPA) which belongs to quinolones and becomes an “old drug” due to its low aqueous solubility that restricts its application, two unreported pharmaceutical salts of PPA with catecholcarboxylic acid (CCA) (HPPA·C7H5O4·2(H2O)) and m-hydroxybenzoic acid (MHA) (HPPA·C7H5O3·C7H6O3·2(H2O)) have been designed, synthesized and characterized. A comprehensive analysis of the structure and Hirshfeld surface reveals that the CAHBs formed from the N atoms in the piperazine ring from PPA molecules with the carboxylic acid group in the coformers could have a stable crystal structure. As expected, the solubility experiments showed that the solubilities of the PPA–CCA and PPA–MHA were significantly improved compared with that of the PPA, which may be due to the increased hydration enthalpy resulting from the formation of CAHBs between PPA and coformers, which leads to increased solubility. Moreover, the antibacterial activities of PPA–CCA and PPA–MHA are also improved. At the same time, surprisingly, the permeability of PPA–CCA and PPA–MHA was also better than that of PPA. In addition, the hygroscopic stabilities of PPA–CCA and PPA–MHA were significantly improved compared with that of PPA. The reason may be due to that the hydrogen bonds between PPA and CCA weaken their attraction to external water molecules. Thus, the present work implies that CAHBs play a key role in adjusting the molecular packing via a cocrystallization strategy to improve the physicochemical properties of quinolones, which could offer a tremendous opportunity to recycle these “old” drugs and give them a new life.
研究领域:
药学
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化学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Hui-Min Qin,Zheng-Kang Luo,Hui-Ling Zhou,Jin Zhu,Xin-Yi Xiao,Yang Xiao,Tao Zhuang,Gui-Sen Zhang
As the monotherapy of available analgesics is usually accompanied by serious side effects or limited efficacy in the management of chronic pain, multimodal analgesia is widely used to achieve improved benefit-to-risk ratios in clinic. Drug-drug salts are extensively researched to optimize the physicochemical properties of active pharmaceutical ingredients (APIs) and achieve clinical benefits compared with individual APIs or their combination. New drug-drug salt crystals metformin-ibuprofen (MET-IBU) and metformin-naproxen (MET-NAP) were prepared from metformin (MET) and two poorly water-soluble anti-inflammatory drugs (IBU and NAP) by the solvent evaporation method. The structures of these crystals were confirmed by single crystal and powder X-ray diffraction, Hirshfeld surface, Fourier transform infrared spectroscopy and thermal analysis. Both MET-IBU and MET-NAP showed significantly improved solubility and intrinsic dissolution rate than the pure IBU or NAP. The stability test indicated that MET-IBU and MET-NAP have excellent physical stability under stressing test (10 days) and accelerated conditions (3 months). Moreover, isobolographic analysis suggested that MET-IBU and MET-NAP exerted potent and synergistic antinociceptive effects in λ-Carrageenan-induced inflammatory pain in mice, and both of them had an advantage in rapid pain relief. These results demonstrated the potential of MET-IBU and MET-NAP to achieve synergistic antinociceptive effects by developing drug-drug salt crystals.
研究领域:
药学
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疼痛管理
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晶体化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2025
·
IF 5.2
Yuning Wang,Lixin Liu,Yunan Zhang,Yufeng Jiao,Lili Wu,Ji Zhao,Qiumei Zhang,Xinyu Tian,Huiyi Yang
To improve the physicochemical properties and biological activities of the nonsteroidal anti-inflammatory drug tolfenamic acid (TA) and the fluoroquinolone enrofloxacin (ENR). Based on the previous experience of our group in designing and synthesizing quinolone pharmaceutical co-crystals/salts single crystals by non-covalent bonding to improve their physicochemical properties, a drug-drug salt single crystal of tolfenamic acid-enrofloxacin was prepared for the first time using TA and ENR(TA-ENR, C 19 H 23 FN 3 O 3 ·C 14 H 11 ClNO 2 ·C 2 H 3 N). Single-crystal X-ray diffraction (SCXRD) analysis indicated that TA and ENR interacted predominantly through charge-assisted hydrogen bonds (CAHBs) within non-covalent bonds to form asymmetric units. Subsequently, the formation of dimers between ENR + cations in adjacent asymmetric units was promoted, leading to the formation of a stable crystalline structure through C6-H6···O2 and π···π stacking. Solubility experiments demonstrated that the solubility of TA-ENR was notably increased compared to TA. This can be ascribed to the CAHBs formed between TA and ENR, which facilitated the dissociation of TA in the dissolution medium, thereby enhancing TA’s affinity for the dissolution medium. Permeability experiments also revealed that the permeability of TA-ENR was significantly improved compared to both TA and ENR. The in vitro antimicrobial activity and anti-inflammatory activity of TA-ENR were also somewhat improved compared to TA and ENR. The success of this work implies that we may provide new ideas for designing and synthesizing solid drugs with better physicochemical properties and bioactivity, as well as for the treatment of septic arthritis, through the formation of drug-drug co-crystals/salts.
