Scientific paper Nonsteroidal Anti-Inflammatory Drugs Ion Mobility: A Conductometric Study of Salicylate, Naproxen, Diclofenac and Ibuprofen Dilute Aqueous Solutions Marija Be{ter-Roga~ Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia * Corresponding author: E-mail: marija.bester@fkkt.uni-lj.si Phone: +386 1 2419 410; fax: +386 1 2419 425 Received: 12-10-2008 Dedicated to Professor Josef Barthel on the occasion of his 80'' birthday Abstract The electric conductivities of aqueous solutions of nonsteroidal anti-inflammatory drugs salicylate, naproxen, Ibuprofen sodium and diclofenac sodium salts and diclofenac potassium salt were measured in the temperature range from 278.15 K to 313.15 K (in steps of 5 K) and in the concentration range 3 x 10-4 < c(mol/dm-3) < 0.007. Data analysis based on the low concentration chemical model of electrolyte solutions yielded the limiting molar conductivity, A", and the association constant, K^. Using the known data of the limiting conductivities of sodium and potassium ions the limiting conductivities of the salicylate, naproxen, diclofenac and ibuprofen anions were evaluated, and the radii of anions in water were estimated. Total dissociation of the investigated salts in water is evident and the considerable differences in the anion mobilities are observed. They are discussed in terms of possible hydration and hydrophobic interactions. Keywords: Electrolyte conductivity, electrolyte solution, sodium salicylate, naproxen sodium salt, diclofenac sodium salt, diclofenac potassium salt, ibuprofen sodium salt, chemical model 1. Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed categories of drugs worldwide in the treatment of pain, inflammation and some of them even fever in many conditions. Their mechanism for action likely relates to the inhibition of prostaglandin synthesis1 Although they are now used widely in therapeutics, physicochemical information about them are rather scarce. However, the effects of a drug in a biological system is the ultimate consequence of physicochemical interactions between a drug and functionally important molecules in the living organism. The dominant fluid media in the biological systems through which the drugs are transported and in which they interact are water and lipids. The drugs usually undergo a number of complicated interactions in solution which may cause not only structural changes of biological fluids but also metabolic and structural changes of drugs. Therefore drug-drug and drug-sol- vent interactions may be of great importance to understand their physiological action. The temperature and concentration dependence of the electrolyte conductance has been proved as one of the most appropriate methods for studying ion-ion, ion-solvent and solvent-solvent interactions in solutions.2 Recently a conductivity study of some drugs in ace-tonitrile at 298.15 K has been carried out3 but there is no literature data on the drug ion mobility in water so far. In the present work electrical conductivity measurements of aqueous solutions of some NSAIDs: sodium salicylate (NaSal), naproxen sodium salt (NaNap), diclofenac sodium salt (NaDic), diclofenac potassium salt (KDic), and ibu-profen sodium salt (NaIbu) at the temperatures from 278.15 K to 313.15 K (in steps of 5 K) in the concentration range 3 x 10-4 99.5%, Fluka, Germany), naproxen sodium ((S)-6-Methoxy-a-methyl-2-naphthaleneacetic acid sodium salt, C14H13NaO3, >98% , Sigma-Aldrich, Germany), diclofenac sodium (2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid sodium salt, C14H10a2NNaO2, > 99.7%, Titan Pharma, India) diclofe-nac potassium salt (2-[(2,6-Dichlorophenyl)amino]benze-neacetic acid potassium salt, C14H10Cl2NKO2, > 99.7%, Titan Pharma, India), and ibuprofen sodium salt (a-Methyl-4-(isobutyl)phenylacetic acid, C13H17O2Na, Sigma, Germany) were stored in a desiccator over P2O5 and used without further purification. Stock solutions were prepared by weighing pure compounds and deminerali-zed distilled water. Demineralized water was distilled two times in a quartz bidistillation apparatus (Destamat Bi 18E, Hera-eus). The final product with specific conductivity < 6 x 10-7 S cm-1 was distilled into a flask permitting storage under an atmosphere of nitrogen. 