The thermodynamic dissociation constants of losartan, paracetamol, phenylephrine and quinine by the regression analysis of spectrophotometric data

The mixed dissociation constants of four drug acids - losartan, paracetamol, phenylephrine and quinine - at various ionic strengths I of range 0.01 and 1.0 and at temperatures of 25 and 37 °C were determined using SPECFIT32 and SQUAD(84) regression analysis of the pH-spectrophotometric titration data. A proposed strategy of efficient experimentation in a dissociation constants determination, followed by a computational strategy for the chemical model with a dissociation constants determination, is presented on the protonation equilibria of losartan. Indices of precise methods 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. Improved identification of the number of species uses the second or third derivative function for some indices, namely when the number of species in the mixture is higher than 3 and when, due to large variations in the indicator values even at logarithmic scale, the indicator curve does not reach an obvious point where the slope changes. The thermodynamic dissociation constant was estimated by nonlinear regression of {pK_a, I} data at 25 and 37 °C: for losartan and 3.57(3), and 4.80(3), for paracetamol and 9.65(1), for phenylephrine and 8.95(1), and 10.22(1), for quinine and 4.12(1), and 8.46(2). Goodness-of-fit tests for various regression diagnostics enabled the reliability of the parameter estimates to be found.     

The thermodynamic dissociation constants of ambroxol, antazoline, naphazoline, oxymetazoline and ranitidine by the regression analysis of spectrophotometric data

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 °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 °C: for ambroxol and 8.25 (4), log  and 11.83 (8), for antazoline and 7.83 (6), and 9.55 (2), for naphazoline and 10.63 (1), for oxymethazoline and 10.77 (7), pK_a,2^T=12.03(3) and 11.82 (4) and for ranitidine and 1.77 (1). Goodness-of-fit tests for various regression diagnostics enabled the reliability of the parameter estimates to be found.     

The thermodynamic dissociation constants of the anticancer drugs camptothecine, 7-ethyl-10-hydroxycamptothecine, 10-hydroxycamptothecine and 7-ethylcamptothecine by the least-squares nonlinear regression of multiwavelength spectrophotometric pH-titration data

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 °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 was estimated by nonlinear regression of {pK_a, I} data at 25 and 37 °C: for camptothecine and 3.02(8), and 10.23(8); for 7-ethyl-10-hydroxycamptothecine, and 2.46(6), and 8.74(3), and 9.47(8); for 10-hydroxycamptothecine and 2.84(5), and 8.92(2), and 9.98(4); and for 7-ethylcamptothecine and 3.30(16), 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.     

Tutorial on a chemical model building by least-squares non-linear regression of multiwavelength spectrophotometric pH-titration data

Although the modern instrumentation enables for the increased amount of data to be delivered in shorter time, computer-assisted spectra analysis is limited by the intelligence and by the programmed logic tool applications. Proposed tutorial covers all the main steps of the data processing which involve the chemical model building, from calculating the concentration profiles and, using spectra regression, fitting the protonation constants of the chemical model to multiwavelength and multivariate data measured. Suggested diagnostics are examined to see whether the chemical model hypothesis can be accepted, as an incorrect model with false stoichiometric indices may lead to slow convergence, cyclization or divergence of the regression process minimization. Diagnostics concern the physical meaning of unknown parameters beta(qr) and epsilon(qr), physical sense of associated species concentrations, parametric correlation coefficients, goodness-of-fit tests, error analyses and spectra deconvolution, and the correct number of light-absorbing species determination. All of the benefits of spectrophotometric data analysis are demonstrated on the protonation constants of the ionizable anticancer drug 7-ethyl-10-hydroxycamptothecine, using data double checked with the SQUAD(84) and SPECFIT/32 regression programs and with factor analysis of the INDICES program. The experimental determination of protonation constants with their computational prediction based on a knowledge of chemical structures of the drug was through the combined MARVIN and PALLAS programs. If the proposed model adequately represents the data, the residuals should form a random pattern with a normal distribution N(0, s2), with the residual mean equal to zero, and the standard deviation of residuals being near to experimental noise. Examination of residual plots may be assisted by a graphical analysis of residuals, and systematic departures from randomness indicate that the model and parameter estimates are not satisfactory.     

