Solubility and preferential solvation of meloxicam in methanol + water mixtures at 298.15 K

MOLLIQ-04301; No of Pages 6 Journal of Molecular Liquids xxx (2014) xxx–xxx

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Solubility and preferential solvation of meloxicam in methanol + water mixtures at 298.15 K Daniel R. Delgado a, Abolghasem Jouyban b,c, Fleming Martínez a,⁎ a b c

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

a r t i c l e

i n f o

Article history: Received 25 March 2014 Received in revised form 3 June 2014 Accepted 4 June 2014 Available online xxxx Keywords: Meloxicam Solubility Inverse Kirkwood–Buff integrals Preferential solvation Jouyban–Acree model

a b s t r a c t The equilibrium solubility of meloxicam in methanol + water binary mixtures at 298.15 K was determined and the preferential solvation parameters 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 methanol δx1,3, is negative in water-rich mixtures but positive in compositions from 0.30 in mole fraction of methanol to pure methanol. It is conjecturable that in the former case the hydrophobic hydration around aromatic rings and/or methyl groups plays a relevant role in the solvation. The more solvation by methanol in mixtures of similar co-solvent compositions and in methanol-rich mixtures could be explained in terms of the bigger basic behavior of the co-solvent interacting with hydrogen-donor groups of the drug. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Meloxicam (MEL, 351.40 g mol − 1 , 4-hydroxy-2-methyl-N-(5methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, CAS: 71125-38-7, Fig. 1) is a non-steroidal anti-inflammatory drug used as analgesic and antipyretic, among other indications [1]. Although MEL is widely used in therapeutics, physicochemical information about its solubility in aqueous media is scarce, as it is for other drugs [2]. Nevertheless, it is well known that its solubility in water is very low [3], so that some water + co-solvent mixtures have been evaluated to increase the solubility of this drug in order to develop homogeneous pharmaceutical dosage forms [4–7]. Experimental drug behavior in solvent mixtures is frequently evaluated for purification, pre-formulation studies, and pharmaceutical dosage design [8]. It is, therefore, important to determine systematically their solubilities in solvent mixtures to obtain complete physicochemical data about liquid pharmaceutical systems. Although co-solvency has been widely employed in pharmacy it has been recently that the mechanisms involved in the increasing or decreasing drugs solubility started to be approached from a thermodynamic point of view, including the analysis of the preferential solvation of the solute [9,10]. Therefore, the main goal of this paper is to determine the equilibrium solubility of MEL in several methanol + water mixtures at 298.15 K to ⁎ Corresponding author. Tel.: +57 1 3165000x14608; fax: +57 1 3165060. E-mail address: [email protected] (F. Martínez).

evaluate the preferential solvation of the drug, based on well established thermodynamic definitions. Thus, this work is similar to those presented previously in the literature for MEL in other co-solvent mixtures [6,7]. It is important to note that methanol is not used to develop liquid medicines due to its big toxicity but in some instances is used in drug purification procedures [2,3]. The use of inverse Kirkwood–Buff integral (IKBI) is a powerful tool for evaluating the preferential solvation of non-electrolyte compounds as MEL in solvent mixtures, describing the local solvent proportions around the solute with respect to the composition of the co-solvent mixtures [9,10]. 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 methanol + water mixtures and the excess molar Gibbs energy of mixing for the co-solvent binary mixtures. As has been indicated previously, this treatment is very important to understand the respective solute–solvent molecular interactions [11]. Therefore, the results are expressed in terms of the preferential solvation parameter (δx1,3) of the solute MEL by the methanol molecules. 2. Experimental 2.1. Reagents The meloxicam sample analyzed (compound 3, purity at least 0.998 in mass fraction) and used was in agreement with the quality requirements of the American Pharmacopeia, USP [12]. Methanol (Merck A.R., solvent component 1, purity at least 0.998 in mass fraction) and the

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Please cite this article as: D.R. Delgado, et al., Journal of Molecular Liquids (2014), http://dx.doi.org/10.1016/j.molliq.2014.06.006

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OH

O

N NH

O

N

S

O

CH3

S

CH3

Fig. 1. Molecular structure of meloxicam.

