Solvent Effects on pKa Values of Some Anticancer ... - ACS Publications

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Solvent Effects on pKa Values of Some Anticancer Agents in Acetonitrile−Water Binary Mixtures Senem Sanli,*,† Yuksel Altun,‡ and Gulsen Guven§ †

Department of Chemistry, Faculty of Science and Arts, Uşak University, 64200, Uşak, Turkey Department of Chemistry, Faculty of Gazi Education, Gazi University, 06500, Ankara, Turkey § Department of Chemistry, Faculty of Science and Arts, Adnan Menderes University, 09100, Aydın, Turkey ‡

ABSTRACT: The solute−solvent interactions of four anticancer drugs, daunorubicin, doxorubicin, vincristine sulfate, and 6-thioguanine, have been studied in acetonitrile− water mixtures up to 50 % acetonitrile by volume fraction using a UV/pH titration method. The acidity constants have been calculated with the STAR (stability constants by absorbance readings) program. The interactions between the four anticancer drugs and the solvent studied, acetonitrile−water mixtures, was identified using the microscopic parameters (Kamlet and Taft’s solvatochromic parameters: α, β, and π*). The Kamlet and Taft general equation for pKa1 and pKa2 values of 6-thioguanine, doxorubicin, daunorubicin, and vincristine sulfate was reduced to two terms (the independent term and the hydrogen-bond-donating ability, α) or three terms (the independent term, polarity/polarizability, π*, and the hydrogen-bond-donating ability, α) using linear regression analysis in acetonitrile−water mixtures. The Kamlet and Taft equations can be used to predict the acidity constants of daunorubicin, doxorubicin, vincristine sulfate, and 6-thioguanine at any acetonitrile composition, which would be helpful in practical work during chromatographic method development.

1. INTRODUCTION Daunorubicin and doxorubicin, two antibiotics belonging to the anthracycline group, are widely used in human cancer chemotherapy. Doxorubicin is isolated from Streptomyces peucetius var. caesius clinically and used in the treatment of tumors such as lung or breast, Hodgkin’s disease, and various types of leukemias.1 Both molecules consist of a tetracyclic quinoid aglycone and an amino sugar−daunosamine, which are linked by a glycoside bond. Vincristine is a natural alkaloid; it was first extracted from the leaves of the periwinkle plant, Catharanthus roseus.2 Thioguanine, a chemical analogue of the physiological purines, guanine and hypoxanthine, is a chemotherapeutic drug and is used as a component of various chemotherapeutic regimens for remission induction in acute and chronic myelogeneous leukemias. It is used in the treatment of various childhood and adult malignancies, including acute lymphoblastic leukemia. Consciousness of the effect of pKa values on the pharmaceutical features of drugs and chemical substances has been established for a long time within medical products and industry. Most of the drugs are weak acids and/or bases. Therefore, information about the dissociation constant helps in understanding the ionic form a molecule will take across a range of pH values. This is important in the situation such as the blood−brain barrier (BBB) where the ionization state affects the rate at which the compound is able to diffuse across membranes and obstacles. The pKa of a drug influences lipophilicity, solubility, protein binding, and permeability which in turn directly affects pharmacokinetic (PK) characteristics such as absorption, distribution, metabolism, and excretion (ADME).3−7 © XXXX American Chemical Society

So far, several techniques have been used for pKa determination techniques such as potentiometry, liquid chromatography (LC), spectrophotometric methods, and capillary zone electrophoresis (CZE). In these techniques the potentiometric method is widely used. The advantage of this technique is that it does not require the presence of chromophore groups for pKa determination. CZE is used in a wide pH range for mono- and polyprotic substances. This method is based on the dependence of electrophoretic mobility with respect to the pH of the electrophoretic buffer. Spectrophotometric methods are excellent methods for pKa determination.8−16 Most of the drugs have low water solubility. The usage of spectroscopic techniques can solve this problem for the determination of dissociation constants. In this technique, low analyte concentration is used and allows suitable absorbance measurement in aqueous solution even for products with low aqueous solubilities. Also, several computer programs using data from multiwavelength spectrophotometry are frequently used for the determination of pKa.17,18 The selection of mixed aqueous solvents (e.g., acetonitrile/ water, methanol/water, dioxane/water, and tetrahydrofuran/ water) in analytical applications has spread during the past few decades. The effect of solute−solvent interaction on the physicochemical solute properties in mixed aqueous solvents was typically explained by phenomena of electrostatic interactions. To clarify the influence of solute−solvent interaction, one important approach has been based on solvatochromism. Received: July 1, 2014 Accepted: November 19, 2014