Determination of acid dissociation constants based on continuous titration by feedback-based flow ratiometry

We propose a method for the determination of acid dissociation constants based on the rapid detection of the equivalence point (EP) by feedback-based flow ratiometry and the subsequent estimation of the half equivalence point (EP_1/2). The titrant (e.g., NaOH) flow rate F_B was varied in response to a control voltage V_c from a controller, while the titrand (e.g., CH₃COOH) flow rate F_A was held constant. The pH of the mixed solution was monitored downstream from the confluence point of the solutions following a knotted tubular mixer. Initially, V_c was increased linearly. At the instance the detector sensed EP, the ramp direction of V_c changed downward. The pH increased further because of the lag time between the mixing of solutions and the sensing of pH. Following the pH maximum, the pH decreased. The EP was sensed again in this downward scan. The V_c that gives EP_1/2 was computed from the V_c just at the time of the EP detection. The V_c was held constant at this level for 18 s, and the plateau pH value thus obtained was taken to be the pK_a of the analyte subject to activity corrections. Studies on the dependence of the pK_a on the ionic strength or dielectric constant of the solution were conducted in an automated fashion by delivering NaCl solution or acetonitrile through an additional channel. Satisfactory results were obtained with good throughput (53 s per determination) and precision (R.S.D.≈0.3%) for various acids.     

Thermodynamic dissociation constants of isocaine, physostigmine and pilocarpine by regression analysis of potentiometric data

Concentration and mixed dissociation constant(s) of three drug acids, H(J)L, isocaine, physostigmine and pilocarpine, at various ionic strengths, I, in the range 0.03-0.81 and 25 degrees C have been determined with the use of regression analysis of potentiometric titration data when common parameter, pK(a), and group parameters E'(0), L(0), and H(T) are simultaneously refined. Internal calibration of the glass electrode cell in the concentration scale [H(+)] performed during titration was used. The estimate of ill-conditioned group parameters has a great influence on a systematic error in estimated pK(a) and therefore it makes the computational strategy important. As more group parameters are refined and a better fit achieved, a more reliable estimate of dissociation constants results. The thermodynamic dissociation constant, pK(a)(T), an ill-conditioned ion-size parameter, ?, and the salting-out coefficient, C, were estimated by non-linear regression of {pK(a), I} data and an extended Debye-Hückel equation. The goodness-of-fit test based on regression diagnostics is a measure of the reliability of parameters, and proves that reliable estimates for isocaine pK(a)(T)(=)8.96(1), ?=8(3) A and C=0.50(3) at 25 degrees C, for physostigmine pK(a)(T)(=)8.07(3), ?=19(26) A and C=0.64(3) at 25 degrees C, and for pilocarpine pK(a)(T)(=)7.00(1), ?=7(1) A and C=0.53(2) at 25 degrees C were found.     

Potentiometric and spectrophotometric determination of the dissociation constants of cefetamet

Summary The dissociation constants of cefetamet-Na have been determined using potentiometric titrations and spectrophotometry. The investigations were carried on in water solutions at constant temperature and ionic strength, and at differentH ₀ andpH values. Potentiometric investigations were performed at three different temperatures and ionic strengths. The concentration dissociation constants and the corresponding thermodynamic dissociation constants were calculated by a computer program. The mixed dissociation constants (pK) of cefetamet-Na have been determined spectrophotometrically in theH ₀ range from -5.80 to 0.00 and atpH values from 0.00 to 12.70 and are in good agreement with values achieved by graphical methods as well as with those obtained by potentiometric methods. Based on the determined values, the thermodynamic parameters (G, H, S) were calculated atI=0.1M.

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Potentiometrische und spektrophotometrische Bestimmung der Dissoziationskonstanten von Cefetamet

Zusammenfassung Die Dissoziationskonstanten von Cefetamet-Na wurden mittels potentiometrischer Titrationen und auf spektrophotometrischem Weg bestimmt. Die Untersuchungen wurden in wäßriger Lösung bei konstanter Temperatur und Ionenstärke und verschiedenenH ₀- undpH-Werten durchgeführt. Potentiometrische Messungen wurden bei drei verschiedenen Temperaturen und Ionenstärken vorgenommen. Die stöchiometrische Dissozation und die entsprechenden thermodynamischen Dissoziationskonstanten wurden mit Hilfe eines Computerprogramms berechnet. Die gemischten Dissoziationskonstanten (pK) wurden spektrophotometrisch imH ₀-Bereich von -5.80 bis 0.00 und impH-Bereich von 0.00 bis 12.70 bestimmt und stimmen sowohl mit Werten, die mit Hilfe der graphischen Methode erhalten wurden, als auch mit potentiometrisch bestimmten gut überein. Aus den ermittelten Werten der Dissoziationskonstanten wurden die thermodynamischen Parameter (G, H, S) fürI=0.1M berechnet.