distilled water with conductivity b 2 μS cm−1 (the solvent component 2) were also used. 2.2. Preparation of solvent mixtures All methanol + water solvent mixtures were prepared by mass, using an Ohaus Pioneer TM PA214 analytical balance with sensitivity ± 0.1 mg, in quantities of 20 g. The mole fractions of methanol, x1, of the nineteen mixtures prepared varied by 0.05 from 0.05 to 0.95. 2.3. Solubility determinations An excess of MEL was added to approximately 10 g of each solvent mixture or neat solvent, in stoppered dark glass flasks. Solid–liquid mixtures were placed with stirring in a thermostatic mechanical shaker (Julabo SW23) kept at 298.15 K for at least seven days to reach the equilibrium. In the case of neat water or water-rich mixtures the equilibration time was fourteen days. These equilibrium times were 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. Drug concentrations were determined by using an Agilent 1200 series HPLC system equipped with a photodiode array UV–vis (DAD) detector. Temperature was maintained using a column thermostat at 45 °C. Isocratic elution was performed on a quaternary pump with a flow rate of 1.2 mL min−1 and 10 μL of samples was injected. The

method was applied in a 5 μm particle size Eclipse XDB-C18 chromatographic column (100 mm length × 4.5 mm i.d.). Mobile phase consisted of a mixture of acetonitrile and water (60:40 v/v) that was filtered (0.45 μm) and degassed before use [13]. All the solubility experiments were run at least in triplicates. In order to transform mole fractions to molar concentrations (mol L− 1), the density of the saturated solutions was determined by using a digital density meter (DMA 45 Anton Paar) connected to a re-circulating thermostatic bath (Neslab RTE 10 Digital One Thermo Electron Company) at 298.15 K. 3. Results and discussion Table 1 reports the experimental solubilities of MEL expressed in mole fraction and molarity at 298.15 K. As can be seen the experimental uncertainty of solubility measurements in all cases was lower than 2.0%. Equilibrium MEL solubility in mole fraction increased from 4.23 × 10−7 in pure water to 3.93 × 10−5 in pure methanol, indicating an increase in two orders of magnitude. Our solubility value in water expressed in mole fraction is only 37% of that reported previously by Delgado et al. (x3 = 1.137 × 10−6[6]). This discrepancy could be due to several reasons, such as, differences in drug crystals, equilibration times, and saturation dynamics, among others, as has been described in the literature [2,8]; this is also valid for the following comparisons. In a different way, if the molarity scale is considered, it is 69% of that calculated according to the information reported by Seedher and Bhatia (C = 3.41 × 10−5 mol L−1[4]). Otherwise, our solubility value in pure methanol expressed in molarity is similar to those calculated according to the information reported by Seedher and Bhatia [4] and by Greene et al. [14], i.e. C = 1.087 × 10−3 mol L−1[4] and C = 8.82 × 10−4 mol L−1 [14]. Up to the best of our knowledge, no solubility values for this drug in methanol + water mixtures have been reported and therefore, no other comparisons are possible. On the other hand, in order to evaluate the effect of other co-solvents on the solubility of this drug in aqueous mixtures, Fig. 2 shows the solubility profiles of MEL in methanol + water, ethanol + water [6], and propylene glycol + water [7] mixtures as a function of the polarity of the co-solvent mixtures, expressed by the Hildebrand solubility

Table 1 Experimental solubility and some solution thermodynamic properties of meloxicam at 298.15 K. x1a

w1a

f1a

Drug solubility −1

x3 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00 a b c d e

0.0000 0.0856 0.1650 0.2389 0.3078 0.3722 0.4325 0.4892 0.5425 0.5927 0.6401 0.6849 0.7274 0.7676 0.8058 0.8422 0.8768 0.9097 0.9412 0.9713 1.0000

0.0000 0.1060 0.2002 0.2845 0.3604 0.4289 0.4913 0.5482 0.6004 0.6484 0.6926 0.7336 0.7717 0.8071 0.8402 0.8711 0.9001 0.9274 0.9530 0.9772 1.0000

4.23 5.65 8.11 1.25 1.76 2.30 2.90 3.84 4.95 6.47 8.71 1.09 1.30 1.61 1.91 2.19 2.50 2.82 3.22 3.61 3.93