2. 2. Conductivity Measurement The conductivities of solutions were determined with the help of a three-electrode measuring cell, described elsewhere.2 The cell was calibrated with dilute potassium chloride solutions5 and immersed in the high precision thermostat described previously6 The temperature dependence of the cell constant was taken into account.5 The oil bath can be set to each temperature of a temperature program with a reproducibility within 0.005 K. The temperature in the precision thermostat bath was additionally checked with calibrated Pt100 resistance ther- mometer (MPMI 1004/300 Merz) in connection with a HP 3458 A. The resistance measurements of solutions in the cell were performed using a precision LCR Meter Agilent 4284 A. At the beginning of every measuring cycle the cell was filled with a weighed amount (~660 g) of water. After the measurement of the solvent conductivity at all temperatures of the program a weighed amount of a stock solution was added using a gas-tight syringe. After every addition the temperature program was run and all measured data (frequency dependent resistance, temperature) were stored by the computer and partially shown on a display to track the measuring process.6 The measuring procedure, including corrections and the extrapolation of the sample conductivity to infinite frequency, is described in the literature.5,6 Table 1. Densities, viscosities and dielectric constants of pure water and limiting ionic conductivities of sodium and potassium ions in water.a T/K 103 • n ed (Na+)e (K+y 278.15 0.99997 1.5192 85.897 30.30 46.72 283.15 0.99970 1.3069 83.945 34.88 53.03 288.15 0.99910 1.1382 82.039 39.72 59.61 293.15 0.99821 1.002 80.176 44.81 66.44 298.15 0.99704 0.8903 78.358 50.15 73.50 303.15 0.99565 0.7975 76.581 55.72 80.76 308.15 0.99404 0.7195 74.846 61.53 88.20 313.15 0.99222 0.6530 73.157 67.55 95.79 a Units: T^, K; ds, kg • dm-3; n, Pa • s, b Ref.7; c Ref.8; ^ Ref.9; e Ref.10 • X~, S • cm 2 • mol-1 From the weights and the corresponding solution densities d the molar concentrations c were determined. A linear change of d with increasing salt content for diluted solutions was assumed, d = ds + bm, where ds is the density of water, given in Table 1, and m is the molonity of Table 2. Experimental molar conductivities of the investigated drugs in water". T 278,15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 103 • ni A NaSal, b = 0.067 0.77992 49.253 56.908 65.027 73.586 82.537 91.902 101.590 111.597 1.22321 48.905 56.523 64.585 73.083 81.988 91.275 100.902 110.859 1.76798 48.587 56.152 64.163 72.605 81.432 90.671 100.228 110.114 2.39229 48.312 55.832 63.793 72.175 80.958 90.134 99.691 109.468 3.15281 48.025 55.504 63.432 71.761 80.490 89.603 99.056 108.813 3.95367 47.768 55.192 63.064 71.357 80.030 89.087 98.491 108.212 4.65674 47.557 54.962 62.785 71.030 79.664 88.676 98.033 107.711 5.50706 47.344 54.699 62.492 70.697 79.279 88.258 97.556 107.161 6.24124 47.177 54.501 62.268 70.442 78.996 87.930 97.197 106.770 7.01312 47.002 54.298 62.042 70.180 78.704 87.615 96.845 106.375 NaNap, b = 0.079 0.26893 43.613 50.395 57.599 65.208 73.190 81.549 90.268 99.274 0.52218 43.345 50.145 57.353 64.948 72.914 81.251 89.912 98.855 0.78955 43.103 49.863 57.034 64.593 72.513 80.817 89.437 98.355 1.0766 42.900 49.730 56.776 64.311 72.201 80.464 89.050 97.932 1.38111 42.721 49.414 56.525 64.022 71.891 80.120 88.672 97.523 1.76852 42.509 49.181 56.262 63.731 71.552 79.745 88.259 97.100 2.28148 42.279 48.920 