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Byla stanovena rozpustnost nového antileukotrienického léčiva quinlukast (kyselina 4-{[4-(2-chinolylmethoxy) fenyl]sulfanyl}benzoová) ve vodě a ve vodných roztocích α-cyklodextrinu (α-CD), ß-cyklodextrinu (ß-CD), hydroxypropyl-ß-cyklodextrinu (HP-ß-CD, průměrný stupeň substituce 0,8) a methyl-ß-cyklodextrinu (M-ß-CD, průměrný stupeň substituce 1,8). Stanovená rozpustnost quinlukastu ve vodě byla 0,081±0,008 mmol/l (3,12±0,30 mg/100ml) a v roztocích ß-CD se pozorovalo pouze nevýznamné zvýšení rozpustnosti quinlukastu. Tři dobře rozpustné cyklodextriny však byly solubilizačně účinné, ve vodných roztocích s nevelkou koncentrací cyklodextrinu 5 g/100 ml se pozorovalo 12násobné zvýšení rozpustnosti quinlukastu v případě M-ß-CD a 10násobné zvýšení rozpustnosti v případě HP-ß-CD a α-CD. Byly stanoveny fázové diagramy rozpustnosti quinlukastu ve vodných roztocích těchto cyklodextrinů (do 0,05 mol/l). V případě M-ß-CD a HP-ß-CD byly diagramy rozpustnosti lineární (AL) a odpovídaly tvorbě rozpustného inkluzního komplexu quinlukast–cyklodextrin 1:1, s vyhodnocenými konstantami stability K11 300±35 l/mol (M-ß-CD) resp. 260± 30 l/mol (HP-ß-CD). Fázový diagram rozpustnosti quinlukastu ve vodných roztocích α-CD se vyznačoval výraznou pozitivní odchylkou od linearity (AP), solubilizační účinnost zředěných roztoků α-CD byla poměrně nízká, avšak progresivně vzrůstala s koncentrací α-CD. Při celkovém hodnocení se cyklodextriny α-CD, HP-ß-CD a M-ß-CD ukázaly být vhodnými solubilizéry quinlukastu do vodného roztoku.
Solubility of the new antileukotrienic drug quinlukast (4-{[4-(2-quinolylmethoxy)phenyl]sulfanyl}benzoic acid) was determined in water and in aqueous solutions of α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), hydroxypropyl- β-cyclodextrin (HP-β-CD, average degree of substitution 0.8), and methyl-β-cyclodextrin (M-β-CD, average degree of substitution 1.8). The determined solubility of quinlukast in water was 0.081±0.008 mmol/l (3.12± 0.30 mg/100ml) and only an insignificant increase in quinlukast solubility was observed in aqueous solutions of β-CD. However, three well soluble cyclodextrins showed a marked solubilizing effect, in aqueous solutions with a moderate cyclodextrin concentration 5 g/100ml, a 12-fold increase in quinlukast solubility was observed in the case of M-β-CD, and a 10-fold increase in the case of both HP-β-CD and α-CD. Phase solubility diagrams of quinlukast in aqueous solutions of these cyclodextrins (up to 0.05 mol/l) were determined. In the cases of M-β-CD and HP-β-CD, the solubility diagrams were linear (AL) and they corresponded to the formation of a soluble inclusion complex quinlukast – cyclodextrin 1:1 with the evaluated stability constants K11 300±35 l/mol and 260±30 l/mol for M-β-CD and HP-β-CD, respectively. The phase solubility diagram of quinlukast in aqueous solutions of α-CD showed a marked positive deviation (AP) from linearity, the solubilization efficiency of dilute α-CD solutions was relatively low but it increased progressively with the increasing α-CD concentration. In the overall evaluation, the cyclodextrins α-CD, HP-β-CD and M-β-CD appeared to be suitable for the quinlukast solubilization into aqueous solutions.
Metallacarboranes and their derivatives are the recently discovered inhibitors of HIV protease. The main goal of this work was to study the interaction of parent metallacarborane derivatives with cyclodextrins (CD) differing in the inner cavity size. This interaction can improve the drug solubility and its transport to the cells. For ?-, ß- and ?-CD, NMR titrations with sodium cobalt(III) bis(1,2-dicarbollide) were performed at various CD concentrations. It was found that the greatest change in the 1H NMR chemical shift is observed at position 3 of CD on the inner broader rim of the cone-shaped molecule of CD. For ?-CD, the NMR titration curves correspond to the 1:1 stoichiometry and to the stability constant ca. 900. For ß- CD, simultaneous formation of 1:1 and 2:1 complexes and higher stability constants at least by two orders of magnitude follow from the titration curves. For ?-CD, more than two types of complexes are present. It was shown for ß- CD that the increased temperature does not significantly influence the titration curves. The model, consisting of a high number of adjustable parameters, for the determination of stability constants of the complexes must be confirmed by independent analytical methods such as isothermal calorimetry and X-ray structure determination.
The model of electromigration of a multivalent weak acidic/basic/amphoteric analyte that undergoes complexation with a mixture of selectors is introduced. The model provides an extension of the series of models starting with the single-selector model without dissociation by Wren and Rowe in 1992, continuing with the monovalent weak analyte/single-selector model by Rawjee, Williams and Vigh in 1993 and that by Lelièvre in 1994, and ending with the multi-selector overall model without dissociation developed by our group in 2008. The new multivalent analyte multi-selector model shows that the effective mobility of the analyte obeys the original Wren and Row's formula. The overall complexation constant, mobility of the free analyte and mobility of complex can be measured and used in a standard way. The mathematical expressions for the overall parameters are provided. We further demonstrate mathematically that the pH dependent parameters for weak analytes can be simply used as an input into the multi-selector overall model and, in reverse, the multi-selector overall parameters can serve as an input into the pH-dependent models for the weak analytes. These findings can greatly simplify the rationale method development in analytical electrophoresis, specifically enantioseparations.