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dx.doi.org/10.1021/je500595w | J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

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versa, through Teflon or Tygon tubes in a closed loop circuit with continuous flow. For all titrations N2 was used and the temperature was kept constant at 298.2 (± 0.1) K by using a constant-temperature thermostat (Heto CBN8-30 and temperature control unit HetoHMT200) through a double-walled Pyrex titration cell of 80 mL capacity. 2.3. Procedures. The dissociation constants of drugs studied were calculated by means of the data obtained from spectrophotometric titrations in 0, 0.10, 0.20, 0.30, 0.40, and 0.50 (volume fraction) MeCN−water mixtures. All the potentiometric and spectrophotometric measurements were carried out 0.1 mol L−1 ionic strength (KCl) in and at 298.2 K. For multiwavelength spectrophotometric−pH-metric titration, first, Gran’s method was used for calibration of the electrode system in order to obtain the standard electromotive force (emf) values, E0, of the potentiometric cell.26 For this purpose, a calculated amount of solution was added in a double-walled, thermostated vessel. Temperature, ionic strength, and solvent composition were kept at the same conditions. The electrode was immersed in that solution which was then titrated with a strong base under the same experimental conditions of ionic strength and solvent composition. The other details of the experimental procedure have been detailed elsewhere.27 The amounts of 1 M KOH solution should be large enough to provoke a measurable change in the pH of the test solution, but also small enough to allow the increase of volume to be neglected. During spectrophotometric titrations, the test sample was pumped to a spectrophotometric flow cell by use of a peristaltic pump. When the emf was stable, the spectra of the drugs were recorded with 1 nm resolution over the 200 to 400 nm interval for 6-thioguanine and vincristine sulfate and the 200 to 700 nm interval for daunorubicin and doxorubicin to obtain spectra around the maximum λ. 2.4. Data Treatment. For all media five spectrophotometric titrations were performed and data were treated using the program STAR (Stability Constants by Absorbance Readings).18 This program uses multilinear regression for the calculation of stability constants and molar absorptivities of the pure species. This program allows the handling of systems with up to five components, which form up to 25 species. The program requires a previous model of the chemical equilibria, based upon the existence of certain chemical species, to be postulated. The refinement of equilibrium constants is done using the Gauss−Newton nonlinear-least-squares algorithm by numerical differentiation, until a minimum in the sum of squares residual (U) is attained. This function is defined as

Particularly successful and very extensive applications of solvatochromism have evolved from a “solvatochromic comparison” approach used by Kamlet and Taft. Taft, Kamlet, and co-workers have developed a number of quantitative relationships between a variety of physicochemical solute properties and certain solvent properties (α, solvent hydrogen-bond acidity; β, solvent hydrogen-bond basicity; π*, polarity/polarizability).19−25 In this study pKa values of the anticancer drugs 6-thioguanine (TG), doxorubicin (DOX), daunorubicin (DAU), and vincristine sulfate (VCR) (Figure 1) were determined in 0, 0.10, 0.20,

Figure 1. Chemical structures of studied compounds.

0.30, 0.40, and 0.50 (volume fraction) MeCN−water compositions at 298.15 (± 0.1) K by a UV/pH titration method.

