Thermodynamic acid dissociation constant Dotaz Zobrazit nápovědu
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
The mixed dissociation constants of five drug acids-ambroxol, antazoline, naphazoline, oxymetazoline and ranitidine-at various ionic strengths I of range 0.01 and 1.0 and at temperatures of 25 and 37 degrees C were determined using SQUAD(84) regression analysis of the pH-spectrophotometric titration data. A proposed strategy of efficient experimentation in a protonation constants determination, followed by a computational strategy for the chemical model with a protonation constants determination, is presented on the protonation equilibria of ambroxol. The thermodynamic dissociation constant pK(a)(T) was estimated by non-linear regression of {pK(a), I} data at 25 and 37 degrees C: for ambroxol p K (a ,1)(T )=8.05 (6) and 8.25 (4), logbeta (21)(T )=11.67 (6) and 11.83 (8), for antazoline p K (a ,1)(T )=7.79 (2) and 7.83 (6), p K (a ,2)(T )=9.74 (3) and 9.55 (2), for naphazoline pK (a ,1)(T )=10.81 (1) and 10.63 (1), for oxymethazoline pK (a ,1)(T )=10.62 (2) and 10.77 (7), pK(a,2)(T)=12.03(3) and 11.82 (4) and for ranitidine p K (a ,1)(T )=1.89 (1) and 1.77 (1). Goodness-of-fit tests for various regression diagnostics enabled the reliability of the parameter estimates to be found.
CZE has been applied for determination of acid-base dissociation constants (pKa) of ionogenic groups of newly synthesized amino- and (amino)guanidinopurine nucleotide analogs, such as acyclic nucleoside phosphonate, acyclic nucleoside phosphonate diesters and other related compounds. These compounds bear characteristic pharmacophores contained in various important biologically active substances, such as cytostatics and antivirals. The pKa values of ionogenic groups of the above compounds were determined by nonlinear regression analysis of the experimentally measured pH dependence of their effective electrophoretic mobilities. The effective mobilities were measured by CZE performed in series of BGEs in a broad pH range (3.50-11.25), at constant ionic strength (25 mM) and temperature (25 degrees C). pKa values were determined for the protonated guanidinyl group in (amino)guanidino 9-alkylpurines and in (amino)guanidinopurine nucleotide analogs, such as acyclic nucleoside phosphonates and acyclic nucleoside phosphonate diesters, for phosphonic acid to the second dissociation degree (-2) in acyclic nucleoside phosphonates of amino and (amino)guanidino 9-alkylpurines, and for protonated nitrogen in position 1 (N1) of purine moiety in acyclic nucleoside phosphonates of amino 9-alkylpurines. Thermodynamic pKa of protonated guanidinyl group was estimated to be in the range of 7.75-10.32, pKa of phosphonic acid to the second dissociation degree achieved values of 6.64-7.46, and pKa of protonated nitrogen in position 1 of purine was in the range of 4.13-4.89, depending on the structure of the analyzed compounds.
Thermodynamic acid-base dissociation (ionization) constants (pK(a)) of seven zwitterionic heterocyclic bases, first representatives of new heterocyclic family (2,3,5,7,8,9-hexahydro-1H-diimidazo[1,2-c:2',1'-f][1,3,2]diazaphosphinin-4-ium-5-olate 5-oxides), originally designed as chiral Lewis base catalysts for enantioselective reactions, were determined by capillary zone electrophoresis (CZE). The pK(a) values of the above very weak zwitterionic bases were determined from the dependence of their effective electrophoretic mobility on pH in strongly acidic background electrolytes (pH 0.85-2.80). Prior to pK(a) calculation by non-linear regression analysis, the CZE measured effective mobilities were corrected to reference temperature, 25°C, and constant ionic strength, 25 mM. Thermodynamic pK(a) values of the analyzed zwitterionic heterocyclic bases were found to be particularly low, in the range 0.04-0.32. Moreover, from the pH dependence of effective mobility of the bases, some other relevant characteristics, such as actual and absolute ionic mobilities and hydrodynamic radii of the acidic cationic forms of the bases were determined.