55.965 63.396 71.181 79.342 87.809 96.572 2.78946 42.086 48.694 55.714 63.108 70.865 78.982 87.412 96.153 3.45331 41.891 48.466 55.447 62.791 70.504 78.579 86.964 95.675 4.39937 41.628 48.165 55.103 62.429 70.092 78.102 86.433 95.042 NaDic, b = 0.122 0.42170 40.651 47.105 54.008 61.212 68.761 76.657 84.877 93.378 0.76619 40.409 46.843 53.684 60.882 68.386 76.258 84.439 92.864 1.12796 40.164 46.542 53.344 60.480 67.931 75.766 83.905 92.323 1.54946 39.962 46.349 53.078 60.189 67.582 75.352 83.466 91.984 1.92452 39.801 46.117 52.875 59.924 67.357 75.073 83.138 91.650 2.3694 39.646 46.001 52.602 59.672 67.053 74.770 82.800 91.273 2.8900 39.483 45.746 52.454 59.437 66.770 74.457 82.458 90.846 3.5492 39.303 45.539 52.170 59.157 66.472 74.107 82.063 90.530 4.3967 39.100 45.300 51.909 58.839 66.114 73.718 81.631 89.997 KDic, b = 0.128 0.38303 56.714 65.022 73.736 82.708 92.011 101.605 111.521 121.689 0.75913 56.487 64.687 73.294 82.260 91.519 101.140 111.036 121.048 1.1398 56.247 64.413 72.942 81.874 91.137 100.641 110.422 120.607 1.5130 56.013 64.176 72.706 81.533 90.749 100.246 110.067 120.152 1.9805 55.877 63.984 72.428 81.242 90.488 99.947 109.743 119.763 2.4831 55.658 63.714 72.194 81.048 90.149 99.621 109.274 119.302 3.0674 55.533 63.536 72.010 80.756 89.827 99.260 108.945 118.833 3.7672 55.241 63.278 71.678 80.402 89.423 98.831 108.485 118.353 4.4672 55.101 63.064 71.421 80.114 89.117 98.459 108.094 117.938 5.2400 54.896 62.818 71.136 79.796 88.752 98.033 107.614 117.401 Nalbu, b = 0.043 0.73682 36.744 42.442 48.544 55.024 61.816 68.803 76.325 83.961 0.92933 36.581 42.271 48.373 54.825 61.605 68.604 76.092 83.753 1.1335 36.438 42.129 48.226 54.664 61.483 68.474 75.881 83.508 1.3552 36.310 41.986 48.064 54.486 61.252 68.256 75.650 83.301 1.5799 36.202 41.872 47.931 54.348 61.104 68.091 75.460 83.102 1.8264 36.094 41.745 47.801 54.207 60.932 67.909 75.251 82.871 2.0501 35.998 41.647 47.694 54.085 60.797 67.762 75.089 82.690 2.3416 35.894 41.537 47.578 53.948 60.639 67.590 74.881 82.472 2.6734 35.766 41.391 47.409 53.772 60.452 67.374 74.655 82.207 3.0726 35.649 41.261 47.254 53.593 60.256 67.170 74.406 81.900 a Units: rn, mol • kg-1; T, K; A, S • cm2 • mol- -1; b, kg2 • dm-3 • mol-1 the electrolyte (moles of electrolyte per kilogram of solution). The densities of the solutions were determined by the method of Kratky et al.11 using a Paar densimeter (DMA 60, DMA 601 HT) at 298.15 K combined with a precision thermostat. As usual the density gradient b is considered to be independent of temperature, see Table 2. The measured conductivity data of all investigated salts are given in Table 2 as a function of the temperature independent molonities. They can be converted to the temperature-dependent molarities by using the relationship c = m d. Taking into account the sources of error (calibration, measurements, impurities) the molar conductivities are accurate to within 0.1%. 3. Data Analysis The analysis of the conductivity data in the framework of the low concentration chemical model (lcCM) given in Ref.4 and the literature cited there, uses the set of equations ca y t \ + kR (2a-b) (3) where A and A" are the molar conductivities at molarity c and in the infinite dilution, respectively, (l-a) is the fraction of oppositely charged ions acting as ion pairs, and KA is the equilibrium constant of the lcCM with upper association limit R; y'± is the corresponding activity coefficient of the free ions, (y'±)2 = y'+ y' , k is the Debye parameter, e0 is the proton charge, e is the relative permittivity of the solvent, e^ is the permittivity of vacuum and T the absolute temperature. The other symbols have their usual meaning. W* is a step function for the potential of mean force between cation and anion due to non-Coulombic interactions. The coefficients of Eq. (1) are given in Ref .4 The limiting slope S and the parameter E are completely