2. EXPERIMENTAL SECTION 2.1. Chemical and Reagents. All chemicals were used without further purification. DOX, VCR, TG, and DAU were from Sigma (as for all compounds ≥ 98). HPLC grade acetonitrile (Merck, Darmstadt, Germany) was used as organic modifier. Sodium hydroxide, hydrochloride acid, potassium hydrogen phthalate, and potassium chloride (ionic strength adjuster; 0.1 mol L−1) were all supplied from Merck (Darmstadt, Germany). Water used for the preparation of all aqueous solutions, with conductivity 18.2 μS cm−1, was obtained using a Zeneer Power I water system (Human Corp. Korea). 2.2. Apparatus. For potentiometric measurements, a Mettler-Toledo MA 235 pH/ion (resolution ± 0.1 mV) analyzer system was used. For each pH, the UV−vis absorbance spectra were recorded by a PerkinElmer LAMBDA 25 spectrophotometer. A peristaltic pump was used to circulate the solution from the titration vessel to the spectrophotometer cell, and vice

ns

U=

nw

∑ ∑ (Ai ,j ,exp − Ai ,j ,calc)2 i=1 j=1

(1)

where ns and nw are the number of solutions and the number of wavelengths, respectively, Aexp is the experimental data of absorbance, and Acalc is obtained by Beer’s law from the calculated concentrations of each species and their molar absorptivities. The wavelength (nanometers)−absorbance spectra for 6-thioguanine in water and daunorubicin in 20 % MeCN water are shown in Figure 2.

3. RESULTS AND DISCUSSION 3.1. pKa Calculations. The values determined for the pKa values of the 6-thioguanine (TG), doxorubicin (DOX), daunorubicin (DAU), and vincristine sulfate (VCR) (Figure 1) in B



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oxygen donor. This means that the ligands containing phenolic oxygen will have a lower pKa than that of the amine nitrogen atom (−NH2). Thus, the first dissociation equilibrium of DOX (pKa1 = 7.84 ± 0.05) and that of DAU (pKa1 = 7.48 ± 0.06) studied in this study refer to the primary amine in the sugar moiety. The second dissociation equilibriums (pKa2) of these two drugs are assigned to the dissociation at the phenolic oxygen (present on the sugar moieties of DOX and DAU).34−36 6-Thioguanine (TG) belongs to the thiopurine family of drugs. It consists of a pyrimidine ring fused to an imidazole ring. The first (pKa1) and second dissociation equilibriums (pKa2) of TG refer to the pyrimidine nitrogen and imidazole nitrogen, respectively. Vincristine sulfate isolated from the Madagascar periwinkle is an alkaloid. The first and second pKa values of vincristine sulfate are closely related to those of the alkaloid leurosine.37 The acidity of the alkaloids depends upon the electrostatic status of the N atom (the number of N atoms, whether the N atom is located in the ring or in the side chain, etc.) and the presence of a primary, secondary, tertiary, or quaternary N atom in the alkaloids. The various structural features of alkaloids are reflected by the different pKa values (e.g., berberine, pKa = 2.47; reserpine, pKa = 6.6; vinblastine sulfate, pKa1 = 5.4, pKa2 = 7.4; colchicine, pKa = 12.35; morphine, pKa = 9.85).38 The DAU spectrum does not change in most of the spectra, and so a small change corresponds to pKa1 (Figure 2b). About the pKa2 values, the spectra started to change clearly. Therefore, the pKa1 standard deviation is higher than that of the pKa2. 3.2. Procedure for Modeling of Solvent Effect. The reaction medium is one of the most important factors determining equilibrium constants. In order to explain the solvent effect, the acid−base equilibrium should be discussed on the basis of both macroscopic and microscopic structures around the solute. The complex solute and solvent interactions in solutions easily form inhomogeneous clusters because intermolecular distance is quite short in solutions. It is clear that the acetonitrile−water mixture is not a simple homogeneous mixture, but rather is a concentration-dependent structural composition. There are three main concentration regions over the mixture composition range39−46 which can be characterized by different structural patterns. In the first region, the water-rich region of acetonitrile−water mixtures (0 ≤ xMeCN ≤ 0.2), the structure of the acetonitrile−water mixture largely resembles pure water with acetonitrile occupying vacancies in the threedimensional hydrogen-bond network of water molecules. Therefore, in this water-rich region, there are small changes in the pKa values of 6-thioguanine, doxorubicin, daunorubicin, and vincristine sulfate, but these pKa values change if the percentage of MeCN increases (Table 1). At the intermediate (microheterogeneity) region (0.2 ≤ xMeCN ≤ 0.75), there are clusters of molecules of the same kind surrounded by a region. The third region (0.75 ≤ xMeCN ≤ 1.0) can be visualized as an acetonitrile arrangement disturbed by water molecules. In the three regions, the preferential solvation, δw, of hydrogen by water in acetonitrile−water mixtures continuously increases, which might explain the increase in the acidity of TG, DOX, DAU, and VCR drugs when the percentage of acetonitrile increases (Table 1).47 As mentioned above, the variation of pKa vs solvent composition depends upon the extent and characteristics of the solute−solvent interactions on equilibrium behavior in aqueous−organic cosolvent mixtures. pKa1 and pKa2 values of the anticancer drugs 6-thioguanine, doxorubicin, daunorubicin,

