Solubility and Solution Thermodynamics of Meloxicam in 1,4-Dioxane

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Solubility and Solution Thermodynamics of Meloxicam in 1,4Dioxane and Water Mixtures Daniel M. Jiménez,† Zaira J. Cárdenas,† Daniel R. Delgado,† Abolghasem Jouyban,‡,§ and Fleming Martínez*,† †

Grupo de Investigaciones Farmacéutico-Fisicoquímicas, Departamento de Farmacia, Universidad Nacional de Colombia, A.A. 14490, Bogotá D.C., Colombia ‡ Pharmaceutical Engineering Laboratory, School of Chemical Engineering, College of Engineering, University of Tehran, P.O. Box 11155/4563, Tehran, Iran § Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz 51664, Iran S Supporting Information *

ABSTRACT: The equilibrium solubility of meloxicam in 1,4-dioxane and water binary mixtures at temperatures from 293.15 to 313.15 K was determined, and the respective thermodynamic quantities of solution were calculated. Additionally, the preferential solvation parameters of the drug were derived from their thermodynamic solution properties by means of the inverse Kirkwood− Buff integrals method. From solvent effect studies, it is found that this drug is sensitive to specific solvation effects. The preferential solvation parameter by 1,4-dioxane, δx1,3, is negative in water-rich mixtures but positive in compositions in which 0.18 < x1 < 1.00. It could be possible that in water-rich mixtures the hydrophobic hydration around aromatic rings and/or methyl groups plays a relevant role in the drug solvation. The greater solvation by 1,4-dioxane in mixtures of similar cosolvent compositions and 1,4-dioxane-rich mixtures could be explained in terms of the greater basic behavior of the cosolvent interacting with the hydrogen-donor groups of the drug.

1. INTRODUCTION Meloxicam (MEL, Figure 1; molar mass, 351.40 g mol−1; IUPAC name, 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-

solubility started to be approached from a thermodynamic point of view, including the evaluation of the preferential solvation of the solute by the solvents present in the mixtures.8,9 The main goal of this paper is to determine the equilibrium solubility of MEL in several 1,4-dioxane and water mixtures at five temperatures from 293.15 to 313.15 K to evaluate the respective thermodynamic quantities of solution and the preferential solvation of the drug in these cosolvent systems. Thus, this work is similar to those presented previously in the literature for MEL in other cosolvent mixtures.5,6,10 It is important to note that 1,4-dioxane is not used to develop liquid medicines because of its high toxicity, but it is used widely as a model cosolvent because it is miscible with water in the entire range of compositions although it exhibits a very low polarity (its dielectric constant is 2.21 at 298.15 K).11 Inverse Kirkwood−Buff integrals (IKBI) are commonly used to evaluate the preferential solvation of nonelectrolyte compounds such as MEL in cosolvent mixtures, describing the local solvent proportions around the solute with respect to the composition of the cosolvent mixtures.8,9 In the present case, this treatment depends on the values of the standard molar Gibbs energies of transfer of MEL from neat water to the 1,4-dioxane and water mixtures and the excess molar Gibbs energy of mixing for the cosolvent binary mixtures. As has been

Figure 1. Molecular structure of meloxicam (3).

2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide; CAS number, 71125-38-7) is a nonsteroidal anti-inflammatory drug whose physicochemical properties in solutions, in particular those regarding solubility in aqueous media, are still little-known.1,2 Nevertheless, its equilibrium solubility in water is very low;2 for this reason, some cosolvent and water mixtures have been evaluated to increase the solubility of this drug in order to provide useful information for developing homogeneous pharmaceutical dosage forms.3−6 Otherwise, the experimental drug behavior in cosolvent mixtures is frequently evaluated for purification, preformulation studies, and pharmaceutical dosage design stages.7 It is, therefore, very important to determine systematically their solubilities in several cosolvent mixtures to obtain complete physicochemical data about liquid pharmaceutical systems. Although the cosolvency as solubilizing technique has been widely employed in pharmacy, it has been just recently that the mechanisms involved in the increasing or decreasing drug © 2014 American Chemical Society

