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Solubility and apparent specific volume at saturation of some pharmaceutical salts in methanol + water mixtures at 298.15 K
Journal of Molecular Liquids 220 (2016) 842–847
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Solubility and apparent specific volume at saturation of some pharmaceutical salts in methanol + water mixtures at 298.15 K María M. Muñoz a, María Á. Peña b, Ovidio A. Almanza c, Abolghasem Jouyban d,e, Fleming Martínez a,⁎, William E. Acree Jr. f a Grupo de Investigaciones Farmacéutico-Fisicoquímicas, Departamento de Farmacia, Facultad de Ciencias, Universidad Nacional de Colombia –Sede Bogotá, Cra. 30 No. 45-03, Bogotá D.C., Colombia b Departamento de Ciencias Biomédicas, Facultad de Farmacia, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain c Grupo de Física Aplicada, Departamento de Física, Facultad de Ciencias, Universidad Nacional de Colombia –Sede Bogotá, Cra. 30 No. 45-03, Bogotá D.C., Colombia d Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz 51664, Iran e Kimia Idea Pardaz Azarbayjan (KIPA) Science Based Company, Tabriz University of Medical Sciences, Tabriz 51664, Iran f Department of Chemistry, University of North Texas, Denton, TX 76203-5070, USA
a r t i c l e
i n f o
Article history: Received 1 February 2016 Received in revised form 27 April 2016 Accepted 28 April 2016 Available online 22 May 2016 Keywords: Sodium naproxen Procaine hydrochloride Lysine clonixinate Methanol + water mixtures Solubility Cosolvency Apparent specific volume
a b s t r a c t Equilibrium solubility of sodium naproxen (Na·NAP), procaine hydrochloride (PC·HCl), and lysine clonixinate (Lys·Clon), was determined in methanol + water mixtures at 298.15 K. Mole fraction solubility of Na·NAP increases from neat water (x3 = 1.71 × 10−2) to reach a maximum in the mixture with w1 = 0.90 (x3 = 5.05 × 10−2); the solubility of PC·HCl increases from neat water (x3 = 9.68 × 10−2) to reach a maximum in the mixture with w1 = 0.20 (x3 = 0.1032); whereas, the solubility of Lys·Clon increases from neat water (x3 = 3.54 × 10−2) to reach a maximum in the mixture with w1 = 0.60 (x3 = 6.33 × 10−2). The generated solubility data are mathematically represented by using the Jouyban-Acree model with very good error level (average of 1.2% for molar solubilities). In addition, the apparent specific volumes at saturation of these drugs were also calculated in all the mixtures under study using the measured densities of the saturated solutions. In this way, the average apparent volumes at saturation in these mixtures could be considered as follows: 0.699 cm3 g−1 for Na·NAP, 0.821 cm3 g−1 for PC·HCl, and 0.730 cm3 g−1 for Lys·Clon. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Sodium naproxen (Na·NAP) and lysine clonixinate (Lys·Clon) are analgesic drugs commonly used in therapeutics, whereas, procaine hydrochloride (PC·HCl) is a local anesthetic drug used in current classical and alternative therapeutics [1,2]. Although these three pharmaceutical compounds are widely used in current therapeutics, the physicochemical data about their aqueous solutions is still not complete [1–3]. Nevertheless, the dissolution thermodynamic quantities of these drugs in ethanol (1) + water (2) mixtures [4–6] and propylene glycol (1) + water (2) mixtures [7] have been reported in the literature. In similar way, the thermodynamic properties of the hypothetical mixing processes of Na·NAP and PC·HCl in ethanol (1) + water (2) mixtures have also been reported [8]. Moreover, the apparent molar volumes of Na·NAP and PC·HCl in neat water at several concentrations and temperatures have also been reported [9–11]. Finally, other contributions to the physicochemical characterization of PC·HCl in neat water were reported previously, such as the calorimetric determination of ⁎ Corresponding author. E-mail address: [email protected] (F. Martínez).