     

The thermodynamic dissociation constants of methotrexate by the nonlinear regression and factor analysis of multiwavelength spectrophotometric pH-titration data

The mixed dissociation constants of methotrexate — chemically (2S)-2-[(4-{[(2,4-diamino-7,8-dihydropteridin-6-yl)methyl] (methyl)amino}phenyl)formamido]pentanedioic acid (the cas number 59-05-2) at various ionic strengths I of range 0.01–0.4, and at temperatures of 25°C and 37°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 according to a general rule of first, determining the number of components, and then calculating the spectral responses and concentrations of the components. Concurrently, the experimental determination of the thermodynamic dissociation constants was in agreement with its computational prediction of the PALLAS programme based on knowledge of the chemical structures of the drug. The factor analysis in the INDICES programme predicts the correct number of light-absorbing components when the data quality is high and the instrumental error is known. Three thermodynamic dissociation constants were estimated by nonlinear regression of {pK _a , I} data: for methotrexate pK_a1^T= 2.895(13), pK_a2^T= 4.410(14), pK_a3^T= 5.726(15) at 25°C and pK_a1^T= 3.089(15), pK_a2^T= 4.392(12), pK_a3^T= 5.585(11) at 37°C, where the figure in brackets is the standard deviation in last significant digits. The reliability of the dissociation constants of the drug were proven by conducting goodness-of-fit tests of the multiwavelength spectrophotometric pH-titration data.      

The effect of aqueous organic solvents on the dissociation constants and thermodynamic properties of alkanolamines

The dissociation constants of protonated monoethanolamine and N-methyldiethanolamine have been determined in methanol–water, ethanol–water, and t-butanol–water solvents. The alcohol mole fractions were ranging from 0.2 to 0.95 and the temperatures from 283 to 323 K, 283 to 333 K, and at 298.15 K, respective to the different solvents. The experimental results are reported with the standard state thermodynamic properties. The basic strength of the protonated alkanolamine decreases with decreasing dielectric constant and increasing temperature of the solvent.     

Reliability and uncertainty in the estimation of p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> by least squares nonlinear regression analysis of multiwavelength spectrophotometric pH titration data

When drugs are poorly soluble then, instead of the potentiometric determination of dissociation constants, pH-spectrophotometric titration can be used along with nonlinear regression of the absorbance response surface data. Generally, regression models are extremely useful for extracting the essential features from a multiwavelength set of data. Regression diagnostics represent procedures for examining the regression triplet (data, model, method) in order to check (a) the data quality for a proposed model; (b) the model quality for a given set of data; and (c) that all of the assumptions used for least squares hold. In the interactive, PC-assisted diagnosis of data, models and estimation methods, the examination of data quality involves the detection of influential points, outliers and high leverages, that cause many problems when regression fitting the absorbance response hyperplane. All graphically oriented techniques are suitable for the rapid estimation of influential points. The reliability of the dissociation constants for the acid drug silybin may be proven with goodness-of-fit tests of the multiwavelength spectrophotometric pH-titration data. The uncertainty in the measurement of the pK _a of a weak acid obtained by the least squares nonlinear regression analysis of absorption spectra is calculated. The procedure takes into account the drift in pH measurement, the drift in spectral measurement, and all of the drifts in analytical operations, as well as the relative importance of each source of uncertainty. The most important source of uncertainty in the experimental set-up for the example is the uncertainty in the pH measurement. The influences of various sources of uncertainty on the accuracy and precision are discussed using the example of the mixed dissociation constants of silybin, obtained using the SQUAD(84) and SPECFIT/32 regression programs.     

