ABSTRACT
Abstract Posaconazole exerts an extended spectrum of antifungal activity against various strains of clinically relevant moulds and yeasts. In recent years, antifungal triazole posaconazole has become increasingly important for the prophylaxis and treatment of systemic mycoses. After oral administration of posaconazole, absolute bioavailability has been estimated to range from 8% to 47%. Pharmaceutical co-crystallization is a promising approach for improving dissolution rate or manipulating other physical properties of API. The objective of this study is to improve the dissolution rate of posaconazole by co-crystallization. A 1:1 stoichiometric co-crystals of adipic acid were prepared by solvent assisted grinding method. The prepared co-crystals were subjected to solid-state characterization by FTIR, PXRD and DSC studies. The physicochemical properties of posaconazole and co-crystals were assessed in terms of melting point, flowability and dissolution rate. The results indicated improvement in flow property and dissolution rate. In vitro dissolution profile of co-crystals showed a significant increased dissolution of posaconazole from initial period in 0.1 N hydrochloric acid solution. The dissolution efficiency for posaconazole-adipic acid co-crystal was 61.65 % against posaconazole, 46.58 %. Thus, co-crystallization can be a promising approach to prepare posaconazole-adipic acid co-crystals with improved physicochemical properties.
Subject(s)
Administration, Oral , Crystallization/instrumentation , Hydrochloric Acid , Sprains and Strains/diagnosis , Yeasts/classification , In Vitro Techniques/methods , Pharmaceutical Preparations , Biological Availability , Spectroscopy, Fourier Transform Infrared , Efficiency , Dissolution , Mycoses/pathologyABSTRACT
The pharmaceutical co-crystal has attracted a lot of attention in recent years as a new direction in the research of polymorphism drugs. The research on pharmaceutical co-crystal has scientific significance for improving the solubility, bioavailability and physical or chemical stability of drugs. In this paper, from the perspective of drugs for the treatment of cardiovascular diseases(including five major types: heart failure, hypertension, coronary heart disease and arrhythmia, stroke) , the latest research results of pharmaceutical co-crystal reported in recent years are reviewed, hope to provide reference for the follow-up research and promote the development of pharmaceutical co-crystal in China.
ABSTRACT
OBJECTIVE: To prepare a novel naringenin co-crystal to improve the poor water solubility of the compound. METHODS: Solvent volatilization method was used to prepare naringenin nicotinamide co-crystal, with ethyl acetate as solvent. It is characterized by the technology of infrared spectroscopy (IR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), scanning electron microscopy (SEM) and other techniques. RESULTS: By measuring the equilibrium solubility of different pH solutions, it was found that the naringenin nicotinamide co-crystal has a significantly improved equilibrium solubility compared with naringenin. CONCLUSION: This method can improve the solubility of naringenin, which is simple and easy, and lays the foundation for further study of naringenin co-crystal.