Mol L × 10−7c × 10−7 × 10−7 × 10−6 × 10−6 × 10−6 × 10−6 × 10−6 × 10−6 × 10−6 × 10−6 × 10−5 × 10−5 × 10−5 × 10−5 × 10−5 × 10−5 × 10−5 × 10−5 × 10−5 × 10−5

2.34 2.99 4.11 6.07 8.15 1.02 1.24 1.58 1.96 2.46 3.18 3.86 4.40 5.23 5.96 6.56 7.20 7.81 8.57 9.23 9.66

× 10−5d × 10−5 × 10−5 × 10−5 × 10−5 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4 × 10−4e

ΔtrG (kJ mol−1)

D (kJ mol−1)

0.00 −0.72 −1.61 −2.69 −3.53 −4.19 −4.77 −5.47 −6.10 −6.76 −7.50 −8.06 −8.50 −9.02 −9.45 −9.78 −10.11 −10.41 −10.74 −11.02 −11.23

−18.56 −17.85 −17.15 −16.44 −15.72 −15.00 −14.28 −13.55 −12.82 −12.08 −11.34 −10.60 −9.85 −9.10 −8.34 −7.58 −6.81 −6.04 −5.27 −4.49 −3.71

b

RSD

1.19 1.75 0.41 1.87 1.18 0.56 1.55 0.87 0.49 0.48 1.32 0.24 1.56 1.53 0.12 0.79 0.59 0.63 0.24 0.26 0.21

x1, w1 and f1 are the mole, mass, and volume fractions of methanol in the methanol + water co-solvent mixtures free of meloxicam, respectively. RSD is the relative standard deviation of drug solubility in mole fraction and molarity. Other value reported by Delgado et al., x3 = 1.137 × 10−6[6]. Other value reported by Seedher and Bhatia, C = 3.41 × 10−5 mol L−1[4]. Other value reported by Seedher and Bhatia, C = 1.087 × 10−3 mol L−1[4] and other more by Greene et al., C = 8.82 × 10−4 mol L−1[14].

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Fig. 2. Mole fraction solubility of meloxicam in methanol + water (●), ethanol + water (○), and propylene glycol + water (□) co-solvent mixtures as a function of the Hildebrand solubility parameter of the mixtures at 298.15 K.

Fig. 4. Logarithmic mole fraction solubility of meloxicam in methanol + water co-solvent mixtures as a function of the volume fraction of methanol at 298.15 K.

parameters (δmix), at T = 298.15 K. For a binary mixture δmix can be calculated as δ1f1 + δ2(1 − f1) from the solubility parameter of the neat solvents (δ1 = 29.6 MPa1/2 for methanol, 26.5 MPa1/2 for ethanol, and 30.2 MPa1/2 for propylene glycol, and finally, δ2 = 47.8 MPa1/2 for water [15]) and the volume fraction (f) of each component in the mixture, which is calculated assuming additive volumes [16]. It is interesting to note that in this case the drug solubility is similar in all these three co-solvent systems when the Hildebrand solubility parameter of the mixtures free of MEL is the same. Otherwise, it is well known that the different strategies intended to estimate physicochemical properties of drugs in mixtures are highly valued. Thus, several methods to estimate the solubility in co-solvent mixtures have been reported in the pharmaceutical and chemical literature. Some of them have been challenged recently in the correlation of the equilibrium solubility of several drugs [2]. The simplest model to predict drug solubility in co-solvent mixtures is the one based on the algebraic rule of mixing [17], which for semipolar compounds in binary mixtures could take the following form:

(Fig. 4). Thus, the behavior of MEL in water-rich mixtures is similar to those exhibited by other drugs in similar co-solvent systems, where some negative deviations were reported in these mixture compositions, i.e. alkyl p-hydroxybenzoates and alkyl p-aminobenzoates in propylene glycol + water mixtures [18], naproxen in propylene glycol + water mixtures [19], ketoprofen in ethanol + water mixtures [20], and sulfapyridine in propylene glycol + water mixtures [21]; otherwise, in co-solvent-rich mixtures the deviations of MEL are also negative, whereas they are positive for the mentioned drugs [18–21]. As has been shown in this work, preferential solvation takes place in the investigated solutions, therefore, the algebraic rule of mixing could not be employed for modeling this data set [22]. For such case, the combined nearly ideal binary solvent/Redlich–Kister model could be used as an alternative model in which the model constants represent the preferential solvation of the solute [23]. The model is presented as: ln x3−ð1þ2Þ ¼ x1 ln x3−1 þ x2 ln x3−2 þ x1 x2

