226-234 Martinez LAJP 2782:Martinez

Latin American Journal of Pharmacy (formerly Acta Farmacéutica Bonaerense)

Regular Article Received: February 1, 2012 Revised version: March 5, 2012 Accepted: March 8, 2012

Lat. Am. J. Pharm. 31 (2): 226-34 (2012)

Solution Thermodynamics of Lysine Clonixinate in Some Ethanol + Water Mixtures Rahumir A. GUTIÉRREZ, Daniel R. DELGADO & Fleming MARTÍNEZ * Grupo de Investigaciones Farmacéutico-Fisicoquímicas, Departamento de Farmacia, Universidad Nacional de Colombia, A.A. 14490, Bogotá D.C., Colombia.

SUMMARY. The solubility of lysine clonixinate (LysClon) in several ethanol + water mixtures was determined at 293.15 to 313.15 K. The thermodynamic functions, Gibbs energy, enthalpy, and entropy of solution and of mixing were obtained from these solubility data by using the van’t Hoff and Gibbs equations. In general this drug exhibit good solubility and the greatest value was obtained in the mixture 0.60 in mass fraction of ethanol. A non-linear enthalpy–entropy relationship was observed from a plot of enthalpy vs. Gibbs energy of solution. Accordingly, the driving mechanism for LysClon solubility in water-rich and ethanol-rich mixtures is the entropy, probably due to water-structure losing around the drug non-polar moieties by ethanol or increased ionic solvation; whereas, in the medium composition mixtures the driving mechanism is the enthalpy, probably due to LysClon solvation increase by the co-solvent molecules.

INTRODUCTION Clonixin is an analgesic drug sometimes used in therapeutics 1; nevertheless its aqueous solubility is too low 2. For this reason some of its salts, which are much more soluble in water, have also been employed. In particular lysine clonixinate (LysClon, Figure 1, molar mass of 408.88 g/mol) has been used due to its analgesic properties for the treatment of migraine headaches and other painful conditions 3-5. It is well known that the behavior of drugs in solvent mixtures is evaluated for the purposes of substances purification, pre-formulation studies, and pharmaceutical dosage forms design 6. Hence, it is very important to determine systematically their solubilities in order to obtain complete physicochemical data about relevant liquid pharmaceutical systems. In the other hand, the temperature dependence of the solubility allows a thermodynamic analysis that permits insight into the molecular mechanisms involved in the drug dissolution processes 7.

Figure 1. Molecular structure of lysine clonixinate.

Although LysClon has been widely used in therapeutics the physicochemical information about its solubility in aqueous media is not abundant. For this reason, the main objective of this study was to evaluate the effect of the cosolvent composition on solubility and solution thermodynamics of LysClon in ethanol + water mixtures, based on the van’t Hoff method, including the respective contributions by mixing of this compound toward the solution processes. Thus, this work is a continuation of the ones developed with some sodium or hydrochloride

KEY WORDS: Cosolvency, Ethanol, Lysine clonixinate, Solubility, Solution thermodynamics. *

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Author to whom correspondence should be addressed: E-mail: [email protected].

ISSN 0326-2383

Latin American Journal of Pharmacy - 31 (2) - 2012

form of drugs 8-14. Nevertheless it is important to note that LysClon is composed by two organic ions instead of just one as in the cases studied before.

the saturated solutions was determined with a digital density meter (DMA 45 Anton Paar) connected to the same re-circulating thermostatic baths 16.

MATERIAL AND METHODS Reagents Lysine clonixinate (l-lysine mono(2-((3chloro-2-methylphenyl)amino)-3-pyridinecarboxylate), CAS [55837-30-4]) from Hangzhou Dayangchem Co., Ltd. (China) was used in this research. The solvents, absolute ethanol A.R. (Merck, Germany) and distilled water with conductivity of < 2 µS/cm were used conformed to the quality requirements of the American Pharmacopeia, USP 15.

Calorimetric study Melting point and enthalpy of fusion of LysClon were determined by DSC studies (DSC 823E Mettler Toledo). Thermal analyses were performed at a heating rate of 10 K/min in a dynamic nitrogen atmosphere (60 cm3/min). Nearly 1.5 mg of drug was used. The equipment was calibrated using Indium as standard.