The mixed dissociation constants of four anticancer drugs--camptothecine, 7-ethyl-10-hydroxycamptothecine, 10-hydroxycamptothecine and 7-ethylcamptothecine, including diprotic and triprotic molecules at various ionic strengths I of range 0.01 and 0.4, and at temperatures of 25 and 37 degrees C--were determined with the use of two different multiwavelength and multivariate treatments of spectral data, SPECFIT32 and SQUAD(84) nonlinear regression analyses and INDICES factor analysis. A proposed strategy for dissociation constants determination is presented on the acid-base equilibria of camptothecine. Indices of precise modifications of the factor analysis in the program INDICES predict the correct number of components, and even the presence of minor ones, when the data quality is high and the instrumental error is known. The thermodynamic dissociation constant pK(a)(T) was estimated by nonlinear regression of {pK(a), I} data at 25 and 37 degrees C: for camptothecine pK(a,1)(T)=2.90(7) and 3.02(8), pK(a,2)(T)=10.18(30) and 10.23(8); for 7-ethyl-10-hydroxycamptothecine, pK(a,1)(T)=3.11(2) and 2.46(6), pK(a,2)(T)=8.91(4) and 8.74(3), pK(a,3)(T)=9.70(3) and 9.47(8); for 10-hydroxycamptothecine pK(a,1)(T)=2.93(4) and 2.84(5), pK(a,2)(T)=8.93(2) and 8.92(2), pK(a,3)(T)=9.45(10) and 9.98(4); and for 7-ethylcamptothecine pK(a,1)(T)=3.10(4) and 3.30(16), pK(a,2)(T)=9.94(9) and 10.98(18). Goodness-of-fit tests for various regression diagnostics enabled the reliability of the parameter estimates found to be proven. Pallas and Marvin predict pK(a) being based on the structural formulae of drug compounds in agreement with the experimental value.
Thermodynamic acidity constants (acid or acid-base dissociation constants, sometimes called also as ionization constants) and limiting ionic mobilities (both of them at defined temperature, usually 25°C) are the fundamental physicochemical characteristics of a weak electrolyte, that is, weak acid or weak base or ampholyte. We introduce a novel method for determining the data of a weak electrolyte by the nonlinear regression of effective electrophoretic mobility versus buffer composition dependence when measured in a set of BGEs with various pH. To correct the experimental data for zero ionic strength we use the extended Debye-Hückel model and Onsager-Fuoss law with no simplifications. Contrary to contemporary approaches, the nonlinear regression is performed on limiting mobility data calculated by PeakMaster's correction engine, not on the raw experimental mobility data. Therefore, there is no requirement to perform all measurements at a constant ionic strength of the set of BGEs. We devised the computer program AnglerFish that performs the necessary calculations in a user-friendly fashion. All thermodynamic pKa values and limiting electrophoretic mobilities for arbitrarily charged substances having any number of ionic forms are calculated by one fit. The user input consists of the buffer composition of the set of BGEs and experimentally measured effective mobilities of the inspected weak electrolyte.
Potentiometric and spectrophotometric pH-titrations of the lesinurad for three consecutive dissociation constants determination were compared. Lesinurad is a selective inhibitor of uric acid reabsorption as part of a combination of medicines to treat high levels of uric acid in blood, also called hyperuricemia. Nonlinear regression of the pH-spectra with REACTLAB and SQUAD84 and of the pH-titration curve with ESAB determined three multiple close dissociation constants. The protonation scheme of lesinurad was suggested. A sparingly soluble anion L- of lesinurad was protonated to the still soluble species LH, LH2+ and LH32+ in pure water. Three consecutive thermodynamic dissociation constants were estimated pKTa1 = 2.09, pKTa2 = 4.25, pKTa3 = 6.58 at 25 °C and pKTa1 = 1.96, pKTa2 = 4.16, pKTa3 = 6.32 at 37 °C by UV-metric spectra analysis. The graph of molar absorption coefficients shows that the spectrum of species LH2+ and LH vary in colour, while protonation of chromophore LH2+ to LH32+ has less influence on chromophores in the lesinurad molecule. Three multiple thermodynamic dissociation constants of 1 × 10-4 M lesinurad were determined by the pH-metric analysis pKTa1 = 2.39, pKTa2 = 3.47, pKTa3 = 6.17 at 25 °C and pKTa1 = 2.08, pKTa2 = 3.29, pKTa3 = 6.03 at 37 °C. The values of enthalpy ΔH0(pKa1) = 19.19 kJ mol-1, ΔH0(pKa2) = 13.29 kJ mol-1, ΔH0(pKa3) = 38.39 kJ mol-1, show the dissociation process is endothermic. The positive values of ΔG0(pKa1) = 11.93 kJ mol-1, ΔG0(pKa2) = 24.26 kJ mol-1, ΔG0(pKa3) = 37.56 kJ mol-1 at 25 °C indicate that the dissociation process of pKa2 is not spontaneous, which was confirmed by its value of entropy ΔS0(pKa1) = 24.37 J mol-1, ΔS0(pKa2) = -36.79 J mol-1, ΔS0(pKa3) = 2.79 J mol-1. Three macro-dissociation constants of lesinurad and protonation locations were predicted by MARVIN and ACD/Percepta.