Received: Revised: Accepted: Published: 16550

August 2, 2014 September 23, 2014 September 26, 2014 September 26, 2014 dx.doi.org/10.1021/ie503101h | Ind. Eng. Chem. Res. 2014, 53, 16550−16558

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Table 1. Experimental Solubility of Meloxicam (3) in 1,4-Dioxane (1) and Water (2) Mixtures at Several Temperatures (± 0.05 K)a x3 w1b 0.000 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.750 0.800 0.850 0.900 0.925 0.950 0.975 1.000 ideale w1 b 0.000 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.750 0.800 0.850 0.900 0.925 0.950 0.975 1.000

T = 293.15 K 2.41 (±0.05) × 4.26 (±0.08) × 5.399 (±0.027) 1.453 (±0.018) 5.19 (±0.04) × 1.288 (±0.013) 2.86 (±0.04) × 1.298 (±0.020) 1.964 (±0.016) 2.634 (±0.021) 5.141 (±0.020) 7.80 (±0.05) × 9.70 (±0.10) × 1.133 (±0.009) 1.256 (±0.030) 1.150 (±0.007) 2.607 (±0.024)

10−7 10−7 × 10−7 × 10−6 10−6 × 10−5 10−5 × 10−4 × 10−4 × 10−4 × 10−4 10−4 10−4 × 10−3 × 10−3 × 10−3 × 10−3

T = 293.15 K 1.336 (±0.027) 2.19 (±0.04) × 2.561 (±0.013) 6.28 (±0.08) × 2.024 (±0.016) 4.46 (±0.05) × 8.64 (±0.14) × 3.32 (±0.05) × 4.57 (±0.03) × 5.53 (±0.04) × 9.59 (±0.04) × 1.273 (±0.008) 1.473 (±0.014) 1.587 (±0.012) 1.61 (±0.04) × 1.346 (±0.009)

× 10−5 10−5 × 10−5 10−5 × 10−4 10−4 10−4 10−3 10−3 10−3 10−3 × 10−2 × 10−2 × 10−2 10−2 × 10−2

T = 298.15 K 4.23 (±0.05) × 6.74 (±0.05) × 8.18 (±0.17) × 1.96 (±0.04) × 6.62 (±0.04) × 1.553 (±0.007) 3.414 (±0.019) 1.493 (±0.025) 2.421 (±0.020) 3.16 (±0.04) × 6.11 (±0.04) × 9.09 (±0.06) × 1.147 (±0.011) 1.277 (±0.029) 1.433 (±0.012) 1.394 (±0.011) 3.079 (±0.028)

10−7c 10−7 10−7 10−6 10−6 × 10−5 × 10−5 × 10−4 × 10−4 10−4 10−4 10−4 × 10−3 × 10−3 × 10−3 × 10−3d × 10−3

T = 303.15 K 6.27 (±0.08) × 10−7 1.046 (±0.014) × 10−6 1.061 (±0.027) × 10−6 2.69 (±0.01) × 10−6 8.595(±0.024) × 10−6 1.908 (±0.011) × 10−5 4.380 (±0.018) × 10−5 1.73 (±0.04) × 10−4 2.826 (±0.022) × 10−4 3.874 (±0.030) × 10−4 7.37 (±0.11) × 10−4 1.128 (±0.027) × 10−3 1.305 (±0.008) × 10−3 1.524 (±0.025) × 10−3 1.683 (±0.014) × 10−3 1.591 (±0.007) × 10−3 3.63 (±0.05) × 10−3 mol dm−3

T = 298.15 K 2.344 (±0.028) 3.462 (±0.023) 3.87 (±0.08) × 8.46 (±0.19) × 2.574 (±0.016) 5.357 (±0.021) 1.024 (±0.004) 3.81 (±0.06) × 5.61 (±0.05) × 6.60 (±0.09) × 1.133 (±0.008) 1.48 (±0.01) × 1.730 (±0.017) 1.78 (±0.04) × 1.835 (±0.012) 1.623 (±0.013)