Solvent mixtures preparation All ethanol + water solvent mixtures were prepared by mass, using an Ohaus Pioneer TM PA214 analytical balance with sensitivity of ± 0.1 mg, in quantities of 50 g. The mass fractions of ethanol, wEtOH, of the nine binary mixtures prepared varied by 0.10 from 0.10 to 0.90. Solubility determinations An excess of LysClon was added to approximately 10 g of each co-solvent mixture or neat solvents, in stoppered dark glass flasks. The flasks with the solid-liquid mixture were placed in thermostatic mechanical shakers (Julabo SW23) kept at 303.15, 308.15, or 313.15 (± 0.05) K or placed in re-circulating thermostatic baths (Neslab RTE 10 Digital One Thermo Electron Company) kept at 293.15 or 298.15 (± 0.05) K for at least 7 days to reach the equilibrium. This equilibrium time was established by measuring the drug concentrations till they became constant. After this time the supernatant solutions were filtered at isothermal conditions (Millipore Corp. Swinnex®-13) to ensure that they were free of particulate matter before sampling. LysClon concentrations were determined by mass balance by weighing a specified quantity of the respective saturated solution and allowing the solvent evaporation up to constant mass. This method has been employed in other similar works because the high solubility exhibited by this kind of drugs in the solvents and mixtures studied here 9 . The main advantage of this method is that it does not require dilutions. All the solubility experiments were run at least in triplicates. In order to transform mole fractions to molar concentrations (mol/L), the density of

RESULTS AND DISCUSSION It is important to consider that this drug has electrolyte behavior, and thus, it dissociates in aqueous solution interacting with the solvent by ion-dipole interactions, among other non-covalent interactions; on this way, it also could acts as a Lewis acid or base, in order to establish hydrogen bonds with proton-acceptor or donor functional groups present in the solvents (–OH groups) 17. Experimental and ideal solubility Table 1 shows the experimental solubilities of LysClon expressed in mole fractions, x2. In almost all cases the coefficients of variation of the solubility were smaller than 2.0 %. Solubility values expressed in molarity are presented in Figure 2, where the respective trends at each temperature could be described as regular polynomials in order three. If the mole fraction scale is considered the highest solubility of LysClon was obtained in the mixture 0.60 in mass fraction of ethanol at

Figure 2. Experimental solubility of lysine clonixinate in ethanol + water mixtures, expressed in molarity, as a function of co-solvent mixtures composition. (O): 293.15 K; (n): 298.15 K; (Δ): 303.15 K; (l): 308.15 K; (n): 313.15 K.

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GUTIÉRREZ R.A., DELGADO D.R. & MARTÍNEZ F.

100 x2

wEtOH a

0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Ideal

T = 293.15 K

T = 298.15 K

T = 303.15 K

T = 308.15 K

T = 313.15 K

0.2694 (0.0002) 0.3471 (0.0009) 0.436 (0.005) 0.530 (0.003) 0.6459 (0.0003) 0.773 (0.003) 0.8854 (0.0013) 0.990 (0.009) 1.015 (0.014) 0.977 (0.003) 0.658 (0.005) 0.2676

0.3863 (0.0004) 0.5471 (0.0002) 0.7510 (0.0004) 0.959 (0.003) 1.141 (0.001) 1.259 (0.001) 1.496 (0.001) 1.609 (0.001) 1.542 (0.002) 1.386 (0.001) 0.790 (0.001) 0.3246

0.514 (0.004) 0.850 (0.000) 1.272 (0.001) 1.667 (0.002) 1.980 (0.001) 2.431 (0.002) 2.362 (0.002) 2.440 (0.001) 2.279 (0.003) 1.940 (0.001) 0.942 (0.001) 0.3925

0.768 (0.001) 1.306 (0.001) 2.124 (0.001) 2.862 (0.023) 3.475 (0.020) 4.082 (0.022) 4.059 (0.003) 4.040 (0.002) 3.323 (0.005) 2.614 (0.016) 1.117 (0.002) 0.4732

1.068 (0.013) 2.015 (0.011) 3.461 (0.021) 4.857 (0.051) 5.785 (0.051) 6.514 (0.030) 6.534 (0.069) 6.275 (0.050) 4.730 (0.032) 3.671 (0.035) 1.317 (0.012) 0.5687

Table 1. Experimental solubility of lysine clonixinate in ethanol + water mixtures, expressed in mole fraction, including ideal solubility at several temperatures (values in parentheses are the standard deviations). a wEtOH is the mass fraction of ethanol in the co-solvent mixtures free of lysine clonixinate.