2 X

i

Si ðx1 −x2 Þ

ð2Þ

i¼0

lnx3‐ð1þ2Þ ¼ x1 ln x3–1 þ x2 ln x3–2

ð1Þ

where x3−(1+2) is the drug solubility calculated in the respective cosolvent mixture, x3−1 is the drug solubility in the pure methanol (component 1), x3−2 is the drug solubility in pure water (component 2), and x1 and x2 are the mole fractions of co-solvent and water in drug free mixture. In this way, Fig. 3 shows that positive deviations in the experimental drug solubilities with respect to the ones estimated using Eq. (1) are found in all the compositions studied. Nevertheless, if the co-solvent mixture composition is expressed in volume fraction the deviations exhibited are negative in all the mixtures evaluated

where Si is the model constant [23]. This equation was extended to represent both effects of solvent composition and temperature on the solubility of a solute as [24]: i

ln x3;T−ð1þ2Þ ¼ x1 ln x3;T−1 þ x2 ln x3;T−2 þ

2 x1 x2 X A ðx −x2 Þ : T i¼0 i 1

ð3Þ

Eq. (3) could be used to predict the solute solubility at various temperatures after training by solubility data of the solute in binary solvents at 298 K as shown in earlier works [25,26]. The obtained model for solubility of MEL in methanol + water mixtures is: ln x3;T−ð1þ2Þ ¼ x1 ln x3;T−1 þ x2 ln x3;T−2 þ

1736:663x1 x2 T

ð4Þ

which correlates the mole fraction solubility of MEL in methanol + water mixtures with the correlation coefficient of 0.998 and F value of 4803. The error percentage of the back-calculated solubility data points is 2.9%. The existence of a significant model constant in Eq. (4) reveal that the mixing of methanol and aqueous solutions of MEL is not an ideal mixing and some other interactions take place. As another evidence, if error percentage of the calculated values from Eq. (1), i.e. 34.5%, is compared with that of Eq. (4), the significant error difference approves the preferential solvation in the solutions. On the other hand, in methanol + water mixtures the preferential solvation parameter by methanol (1) is defined as: Fig. 3. Logarithmic mole fraction solubility of meloxicam in methanol + water co-solvent mixtures as a function of the mole fraction of methanol at 298.15 K.

L

δx1;3 ¼ x1;3 −x1 ¼ −δx2;3

Please cite this article as: D.R. Delgado, et al., Journal of Molecular Liquids (2014), http://dx.doi.org/10.1016/j.molliq.2014.06.006

ð5Þ

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L where x1,3 is the local mole fraction of methanol in the environment near to MEL (component 3). If δx1,3 N 0 then the drug is preferentially solvated by methanol; on the contrary, if this parameter is b0 the drug is preferentially solvated by water. Values of δx1,3 are obtainable from the inverse Kirkwood–Buff integrals for the individual solvent components analyzed in terms of some thermodynamic quantities as shown in Eqs. (6) and (7)[9,10]:

G1;3 ¼ RTκ T −V 3 þ x2 V 2 D=Q

ð6Þ

G2;3 ¼ RTκ T −V 3 þ x1 V 1 D=Q

ð7Þ

where κT is the isothermal compressibility of the methanol + water solvent mixtures (in GPa−1), V1 and V2 are the partial molar volumes of the solvents in the mixtures (in cm3 mol− 1), similarly, V3 is the partial molar volume of MEL in these mixtures (in cm3 mol−1). The function D is the derivative of the standard molar Gibbs energies of transfer of the drug (from neat water to methanol + water mixtures) with respect to the solvent composition (in kJ mol−1, as also is RT) and the function Q involves the second derivative of the excess molar Gibbs energy of mixing of the two solvents (GExc 1+ 2) with respect to the water proportion in the mixtures (also in kJ mol−1) [9,10]:

D¼

∂Δtr Gð03;2→1þ2Þ

!