× 10−5f × 10−5 10−5 10−5 × 10−4 × 10−4 × 10−3 10−3 10−3 10−3 × 10−2 10−2 × 10−2 10−2 × 10−2 × 10−2

T = 303.15 K 3.47 (±0.05) × 5.36 (±0.07) × 5.01 (±0.13) × 1.154 (±0.003) 3.331 (±0.009) 6.56 (±0.04) × 1.309 (±0.005) 4.40 (±0.11) × 6.52 (±0.05) × 8.05 (±0.06) × 1.360 (±0.021) 1.82 (±0.04) × 1.957 (±0.012) 2.11 (±0.03) × 2.220 (±0.021) 1.842 (±0.008)

10−5 10−5 10−5 × 10−4 × 10−4 10−4 × 10−3 10−3 10−3 10−3 × 10−2 10−2 × 10−2 10−2 × 10−2 × 10−2

T = 308.15 K 9.47 (±0.20) × 1.379 (±0.019) 1.732 (±0.018) 3.71 (±0.06) × 1.039 (±0.012) 2.46 (±0.04) × 5.09 (±0.04) × 2.19 (±0.07) × 3.43 (±0.04) × 4.597 (±0.011) 8.85 (±0.12) × 1.333 (±0.012) 1.540 (±0.026) 1.740 (±0.018) 1.937 (±0.017) 1.800 (±0.005) 4.26 (±0.04) ×

10−7 × 10−6 × 10−6 10−6 × 10−5 10−5 10−5 10−4 10−4 × 10−4 10−4 × 10−3 × 10−3 × 10−3 × 10−3 × 10−3 10−3

T = 308.15 K 5.22 (±0.11) × 7.06 (±0.10) × 8.15 (±0.08) × 1.588 (±0.026) 4.01 (±0.05) × 8.41 (±0.13) × 1.515 (±0.009) 5.52 (±0.17) × 7.88 (±0.08) × 9.508 (±0.017) 1.624 (±0.022) 2.141 (±0.020) 2.30 (±0.04) × 2.396 (±0.024) 2.451 (±0.020) 2.072 (±0.005)

10−5 10−5 10−5 × 10−4 10−4 10−4 × 10−3 10−3 10−3 × 10−3 × 10−2 × 10−2 10−2 × 10−2 × 10−2 × 10−2

T = 313.15 K 1.337 (±0.025) 1.997 (±0.017) 2.35 (±0.04) × 4.72 (±0.10) × 1.298 (±0.021) 2.91 (±0.07) × 5.84 (±0.05) × 2.669 (±0.029) 4.098 (±0.025) 5.419 (±0.024) 1.062 (±0.014) 1.565 (±0.009) 1.888 (±0.016) 2.07 (±0.05) × 2.26 (±0.06) × 2.063 (±0.009) 4.99 (±0.05) ×

× 10−6 × 10−6 10−6 10−6 × 10−5 10−5 10−5 × 10−4 × 10−4 × 10−4 × 10−3 × 10−3 × 10−3 10−3 10−3 × 10−3 10−3

T = 313.15 K 7.36 (±0.13) × 1.020 (±0.008) 1.102 (±0.017) 2.02 (±0.04) × 5.00 (±0.08) × 9.94 (±0.26) × 1.732 (±0.013) 6.71 (±0.07) × 9.37 (±0.05) × 1.116 (±0.004) 1.939 (±0.024) 2.497 (±0.015) 2.804 (±0.019) 2.83 (±0.07) × 2.84 (±0.08) × 2.359 (±0.010)

10−5 × 10−4 × 10−4 10−4 10−4 10−4 × 10−3 10−3 10−3 × 10−2 × 10−2 × 10−2 × 10−2 10−2 10−2 × 10−2

a Pressure, 73.9 ± 2.2 kPa. Values in parentheses are standard deviations. bw1 is the mass fraction of 1,4-dioxane (1) in the 1,4-dioxane (1) and water (2) cosolvent mixtures free of meloxicam (3). cOther value reported by Delgado et al.,5 x3 = 1.137 × 10−6. dOther value reported by Sathesh-Babu et al.,15 x3 = 1.796 × 10−3. eData from Delgado et al.5 fOther value reported by Seedher and Bathia,3 C = 3.41 × 10−5 mol dm−3 and other by Ambrus et al.,14 C = 1.25 × 10−5 mol dm−3.