calculable when the solvent data are available (Table 1). The coefficients J1 and J2 are also functions of the distance parameter R, representing the distance to which oppositely charged ions can approach as freely moving particles in solution. Analysis of the conductivity data of associated electrolytes are carried out by setting the coefficients S, E and J^ of Eq. (1) to their calculated values4 and then usually using three-parameter fits to obtain the limiting values of molar conductivity A", the association KA and the coefficient J2 by non-linear least squares iterations. A three-parameter evaluation is reduced to a two-parameter procedure for nonassociating electrolytes,2 where usually coefficient J2 is also fixed. The input data for the calculation of the coefficients are the known solvent properties (Table 1) and the distance parameter R. The lower limit a of the association integral is the distance of closest approach of cation and anion (contact distance), a = a+ + a . It was calculated from the ionic radii of the cations;4 a+ = 0.098 nm for Na+ and 0.133 nm for K+. Organic anions such as car-boxylates, sulfonates, etc., bear their negative charge in an oxygen atom on the surface of the ionic molecule. The "radius" of such ions may be taken to be the effective van der Waals radius of the carboxylate or sulfonate group.4 We used the value a = 0.162 nm which was estimated for formic acid4 assuming that the radicals in the anions of the investigated drugs do not change the interionic distance between the cation and the basic oxygen atom in their structure. From extended investigations of electrolyte solutions in amphiprotic hydroxylic solvents (water, alcohols) it is known that the upper limit of association is given by an expression of the type R = a+ ns, where s is the length of an oriented solvent molecule, n is an integer, n = 0, 1, 2, ... Here, s is the length of an OH-group, dOH, and s = dOH = 0.28 nm. In this study we fixed the distance parameter R at R = 0.820 nm for sodium and 0.855 nm for potassium salts, allowing thus three types of ion pairs in the solutions: contact ion pairs, solvent-shared and solvent-separated ion pairs. 4. Results and Discussion Figure 2 shows a comparison of the experimental data for molar conductivities, A, of the NaNap aqueous Figure 2. Molar conductivities, A, of aqueous NaNap solutions from 278.15 to 318.15 K (steps of 5 K). (A) experiment, full line: lcCM calculations. kJ k k k k \D .2 \D 2 8 .2 3 .5 5 .2 8 N!^ 5 .3 0. 0. 0. 0. 0. 1. 0. 0. +1 +1 +1 +1 +1 +1 +1 +1 2 S 1 1 1 1 1 1 .0 2. 0. 0. 0. 0. 0. 0. 0. .02 .01 .01 .03 5 .0 ^ ^ .05 0. 0. 0. 0. 0. 0. 0. 0. +1 +1 +1 +1 +1 +1 +1 +1 3 .8 0 .7 7 5 7 7 .8 3 N^ 2 7. 3 3. 5 3. 0. 7 8. 7 N!D 8 c^ .0 8 .0 8 .0 8 .0 8 .0 8 .0 7 .0 8 .0 0. 0. 0. 0. 0. 0. 0. 0. +1 +1 +1 +1 +1 +1 +1 +1 0 2 .7 8 3 .7 \D 2 .7 7 5 .7 ON NO .7 5 5 .205 1 1 1 1 1 1 1 2. 2 .0 2 .0 2 .0 2 .0 2 .0 2 .0 2 .0 3 .0 0. 0. 0. 0. 0. 0. 0. 0. +1 +1 +1 +1 +1 +1 +1 +1 0 .3 3 2 2 .2 ON 2 .3 0. 5 8. 5 '■O 5. 7 8 c^ 104.1 7 .2 8 0 .2 .21 3 .2 0 .2 7 0. 0. 0. 0. 0. 0. 0. 0. +1 +1 +1 +1 +1 +1 +1 +1 8 Ch 0 .8 7 '■O .2 5 3 2 NO .0 3 0 .0 N!^ 1 1 1 1 1 1 1 1 2 .0 2 .0 2 .0 3 .0 3 .0 3 .0 3 .0 0. 0. 0. 0. 0. 0. 0. 0. +1 +1 +1 +1 +1 +1 +1 +1 .31 7 .2 8 .3 2 .5 5 .0 3 51 8. 5 '■O 7 3. 8 100. .2 .2 .1 .2 .2 .1 .2 0. 0. 0. 0. 0. 0. 0. +1 +1 +1 +1 +1 +1 +1 +1 1 .3 1 1 1 1 0. 0. 0. 0 0. 0. 0. 0. .01 .02 .02 .02 .02 .02 .03 0. 0. 0. 0. 0. 0. 0. 0. +1 +1 +1 +1 +1 +1 +1 +1 .51 2 5 .5 NO .2 5 .3 7 .7 3 .3 8. 5. 5 2. 0. 7 8. 7 N!D 8 5. c^ .2 .1 .1 .2 .1 .2 .2 .2 0. 0. 0. 0. 0. 0. 0. 0. +1 +1 +1 +1 +1 +1 +1 +1 1 1 1 1 .3 1 1 1 0. 0. 0. 0. 0. 0. 0. 0. 3 .0 2 .0 2 .0 3 .0 3 .0 5 .0 NO .0 NO .0 0. 0. 0. 0. 0. 0. 0. 0. +1 +1 +1 +1 +1 +1 +1 +1 \D ON .0 ON .8 7 .0 0 0 2 .5 8 .8 7. 5 '■O 7 8 3. c^ 3. 10 3. 3. 2 5 5 5 5 5 5 5 5 8. 7 2 3. 8 2 8. 8 2 3. 2 8. 2 3. 0 3 8. 0 3 3. 