313.15 K, whereas the lowest value was found in pure water at 293.15 K. Nevertheless, it is important to note that the maximum solubility is obtained in different co-solvent mixtures according to the temperature (Table 1). On the other hand, it is interesting to note that if the molarity scale is considered, the maximum solubility is obtained in the mixture 0.50 in mass fraction of ethanol at the maximum temperature again (313.15 K). This apparent contradiction is just a consequence of the definitions of each concentration scale 17. Because LysClon is an electrolyte drug, it is important to note that, in general terms, it could be stated that a strong electrolyte dissociates according to the expression, Cv+Av-→v+C z+ +v_Az16,

where v+ is the number of cations (C z+) of valence z+ and v_ is the number of anions (Az-) of valence z–. Because it is not possible to determine experimentally the activity of ions separately, the concept of mean ionic activity (av±) is used. Thus, the thermodynamic activity for an v velectrolyte can be defined as, a2 = av+ + a - = a± 17-20. On the same way, in terms of individual ionic activity coefficients (γ+ and γ–), the mean activity coefficient (γ±) could be defined as, γ± = v+ v- 1/v vγv+ + γ -, which is equal to, γ± = (γ + γ -) . Thus, if the drug concentration is expressed in mole fraction, the solute thermodynamic activity in the solution could be calculated as, ax± = γ x± x± where γ x± is the rational activity coefficient and is a deviation criterion with respect to the ideal solution. LysClon is an electrolyte solute of type one-

228

one, that is, it dissociates to generate two species, a monovalent cation and a monovalent anion, respectively. If the inter-ionic interactions are not considered, in a first approach v could be ideally assumed as two for this drug 20. On the other hand, the ideal solubility of a crystalline solute in a liquid solvent can be calculated by Eq. [1] 7: [1] where x2-id is the ideal solubility of the solute as mole fraction, ΔfusH is the molar enthalpy of fusion of the pure solute (at the melting point), T fus is the absolute melting point, T is the absolute solution temperature, R is the gas constant (8.314 J/mol.K), and ΔCp is the difference between the molar heat capacity of the crystalline form and the molar heat capacity of the hypothetical supercooled liquid form, both at the solution temperature 10,11,14. Although Eq. [1] was developed for non-electrolyte compounds, it has also been used to estimate ideal solubilities of some electrolyte drugs 21. Since ΔCp cannot be easy experimentally determined it is usual assuming that it may be approximated to the entropy of fusion, ΔfusS calculated as the quotient Δ fusH/T fus. The values obtained by means of DSC for ΔfusH and T fus were 46.77 kJ/mol and 492.3 K, respectively. LysClon ideal solubility values are also presented in Table 1. In all cases the ideal solubilities were lower than the experimental ones despite of co-solvent mixtures composition.


wEtOH a

0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00

T = 293.15 K

0.9932 0.7709 0.6131 0.5045 0.4143 0.3463 0.3022 0.2702 0.2636 0.2738 0.4064

(0.0006) (0.0021) (0.0068) (0.0033) (0.0002) (0.0014) (0.0004) (0.0023) (0.0037) (0.0009) (0.0034)

T = 298.15 K

0.8402 0.5933 0.4323 0.3386 0.2845 0.2578 0.2171 0.2018 0.2105 0.2343 0.4109

(0.0010) (0.0002) (0.0002) (0.0012) (0.0002) (0.0002) (0.0001) (0.0001) (0.0003) (0.0001) (0.0006)

T = 303.15 K

0.7635 (0.0063) 0.4616 (0.0002) 0.3087 (0.0002) 0.2355 (0.0002) 0.1982 (0.0001) 0.1615) (0.0001) 0.1662 (0.0001) 0.1609 (0.0001) 0.1722 (0.0003) 0.2023 (0.0001) 0.4167 (0.0006)

T = 308.15 K

0.6158 0.3624 0.2228 0.1653 0.1362 0.1159 0.1166 0.1171 0.1424 0.1810 0.4238

(0.0007) (0.0001) (0.0001) (0.0013) (0.0008) (0.0006) (0.0001) (0.0001) (0.0002) (0.0011) (0.0006)