http://dx.doi.org/10.1016/j.molliq.2016.04.116 0167-7322/© 2016 Elsevier B.V. All rights reserved.
the dissolution enthalpy and the calculation of the respective osmotic and activity coefficients at several concentrations [12,13]. On the other hand, as has already been mentioned in the literature, the solubility of electrolyte and non-electrolyte drugs in cosolvent mixtures is crucial in the pharmaceutical field because this knowledge is frequently used in purification methods, preformulation studies, and design of liquid dosage forms [14–16]. Thus, it is very important to systematically determine the solubility of pharmaceutical compounds such as drugs and excipients in mixed solvents. It is noteworthy that the systematic study of the solubility as a function of the dielectric constant (ε) of the solvent mixtures could allow the identification of maximum solubility peaks. The ε value of these maximum peaks is almost coincident with the “approximate dielectric requirement” of the drug and it normally occurs at a common range of ε values, despite of the cosolvent used in the aqueous mixtures, i.e. ethanol, propylene glycol, polyethylene glycol 400, or glycerol [17, 18]. In this way, taking into account the approximate dielectric requirement of the drug is advantageous during the design of homogeneous liquid dosage forms because it could reduce costs by diminishing the number of experiments required to obtain an adequate cosolvent mixture [7,19]. Moreover, the use of pharmaceutical salts is the most
M.M. Muñoz et al. / Journal of Molecular Liquids 220 (2016) 842–847
common and effective method to increase the solubility and dissolution rates of acidic and basic drugs in aqueous media [20,21]. The present research studied the solubility, density and apparent specific volume at saturation of Na·NAP, PC·HCl and Lys·Clon (solutes identified as component 3) in methanol (component 1) + water (component 2) mixtures at 298.15 K. This research is a continuation of that developed in propylene glycol (1) + water (2) mixtures at the same temperature [7]. Similar studies have been reported with propranolol hydrochloride in several cosolvent (1) + water (2) mixtures [22] and some structurally related sodium sulfonamides in propylene glycol (1) + water (2) mixtures [23]. It is important to note that methanol is not used to develop liquid pharmaceutical dosage forms owing its high toxicity but it is a very good model solvent for cosolvency studies and in some instances is used in drug purification procedures [24]. Otherwise, methanol is used in some microencapsulation techniques and also as the most common mobile phase in high performance liquid chromatography [25,26].
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(mol dm−3) concentration scales, the density of the saturated solutions was determined by using a digital density meter with an accuracy of ± 0.0001 g cm−3 (DMA 45 Anton Paar, Austria) connected to a recirculating thermostatic bath at 298.15 ± 0.05 K (Neslab RTE 10 Digital One Thermo Electron Company, USA). Densities were also used to calculate the volumetric contribution of the drugs to the saturated solutions. 2.4. Calorimetric study Melting point and enthalpy of fusion of Na·NAP, Lys·Clon and PC·HCl as original samples were determined by DSC studies (TA Instruments DSC 2920, USA). Thermal analyses were performed at a heating rate of 10 K min−1 in a dynamic nitrogen atmosphere (10 cm3 min− 1). Nearly 7.0 mg of every drug was used in each case. The equipment was calibrated using Indium as standard. 2.5. X-ray diffraction analysis