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OBJECTIVE: To study anti-inflammatory effect and mechanism of the luteolin · 4, 4' -dipyridy co-crystal.METHODS: Using macrophage RAW264. 7 of normal mice as control, the inflammation model was established with lipopolysaccharide (LPS) -induced RAW264. 7 cells. MTT assay was used to detect cells activity 2 h after treatment of different concentrations of luteolin (10, 20, 40, 80 μmol/L), 4, 4' -dipyridy (10,20, 40,80 μmol/L) and luteolin·4, 4' -dipyridy co-crystal (10, 20, 40, 80 μmol/L). The mRNA expression of iNOS and COX-2 in RAW264. 7 cells at 40 μmol/L were determined by qRT-PCR. The protein expression of TNF-α and IL-6 in RAW264. 7 cells at 40 μmol/L were determined by ELISA. The protein expression of NF-κB p65 in RAW264. 7 cells at 40 μmol/L were determined by Western bolt. RESULTS: Compared with normal cells, the activity of RAW264. 7 cells was decreased significantly after induced by LPS (P<0. 01); mRNA expression of iNOS and COX-2, protein expression of TNF-α, IL-6 and NF-κB p65 were increased significantly (P<0. 01). Both luteolin and luteolin · 4, 4' -dipyridy co-crystal could enhance the activity of RAW264. 7 cells after induced by LPS (P<0. 05 or P<0. 01) in concentration-dependent manner. 4, 4' -dipyridy had no significant effect on the activity of RAW264. 7 cells after induced by LPS. After luteolin and luteolin· 4, 4' -dipyridy co-crystal at 40 μmol/L, mRNA expression of iNOS and COX-2, protein expression of TNF-α, IL-6 and NF-κB p65 in RAW264. 7 cells after induced by LPS were decreased significantly (P<0. 05 or P<0. 01); the luteolin · 4, 4' -dipyridy co-crystal was better than luteolin (P<0. 05 or P<0. 01). CONCLUSIONS: The luteolin·4, 4' -dipyridy co-crystal can inhibit the generation of inflammatory factors by down-regulating NF-κB signal, and its anti-i nflammatory effect is better than luteolin.
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Objective Two co-crystals of isonicotinic acid hydrazide(INH)-malonic acid and INH-glutaric acid were prepared.The formation mechanism and intermolecular interaction were studied. Methods Three-dimensional structure of 2 co-crystals were obtained though single crystal X-ray diffraction(SXRD), and intermolecular interaction was analyzed using Hirshfeld surface method. Results INH-malonic acid crystalized in stoichiometric ratio of 1:0.5,while INH-glutaric acid in 1:1.Two co-crystals maintain their stable arrangement in space by hydrogen bond and van der Waals force. Conclusion With the existence of pyridine ring and carbohydrazide group in INH,which mainter-molecular interaction in co-crystal can be directly and clearly revealed by Hirshfeld surface analysis.
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In this study, 1-(3-(4-chlorophenyl)-5-methylthio-1H-1,2,4-triazol-1-yl)-butan-1-one discovered previously in our lab was selected as a inhibitor of human dihydroorotate dehydrogenase (HsDHODH) for structural optimization. The co-crystal of HsDHODH with the hit was obtained and analyzed for guiding the subsequent structural optimization. As a result, a series of novel triazole derivatives were designed and synthesized as potent HsDHODH inhibitors. Among them, compound (3-(4-chlorophenyl)-5-ethylthio-1H-1,2,4-triazol-1-yl)-furan-2-yl-methanone displayed high potency in the inhibition of HsDHODH with an IC50 value of 1.50 μmol·L-1. Meanwhile, the structure-activity relationships were analyzed based on the biological data and the co-crystal structure. These results provide a valuable reference for optimization of 1H-1,2,4-triazole derivatives as HsDHODH inhibitors in the future.
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Ketoprofen or [2-(3-benzoylphenyl)propionic acid] is a nonsteroidal antiinflammatory and analgesic agent. The positive qualities of ketoprofen are based on optimal physicochemical and structural characteristics, its ability to penetrate into and accumulate in the inflammation centers and compatibility with other classes of drugs. This compound is practically insoluble in water, therefore as most of NSAID drugs, it is categorized as Biopharmaceutics Classification System (BCS) class II. A widely used to enhance the solubility of poorly water soluble drugs is co-crystallization. A co-crystal is a multi-component crystal which involves non-covalent interactions between API and its co-formers. In this work, we developed virtual screening of co-formers for ketoprofen by employing molecular docking method. AutoDock was used for docking. Parameters observed were type and energy (Ei) of interaction. The work was continued by co-crystallization process and solubility assay of the mixtures according to Higuchi and Connor method using UV spectrophotometer. Based on molecular docking, the best co-former is saccharin (Ei = -3.14 kcal/mol). The docking result fits the solubility assay of the ketoprofen-saccharin co-crystal (300.62 μg/mL in water or 256.54% increasing of solubility compared to ketoprofen). Ketoprofen co-crystal shows better curve (90.15 % in 60 minutes) than ketoprofen (78.87 % in 60 minutes). Co-crystallization of ketoprofen with saccharin increases the dissolution profile of ketoprofen.