Figure 2. Wavelength (nm)−absorbance spectra for (a) 6-thioguanine in water and (b) daunorubicin in 20 % (v/v) acetonitrile−water mixture as a function of pH.

0, 0.10, 0.20, 0.30, 0.40, and 0.50 (volume fraction) MeCN−water mixtures at 298.15 (± 0.1) K were reported along with the respective standard deviations. A survey of the literature shows no research on the determination of the acidity constants of TG, DOX, DAU, and VCR by spectrophotometric methods and on solute− solvent interactions of these drugs in MeCN−water mixtures. There are some published data for the acidity constant of DOX, DAU, and VCR,28−33 but there is no data for TG. Differences are minor and expected, considering the distinct experimental conditions employed (solvent media, ionic strength, and temperature). All the anticancer drugs studied here have only two acidity constants. In multiple dissociation equilibriums, it is very important to know in which dissociation region the first dissociation occurs. The two anthracyclines used in this study, doxorubicin (DOX) and daunorubicin (DAU), have the same amino sugar moiety including amino (−NH2) and phenolic (−OH) groups as shown in Figure 1. It is known that the amine nitrogen atom (−NH2) can gain a proton, while the phenolic oxygen atom (−OH) can lose a proton under specific pH conditions. The phenolic group is known to be weakly acidic, indicating strong bonding between the proton and the C



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Table 1. Acidity Constants of 6-Thioguanine, Doxorubicin, Daunorubicin, and Vincristine Sulfate at 298.15 (± 0.1) K, for Different Aqueous Solutions of Acetonitrile and an Ionic Strength of 0.1 mol L−1 (KCl) TG vol fraction MeCN

mole fraction MeCN

DOX

pKa1

pKa2

water

0

3.02 ± 0.04

8.27 ± 0.03

0.10 0.20 0.30 0.40 0.50

0.0370 0.0796 0.1291 0.1874 0.2570

2.91 2.80 2.69 2.63 2.56

± ± ± ± ±

0.06 0.05 0.04 0.07 0.06

8.08 7.95 7.83 7.75 7.66

± ± ± ± ±

0.04 0.02 0.02 0.01 0.02

pKa1 7.84 ± 8.429 8.230 8.2531 8.232 7.74 ± 7.57 ± 7.42 ± 7.30 ± 7.21 ±

pKa2

pKa1

pKa2

pKa1

pKa2

10.04 ± 0.03 10.230

7.48 ± 0.06

9.68 ± 0.02

5.95 ± 0.07 5.033

8.31 ± 0.01 7.433

0.04 0.05 0.04 0.06 0.05

9.93 ± 9.69 ± 9.84 ± 9.76 ± 9.64 9.4934

7.28 7.16 7.05 7.00 6.95

9.56 ± 9.44 ± 9.32 ± 9.24 ± 9.20 ± 9.5434

5.80 ± 5.68 ± 5.54 ± 5.45 ± 5.38 ± 5.3434

8.18 ± 8.10 ± 8.00 ± 7.90 ± 7.80 ± 8.1934

doxorubicin (DOX)

daunorubicin (DAU)