2. Experimental section 2.1. Reagents and materials Sodium naproxen (Na·NAP, (+)-2-(6-Methoxy-2naphthyl)propionic acid sodium salt), lysine clonixinate (Lys·Clon, 2[(3-Chloro-2-methylphenyl)amino]nicotinic acid, L-lysine (1:1)), procaine hydrochloride (PC·HCl, 2-(Diethylamino)ethyl p-aminobenzoate monohydrochloride), methanol and distilled water with conductivity b2 μS cm−1, were used in this research. Molecular sieve (numbers 3 and 4, Merck, Germany) and Millipore Corp. Swinnex®-13 (USA) filter units were also used. Table 1 summarizes the characteristics of the compounds studied. 2.2. Solvent mixtures preparation All methanol (1) + water (2) solvent mixtures were prepared gravimetrically in quantities of 10.00 g by using an Ohaus Pioneer TM PA214 analytical balance with sensitivity ±0.1 mg. The mass fractions of methanol, w1, of the nine binary mixtures studied varied by w1 = 0.10 from w1 = 0.10 to w1 = 0.90 to cover the entire range of compositions. 2.3. Solubility determinations The procedures followed in this research were similar to those used previously to evaluate the solubility of acetaminophen in the same mixtures [27]. Briefly, an excess of drug was added to 5.00 g of each solvent mixture or neat solvent, in stoppered dark glass flasks. Solidliquid mixtures were placed in ultrasonic bath (Elma® E 60H Elmasonic, Germany) during 15 min followed by stirring in a thermostatic mechanical shaker (Julabo SW23, Germany) kept at 298.15 K for at least four days to reach the equilibrium. After this time the supernatant solutions were filtered at isothermal conditions (Millipore Corp. Swinnex®-13, USA) to ensure that they were free of particulate matter before sampling. Drug 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. All the solubility experiments were developed at least in triplicate and averaged. To make the equivalence between mole fraction (x3) and molarity
In order to identify the drugs' polymorphs employed in this research, the respective X-ray diffraction spectra were carried out on the original samples. The spectra were obtained by using a PANalytical X'Pert PRO diffractometer with Cu Kα1 radiation line (λ = 0.1540598 nm) and Bragg-Brentano geometry. It was operated in continuous mode between 2θ = 5° and 2θ = 90° and angle variation of 0.02° with detector data acquisition time of 60 s. 3. Results and discussion 3.1. Experimental solubility of the pharmaceutical salts Table 2 summarizes the experimental solubility of these drugs in all the methanol (1) + water (2) mixtures at 298.15 K, expressed in mole fraction (x3) and molarity (mol dm−3), respectively. In almost all cases the relative standard deviations were lower than 2.2%. Regarding the solubility of these drugs in neat water, our value for Na·NAP is in good agreement with those reported in the literature [4, 7,28,29]; in a similar way, a good agreement is also observed for PC·HCl [5,7]; nevertheless, no agreement is observed in the case of Lys·Clon with the value reported by Gutiérrez et al. [6] but a very good agreement is observed regarding the value reported by Jiménez et al. [7]. The high discrepancy between our value and that of ref. [6] for Lys·Clon could possibly be attributed to significant differences in quantification analytic techniques, saturation times, or even, polymorphic solid states, as described in the literature [3]. Contrary to this research and the one by Jiménez et al. [7], no ultrasonic treatment was applied when the Lys·Clon solubility was studied in ethanol (1) + water (2) mixtures [6]. As has been described, this vigorous acoustic treatment could affect the dissolution rate and, possibly, the