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Baicalein-nicotinamide(BE-NCT)co-crystal was chosen as model drug to investigate the thermody-namic characteristics.Solubilities of BE in NCT solutions in ethyl acetate at different temperatures were deter-mined in order to explain the complexation behavior of BE-NCT co-crystal.Thermodynamic parameters of co-crys-tal formation progress were calculated.Ternary phase diagrams (TPDs)of the BE-NCT-ethyl acetate systems at various temperatures were established.The non-linear fitting equation according to 1 ∶1 complexation mechanism of BE-NCT co-crystal demonstrated a good correlation between calculated and experimental data (R2 >0.98). Co-crystal formation is a spontaneous process(ΔG°<0).Increase in temperature resulted in the increase of Ksp;decrease of K11 and a narrowed co-crystal zone.The degree of spontaneous reaction also decreased with increased temperature.The spontaneous reaction no longer carried out if the temperature reached T* =315 K sinceΔG°=0(ΔH°=-6.314 ×10 -2 kJ/mol;ΔS°=-0.200 5 J/mol.K).A drop in temperature favors the complexation between BE and NCT in ethyl acetate.Since NCT has higher solubility than BE in ethyl acetate;the TPDs of co-crystal was asymmetric.The DSC diagrams of products prepared via three presupposed methods confirmed that the BE-NCT co-crystal could be generated in solutions of nonstoichiometric compositions.
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Objective: To use co-crystal and solid dispersion technology, screen a suitable carrier material to prepare ursolic acid (UA) co-crystal solid dispersion in order to improve the solubility and dissolution of UA. Methods: UA and UA piperazine co-crystal (UA-PP) solid dispersions were prepared with solvent method by using four carriers, respectively. The solubility and in vitro dissolution of free drug, co-crystal, and solid dispersions were determined. Results: The solubility of UA and UA-PP solid dispersions was significantly higher than free drug and its physical mixtures. Solid dispersion technology could further increase the solubility of UA-PP and accelerate its in vitro dissolution rate. The result layed the foundation for the development of a novel oral formulation of ursolic acid. Conclusion: The co-crystal and solid dispersion technology could improve the solubility and dissolution of UA. The UA-PP solid dispersions show the best improvement in the solubility and dissolution of UA.
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Pharmaceutical materials science being a fundamental branch that continuously provides important insights, theories, and technologies to formulation sciences. The recent advances in this area have brought the possibility to produce pharmaceutical materials by design. In particular, the formation of co-crystals, i.e. crystalline molecular complexes of twoor more neutral molecules, represents a potential route to achieve pharmaceutical materials with improved properties of interest, including dissolution rate and stability under conditions of high relative humidity. Co-crystals consists of API and a stoichiometric amount of a pharmaceutically acceptable co-crystal former. Pharmaceutical co-crystals are nonionic supramolecular complexes and can be used to address physical property issues such as solubility, stability and bioavailability in pharmaceutical development without changing the chemical composition of the API. These can be constructed through several types of interaction, including hydrogen bonding, pi-stacking, and van der Waals forces. Phase transformations induced during processing/storage affects the mechanisms of conversion of crystalline drugs to co-crystals. Pharmaceutical co-crystals considered better alternatives to optimize drug properties could play a major part in the future of API formulation and can be employed for chiral resolution. This review introduces co-crystals as an emerging class of pharmaceutical materials, focusing on the experimental methods applicable to their crystallization. In addition, the examples illustrating how the co-crystal approach can be utilized to enhance the specific properties of pharmaceutical solids, such as dissolution rate of poorly-water soluble APIs and physical stability of moisture-labile APIs.