研究领域:
药学
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化学
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生物学
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产品关联
DOI
PubMed
高影响因子
CRYSTENGCOMM
·
2019
·Vol. 21
·期 35
·5284-5291
·
IF 3.382
Xinyi Wang,Shijie Xu,Lina Jia,Yujia Yang,Yu Liu,Junbo Gong,Songgu Wu
The incorporation of drug–drug salts is known as an attractive strategy to not only improve physicochemical properties but also extend the field of combination drug delivery. Mefenamic acid (MFA) and tolfenamic acid (TFA) belong to effective but poorly soluble anti-inflammatory drugs used for treating both humans and animals. Piperazine (PPZ) has anthelmintic activities with a serious hygroscopic problem. To improve the physicochemical properties of such drugs and seek possible drug combinations, herein, four novel MFA\TFA–piperazine (PPZ) drug–drug salts with different stoichiometry (2 : 1 and 1 : 1) were designed and synthesized. As we expected, the experiments proved that their solubilities and dissolution properties were much better than that of MFA and TFA. Among them, the apparent solubility of the MFA–PPZ salt (1 : 1) improved about 130 times more than that of MFA in a mixture of water and ethanol. Meanwhile, these salts were non-hygroscopic based on dynamic vapor sorption analysis. Moreover, the obtained crystals were fully analyzed by single-crystal X-ray diffraction (SXRD), Hirshfeld surface analysis and a solvent mediated phase transformation study, which provided a better understanding of the crystal structure. The MFA–PPZ salt (2 : 1) and TFA–PPZ salt (2 : 1) possessed a similar crystal structure and their solubilities were also similar. In addition, the incorporation of PPZ in the crystal lattice destroyed the dimer form in the original MFA\TFA crystal and resulted in the formation of salts through a new ionic hydrogen bond. After contact with the solvents, PPZ was more likely to interact with the solvent molecules, which may have led to the acceleration of dissolution.
研究领域:
药学
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材料科学
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兽医学
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产品关联
DOI
高影响因子
CRYSTAL GROWTH & DESIGN
·
2024
·
IF 3.2
Yanshan Zhu,Qiongxi Lin,Hongying Fan,Li Zhang,Shiying Yang,Dezhi Yang,Yang Lu,Zhengzheng Zhou
This study aims to prepare a stable crystal-co-agglomeration (CCA) process for combining the antibiotics trimethoprim (TMP) and the anti-inflammatory niflumic acid (NFA) as well as the enhancement of powder properties. A novel TMP–NFA salt monohydrate was synthesized and characterized through multitechniques for the first time. Subsequently, the antibacterial effectiveness of TMP–NFA salt monohydrate against Staphylococcus aureus and Shigella flexneri was found to be improved (P < 0.05) compared with that of TMP at certain concentrations, achieving a synergistic effect of TMP and NFA. Based on these findings, spherical agglomerates of TMP–NFA salt monohydrate with superior powder properties including improved flowability (Carr’s index decreased by 37.5% and Hausner’s ratio decreased by 16.3%) and tabletability were produced using an efficient CCA process. Hence, the optimized spherical agglomerates of the drug–drug salt technique provide a promising approach to simultaneously enhance the powder properties and synergistic effect of active pharmaceutical ingredients. The development of such drug–drug salts holds great potential for advancing pharmaceutical formulations and therapeutic outcomes.
研究领域:
药学
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化学
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微生物学
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产品关联
DOI
高影响因子
JOURNAL OF MOLECULAR LIQUIDS
·
2023
·
IF 6
Jianting Li,Shifang Song,Wanwen Huang,Hongying Fan,Zhengzheng Zhou
Enoxacin (ENX), a third-generation fluoroquinolone, demonstrates broad-spectrum antibacterial activities and is widely applied for the treatment of various bacterial infections. However, it is challenging to improve its antibacterial activity and drug resistance effects based on solubility changes owing to ENX being categorized as a class II drug in the Biopharmaceutics Classification System (BCS). In this experiment, three novel salts formed between ENX and non-steroidal anti-inflammatory drugs (NSAIDs) involving diclofenac (ENX-DFA), flufenamic acid (ENX-FFA) and niflumic acid (ENX-NFA) were firstly synthesized and then characterized. X-ray diffraction, thermodynamic analysis and infrared spectroscopy confirmed the salt formation. Interestingly, all the new salts demonstrated superior antibacterial activities against Escherichia coli ( E. coli ), Shigella flexneri ( Sh. flexneri ), Staphylococcus aureus ( S. aureus ) and Staphylococcus albicans ( S. albus ) compared with ENX. Further investigation of the pharmaceutical properties of the three salts revealed that they possessed lower aqueous solubility and intrinsic dissolution compared with ENX but exhibited better solubility than the three NSAIDs. Moreover, our results demonstrated that fluctuations in the solubility of ENX salts were pH-dependent. Thus, the solubility changes of ENX salts were assessed using pH-window diagrams. The order of lipid-water partition coefficient ( P ) was consistent with antibacterial performance (ENX-FFA > ENX-DFA > ENX-NFA > ENX) and was 2.04, 1.95, and 1.69 times greater than that of ENX, indicating that the higher Log P values of salts with strong cell membrane penetration ability improved the efficacy of the drug to inhibit bacterial growth. In summary, this study provides new insights to elucidate antibacterial effects from solubility and Log P values.
研究领域:
药理学
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微生物学
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药物开发
✓ 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）