vincristine sulfate (VCR)

equation

R2

SE

F

pKa1 = [−0.0918(0.0206)] (1/ε) + 3.0907(0.1231)a pKa2 = [−0.1179(0.06216)] (1/ε) + 8.3353(0.6513) pKa1 = [−0.1315 (0.0107)] (1/ε) + 7.9724(0.2348) pKa2 = [−0.067(0.04673)] (1/ε) + 10.051(2.0798) pKa1 = [−0.1019(0.0278)] (1/ε) + 7.5098(0.4563) pKa2 = [−0.0981(0.05478)] (1/ε) + 9.7487(0.7698) pKa1 = [−0.115(0.0164)] (1/ε) + 6.0361(0.1563)

0.986

0.021 31

368.012

0.973

0.012 63

308.001

0.992

0.008 13

976.013

0.702

0.008 20

46.121

0.934

0.137 15

198.112

0.972

0.019 65

301.986

0.983

0.019 68

356.501

0.998

0.011 87

998.098

pKa2 = [−0.0989(0.0143)] (1/ε) + 8.3945(0.0769) a

0.02 0.03 0.04 0.02

± ± ± ± ±

0.07 0.08 0.06 0.07 0.05

0.03 0.02 0.03 0.01 0.02

0.08 0.06 0.07 0.05 0.07

0.02 0.02 0.01 0.01 0.03

It is therefore desirable to develop some empirical scales that take into account a more complete picture of all possible solute and solvent interactions.50−56One of the most extensively used methods is that based on the use of solvatochromic parameters. Kamlet and Taft scaled their solvatochromic solvent, α, β, and π*, describing hydrogen-bond-donating acidity, HBD, hydrogen-bond-accepting basicity, HBA, and polarity/polarizability properties of solvent, respectively (α, β, and π*) by introducing a developed solvatochromic comparison method.23,24 The sum of these solvent properties can be used to treat molecular solvent effects with the framework of the concept of linear solvation free energy relationships (LSFERs).56 XYZ = XYZ0 + aα + bβ + sπ *

where XYZ is the acidity constant for the ith solute measured in different volume percents of mixed solvent and α, β, and π* are the vectors of solvatochromic parameters of the mixed solvents. The parameters a, b, and s are regression coefficients, and XYZ0 represents the hypothetical value of the acidity constant in a hypothetical solvent with α = β = π* = 0. The solvatochromic parameters (α, π*, and β) of Kamlet− Taft for MeCN−water mixtures were taken from ref 22. A linear interpolation was used to approximate the unknown solvatochromic parameters at the acetonitrile−water mixtures studied. These parameters were used as independent variables to account for the solvent effects on each one of the acidity constants of TG, DOX, DAU, and VCR drugs in 0, 0.10, 0.20, 0.30, 0.40, and 0.50 (volume fraction) MeCN−water mixtures. The Kamlet−Taft linear solvation free energy relationship57,58 has been applied to describe solvent effects for TG, DOX, DAU, and VCR using a subset of solvatochromic parameters selected by a stepwise selection procedure, which uses a combination of both forward selection and backward elimination of variables. The goodness of fit of the model was measured by conventional statistical parameters including the standard error of the estimate (SE), the squared multiple correlation coefficient (R2), and the variance ratio (F). The obtained correlations using the SPSS program are shown in Table 3. In Table 3, the conventional statistical parameters including SE, R2, and F are also given. Obviously, one could not describe the quantitative effect of the solvent properties on the acidity constants of TG, DOX, DAU, and VCR by a unique LSFER model. This is not so strange since TG, DOX, DAU, and VCR behave differently due to their acidity.