±0.1 mg, in quantities of 30 g. The mass fractions of 1,4dioxane, w1, of the 14 mixtures prepared varied by 0.10 from 0.10 to 0.90; compositions of w1= 0.75, 0.85, 0.925, and 0.975 were also analyzed. 2.3. Solubility Determinations. An excess of MEL was added to approximately 30 g of each solvent mixture or neat solvent in stoppered dark glass flasks. These flasks with the solid−liquid mixtures were placed in an ultrasonic bath (Elma E 60 H Elmasonic, Germany) for 15 min, and later they were placed in thermostatic mechanical shakers (Julabo SW23, Germany) kept at 313.15 K for at least 7 days until saturation was reached. This equilibrium time was established by measuring the drug concentrations until they became constant. After these times, the supernatant solutions were filtered at isothermal conditions (Millipore Corp. Swinnex-13, United States) to ensure that they were free of particulate matter before sampling. MEL concentrations were determined after appropriate alkaline aqueous dilution by measuring the UV

indicated previously, this treatment is very important for understanding the respective solute−solvent molecular interactions.12 In this way, the results are expressed in terms of the preferential solvation parameter (δx1,3) of the solute MEL by the 1,4-dioxane molecules.

2. EXPERIMENTAL SECTION 2.1. Reagents. The meloxicam sample studied (compound 3, with purity at least 0.998 in mass fraction) was in agreement with the quality requirements of the American Pharmacopeia, USP.13 1,4-Dioxane (Scharlau A.R., Spain, solvent component 1, purity at least 0.998 in mass fraction) and the distilled water with conductivity 0.69), indicating clearly the energetic predominance on the dissolution processes. On the other hand, the ζH value for the ideal solution process is lower than the respective values obtained in all the experimental solution processes studied here, except for that in neat water. Therefore, the entropy contribution (ζTS) is greater for the ideal process, which could indicate in some way the extent of restriction presented in entropy in the real solution processes. 3.5. Thermodynamic Quantities of MEL Mixing. The dissolution process may be represented by the following hypothetical stages:

The apparent standard Gibbs energy change for the solution process (ΔsolnG°), considering the approach proposed by Krug et al.,21 is calculated at 303.0 K by means of Δsoln G° = −R × 303 K × intercept

|T Δsoln S°| |Δsoln H °| + |T Δsoln S°|

Figure 3. Thermodynamic quantities of mixing of meloxicam (3) in 1,4-dioxane (1) and water (2) mixtures at 303.0 K as a function of cosolvent mixtures composition. (●): ΔmixG°. (■): ΔmixH°. (▲): TΔmixS°.