31 g -o 'sa solutions given in Table 2 and the results of the lcCM calculations executed using Eqs. (1-3). All other investigated systems show similar dependence. In Figure 3 the conductivity data for sodium salts (salicylate, naproxen, ibuprofen, diclofenac) and potassium diclofenac at 298.15 K are presented. For Nalbu solutions the experiment was performed in the same concentration range as for other salts but for unknown reason the experimental data can only be satisfactorily fitted over a narrow range of concentration. Table 3 gives a comparison of the calculated lcCM data for all investigated salts. The limiting conductivities are dependent on the structure of the anions, as can be expected. The values of the association constants are very low and all the investigated salts could be regarded as completely dissociated in water solutions ("strong-electrolytes"). The values of KA for NaCl aqueous solutions obtained from precise conductance measurements by using the lcCM, are in the range 0.6 < KA < 2.6 in the temperature range between 278.15 and 303.15 K.12 Whereas the temperature coefficient dKA/dT is usually positive for the alkali salt water solutions, no reliable evidence for the temperature dependence of the association process of aqueous solutions of the discussed drugs was found except at NaSal and NaIbu where slightly higher ion association at lower temperatures can be assumed. Figure 3. Molar conductivities of KDic (T), NaSal (♦), NaNap (A), NaDic (V) and Nalbu (•) in water at 25 °C. Combining the limiting conductivities A" of Table 3 and the known limiting values of cations A°°(M+ ), M+ = Na+, K+ (Table 1) À,"(T, A- ) = A" (T, MA) - À,"(T, M+ ) (4) yields the limiting anion conductivities A"(A ) and their temperature dependence; see Table 4. Table 4. Limiting conductance of anions of investigated drugs in water as a function of temperature" T A" NaDic (Dic) KDic A" (Sal-) A" (Nap-) A" (Dic) A" (Ibu ) 278.15 11.19 10.93 20.14 14.01 11.06 7.53 283.15 13.20 13.06 23.42 16.39 13.13 8.82 288.15 15.40 15.28 26.91 18.89 15.34 10.25 293.15 17.69 17.63 30.61 21.56 17.66 11.84 298.15 20.09 20.10 34.46 24.37 20.09 13.52 303.15 22.61 22.64 38.50 27.33 22.63 15.15 308.15 25.23 25.32 42.66 30.40 25.28 17.10 313.15 27.78 28.08 46.77 33.45 27.93 18.87 a Units: T, K; A", S • cm2 • mol- From the Walden rule4 (5) the solvent dependent ionic radii ajn were estimated (F is the Faraday constant and z the ionic charge). In water af^ are usually called hydrodynamic radii, rh. Values for the hydrodynamic radii of the ions of investigated salts are collected in Table 5. It is well known that comparison of the values of the hydrodynamic radii and the crystal radii of cations show large difference for Na+ ions, whereas the ion size parameter of K+ are close together. Table 5. Hydrodynamic radii, rh, of the investigated salts in water from Walden rule as a function of temperature The obtained hydrodynamic radii for the anions are ranked in Sal- < Nap- < Dic- < Ibu- what is not expected from their molar van der Waals volumes, calculated from the optimized geometries using the Winmostar pro-gram13 and summarized in Table 6. Table 6. Van der Waals volumes, Vvdw, van der Waals radii, rvdw, of the anions and the ratio between van der Waals radii and the hydrodynamic radii at 298.15 K.a V ^vdw rvdw' rh Sal- 67.9 0.300 1.123 Nap- 125.1 0.367 0.973 Dic- 137.4 0.379 0.828 Ibu- 119.2 0.362 0.532 a Units: Vvdw, cm3 • mol- rv^lw,, nm T Na+ K+ Sal- Nap- Dic- Ibu- 278.15 0.178 0.115 0.268 0.385 0.487 0.716 283.15 0.180 0.118 0.267 0.382 0.477 0.710 288.15 0.181 0.121 0.267 0.381 0.469 0.702 293.15 0.182 0.123 0.267 0.379 0.463 0.690 298.15 0.183 0.125 0.267 0.377 0.458 0.680 303.15 0.184 0.127 0.267 0.376 0.454 0.678 308.15 0.185 0.129 0.267 0.374 0.450 0.666 313.15 0.186 0.131 0.268 0.375 0.449 0.665 Sodium ion is relatively small and has, therefore, an exceptionally