CRYSTAL GROWTH & DESIGN
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2022
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IF 4.01
Lu Liu,Yue-Ming Yu,Fan-Zhi Bu,Yan-Tuan Li,Cui-Wei Yan,Zhi-Yong Wu
To give full prominence to the superiority of phenolic acid nutraceuticals syringic acid (SYRA) and gallic acid (GALA) in perfection of in vitro and in vivo performances for cardiotonic drug milrinone (MLN), and ulteriorly attain novice insights in the development of cardiotonic drug-nutraceutical cocrystals, two new solid forms of MLN including one cocrystal with SYRA, and one cocrystal hydrate with GALA─namely, MLN-SYRA (1) and MLN-GALA- H2O (2)─are first assembled and thoroughly characterized. The single-crystal X-ray diffraction showcases that both cocrystal 1 and cocrystal hydrate 2 have three-dimensional supramolecular structures controlled by hydrogen-bonding and aromatic packing interactions, where the hydrogen-bonding dimers of MLN itself still remain in 1 but are broken in 2, forming hydrophobic cavities in the former and hydrophilic ones in the latter. Such structural characteristics and aggregation motifs, because of the introduction of different phenolic acids in the crystalline lattices, have important influence on the improvements of dissolvability and permeability for the two crystalline forms, and in accordance with the theoretical studies. Intriguingly, the optimized in vitro biopharmaceutical properties can be effectually transformed to satisfactory in vivo pharmacokinetic peculiarity, performing the increased bioavailability and extended half-life. Thus, the current research not only offers promising solid-state forms for MLN with development foregrounds, but opens up new applications for nutraceutical phenolic acids in cardiotonic pharmaceutical cocrystals.
研究领域:
药剂学
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药物化学
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药物递送
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生物药剂学
✓ 已验证
DOI
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
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2025
·
IF 4.7
Yue-Ming Yu,Lu Liu,Fan-Zhi Bu,Zhi-Long Zhao,Zhi-Yong Wu,Yan-Tuan Li
The combination of cardiotonic milrinone (MLN) and diuretics furosemide (FSM) is used to treat refractory heart failure clinically. However, the compatibility and stability issues of both limit the curative effect. For highlighting the superiority of cocrystallization technology in regulating drug performances, further getting new understanding for developing dual-drug cocrystals to realize their combination at the molecular level, a cocrystallization-driven drug-drug bidirectional optimization tactic is presented. By cocrystallizing MLN and FSM into the same lattice, for one thing, the in vitro/vivo properties of MLN can be optimized, and the photostability of FSM is raised simultaneously, thereby enhancing the bioavailability, and creating a prerequisite for the bidirectional optimization and the combination of these two drugs at the molecular level. Based on this, the dual-drug cocrystal MLN-FSM is successfully assembled and thoroughly characterized by multiple techniques. The evaluations of in vitro/vivo properties involving theory and experiment methods exhibit that the garnered cocrystal has achieved the simultaneous improvements in solubility and permeability versus pure MLN; meanwhile, the cocrystal formation also prominently enhances the stability of FSM relative to FSM itself. Interestingly, these bidirectional optimized in vitro properties change into in vivo pharmacokinetic strengths effectively, showcasing the raised bioavailability and extended half-life, thus laying a solid foundation for exerting the combined effect of the two drugs at the molecular level. Therefore, this research provides the first dual-drug cocrystal solid form with clinical combination drugs to treat cardiac failures, also offers innovative insights into leveraging the advantages of the cocrystallization-driven strategy for fulfilling the co-treatment of clinical combination drugs from the molecular levels.