T = 313.15 K

0.5327 0.2823 0.1643 0.1171 0.0983 0.0873 0.0870 0.0906 0.1202 0.1549 0.4320

(0.0064) (0.0016) (0.0010) (0.0012) (0.0009) (0.0004) (0.0009) (0.0007) (0.0008) (0.0015) (0.0038)

Table 2. Lysine clonixinate activity coefficients (γ2) in ethanol + water mixtures at several temperatures. a wEtOH

is the mass fraction of ethanol in the co-solvent mixtures free of lysine clonixinate.

Drug Activity coefficients Table 2 shows the LysClon activity coefficients γ 2, calculated as x2-id/x2 from the respective solubility values presented in Table 1. From γ 2 values a rough estimate of solute-solvent intermolecular interactions can be made by considering the following expression 22:

that γ 2 values diminish as the temperature rises except in neat ethanol where they diminish as the temperature raises. In this point it is important to keep in mind that ion-dipole or any other strong solute-solvent interactions should be present here and they could be responsible for the high solubility values obtained for this drug.

[2] Here subscript 1 stands for the solvent [in the present case, the solvent mixture: ethanol + water], e11, e22 and e12 represent the solvent-solvent, solute-solute and solvent-solute interaction energies, respectively; V 2 is the molar volume of the super-cooled liquid solute, and finally, φ 1 is the volume fraction of the solvent. As a first approximation, for relatively low solubilities x2, the term V 2φ 12/RT may be considered constant; thus, γ 2 depends mainly on e11, e22 and e12 22. The e11 and e22 terms are unfavorable for drug solubility, whereas the e12 term favors the solution process. The contribution of the e22 term could be considered as constant in all the mixtures. As a qualitative approach, the following analysis could be made based on the energetic quantities and magnitudes described in Eq. [2]: The term e11 is the highest in neat water (Hildebrand solubility parameter δ = 47.8 MPa1/2) and is smaller in ethanol (δ = 26.6 MPa1/2) 23. Pure water and water-rich mixtures having γ 2 values near to 1.00 would imply an apparent compensation between e11 and e12 values. On the other hand, in ethanol and ethanol-rich mixtures (having γ 2 < 0.40), the e11 values are relatively low and the e12 values would be so high. Accordingly, the solvation of LysClon could be just higher in ethanol-rich mixtures. It is interesting to note

Thermodynamic functions of solution Apparent standard enthalpy change of solution (Δ solnH °) is obtained from the modified van’t Hoff equation by using the mean harmonic temperature (T hm) 24, calculated as: [3] where n is the number of temperatures studied. In the present case (from 293.15 K to 313.15 K) the T hm value obtained is 303.0 K. Thus ΔsolnH ° is obtained from 8-14: [4] The apparent standard Gibbs energy change for the solution process (ΔsolnG °), considering the approach proposed by Krug et al. 24, is calculated at 303.0 K by means of: [5] in which, the intercept used is the one obtained in the analysis by treatment of ln x 2 as a function of 1/T – 1/303K. Finally, the standard apparent entropic change for solution process (ΔsolnS °) is obtained from the respective ΔsolnH ° and ΔsolnG ° values at 303.0 K by using: [6]

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wEtOH a

ΔsolnG° (kJ/mol)

ΔsolnH° (kJ/mol)

ΔsolnS° (J/mol.K)

TΔsolnS° (kJ/mol)

ζH b

ζTS b

0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Ideal

26.35 (0.12) 24.06 (0.05) 22.07 (0.08) 20.72 (0.12) 19.80 (0.06) 19.03 (0.06) 18.75 (0.05) 18.58 (0.07) 19.14 (0.10) 19.95 (0.08) 23.53 (0.10) 27.93

105.0 (1.6) 133.9 (0.4) 158.2 (0.3) 168.6 (0.4) 167.9 (0.5) 166.1 (2.3) 152.5 (1.2) 140.8 (1.3) 117.5 (0.5) 100.2 (0.6) 52.9 (0.3) 57.5