∂x1

Q ¼ RT þ x1 x2

ð8Þ T;p

∂2 GExc 1;2 ∂x22

! :

ð9Þ

T;p

Because the dependence of κT on composition is not known for a lot of the systems investigated and because of the small contribution of RT κT to the IKBI the dependence of κT on composition could be approximated by n

considering additive behavior according to: κ T;mix ¼ ∑ xi κ 0T;i, where xi is i¼1

0 is the isothermal the mole fraction of component i in the mixture and κT,i compressibility of the pure component i[11]. Therefore, the preferential solvation parameter can be calculated from the Kirkwood–Buff integrals as follows:

δx1;3 ¼

  x1 x2 G1;3 −G2;3 x1 G1;3 þ x2 G2;3 þ V cor

:

ð10Þ

Fig. 5. Gibbs energy of transfer of meloxicam from neat water to methanol + water cosolvent mixtures at 298.15 K.

Here, the correlation volume (Vcor) is obtained by means of the following expression [9,10]:  3  1=3 L L −0:085 V cor ¼ 2522:5 r 3 þ 0:1363 x1;3 V 1 þ x2;3 V 2

ð11Þ

where r3 is the radio of the solute (in nm), which is calculated as: r3 = (3 ⋅ 1021 ⋅ V3/4 ⋅ π ⋅ NAv)1/3 in which V3 is the molar volume of the solute and NAv is the Avogadro number. However, the definitive correlation volume requires iteration, because it depends on the local mole fractions. This iteration is done by replacing δx1,3 in Eq. (5) to calculate L until a non-variant value of Vcor is obtained. x1,3 Fig. 5 shows the Gibbs energy of transfer behavior of MEL from neat water to methanol + water mixtures at 298.15 K. These values were calculated and correlated according to the regular polynomial in third degree presented as Eq. (12) from the drug solubility data reported in Table 1 by using MS Excel® and TableCurve 2D v5.01. 0

Δtr G3;2→1þ2 ¼ RT ln

x3;2 x3;1þ2

! 2

3

¼ 0:067−18:557x1 þ 7:004x1 þ 0:280x1 : ð12Þ

It should be added that the solubility of MEL in methanol + water mixtures is a single phenomenon and should be represented using a single mathematical form which is the case for Eqs. (4) and (12). As has been demonstrated in an earlier work, Eq. (12) could be derived from Eq. (4) using simple algebraic manipulations [27]. Thus, D values presented in Table 1 were calculated from the first derivative of the polynomial model, Eq. (12), solved according to the co-solvent mixture composition. In order to calculate the Q values the excess molar Gibbs energies of mixing (GExc 1,2 ) are required. In this way, −1 ) were calculated at 298.15 K by using Eq. (13) GExc 1,2 values (in J mol as reported by Marcus [28].   Exc 2 G1;2 ¼ x1 x2 1200−87ð1−2x1 Þ−330ð1−2x1 Þ :

ð13Þ

It is important to note that a quartic regular polynomial of GExc 1,2 as a function of the mole fraction of water was obtained by using the same software indicated earlier. Q values are shown in Table 2. On the other hand, this table also shows the RT κT values calculated by assuming additive behavior of κT with the values 1.248 and 0.457 GPa−1, for methanol and water, respectively [29].

Table 2 Some physicochemical properties of methanol + water mixtures at 298.15 K. x1

Q (kJ mol−1)

RT κT (cm3 mol−1)

V 1 (cm3 mol−1)

V 2 (cm3 mol−1)

0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00

2.479 2.508 2.469 2.383 2.267 2.140 2.013 1.899 1.807 1.744 1.714 1.718 1.757 1.828 1.925 2.042 2.167 2.289 2.394 2.464 2.479

1.133 1.231 1.329 1.427 1.525 1.623 1.721 1.819 1.917 2.015 2.113 2.211 2.309 2.407 2.505 2.603 2.701 2.799 2.897 2.996 3.094

36.67 37.07 37.45 37.80 38.14 38.46 38.75 39.03 39.28 39.52 39.73 39.93 40.10 40.25 40.39 40.50 40.59 40.66 40.71 40.74 40.75

18.10 18.08 18.05 18.00 17.93 17.84 17.73 17.60 17.44 17.27 17.08 16.86 16.63 16.37 16.10 15.80 15.48 15.15 14.79 14.41 14.02