Re-evaluated data of dissociation constants of alendronic, pamidronic and olpadronic acids

The dissociation constants of (4-amino-1-hydroxybutylidene)bisphosphonic (alendronic) acid, (3-(dimethylamino)-1-hydroxypropylidene)bisphosphonic (olpadronic) acid and (3-amino-1-hydroxypropylidene)bisphosphonic (pamidronic) acid were obtained in aqueous solutions (0.10 M KCl) and micellar solutions of cetylpyridinium chloride (0.10 M CPC) at 25.0°C. With the exception of the third dissociation constant of alendronic acid, the dissociation constants of alendronic, olpadronic and pamidronic acids in aqueous solutions matched literature data. The possibility of sodium alendronate determination by acid-base titration by NaOH solution was theoretically grounded on the basis of re-evaluated data of alendronic acid dissociation constants.      

Determination of dissociation constants of folic acid, methotrexate, and other photolabile pteridines by pressure-assisted capillary electrophoresis

Pressure-assisted CE (PACE) was applied to determine the previously inaccessible complete set of pK values for folic acid and eight related multiprotic compounds. PACE allowed the determination of all acidity macroconstants at low (相似文献   

Determination of the dissociation constants (pKa) of secondary and tertiary amines in organic media by capillary electrophoresis and their role in the electrophoretic mobility order inversion

Non-aqueous capillary electrophoresis (NACE) may provide a selectivity enhancement in separations since the analyte dissociation constants (pKa) in organic media are different from those in aqueous solutions. In this work, we have studied the inversion in mobility order observed in the separation of tertiary (imipramine (IMI) and amitryptiline (AMI)) and secondary amines (desipramine (DES) and nortryptiline (NOR)) in water, methanol, and acetonitrile. We have determined the pKa values in those solvents and the variation of dissociation constants with the temperature. From these data, and applying the Van't Hoff equation, we have calculated the thermodynamic parameters deltaH and deltaS. The pKa values found in methanol for DES, NOR, IMI, and AMI were 10.80, 10.79, 10.38, and 10.33, respectively. On the other hand, in acetonitrile an opposite relation was found since the values were 20.60, 20.67, 20.74, and 20.81 for DES, NOR, IMI, and AMI. This is the reason why a migration order inversion is observed in NACE for these solvents. The thermodynamic parameters were evaluated and presented a tendency that can be correlated with that observed for pKa values.     

一元强碱滴定二元弱酸的林邦滴定曲线方程及pH_(sp)计算

用质子条件式PBE、物料平衡式MBE、副反应系数和条件稳定常数等知识,推导出一元强碱滴定二元弱酸溶液的林邦滴定曲线方程,并用其推导出第一、第二化学计量点pH_(sp1)和pH_(sp2)的计算公式。     

Nonlinear regression by visualization of the sum of residual space applied to the integrated copolymerization equation with errors in all variables. I. Introduction of the model,simulations and design of experiments

A new model for estimating reactivity ratios using the integrated copolymerization equation is presented. The model is a general nonlinear least squares method taking the error in both monomer conversion and monomer fraction into account by a relation between these two variables. Simulations show that the model is able to predict reactivity ratios successfully. Special attention is given to experimental design, i.e., at which initial monomer feed ratios the experiments should be performed in order to obtain reliable values for the reactivity ratios. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 3793–3803, 1999     

NMR shielding constants of CuX,AgX, and AuX (X = F,Cl, Br,and I) investigated by density functional theory based on the Douglas–Kroll–Hess Hamiltonian

Two‐component relativistic density functional theory (DFT) with the second‐order Douglas–Kroll–Hess (DKH2) one‐electron Hamiltonian was applied to the calculation of nuclear magnetic resonance (NMR) shielding constant. Large basis set dependence was observed in the shielding constant of Xe atom. The DKH2‐DFT‐calculated shielding constants of I and Xe in HI, I₂, CuI, AgI, and XeF₂ agree well with those obtained by the four‐component relativistic theory and experiments. The Au NMR shielding constant in AuF is extremely more positive than in AuCl, AuBr, and AuI, as reported recently. This extremely positive shielding constant arises from the much larger Fermi contact (FC) term of AuF than in others. Interestingly, the absolute values of the paramagnetic and the FC terms are considerably larger in CuF and AuF than in others. The large paramagnetic term of AuF arises from the large d‐components in the Au d_π –F p_π and Au sd_σ–F p_σ molecular orbitals (MOs). The large FC term in AuF arises from the small energy difference between the Au sd_σ + F p_σ and Au sd_σ–F p_σ MOs. The second‐order magnetically relativistic effect, which is the effect of DKH2 magnetic operator, is important even in CuF. This effect considerably improves the overestimation of the spin‐orbit effect calculated by the Breit–Pauli magnetic operator. © 2013 Wiley Periodicals, Inc.     