high charge to radius ratio (charge density) and tends to orient the water molecules in its vicinity. Contrarily, its hydrated radius is much larger than similar ions and the large solvation shell around the ion also causes its low mobility and low limiting conductivities A" in solution. The potassium ion has low charge densities and consequently ions are surrounded by water molecules which are more mobile. For the sodium ion the hydration number, h, obtained from transport process measurements, is reported in the literature as h (Na+, 298.15 K) = 5. The van der Waals radii, rvdw, were calculated assuming spherical shapes of anions and Walden rule treats the ionic migration as a movement of a rigid spherical ion through viscous continuum also. The structures of the investigated ions (Figure 1) hardly express the spherical symmetry. Therefore values listed in Tables 5 and 6 can be discussed only as the rough estimation of real dimensions of the drug's anions in water. Nevertheless, values of rh and rvdw for Sal- and Nap- are close together. It appears that no explicit hydration of these anions can be assumed. Larger differences between rh and rvdw for Dic- and Ibu- may lead to the assumption that here the hydration is more pronounced. Despite the fact that chlorine and nitrogen atoms reduce the hydrophobicity of the radical in Dic-anion the hydration can be predicted hardly even here. For Ibu- possessing higly hydrophobic alkyl chain bound to the aromatic ring this is even less likely. Rather it can be assumed that the anions are more extended and the assumption of the spherical symmetry is far from more realistic dimensions obtained by Walden rule. From Table 5 it is evident that rh of Sal- is almost temperature insensitive whereas at all other anions rh is decreasing perceivably with increasing temperature. This again may lead to the conclusion that hydration - which r h a Units: T, K; r,^, nm is more pronounced at lower temperatures - may take place. Finally, the hydrodynamic radii of Sal- and Nap-ions have been found to be smaller than 0.4 nm, a common pore size of membranes so that the direct passage of the drug through the pores of the membranes is possible. The opposite is true for the Dic- and Ibu- and these drugs probably penetrate by partition mechanism. For Dic- anion in acetontrile the value of a/^ = 0.521 nm at 298.15 K has been found recently3 showing completely different interactions of this anion with the solvent. It is known that solvents forming three-dimensional networks (water, alcohols) surround hydrophobic organic ions in clathrate-like structures4 and therefore here the radii of complex organic anions are significantly different from that in organic solvents. Moreover, for the complex hydrophobic organic anions in aqueous solutions coiled configuration can be assumed. The temperature-dependence of limiting conductivity yields Eyring's enthalpy of activation of charge trans- port14 Assuming substantial hydration of Dic- the relatively high value of AH* can be explained by the desolva-tion and rearrangement of water around the moving ion, whereas at Ibu- the hydrophobicity is crucial. , 2, , AH ^ InX =--+B, 3 RT (6) Figure 4. Plot of lnX" + 2/3 lnd^ as a function of 1/r for K+(0), Na+(0), Sal- (♦), Nap- (A), Dsc- (V) and Ibu- (•) in water at 298.15 K. From the slope the activation energy of the ionic movement, AH*, is obtained. where B is the integration constant. Values AH* = 16.50, 14.72, 17.40, 17.94, 19.02 and 19.03 kJ/mol for Na+, K+, Sal-, Nap-, Dicand Ibu-, respectively, were obtained (Figure 4). It has been shown that the ionic migration in a non-structures solvent is very much a solvent property and that the difference in the mobilities of ions is simply the result of different ion sizes.14,15 The observed order of the molar ionic enthalpies of activation, AH*, for the cations Na+ > K+ could be explained by the energy needed for the desol-vation and rearrangement of water molecules in the vicinity of the ion. Thus values of AH* may depend on the expressed hydration. Differences in the Eyring's enthalpy of activation of charge transport of the investigated anions are ranked as Sal-< Nap-< Dic- « Ibu-. They could not be ascribed to the differences in the ion sizes only (rh(Dic-) < rh(Ibu-)) but also to the specific interaction anions with water. In water additional strong - hydrophobic - interactions are presented, resulting not only in the size parameters. Therefore it could be assumed that for the jump of the, for example, Ibu- anion to a prepared vacancy in the solvent - or to produce such a vacancy - higher energy is required than for the Sal- anion (and Nap ) or cations investigated in this work. This could be explained by the repulsion of water molecules by the hydrophobic site of the anions and this part is larger at Dic- and Ibu- than at Sal- and Nap-. The hydroxyl and ether group in the structure of Sal- and Nap-, respectively, reduce the hydrophobicity of these anions obviously . 4. Conclusion Nonsteroidal anti-inflammatory drugs sodium sa-licylate, naproxen sodium salt, diclofenac sodium salt, diclofenac potassium salt and ibuprofen sodium salt are completely dissociated in aqueous solutions. Their anions are weakly hydrated due to its hydrophobicity, whereas the hydration of cations depends on their charge densities. From the Eyring's enthalpy of activation it could be assumed that the repulsion of water molecules by the hydrophobic site of the anion at Ibu- is more pronounced than at Sal- and Nap-, where hydroxyl group and/or ether group reduce the hydrophobicity of the anions. At Dic- the hydration could also play an important role. Despite the fact, that the mechanism of action of NSAIDs is not completely understood,1 it could be expected that the observed differences should have an influence on their potency, duration of action and the way in which they are eliminated from the body. However, more investigations are needed to enlighten the correlation of their transport behaviour with their pharmacological properties. 5. Acknowledgement Financial support by the Agency for Research and Development of Slovenia (ARRS) under grant P1-0201 is gratefully acknowledged. The author owes Professor Barthel a great debt of gratitude for all support and his continued interest in her work. 6. References 1. 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Owen, The physical chemistry of electrolyte solutions, 3rd edn., Reinhold, New York, p. 233, 1958. 11. O. Kratky, H. Leopold, H. Stabinger, Z. Angew. Phys. 1969, 27, 273-277. 12. M. Bešter-Rogač, R. Neueder, J. Barthel, J. Solution Chem. 1999, 28, 1071-1086. 13. N. Senda, Winmostar, version 3.75 http://winmostar.com 14. S. B. Brummer, G. J. Hills, J. Chem. Soc. Faraday Trans. 1961, 57, 1816-1837. 15. F. Barreira, G. J. Hills, J. Chem. Soc. Faraday Trans. 1968, 64, 1359-1375. Povzetek Izmerili smo električne prevodnosti vodnih raztopin salicilat, ibuprofen, diklofenak in naproksen natrijeve soli ter diklofenak kalijeve soli v temperaturnem območju med 278.15 K in 313.15 K v koncentracijskem obsegu 3 x 10-4 < c (mol/dm-3) < 0.007. Na osnovi kemijskega modela smo določili vrednosti molskih prevodnosti pri neskončnem razredčenju, A", ter konstante asociacije ionov, KA, v posameznem sistemu. S pomočjo znanih vrednosti limitnih prevodnosti natrijevega oz. kalijevega iona smo ocenili limitne prevodnosti ter hidrodinamične radije vseh preiskovanih anionov. Ugotovili smo, da je delež ionskih parov v raztopini zanemarljiv in preiskovanim elektrolitom v vodnih raztopinah lahko pripišemo popolno disociacijo v celotnem obravnavanem temperaturnem območju. Opazno razliko v mobilnosti anionov lahko pripišemo različni hidrataciji ter možnim hidrofobnim interakcijam.