equilibrium solubility of the drug, by modifying its solid crystal nature [7]. Unfortunately no calorimetric or spectroscopic characterizations on the solid bottom phases were developed to identify possible polymorphic transitions. Nevertheless, for further comparisons Figs. 1 and 2 depict DSC analyses and X-ray diffraction spectra of the original samples of every pharmaceutical salt studied in this research. If the mole fraction scale is considered, the solubility trends are almost similar for these three drugs. Thus, the solubility of Na·NAP increases from neat water (x3 = 1.71 × 10−2) to reach a maximum in
Table 1 Source and purities of the compounds used in this research. Compound
CAS
Formula
Molar mass / g mol−1
Source
Mass fraction purity
Sodium naproxen Procaine hydrochloride Lysine clonixinate Methanol Water
2615934-2 51-05-8 55837-30-4 67-56-1 7732-18-5
C14H13NaO3 C13H20N2O2·HCl C19H25ClN4O4 CH4O H2O
252.24 272.78 408.88 32.04 18.02
Zhejiang Weishi Biotech. Co., Ltd., China Xi'an Frankherb Biotech. Co., Ltd. China Hangzhou Dayangchem Co., Ltd., China Merck, Germany Obtained by distillation
0.99 0.99 0.99 0.998 N0.999
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M.M. Muñoz et al. / Journal of Molecular Liquids 220 (2016) 842–847
Table 2 Experimental solubility of the pharmaceutical salts (3) in methanol (1) + water (2) mixtures expressed in mole fraction and molarity at 298.15 K and local atmospheric pressure of 73.9 kPa. w1a,b 0.000d 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 1.000
mol dm−3b,c
100 x3b,c Na·NAP
PC·HCl
Lys·Clon
Na·NAP
PC·HCl
Lys·Clon
1.71 2.08 2.75 3.36 3.76 4.05 4.43 4.71 5.03 5.05 3.86
9.68 10.27 10.32 10.18 10.07 9.84 9.40 8.54 7.40 5.70 4.22
3.54 3.83 4.28 4.89 5.35 6.06 6.33 5.76 4.38 2.53 1.11
0.824 0.927 1.112 1.238 1.281 1.285 1.295 1.276 1.256 1.167 0.853
2.533 2.541 2.477 2.389 2.297 2.187 2.047 1.840 1.582 1.219 0.890
1.272 1.283 1.322 1.376 1.390 1.433 1.407 1.262 0.989 0.592 0.256
a w1 is the mass fraction of methanol (1) in the methanol (1) + water (2) mixtures free of drug (3). b Standard uncertainties are u(T) = 0.05 K, u(p) = 2.2 kPa, u(w1) = 0.0005. Average relative standard uncertainties in solubility, ur(x3) and ur(mol dm−3), are 0.022 (or 2.2%). c Na·NAP, PC·HCl, and Lys·Clon, are sodium naproxen, procaine hydrochloride, and lysine clonixinate, respectively. d Other reported molar solubility values in neat water are as follows: Na·NAP: 0.730 mol dm−3 [4] and 0.919 mol dm−3 [7], PC·HCl: 2.51 mol dm−3 [5] and 2.524 mol dm−3 [7], and Lys·Clon: 0.204 mol dm−3 [6] and 1.270 mol dm−3 [7].
the mixture with w1 = 0.90 (x3 = 5.05 × 10−2); the solubility of PC·HCl increases from neat water (x3 = 9.68 × 10−2) to reach a maximum in the mixture with w1 = 0.20 (x3 = 0.1032); whereas, the solubility of Lys·Clon increases from neat water (x3 = 3.54 × 10−2) to reach a maximum in the mixture with w1 = 0.60 (x3 = 6.33 × 10−2). Fig. 3 compares the mole fraction solubility of these drugs in methanol (1) + water (2), ethanol (1) + water (2) [4–6], and propylene glycol (1) + water (2) [7] mixtures at 298.15 K. For Na·NAP the mole fraction solubility decreases as: propylene glycol (1) + water (2) N methanol (1) + water (2) N ethanol (1) + water (2), which is almost coincident with the polarity decreasing of the respective cosolvents [17,30]. For PC·HCl the solubility decreases as: methanol (1) + water (2) N propylene glycol (1) + water (2) N ethanol (1) + water (2), except
Fig. 1. DSC analyses of pharmaceutical salts as original samples.
Fig. 2. X-ray diffraction spectra of pharmaceutical salts as original samples.