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Gibbs energy of mixing is positive in all cases, which is similar to that observed in ethanol (1) and water (2) and propylene glycol (1) and water (2) mixtures.5,6 Otherwise, the ideal dissolution contributions to the enthalpy and entropy of dissolution of MEL (3), ΔsolnH°‑id and ΔsolnS°‑id, are positive as they always are (Table 3). According to Figure 3, the contribution of the mixing processes toward the overall dissolutions is variable. ΔmixH° is positive in all compositions, except in compositions with w1 ≥ 0.95, whereas the entropy of mixing (ΔmixS°) is positive in mixtures with 0.00 ≤ w1 ≤ 0.30 but is negative in the other compositions of this solvent system. Therefore, the molar ΔmixG° values diminish as the 1,4-dioxane (1) proportion increases in the mixtures, whereas the ΔmixH° values decrease nonlinearly from pure water (2) up to pure 1,4dioxane (1). In contrast, the entropy of mixing exhibits two minimum values, i.e. in w1 = 0.60 and pure 1,4-dioxane (1). The net variation in ΔmixH° values (Figure 3) results from the contribution of several kinds of interactions. Thus, the enthalpy of cavity formation is endothermic because some quantity of energy must be supplied against the cohesive forces of the solvent. This process decreases the drug solubility, which is in agreement with the discussion of e11 and the solubility parameters of water (2) and 1,4-dioxane (1) made previously. On the other hand, the enthalpy of solvent−solute interaction (corresponding to the energy e13) is exothermic and results mainly from van der Waals and Lewis acid−base interactions. Otherwise, the structuring of water molecules by hydrophobic hydration around the nonpolar groups of the solute contributes to lowering of the net ΔmixH° to small or even negative values in water-rich mixtures.30 Nevertheless, negative values of this property are not observed for MEL in this study. Otherwise, the energy of cavity formation should be lower as the proportion of 1,4-dioxane (1) increases. This effect is wellobserved for MEL (3) in all the mixtures with 0.00 ≤ w1 ≤ 0.60 because the ΔmixH° diminishes as the proportion of cosolvent increases. According to Romero et al., in the initial portion of the solubility curve the hydrogen bonding of the drug will increase with the cosolvent (1) proportion in the mixtures.26 However, at large cosolvent proportions, this specific interaction may be saturated, becoming a constant contribution. On the other hand, nonspecific and cavity effects are not saturated and vary with the cosolvent proportion. It is noteworthy that in the interval 0.60 ≤ w1 ≤ 0.90 the ΔmixH° remains almost constant. 3.6. Enthalpy−Entropy Compensation Analysis of MEL. The literature reports many cases in which no enthalpy−entropy compensation was observed by studying the solubility of drugs in different aqueous cosolvent mixtures. These analyses have been used to identify the mechanism of the cosolvent action. Weighted graphs of ΔsolnH° as a function of ΔsolnG° at the harmonic mean temperature permit such an analysis.5,6,27 Thus, Figure 4 shows that MEL (3) in 1,4-dioxane (1) and water (2) cosolvent system presents a nonlinear ΔsolnH° versus ΔsolnG° curve with positive but variable slope in the entire composition interval. This trend could be approximated by a regular polynomial as

Figure 4. ΔsolnH° versus ΔsolnG° enthalpy−entropy compensation plot for dissolution process of meloxicam (3) in 1,4-dioxane (1) and water (2) cosolvent mixtures at 303.0 K.

because of better solvation of the drug by 1,4-dioxane (1) molecules, as was already stated. 3.7. Preferential Solvation of MEL. In 1,4-dioxane and water mixtures, the preferential solvation parameter of MEL (3) by 1,4-dioxane (1) is defined as L δx1,3 = x1,3 − x1 = −δx 2,3

where is the local mole fraction of 1,4-dioxane (1) in the environment near MEL (3).28 If δx1,3 > 0, then the drug is preferentially solvated by 1,4-dioxane (1). In contrast, if this parameter is NH groups, Figure 1) to establish hydrogen bonds with proton-acceptor functional groups in the solvents (oxygen atoms in −OH or −O− groups). MEL could also act as a proton-acceptor compound by means of its oxygen atoms in −OH, >CO, and −SO2− groups and its nitrogen atoms, although its heterocyclic sulfur atom could also acts as a Lewis base (Figure 1), to

⎛ x3,2 ⎞ ⎟⎟ = RT ln⎜⎜ ⎝ x3,1 + 2 ⎠ = 0.47 − 64.81x1 + 70.03x12 − 25.87x13 (20)

Thus, D values reported in Table S1 in the Supporting Information were calculated from the first derivative of the polynomial model, solved according to the cosolvent mixtures composition. The values of Q, RTκT, and partial molar volumes of the solvents in 1,4-dioxane (1) and water (2) mixtures were taken from the literature.28 Otherwise, because the partial molar volumes of nonelectrolyte drugs such as MEL (3) are not frequently reported in the literature, this property for MEL (3) is considered here as calculated according to the groups contribution method proposed by Fedors.30 Thus, this value was taken from the literature as 189.1 cm3 mol−1.31 Table S1 in the Supporting Information shows that the G1,3 and G2,3 values for MEL (3) are negative in all cosolvent compositions. These results show in a first approach that this drug exhibits affinity for both solvents. Nevertheless, the G2,3 values obtained in almost equimolar mixtures are too great as negative quantities 16556