Two novel methods for determination of binding constants in the systems with borate and cyclodextrin complexation were developed. The methods enable to determine all binding parameters in these systems and even the binding constants of interaction of a neutral analyte with a neutral cyclodextrin. The first method is based on nonlinear fitting of experimental data and further evaluation of fitting parameters. The second method requires a multiple regression. The methods provide identical results with low experimental error. Only one set of measurements is required for both methods. Thus the binding parameters can be mutually compared. The binding parameters for neutral analytes ((R,R)-(+)-hydrobenzoin and (S,S)-(-)-hydrobenzoin) and neutral cyclodextrin (heptakis(2,6-di-O-methyl)-β-cyclodextrin) were evaluated and the effect of individual types of interaction was revealed. The interaction of the analytes with cyclodextrin governs the chiral recognition, while the complexation of analyte with borate is responsible for electromigration. Very low values of the binding constants of mixed analyte-cyclodextrin-borate complexes indicate that this type of complexation has negligible effect on enantioseparation.
ACE and vacancy affinity capillary electrophoresis (VACE) are the commonly used methods for determination of complexation constants by CE. The applicability and limitations of these methods were tested experimentally and by means of simulations using our simulation software Simul 5 Complex. It was shown that while the ACE method provides reliable and precise values of complexation parameters, those determined by VACE can be incorrect especially in the case of strong complexation. The effective mobilities of the system peaks in the VACE method, and consequently, the resulting complexation parameters were found to be a function of concentration of the analyte present in the BGE. Development of system peaks in VACE is discussed in the frame of the linear theory of electromigration. Dependence of mobility of system peaks on the composition of the BGE cannot be characterized by a simple analytical expression as in the case of ACE method. Thus, the VACE method fails and the resulting complexation constants might seriously differ from the reality.
The interactions of valinomycin, macrocyclic depsipeptide antibiotic ionophore, with ammonium cation NH4+ have been investigated. Using quantum mechanical density functional theory (DFT) calculations, the most probable structure of the valinomycin-NH4+ complex species was predicted. In this complex, the ammonium cation is bound partly by three strong hydrogen bonds to three ester carbonyl oxygen atoms of valinomycin and partly by somewhat weaker hydrogen bonds to the remaining three ester carbonyl groups of the valinomycin ligand. The strength of the valinomycin-NH4+ complex was evaluated experimentally by capillary affinity electrophoresis. From the dependence of valinomycin effective electrophoretic mobility on the ammonium ion concentration in the background electrolyte, the apparent binding (association, stability) constant (Kb) of the valinomycin-NH4+ complex in methanol was evaluated as log Kb = 1.52 +/- 0.22.
Macromolecular conjugates of a natural polysaccharide, hyaluronic acid, with diethylenetriaminepentaacetic acid (DTPA)-metal complexes were synthesized and characterized by FTIR, NMR, SEC-MALLS and ICP analysis. Several parameters of the cross-linking reaction as molecular weight of starting HA, temperature, equivalent of DTPA bis-anhydride, concentration of HA, presence of transacylation catalyst DMAP and reaction time were studied. The mechanism for the reaction was suggested and relationship between the molecular weight assigned by SEC-MALLS, reaction parameters and rheological properties of the final cross-linked products were investigated.
In this paper we determine acid dissociation constants, limiting ionic mobilities, complexation constants with β-cyclodextrin or heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, and mobilities of resulting complexes of profens, using capillary zone electrophoresis and affinity capillary electrophoresis. Complexation parameters are determined for both neutral and fully charged forms of profens and further corrected for actual ionic strength and variable viscosity in order to obtain thermodynamic values of complexation constants. The accuracy of obtained complexation parameters is verified by multidimensional nonlinear regression of affinity capillary electrophoretic data, which provides the acid dissociation and complexation parameters within one set of measurements, and by NMR technique. A good agreement among all discussed methods was obtained. Determined complexation parameters were used as input parameters for simulations of electrophoretic separation of profens by Simul 5 Complex. An excellent agreement of experimental and simulated results was achieved in terms of positions, shapes, and amplitudes of analyte peaks, confirming the applicability of Simul 5 Complex to complex systems, and accuracy of obtained physical-chemical constants. Simultaneously, we were able to demonstrate the influence of electromigration dispersion on the separation efficiency, which is not possible using the common theoretical approaches, and predict the electromigration order reversals of profen peaks. We have shown that determined acid dissociation and complexation parameters in combination with tool Simul 5 Complex software can be used for optimization of separation conditions in capillary electrophoresis.
- MeSH
- antiflogistika nesteroidní chemie MeSH
- beta-cyklodextriny chemie MeSH
- elektroforéza kapilární metody MeSH
- flurbiprofen chemie MeSH
- ibuprofen chemie MeSH
- ketoprofen chemie MeSH
- koncentrace vodíkových iontů MeSH
- magnetická rezonanční spektroskopie MeSH
- naproxen chemie MeSH
- osmolární koncentrace MeSH
- počítačová simulace MeSH
- software MeSH
- termodynamika MeSH
- viskozita MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