- MeSH
- farmaceutická chemie MeSH
- koncentrace vodíkových iontů MeSH
- potenciometrie přístrojové vybavení metody MeSH
- spektrofotometrie ultrafialová přístrojové vybavení metody MeSH
- termodynamika * MeSH
- thioglykoláty chemie MeSH
- triazoly chemie MeSH
- urikosurika chemie MeSH
- Publikační typ
- časopisecké články MeSH
Baricitinib is a drug used for the treatment of rheumatoid arthritis. It is a selective and reversible inhibitor of Janus kinases 1 and 2, which play an important role in signalling the pro-inflammatory pathway activated in autoimmune disorders such as rheumatoid arthritis. The pH-spectrophotometric and pH-potentiometric titrations allowed the measurement of three or four successive dissociation constants of Baricitinib. Baricitinib neutral LH2 molecule was able to protonate into two soluble cations LH42+, LH3+ and dissociate into two soluble anions LH- and L2- in pure water. The graph of molar absorption coefficients of differently protonated species versus wavelength indicated that the spectra εL, εLH, εLH2 were the nearly the same for these species and that the spectra εLH4 and εLH3 were also similar. In the pH range from 2-13, four pKa´s of spectra analysis were reliably estimated by REACTLAB at I =0.0020 mol. dm-3 values pKTa1 = 3.07, pKTa2 = 3.87, pKTa3 = 6.27, pKTa4 = 12.78 at 25 °C and pKTa1 = 3.00, pKTa2 = 3.79, pKTa3 = 6.12, pKTa4 = 12.75 at 37 °C. Potentiometric pH-titration analysis for a higher concentration of 1 × 10-3 mol. dm-3 estimated with ESAB at I =0.0001 mol. dm-3 values pKTa1 = 3.69, pKTa2 = 3.81, pKTa3 = 4.73 at 25 °C and pKTa1 = 3.62, pKTa2 = 3.73, pKTa3 = 4.43 at 37 °C. Molar enthalpy ΔH°, molar entropy ΔS° and Gibbs free energy ΔG° were calculated from the spectra using a dependence ln K to 1/T.
- MeSH
- azetidiny * MeSH
- entropie MeSH
- koncentrace vodíkových iontů MeSH
- puriny MeSH
- pyrazoly MeSH
- sulfonamidy MeSH
- termodynamika MeSH
- Publikační typ
- časopisecké články MeSH
High-pressure methods have become an interesting tool of investigation of structural stability of proteins. They are used to study protein unfolding, but dissociation of oligomeric proteins can be addressed this way, too. HIV-1 protease, although an interesting object of biophysical experiments, has not been studied at high pressure yet. In this study HIV-1 protease is investigated by high pressure (up to 600 MPa) fluorescence spectroscopy of either the inherent tryptophan residues or external 8-anilino-1-naphtalenesulfonic acid at 25°C. A fast concentration-dependent structural transition is detected that corresponds to the dimer-monomer equilibrium. This transition is followed by a slow concentration independent transition that can be assigned to the monomer unfolding. In the presence of a tight-binding inhibitor none of these transitions are observed, which confirms the stabilizing effect of inhibitor. High-pressure enzyme kinetics (up to 350 MPa) also reveals the stabilizing effect of substrate. Unfolding of the protease can thus proceed only from the monomeric state after dimer dissociation and is unfavourable at atmospheric pressure. Dimer-destabilizing effect of high pressure is caused by negative volume change of dimer dissociation of -32.5 mL/mol. It helps us to determine the atmospheric pressure dimerization constant of 0.92 μM. High-pressure methods thus enable the investigation of structural phenomena that are difficult or impossible to measure at atmospheric pressure.
- MeSH
- anilin-naftalen sulfonáty metabolismus MeSH
- atmosférický tlak MeSH
- darunavir metabolismus MeSH
- dimerizace MeSH
- fluorescenční spektrometrie MeSH
- HIV-proteasa chemie metabolismus MeSH
- inhibitory HIV-proteasy metabolismus MeSH
- kinetika MeSH
- konformace proteinů MeSH
- lidé MeSH
- molekulární modely MeSH
- multimerizace proteinu MeSH
- sbalování proteinů * MeSH
- stabilita proteinů účinky léků MeSH
- termodynamika MeSH
- tryptofan metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