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interact with the hydrogen atoms of water.5,6 According to the preferential solvation results, it can be conjectured that in 1,4dioxane-rich mixtures, MEL is acting as a Lewis acid with 1,4dioxane molecules because even when this cosolvent is less basic than water the Kamlet−Taft hydrogen bond acceptor parameters are β = 0.37 for 1,4-dioxane and 0.47 for water.33,34 Moreover, Figure 6 also shows the preferential solvation behavior of MEL in methanol (1) and water (2), ethanol (1) and water (2), and propylene glycol (1) and water (2) cosolvent mixtures at 298.15 K.10 As can be seen, the behavior of MEL in 1,4-dioxane (1) and water (2) mixtures is similar to those obtained in methanol (1) and water (2) and propylene glycol (1) and water (2) mixtures but the magnitudes of preferential solvation by water and cosolvent are of course much greater in 1,4-dioxane aqueous mixtures. Nevertheless, the behavior is different compared with that of ethanolic mixtures in which preferential solvation by water is also found in ethanol-rich mixtures. This is because the maximum solubility of MEL is obtained in a mixture rather than in neat ethanol.5

(3) Seedher, N.; Bhatia, S. Solubility enhancement of Cox-2 inhibitors using various solvent systems. AAPS PharmSciTech 2003, 4, E33. (4) Sathesh-Babu, P. R.; Subrahmanyam, C. V. S.; Thimmasetty, J.; Manavalan, R.; Valliappan, K.; Kedarnath, S. S. Solubility enhancement of Cox-II inhibitors by cosolvency approach. Dhaka Univ. J. Pharm. Sci. 2008, 7, 119−126. (5) Delgado, D. R.; Holguín, A. R.; Almanza, O. A.; Martínez, F.; Marcus, Y. Solubility and preferential solvation of meloxicam in ethanol + water solvent mixtures. Fluid Phase Equilib. 2011, 305, 88− 95. (6) Holguín, A. R.; Delgado, D. R.; Martínez, F.; Marcus, Y. Solution thermodynamics and preferential solvation of meloxicam in propylene glycol + water mixtures. J. Solution Chem. 2011, 40, 1987−1999. (7) Rubino, J. T. Cosolvents and cosolvency. In Encyclopedia of Pharmaceutical Technology, vol 3; Swarbrick, J.; Boylan, J. C., Eds.; Marcel Dekker, Inc.: New York, 1988. (8) Marcus, Y. On the preferential solvation of drugs and PAHs in binary solvent mixtures. J. Mol. Liq. 2008, 140, 61−67. (9) Marcus, Y. Preferential solvation of ibuprofen and naproxen in aqueous 1,2-propanediol. Acta Chim. Slovenica 2009, 56, 40−44. (10) Delgado, D. R.; Jouyban, A.; Martínez, F. Solubility and preferential solvation of meloxicam in methanol + water mixtures at 298.15 K. J. Mol. Liq. 2014, 197, 368−373. (11) Martin, A. N.; Bustamante, P.; Chun, A. H. C. Physical Pharmacy: Physical Chemical Principles in the Pharmaceutical Sciences, 4th ed.; Lea & Febiger: Philadelphia, 1993. (12) Delgado, D. R.; Martínez, F. Preferential solvation of sulfadiazine, sulfamerazine and sulfamethazine in ethanol + water solvent mixtures according to the IKBI method. J. Mol. Liq. 2014, 193, 152−159. (13) Doluisio, J. T.; Bennett, D. R.; Bergen, J. V. et al. US Pharmacopeia, 30th ed.; United States Pharmacopeial Convention: Rockville, MD, 2007. (14) Ambrus, R.; Kocbek, P.; Kristl, J.; Šibanc, R.; Rajkó, R.; SzabóRévész, P. Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam. Int. J. Pharm. 2009, 381, 153−159. (15) Sathesh-Babu, P. R.; Subrahmanyam, C. V. S.; Thimmasetty, J.; Manavalan, R.; Valliappan, K. Extended Hansen’s solubility approach: Meloxicam in individual solvents. Pak. J. Pharm. Sci. 2007, 20, 311− 316. (16) Barton, A. CRC Handbook of Solubility Parameters and Other Cohesion Parameters, 2nd ed.; CRC Press: Boca Raton, FL, 1991. (17) Connors, K. A. Thermodynamics of Pharmaceutical Systems: An Introduction for Students of Pharmacy; Wiley-Interscience: Hoboken, NJ, 2002. (18) Acree, W. E., Jr. Mathematical representation of thermodynamic properties: Part 2. Derivation of the combined nearly ideal binary solvent (NIBS)/Redlich-Kister mathematical representation from a two-body and three-body interactional mixing model. Thermochim. Acta 1992, 198, 71−79. (19) Jouyban-Gharamaleki, A.; Acree, W. E., Jr. Comparison of models for describing multiple peaks in solubility profiles. Int. J. Pharm. 1998, 167, 177−182. (20) Kristl, A.; Vesnaver, G. Thermodynamic investigation of the effect of octanol-water mutual miscibility on the partitioning and solubility of some guanine derivatives. J. Chem. Soc., Faraday Trans. 1995, 91, 995−998. (21) Krug, R. R.; Hunter, W. G.; Grieger, R. A. Enthalpy-entropy compensation. 2. Separation of the chemical from the statistical effects. J. Phys. Chem. 1976, 80, 2341−2351. (22) Bevington, P. R. Data Reduction and Error Analysis for the Physical Sciences; McGraw-Hill Book, Co.: New York, 1969. (23) Barrante, J. R. Applied Mathematics for Physical Chemistry, 2nd ed.; Prentice Hall, Inc.: Upper Saddle River, N.J., 1998. (24) Perlovich, G. L.; Kurkov, S. V.; Kinchin, A. N.; Bauer-Brandl, A. Thermodynamics of solutions III: Comparison of the solvation of