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The partial molar volumes of methanol and water (Table 2) were calculated by means of Eqs. (14) and (15) from the density (ρ) values of methanol + water mixtures reported by Mikhail and Kimel at 298.15 K [30]. V is the molar volume of the mixtures and it is calculated as V = (x 1 ⋅ M1 + x 2 ⋅ M 2) / ρ, where, M1 and M2 are 32.04 and 18.02 g mol− 1, for methanol and water, respectively [3]. dV dx1

ð14Þ

dV : dx1

ð15Þ

V 1 ¼ V þ x2

V 2 ¼ V−x1

Partial molar volumes of non-electrolyte drugs such as MEL are not frequently reported in the literature. This is because of the big uncertainty obtained in its determination due to the low solubilities exhibited particularly in aqueous media. For this reason, in a first approach the molar volume of MEL is considered here as independent of co-solvent composition, as it is calculated according to the group contribution method proposed by Fedors [31]. Thus, this value was taken from the literature as 189.1 cm3 mol−1[32]. Table 3 shows that the G1,3 and G2,3 values for MEL are negative in all co-solvent compositions. These results show in a first approach that this drug exhibit affinity for both solvents. Solute radium value (r3) is required to calculate the correlation volume and was calculated from the molar volume as 0.422 nm. In order to use the IKBI method, the correlation volume was iterated three times by using Eqs. (5), (10) and (11) to obtain the values reported in Table 3. Fig. 6 shows that the values of δx1,3 vary non-linearly with the methanol proportion in the aqueous mixtures. It is important to keep in mind that if the absolute value of δ1,3 obtained in the IKBI calculations is equal or greater than 1.0 × 10−2 the result is a consequence of the preferential solvation instead of the effect of uncertainty propagation [33,34]. Addition of methanol to water tends to make negative the δx1,3 values of this drug from the pure water up to the mixture 0.30 in mole fraction of methanol reaching minimum values near to − 1.264 × 10− 2 in the mixture with 0.15 in mole fraction of methanol (Table 3). Possibly the structuring of water molecules around the non-polar groups of MEL (aromatic rings and/or methyl groups, Fig. 1) by hydrophobic hydration, contributes to lowering of the net δx1,3 to negative values in these water-rich mixtures.

Table 3 Some solvation properties of meloxicam in methanol + water co-solvent mixtures at 298.15 K. x1

G1,3 (cm3 mol−1)

G2,3 (cm3 mol−1)

Vcor (cm3 mol−1)

100 δx1,3

0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00

−323.4 −310.2 −300.6 −293.2 −287.0 −281.3 −275.4 −268.9 −261.4 −252.9 −243.5 −233.7 −224.1 −215.2 −207.5 −201.2 −196.1 −192.3 −189.5 −187.4 −186.0

−188.0 −201.1 −213.8 −226.8 −240.5 −254.9 −269.8 −284.7 −298.6 −310.3 −318.5 −322.3 −321.7 −316.9 −309.1 −299.2 −288.5 −277.5 −266.9 −256.7 −247.0

845 864 885 907 930 955 981 1007 1033 1060 1086 1111 1135 1159 1182 1204 1227 1250 1272 1296 1319

0.000 −0.789 −1.180 −1.264 −1.095 −0.714 −0.165 0.496 1.192 1.832 2.329 2.620 2.685 2.547 2.259 1.879 1.460 1.041 0.648 0.298 0.000

Fig. 6. δx1,3 values for meloxicam in methanol + water (●), ethanol + water (○), and propylene glycol + water (□) co-solvent mixtures at 298.15 K.