Table 2. Correlations for 6-Thioguanine, Doxorubicin, Daunorubicin, and Vincristine Sulfate between pKa Values and the Inverse of the Dielectric Constant of the Organic Modifier compound

VCR

0.05

and vincristine sulfate in the different acetonitrile−water compositions decrease with the percentage of acetonitrile. In other words, the acid character of the solute is increased as the acetonitrile part of the solvent is increased. The values of the acidity constants have been related to the inverse of the dielectric constant. The values of relative permittivity were interpolated from published data.41 In the absence of specific solute−solvent interactions, a plot of pKa values versus these quantities of the media should be linear. These figures show that the linear relationship between pKa values of drugs and the inverse of the dielectric constant of mixed solvent is a good approximation. The correlations of pKa1 and pKa2 with the inverse of the dielectric constant (1/ε) of the organic modifier with correlation coefficients were obtained using the SPSS program (Table 2).

6-thioguanine (TG)

DAU

Errors associated with values are given in parentheses.

These results indicate that the acidity constants of 6-thioguanine, doxorubicin, daunorubicin, and vincristine sulfate in different acetonitrile−water compositions depend on the both electrostatic and nonelectrostatic effects.48,49 Therefore, it is necessary to explain the nature of the solute−solvent interactions for a better understanding of solvent effects on pKa values of these anticancer agents in acetonitrile−water binary mixtures. D



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Table 3. Linear Regression Analysis of the Kamlet and Taft Equation for pKa1 and pKa2 Values of 6-Thioguanine, Doxorubicin, Daunorubicin, and Vincristine Sulfate at 298.2 (± 0.1) K, for Different Aqueous Solutions of Acetonitrile and an Ionic Strength of 0.1 mol L−1 (KCl) compound 6-thioguanine (TG) doxorubicin (DOX) daunorubicin (DAU) vincristine sulfate (VCR)

LSFER pKa1 pKa2 pKa1 pKa2 pKa1 pKa2 pKa1 pKa2

= = = = = = = =

0.569(0.102) 5.775(0.194) 4.090(0.066) 8.606(0.410) 5.234(0.086) 7.105(0.021) 2.962(0.084) 5.547(0.242)

+ + + + + + + +

1.031(0.098)π* 2.152(0.194)α 2.097(0.103)π* 1.213(0.409)α 1.922(0.159)α 0.959(0.033)π* 1.228(0.132)π* 1.454(0.380)π*

+ 1.132(0.159)α + 1.247(0.063)α

+ 1.306(0.020)α + 1.458(0.081)α + 0.992(0.232)α

4. CONCLUSIONS This study confirms the usefulness of solvatochromic parameters such as π* and α in the explanation of microscopic processes. The Kamlet and Taft equations obtained in this study can be used to calculate the acidity constants of TG, DOX, DAU, and VCR in any MeCN−water mixtures up to 50 % volume fraction and can help clarify the acid−base behavior of solutes in these widely used MeCN−water mixtures. AUTHOR INFORMATION

Corresponding Author

*Tel.: 090-505-5917066. Fax: (0)2762212121. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors greatly acknowledge Dr. Jose L. Beltran from Universitat de Barcelona for kindly providing the spectral data processing software, STAR.