in mixtures with 0.30 ≤ w1 ≤ 0.60 where the solubility is higher in ethanol (1) + water (2) compared with propylene glycol (1) + water (2). For Lys·Clon, in mixtures with 0.00 ≤ w1 ≤ 0.60 the solubility is higher in methanol (1) + water (2) mixtures compared with propylene glycol (1) + water (2) mixtures, whereas, in the other compositions the behavior is inverse. For this last drug the lowest solubility is found in ethanol (1) + water (2) mixtures. It is noteworthy that the maximum solubility of all these drugs is obtained in a mixture, instead of neat water or neat methanol. This could be interpreted in terms of the behavior of a hydrophobic ion, because of the big size of the protonated or dissociated compound as has been exposed earlier [7,31]. On the other hand, Fig. 4 shows the molar solubility of these drugs as a function of the dielectric constant in methanol (1) + water (2), ethanol (1) + water (2) [4–6], and propylene glycol (1) + water (2) [7] mixtures at 298.15 K. Only Na·NAP and Lys·Clon exhibit clearly molar solubility maximum peaks in methanol (1) + water (2) mixtures. Thus, the ε value of the cosolvent mixture of maximum solubility (w1 = 0.60 and ε = 48.5 with C = 1.295 mol dm−3 for Na·NAP and w1 = 0.50 and ε = 52.9 with C = 1.433 mol dm−3 for Lys·Clon) could be considered as the “approximate dielectric requirement” for these two electrolyte drugs in methanol (1) + water (2) mixtures. Nevertheless, the maximum solubility of Na·NAP in ethanol (1) + water (2) mixtures is obtained in the mixture with w1 = 0.40 and ε = 53.5 (C = 1.016 mol dm−3) [4]; whereas, in propylene glycol (1) + water (2) mixtures it is obtained in the mixture with w1 = 0.80 and ε = 41.6 (C = 1.720 mol dm−3) [7]. In this way, the practical “approximate dielectric requirement” for this drug should be considered as a ε range from 42 to 53 as was indicated earlier [7]. Fig. 5 compares the logarithmic mole fraction solubility of Na·NAP and molecular naproxen in methanol (1) + water (2) mixtures at 298.15 K [32]. It is clear that the salt form of this drug is much more soluble than the respective molecular form. This is because of the strong ion-dipole interactions exhibited by the carboxylate group of Na·NAP mainly with water compared with the moderately strong hydrogen bonding exhibited by the carboxylic acid and ether groups of molecular naproxen with water and/or methanol [17]. A similar behavior was exhibited by these drugs in propylene glycol (1) + water (2) mixtures [7]. Better solubilization power
M.M. Muñoz et al. / Journal of Molecular Liquids 220 (2016) 842–847
Fig. 3. Solubility of pharmaceutical salts (3), expressed in mole fraction, in some cosolvent (1) + water (2) mixtures at 298.15 K. ○: methanol (1) + water (2) [This work]; □: ethanol (1) + water (2) [4–6]; Δ: propylene glycol (1) + water (2) [7]. Lines are the regular polynomial models describing the solubility behavior with the mixtures composition.
(solubility increase ratio against aqueous solubility) is observed for dissolving naproxen in comparison with Na·NAP. This could be due to better solvation of naproxen in the methanol-rich area. In the case of Na·NAP lower ionization is expected with decreasing the solvent ε values and the slight increase in the observed solubility of Na·NAP could be rationalized by solvation of its ion-pair. 3.2. Solubility (or density) correlations The solubility of solutes in mixed solvents could be mathematically represented by using a number of cosolvency models reported in the literature [33] among them, the Jouyban-Acree model is the most accurate one to represent the solubility of drugs in mixed solvents at various temperatures [34]. The general form of the model is presented as: lnC 3−ð1þ2Þ;T ¼ w1 lnC 3−1;T þ w2 lnC 3−2;T þ
2 w w X 1 2 J i ðw1 −w2 Þi T i¼0
ð1Þ
where w1 and w2 are the mass fractions of solvents 1 (methanol in this work) and 2 (water in this work), C3 − (1 + 2),T is the molar (mol dm−3) drug solubility in the methanol + water mixtures, C3 − 1,T is the molar drug solubility in neat methanol (component 1), C3 − 2,T is the molar drug solubility in neat water (component 2) at temperature T and Ji terms (expressed as K−1) are the model constants computed using a no intercept least square analysis [35]. All computations were carried out using SPSS Ver 11.5 software. One might reduce Eq. (1) in the form of the combined nearly ideal binary solvent/Redlich-Kister equation [36] at isothermal conditions as: 2 X Ai ðw1 −w2 Þi lnC 3−ð1þ2Þ ¼ w1 ln C 3−1 þ w2 ln C 3−2 þ ðw1 w2 Þ i¼0
ð2Þ
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Fig. 4. Solubility of pharmaceutical salts (3), expressed in molarity, as a function of the dielectric constant in some cosolvent (1) + water (2) mixtures at 298.15 K. ○: methanol (1) + water (2) [This work]; □: ethanol (1) + water (2) [4–6]; Δ: propylene glycol (1) + water (2) [7]. Lines are the regular polynomial models describing the solubility behavior with the dielectric constant.