In the mixtures with composition 0.30 b x1 b 1.00, the local mole fractions of methanol are greater than the ones for water. In this way, the co-solvent action may be related to the breaking of the ordered structure of water by hydrogen bonding around the non-polar moieties of the drug. The bigger preferential solvation by the co-solvent reaches a maximum value near to x1 = 0.60 (δx1,3 = 2.685 × 10−2). As has been indicated earlier, MEL could act in solution as a Lewis acid (due to its\OH and NNH groups) to establish hydrogen bonds with proton-acceptor functional groups in the solvents (oxygen atoms in\OH groups). MEL could also act as a proton-acceptor compound by means of their oxygen atoms in\OH, NC_O and\SO2-groups and their nitrogen atoms, although its heterocyclic sulfur atom could also act as Lewis base (Fig. 1), to interact with hydrogen atoms in both solvents [6]. According to the preferential solvation results, it is conjecturable that in intermediate composition and in methanol-rich mixtures, MEL is acting as Lewis acid with methanol molecules because this cosolvent is more basic than water, i.e. the Kamlet–Taft hydrogen bond acceptor parameters are β = 0.66 for methanol and 0.47 for water [35]. Nevertheless, the specific solute-solvent interactions remain unclear despite the treatment developed. Otherwise, Fig. 6 also shows the preferential solvation behavior of MEL in ethanol + water and propylene glycol + water co-solvent mixtures at 298.15 K. These values were calculated from solubility data of MEL reported previously [6,7] and from physicochemical values reported for ethanol + water [36] and propylene glycol + water mixtures [7, 37]. As can be seen the behavior of MEL in methanol + water mixtures is similar to that obtained in propylene glycol + water mixtures but the magnitudes of preferential solvation by water and co-solvent are greater in methanolic mixtures; moreover, the composition region where MEL is preferentially solvated by water is also bigger here than that observed for propylene glycol + water mixtures. Nevertheless, the behavior is different in comparison with ethanolic mixtures where preferential solvation is also found in ethanol-rich mixtures. This is because the maximum solubility is obtained in a mixture instead of neat ethanol [6]. Otherwise, the magnitudes of preferential solvation by water and co-solvent are greater in ethanolic mixtures than in methanolic mixtures, but the composition region where MEL is preferentially solvated by water is also bigger in methanolic mixtures. 4. Conclusions Explicit expressions for the local mole fraction of methanol and water around MEL were derived on the basis of the IKBI method applied to the generated and reported equilibrium solubility values of this drug in methanol + water mixtures. Thus, this drug is preferentially solvated by water in water-rich mixtures but preferentially solvated by methanol in mixtures with intermediate composition and also in methanol-rich

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mixtures. Nevertheless, the specific solute-solvent interactions remain unclear despite the thermodynamic analysis developed due to the complex molecular structure of this drug. Ultimately, it can be said that the data presented in this report expand the physicochemical information about analgesic drugs in binary aqueous-co-solvent mixtures. As has been recently described, this information is very relevant from different chemical and pharmaceutical points of view [38]. Acknowledgments We thank the Department of Pharmacy of the National University of Colombia for facilitating the equipment and laboratories used. References [1] R.B. Raffa, in: A.R. Gennaro (Ed.), Remington, the Science and Practice of Pharmacy, 21st ed., Lippincott, Williams & Wilkins, Philadelphia, 2005. [2] A. Jouyban, Handbook of Solubility Data for Pharmaceuticals, CRC Press, Boca Raton, FL, 2010. [3] S. Budavari, M.J. O'Neil, A. Smith, P.E. Heckelman, J.R. Obenchain Jr., J.A.R. Gallipeau, M.A. D'Arecea, The Merck Index, an Encyclopedia of Chemicals, Drugs, and Biologicals, 13th ed. Merck & Co., Inc., Whitehouse Station, NJ, 2001. [4] N. Seedher, S. Bhatia, AAPS PharmSciTech 4 (2003) 33 (Article). [5] P.R. Sathesh-Babu, C.V.S. Subrahmanyam, J. Thimmasetty, R. Manavalan, K. Valliappan, S.S. Kedarnath, Dhaka Univ. J. Pharm. Sci. 7 (2008) 119–126. [6] D.R. Delgado, A.R. Holguín, O.A. Almanza, F. Martínez, Y. Marcus, Fluid Phase Equilib. 305 (2011) 88–95. [7] A.R. Holguín, D.R. Delgado, F. Martínez, Y. Marcus, J. Solut. Chem. 40 (2011) 1987–1999. [8] J.T. Rubino, in: J. Swarbrick, J.C. Boylan (Eds.), Encyclopedia of Pharmaceutical Technology, vol. 3, Marcel Dekker, Inc., New York, 1988. [9] Y. Marcus, J. Mol. Liq. 140 (2008) 61–67. [10] Y. Marcus, Acta Chim. Slov. 56 (2009) 40–44. [11] D.R. Delgado, F. Martínez, J. Mol. Liq. 193 (2014) 152–159.

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Please cite this article as: D.R. Delgado, et al., Journal of Molecular Liquids (2014), http://dx.doi.org/10.1016/j.molliq.2014.06.006