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SE

F

0.998 0.984 0.999 0.829 0.996 0.999 0.999 0.992

0.012 63 0.044 27 0.008 20 0.093 55 0.019 65 0.002 59 0.010 44 0.030 09

468.087 123.547 2270.012 8.784 500.143 12910.746 1078.568 93.286

solid phase extraction and HPLC. Chromatographia 1999, 49, 557− 561. (2) Johnson, I. S.; Armstrong, J. G.; Gorman, M.; Burnett, J. P. The vinca alkaloids: A new class of oncolytic agents. Cancer Res. 1963, 23, 1390−1427. (3) Manallack, D. T. The pKa distribution of drugs: Application to drug discovery. Perspect. Med. Chem. 2007, 1, 25−38. (4) Kerns, E. H.; Di, L. Physicochemical profiling: Overview of the screens. Drug Discovery Today: Technol. 2004, 1, 343−348. (5) Avdeef, A. Physicochemical profiling (solubility, permeability and charge state). Curr. Top. Med. Chem. 2001, 1, 277−351. (6) Xie, X.; Steiner, S. H.; Bickel, M. H. Kinetics of distribution and adipose tissue storage as a function of lipophilicity and chemical structure. II. Benzodiazepines. Drug Metab. Dispos. 1991, 19, 15−19. (7) Jones, T.; Taylor, G. Quantitative structure-pharmacokinetic relationships amongst phenothiazine drugs. ProceedingsEuropean Congress of Biopharmaceutics and Pharmacokinetics, Third; Imprimerie de l’Universite de Clermont-Ferrand: Clermont-Ferrand, France, 1987; Vol. 2, pp 181−190. (8) Sanli, S.; Altun, Y.; Sanli, N.; Alsancak, G.; Beltran, J. Solvent effects on pKa values of some substituted sulfonamides in acetonitrile−water binary mixtures used in LC by the UV-spectroscopy. J. Chem. Eng. Data 2009, 54, 3014−3021. (9) Sanli, N.; Sanli, S.; Alsancak, G. Determination of dissociation constants of folinic acid (leucovorin), 5-fluorouracil and irinotecan in hydro-organic media by a spectrophotometric method. J. Chem. Eng. Data 2010, 55, 2695−2699. (10) Sanli, S.; Sanli, N.; Alsancak, G. Spectrophotmetric determination acidity constant of some macrolides in acetonitrile−water binary mixtures. Acta Chim. Slov. 2010, 57, 980−987. (11) Sanli, N.; Sanli, S.; Sızır, U.; Gumustas, M.; Ozkan, S. A. Determination of pKa values of cefdinir and cefixime by LC and spectrophotometric methods and their analysis in pharmaceutical dosage forms. Chromatographia 2011, 73, 1171−1176. (12) Sanli, S. UV spectroscopic method for determining pKa values of some antipsychotic drugs in water and acetonitrile−water binary mixtures. J. Solution Chem. 2013, 42, 967−978. (13) Şanlı, S.; Altun, Y.; Alsancak, G. Determination of the dissociation constants of some macrolide antibiotics in methanol− water binary mixtures by UV-spectroscopy and correlations with the Kamlet and Taft solvatochromic parameters. J. Solution Chem. 2012, 41, 1352−1363. (14) Momeni-Isfahani, T.; Niazi, A. Spectrophotometric determination of acidity constants of 2-(2-Thiazolylazo)-Cresol in various water-organic solvent media mixtures using chemometrics methods. Spectrochim. Acta, Part A 2014, 120, 630−635. (15) Pandey, M. M.; Jaipal, A.; Kumar, A.; Malik, R.; Charde, S. Y. Determination of pKa of felodipine using UV-Visible spectroscopy. Spectrochim. Acta, Part A 2013, 115, 887−890. (16) Cunha, A. R.; Duarte, E. L.; Lamy, M. T.; Coutinho, K. Protonation/deprotonation process of Emodin in aqueous solution and pKa determination: UV/Visible spectrophotometric titration and quantum/molecular mechanics calculations. Chem. Phys. 2014, 440, 69−79.

As shown in Table 3, the Kamlet and Taft general equation for the first dissociation constant, pKa1, values of 6-thioguanine, doxorubicin, and vincristine sulfate was reduced to three termsthe independent term; the polarity/polarizability, π*; and the hydrogen-bond-donating ability, αusing linear regression analysis in acetonitrile−water mixtures.Table 3 also shows that for the second dissociation constant, pKa2, of TG and DOX the independent term and the hydrogen-bonddonating ability, α, of the solvent play significant roles. These correlation coefficients indicate the existence of special local electrostatic solute−solvent interactions. The coefficients of the polarity/polarizability, π*, index (s) and solvent hydrogenbond, α, index (a) in the Kamlet and Taft general equation for pKa1 and pKa2 values of TG, DOX, DAU, and VCR are positive. These imply that polarity/polarizability and solvent acidity have a reverse effect on the acidity strength. It is also observed from Table 3 that the hydrogen-bonddonating acidity, α, is an important solvatochromic parameter for the first and second dissociation constants of all compounds. The coefficient (a) of the hydrogen-bond-donating acidity index, α, is positive, which means that the solutes become weak acids as the solvent acidity is increased. This can be attributed to solute-to-solvent hydrogen-bond formation by the acidic part of solvent.

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