研究领域:
药学
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晶体工程
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药物传递
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药物化学
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药理学
✓ 已验证
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Su-Su Meng,Yue-Ming Yu,Fan-Zhi Bu,Cui-Wei Yan,Zhi-Yong Wu,Yan-Tuan Li
The current research leverages the structural features and property superiorities along with benefits in protecting cardiovascular system of gallic acid (GLC) and gentisic acid (HGA) to optimize in vitro/vivo peculiarities of cardiotonic drug milrinone (MIL) through developing a stratagem of cocrystallization-driven double-optimized ternary salt cocrystal. This strategy assembles MIL ternary salt cocrystal by shaping a cocrystallization moiety relying on noncovalent interplays with GLC to obtain permeability advancement and molding a salt segment via the salification of proton transfer between HGA and MIL molecules to facilitate solubility enhancement. While the ameliorative in vitro properties further modulate the in vivo pharmacokinetic behaviors, thus fulfilling a dual optimization of MIL’s biopharmaceutical characteristics on both in vitro and in vivo aspects. Along this line, the first MIL ternary salt cocrystal, viz., [HMIL+-GA–]-MIL-GLC-H2O (denoted as MTSC hereinafter), has been satisfactorily constructed and precisely structurally identified by diversified techniques. The single-crystal X-ray diffraction experiment validates that a molecular salt [HMIL+-GA–] species cocrystallizes with one neutral MIL, two GLC, and five solvent water molecules, among which the organic constituents compose laminated hydrogen bond networks, and then are self-assembled by water molecules to a 3D supramolecular structure. The unique structural feature and stacking pattern of MTSC make both the permeability and solubility be respectively enhanced by 9.69 times and 5.17- to 6.03-fold compared with the parent drug per se. The experimental outcomes are powerfully supported by associated calculations based on density functional theory. Intriguingly, these optimal in vitro physicochemical natures of MTSC have been potently converted into strengths of in vivo pharmacokinetics, showcasing the elevated drug plasma concentration, elongated half-life, alongside advanced bioavailability. Consequently, this presentation not just contributes a brand-new crystalline form with utility values, but ushers in a new dimension of ternary salt cocrystals for improving in vitro/vivo limitations of poor drug bioavailability.
研究领域:
药剂学
·
药物化学
·
药物递送
·
生物药剂学
·
材料科学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2024
·
IF 4
Fan-Zhi Bu,Su-Su Meng,Ling-Yang Wang,Zhi-Yong Wu,Yan-Tuan Li
For the sake of fully laying stress on the advantages of multi-component cocrystals in ameliorating limitations of poor pharmaceutical peculiarities, and further offering fresh insights for the application of salt-type cocrystals in the optimization of anti-heart failure medication milrinone (MIL), the present project exploits the structural characteristic and property preponderance of gallic acid (GLC) and 3,5-dinitrobenzoic acid (HBA) to design and assemble MIL ternary salt cocrystal via a combination tactic of cocrystallization and salification. This strategy organizes the ternary salt-cocrystal by fashioning a salt portion to foster solubility enhancement and shaping a cocrystal moiety to achieve permeability advancement. Following this thread, the MIL ternary salt-cocrystal, namely [HMIL + -BA − ]-GLC H 2 O (indicated as TSC there-in-after), is accurately authenticated by comprehensive characterization means. Single-crystal X-ray diffraction affirms that the asymmetric unit of TSC comprises a [HMIL + -BA − ] salt, one neutral GLC molecule along with three water molecules, all of which build a three-dimensional hydrogen-bonding network containing electrostatic forces and π-π stacking interactions. Such unique structural feature and aggregation motif make MIL in TSC achieve a coinstantaneous elevation of 10.59 times in permeability and 4.76−5.15 folds in solubility versus the parent medicine itself at different physiological pH, which supports well agreement with the DFT-based theoretical investigations including reduced density gradient, molecular electrostatic potential surface, topology, Hirshfeld surface analysis, together with Gibbs free energy of solvation. All of these not only contribute a completely new cocrystalline model for MIL with synchronously optimizing dissolubility and permeability, but demonstrate the feasibility and effectiveness of ternary salt cocrystals in modifying the properties of anti-heart failure medicines.
研究领域:
药学
·
材料科学
·
理论化学
·
晶体学
✓ 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）