259.7 (4.1) 362.6 (1.3) 449.3 (1.9) 488.2 (3.1) 488.8 (2.2) 485.6 (6.9) 441.4 (3.8) 403.4 (3.9) 324.5 (2.2) 264.8 ((2.0) 96.9 (0.7) 97.7

78.7 (1.2) 109.9 (0.4) 136.1 (0.6) 147.9 (0.9) 148.1 (0.7) 147.1 (2.1) 133.7 (1.1) 122.2 (1.2) 98.3 (0.7) 80.2 (0.6) 29.4 (0.2) 29.6

0.572 0.549 0.538 0.533 0.531 0.530 0.533 0.535 0.544 0.555 0.643 0.660

0.428 0.451 0.462 0.467 0.469 0.470 0.467 0.465 0.456 0.445 0.357 0.340

Table 3. Thermodynamic quantities relative to solution process of lysine clonixinate in ethanol + water co-sol-

vent mixtures including ideal process at 303.0 K (values in parentheses are the standard deviations). a wEtOH is the mass fraction of ethanol in the co-solvent mixtures free of lysine clonixinate. b ζH and ζTS are the relative contributions by enthalpy and entropy toward Gibbs energy of solution. These values were calculated by means of equations [7] and [8], respectively.

Table 3 presents the standard molar thermodynamic functions for dissolution of LysClon in ethanol + water mixtures, including those for mono- solvents and the ideal solution process. The propagation of uncertainties in the thermodynamic quantities calculations was made according to the literature 25. The standard Gibbs energy of solution is positive in every case as is also the enthalpy and entropy of solution; therefore the process is always endothermic and entropy-driven. The ΔsolnH ° values increase from pure water to the mixture wEtOH = 0.30 and later they diminish up to ethanol; whereas the ΔsolnS ° values increases from water to the mixture wEtOH = 0.40 and later they diminish. The relative contributions by enthalpy (ζ H) and entropy (ζ TS) toward the solution process are given by Eqs. [7] and [8] 26. [7]

[8] The main contributor to the (positive) standard molar Gibbs energy of solution of LysClon is the (positive) enthalpy (ζ H > 0.53) in all cases, indicating energetic predominance on the dissolution processes. It is interesting to note that ζ H for the ideal process is higher compared with the experimental ones in all the systems studied, except in neat ethanol, where it is similar in magnitude.

230

Thermodynamic functions of mixing The solution process may be represented by the following hypothetic stages 27: Solute(Solid) → Solute(Liquid) at T fus → Solute(Liquid) at T hm → Solute(Solution), where the solution stages are solute fusion, cooling the liquid solute to the harmonic mean temperature T hm (303.0 K), and subsequent mixing of the hypothetical super-cooled liquid solute with the solvent at this temperature. This allows also the calculation of the partial thermodynamic contributions to the overall solution process by means of Eqs. [9] and [10], respectively. ΔsolnH ° = ΔfusH 303 + ΔmixH ° ΔsolnS ° = ΔfusS 303 + ΔmixS °

[9] [10]

where ΔfusH 303 and ΔfusS 303 represent the thermodynamic functions of fusion of LysClon and its cooling to the harmonic mean temperature, 303.0 K. However, in this research the ΔsolnH °-id and ΔsolnS °-id values for the ideal solution processes were used instead of ΔfusH 303 and ΔfusS 303 for reasons described in the literature 10,11. Figure 3 summarizes the thermodynamic quantities of mixing of super-cooled liquid LysClon with all the co-solvent mixtures. Gibbs energy of mixing is negative in all cases, because experimental solubilities are greater than the ideal ones at all temperatures. The ideal dissolution contributions (related to solute fusion process), to the enthalpy and entropy of dissolution of LysClon, i.e. ΔsolnH °-id and ΔsolnS °-id, are positive (Table 3). The contri-


Figure 3. Thermodynamic quantities of mixing of lysine clonixinate in ethanol + water mixtures at 303 K as function of co-solvent mixtures composition. (n): ΔmixH °; (p): TΔmixS °; (O): ΔmixG °.