4. CONCLUSIONS From all topics discussed previously, it could be concluded that the dissolution process of MEL in 1,4-dioxane (1) and water (2) mixtures depends strongly on the solvent composition, as was also reported for this drug in other cosolvent binary mixtures.5,6 Nonlinear enthalpy−entropy compensation was found for this drug in these mixtures. In this context, enthalpydriving was found for transfer processes in all the mixtures evaluated. Otherwise, apparently this drug is preferentially solvated by water in water-rich mixtures but preferentially solvated by 1,4-dioxane in 1,4-dioxane-rich mixtures. Nevertheless, the specific solute−solvent interactions remain unclear despite the thermodynamic analysis developed. Finally, the solubility data presented in this report expand the physicochemical information about analgesic drugs in binary aqueous-cosolvent mixtures.

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ASSOCIATED CONTENT

S Supporting Information *

Some solvation properties of meloxicam (3) in 1,4-dioxane (1) and water (2) cosolvent mixtures at 298.15 K. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +571 3165000, ext 14608. Fax: +571 3165060. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Department of Pharmacy of the National University of Colombia for facilitating the equipment and laboratories used.

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REFERENCES

(1) Budavari, S.; O’Neil, M. J.; Smith, A.; Heckelman, P. E.; Obenchain Jr., J. R.; Gallipeau, J. A. R.; D’Arecea, M. A. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals; 13th ed.; Merck & Co., Inc.: Whitehouse Station, NJ, 2001. (2) Jouyban, A. Handbook of Solubility Data for Pharmaceuticals; CRC Press: Boca Raton, FL, 2010. 16557

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dx.doi.org/10.1021/ie503101h | Ind. Eng. Chem. Res. 2014, 53, 16550−16558