Apparent Molar Volume, Heat Capacity, and Conductance of Lithium Bis(trifluoromethylsulfone)imide in Glymes and Other Aprotic Solvents

Lithium bis(trifluoromethylsulfone)imide (LiTFSI) is a promising electrolyte for high-energy lithium batteries due to its high solubility in most solvents and electrochemical stability. To characterize this electrolyte in solution, its conductance and apparent molar volume and heat capacity were measured over a wide range of concentration in glymes, tetraethylsulfamide (TESA), acetonitrile, -butyrolactone, and propylene carbonate at 25°C and were compared with those of LiClO₄ in the same solvents. The glymes or n(ethylene glycol) dimethyl ethers (nEGDME), which have the chemical structure CH₃–O–(CH₂–CH₂–O) _n –CH₃ for n = 1 to 4, are particularly interesting since they are electrochemically stable, have a good redox window, and are analogs of the polyethylene oxides used in polymer-electrolyte batteries. TESA is a good plasticizer for polymer-electrolyte batteries. Whenever required, the following properties of the pure solvents were measured: compressibilities, expansibilities, temperature and pressure dependences of the dielectric constant, acceptor number, and donor number. These data were used in particular to calculate the limiting Debye-Hückel parameters for volumes and heat capacities. The infinite dilution properties of LiTFSI are quite similar to those of other lithium salts. At low concentrations, LiTFSI is strongly associated in the glymes and moderately associated in TESA. At intermediate concentrations, the thermodynamic data suggests that a stable solvate of LiTFSI in EGDME exists in the solution state. At high concentrations, the thermodynamic properties of the two lithium salts approach those of the molten salts. These salts have a reasonably high specific conductivity in most of the solvents. This suggests that the conductance of ions at high concentration in solvents of low dielectric constant is due to a charge transfer process rather than to the migration of free ions.     

The spectrophotometric multicomponent analysis of a ternary mixture of ascorbic acid, acetylsalicylic acid and paracetamol by the double divisor-ratio spectra derivative and ratio spectra-zero crossing methods

The double divisor–ratio spectra derivative and ratio spectra–zero crossing methods were applied to the analysis of an effervescent tablet containing the title compounds without using a chemical separation procedure. In the use of both methods, the calibration graphs were linear in the range of 8–28 μg ml⁻¹ for three compounds. Comparison of the results obtained by the two methods indicates that both methods gives the best results.     

Thermodynamic and spectroscopic study of the interaction of Cu(II), Ni(II), Zn(II) and Ca(II) ions with 2-amino-N-(2-oxo-2-(2-(pyridin-2-yl)ethyl amino)ethyl)acetamide,a pseudo-mimic of human serum albumin

The protonation equilibria of 2-amino-N-(2-oxo-2-(2-(pyridin-2-yl)ethyl amino)ethyl)acetamide ([H₂(556)–N]) and the complexation of this ligand with Cu(II) Ca(II), Zn(II) and Ni(II) have been studied by glass electrode potentiometry and UV–visible spectrophotometry. From pH ∼2.00–11.00, five models for Cu(II) with the following complexes; MLH, ML, MLH₋₁, MLH₋₂ and MLH₋₃ were generated and observed to describe the experimental data equally well as far as the statistical criteria were concerned. The MLH₋₂ complex predominates at physiological pH in all five models, while the MLH₋₁ complex species exists only at low concentration in two models. The coordination in the MLH₋₂ complex suggested the involvement of one amino, two deprotonated peptides and one pyridyl nitrogen atoms. Molecular mechanics (MM) calculations confirmed the MLH₋₂ complex as the most stable species. Speciation calculations, using a blood plasma model, predicted that the Cu(II)–[H₂(556)–N] complex is able to mobilize Cu(II). Octanol/water partition of CuLH₋₂ showed that 30% of the complex went into the octanol phase, hence promoting percutaneous absorption of copper. The complex is a poor mimic of native copper–zinc superoxide dismutase.