bution of the mixing process toward the overall dissolution is almost proportional, i.e. ΔmixH ° and T ΔmixS ° are positive and similar in magnitude, except in neat ethanol. According to Figure 3, the molar ΔmixG ° values diminish as the ethanol proportion increases in the mixtures up to the mixture with wEtOH = 0.70 and later they increase slightly; whereas, the ΔmixH ° and ΔmixS ° values increase nonlinearly from water up to the mixture with wEtOH = 0.40 where the greatest values are obtained and later they diminish reaching the lowest values in neat ethanol. The net variation in ΔmixH ° values (Fig. 3) results from the contribution of several kinds of interactions. Thus, the enthalpy of cavity formation (required for solute accommodation) is endothermic because energy must be supplied against the cohesive forces of the solvent. This process decreases solubility, which is in agreement with the discussion of e11 and the solubility parameters of water and of ethanol made previously. On the other hand, the enthalpy of solvent-solute interaction (corresponding to the energy e12) is exothermic and results mainly from van der Waals and Lewis acid-base interactions and in the case of LysClon also from strong iondipole interactions. The structuring of water molecules around the non-polar groups of solutes (hydrophobic hydration) contributes to lowering of the net Δ mixH ° to small or even negative values in water-rich mixtures; nevertheless, this fact is not observed with this electrolyte drug in this co-solvent system. The energy of cavity formation should be lower as the proportion of ethanol increases because the mixtures polarity diminishes. This effect is well observed for LysClon in ethanol-rich

mixtures (wEtOH ≥ 0.40), where ΔmixH ° diminish as the proportion of co-solvent increases. According to Romero et al. 28 in the initial portion of the solubility curve the hydrogen bonding of the drug will increase with ethanol concentration in the co-solvent mixtures, as also occurs with the non-electrolyte analgesic drugs naproxen 7, ketoprofen 29, and indomethacin 30 in the same co-solvent system. However, at large cosolvent proportions this interaction may be saturated, becoming a constant contribution. On the other hand, nonspecific and cavity effects are not saturated and vary with the co-solvent proportion in the mixtures. From Figure 3 is clear that for LysClon, the values of ΔmixH ° also diminish as the proportion of ethanol increases in the mixtures, as was already said. Nevertheless it is necessary to keep in mind that LysClon is an electrolyte drug and thus stronger interactions such as ion-dipole need to be also considered in a more rigorous treatment of solute-solvent effects. Thermodynamic functions of transfer In order to verify the effect of co-solvent composition on the thermodynamic function driving the solution process, Table 4 summarizes the thermodynamic functions of transfer of LysClon from the more polar solvents to the less polar ones. These new functions were calculated as the differences between the thermodynamic quantities of solution obtained in the more polar mixtures and in the less polar ones. If the addition of ethanol to water is considered (being the solvent mixture less polar as the ethanol proportion increases), as has been done earlier 8-10, it happens the following, from neat water to 0.30 in mass fraction of ethanol (ΔA→BG ° < 0, ΔA→BH ° > 0, and ΔA→BS ° > 0) the solubility process is driven by the entropy; whereas, from this composition up to 0.40 in mass fraction of ethanol (ΔA→BG ° < 0, ΔA→BH ° < 0, and ΔA→BS ° > 0) the dissolution process is both enthalpy and entropy-driven. From compositions 0.40 to 0.70 in mass fraction of ethanol (ΔA→BG ° < 0, ΔA→BH ° < 0, and ΔA→BS ° < 0) the process is enthalpy-driven. Ultimately, from this ethanol proportion to neat ethanol (ΔA→BG ° > 0, ΔA→BH ° < 0, and ΔA→BS ° < 0), the solution process is entropy-driven. These results could be interpreted as the result of the water-structure losing around the non-polar groups of the drug due to the addition of co-solvent in water-rich mixtures. On the other hand, it may be suggested that more drug solvation by water and co-

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wEtOH a,b A

B

0.00 0.30 0.40 0.70

0.30 0.40 0.70 1.00

ΔA→B G° (kJ/mol)

ΔA→B H° (kJ/mol)

ΔA→B S° (J/mol.K)

TΔA→B S° (kJ/mol)

ζH c

ζTS c

-5.64 (0.17) -0.92 (0.14) -1.22 (0.09) 4.96 (0.12)

63.6 (1.6) -0.7 (0.7) -27.1 (1.4) -87.9 (1.3)

229 (5) 1 (4) -85 (4) -307 (4)

69.3 (1.6) 0.2 (1.2) -25.9 (1.4) -92.9 (1.2)

0.479 0.814 0.512 0.486

0.521 0.186 0.488 0.514

Table 4. Thermodynamic quantities relative to transfer of lysine clonixinate from more polar solvents to less polar solvents in ethanol + water co-solvent mixtures at 303.0 K (values in parentheses are the standard deviations). a wEtOH is the mass fraction of ethanol in the co-solvent mixtures free of lysine clonixinate. b A and B are the more polar and less polar media, respectively. c ζH and ζTS are the relative contributions by enthalpy and entropy toward Gibbs energy of transfer. These values were calculated by means of equations analogous to [7] and [8], respectively.

solvent molecules in the water-rich or co-solvent-rich regions could also play an important role due to the electrolyte nature of this compound. Enthalpy-entropy compensation There are several reports in the literature that have demonstrated the existence of non-enthalpy-entropy compensation effects for the solubility of drugs in various aqueous co-solvent mixtures 27-31. This analysis has been used in order to identify the mechanism of the co-solvent action. Weighted graphs of ΔsolnH ° as a function of ΔsolnG ° at the harmonic mean temperature permit such an analysis 31. Figure 4 shows that LysClon in the ethanol + water solvent system presents a non-linear ΔsolnH ° vs. ΔsolnG ° curve with a variable negative slope in the interval from pure water up to wEtOH = 0.30. In the interval 0.30 ≤ wEtOH ≤ 0.70

variable but positive slope is obtained. Beyond this ethanol proportion up to neat ethanol a slightly variable but negative slope is obtained again. Accordingly, the driving mechanism for solubility is the entropy in the former and later cases, probably implying water-structure loosening or even ions separation; whereas in the second case the driving mechanism is the enthalpy, probably due to better solvation of the drug, as was already said. On the other hand, accordingly with the literature 29, 32-34, another interesting compensation graph is obtained by plotting ΔsolnH ° as a function of T Δ solnS °. Normally two lines are obtained according to the mixtures composition, and in this way, linear equations with slopes lower than 1.0 are corresponding to entropydriven solution processes, whereas those with slopes greater than 1.0 would be corresponding to enthalpy-driven processes. Nevertheless, Fig-

Figure 4. ΔsolnH ° vs. ΔsolnG ° enthalpy-entropy compensation plot for dissolution process of lysine clonixinate in ethanol + water co-solvent mixtures at 303.0 K. The points represent the values obtained at each mass fraction of ethanol in the solvent mixtures free of lysine clonixinate.

Figure 5. ΔsolnH ° vs. ΔsolnG ° enthalpy-entropy compensation plot for dissolution process of lysine clonixinate in ethanol + water co-solvent mixtures at 303.0 K. The points represent the values obtained at each mass fraction of ethanol in the solvent mixtures free of lysine clonixinate.

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ure 5 shows that just one linear equation is obtained for LysClon as follows: ΔsolnH ° = 0.964 (0.019) × T ΔsolnS ° + 25.1 (2.3), with r2 adjusted: 0.996 and typical error: 2.32. This result apparently indicates linear compensation and therefore the same mechanism toward drug dissolution process despite of mixtures composition, which clearly is non-correct, based on the thermodynamic quantities of transfer (Table 4) and the ΔsolnH ° vs. ΔsolnG ° plot (Fig. 4) already analyzed. This point, concerning to the apparent contradiction between the types of axis coordinates employed, has been earlier analyzed in the literature 24,35. CONCLUSIONS From all topics discussed here it can be concluded that the solution process of LysClon in ethanol + water mixtures depends strongly on the solvent composition. Non-linear ΔsolnH ° vs. ΔsolnG ° compensation was found for this drug in this solvent system. In this context, entropydriving was found for the solution processes in compositions 0.00 ≤ wEtOH ≤ 0.30 and 0.70 ≤ wEtOH ≤ 1.00; whereas, for the other mixtures enthalpy-driving was found. Nevertheless the molecular or ionic events involved are unclear. Ultimately, it can be said that the data presented in this report amplify the physicochemical information about electrolyte analgesic drugs in aqueous-co-solvent solutions. Acknowledgments. We thank the Department of Pharmacy of the Universidad Nacional de Colombia for facilitating the equipment and laboratories used. We also thank the Laboratorio Procaps de Colombia for facilitating us the DSC equipment. REFERENCES

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