The main advantage that Eq. (1) has over Eq. (2) is that it represents both effects of solvent composition and temperature on solute solubility in binary solvent mixtures. The model thus could be used to predict the solubility in any solvent composition and temperature of interest using interpolation as has been shown in earlier works [37,38]. The experimental solubilities of the investigated drugs in methanol + water mixtures were fitted to Eq. (1) and the obtained model constants and other statistical parameters are listed in Table 3. Eq. (1) with the reported J terms for each drug is valid for calculating the solubility of the drug in methanol + water mixtures at various temperatures by employing the solubility data of the drug in methanol and water at T. The reported mean percentage deviation (MPD) values in Table 3 for the backcalculated solubility (or density) data of drugs are computed using: MPD ¼
100 X jCalculated−Observedj N Observed
ð3Þ
where N is the number of experimental data points. The overall MPD for back-calculated molar solubilities is 1.2%. The Jouyban-Acree model could be trained for representing the mole fraction solubility of drugs as: w w 1 2 ln x3−ð1þ2Þ ¼ w1 ln x3−1 þ w2 ln x3−2 þ T h i S0 þ S1 ðw1 −w2 Þ þ S2 ðw1 −w2 Þ2
ð4Þ
where x is the mole fraction solubility of the solute and the subscripts are defined the same as Eq. (1). The obtained model constants and the statistical parameters were reported in Table 3. Eq. (4) back-calculates the solubility of the investigated drugs in methanol + water mixtures with the overall MPD of 1.6%.
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M.M. Muñoz et al. / Journal of Molecular Liquids 220 (2016) 842–847 Table 4 Volumetric properties of the saturated solutions of pharmaceutical salts (3) in methanol (1) + water (2) mixtures at 298.15 K and local atmospheric pressure of 73.9 kPa. ρ / g cm−3b,c w1a,b
0.000 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 1.000
Fig. 5. Logarithmic mole fraction solubility of sodium naproxen (3, ○) and molecular naproxen (3, □) in methanol (1) + water (2) mixtures at 298.15 K. Lines are the regular polynomial models describing the solubility behavior with the mixtures composition.
The Jouyban-Acree model was also used to represent the density of mixed solvents and/or saturated solutions of drugs in the solvent mixtures as has been shown in earlier works [39–41]. One may train the model using the density data of solute free methanol + water mixtures at various temperatures and then to use it for prediction of the solute saturated solution in the solvent mixtures by employing the density values of the solute saturated solutions in the mono-solvents 1 (ρSat 1 , T) and 2 (ρSat 2 , T). When the model is trained using the density of solute free methanol + water mixtures reported in the second column of Table 4, the obtained equation with the model constants (± their standard errors) is: log ρ1þ2;T ¼ w1 log ρ1;T þ w2 log ρ2;T w1 w2 34:827ð0:275Þ þ 9:367ð0:548Þðw1 −w2 Þ þ 2 −6:001ð1:264Þðw1 −w2 Þ T
ð5Þ
which predicts the density of drug saturated solutions (ρ1 + 2 , T) Sat (replacing ρ1 , T and ρ2 , T with ρSat 1 , T and ρ1 , T) of the investigated drugs with the overall MPD of 3.0%. 3.3. Apparent specific volumes at saturation The volumetric properties of drugs and other components in aqueous solutions are relevant from several practical and theoretical points of view [42]. A relevant property of drugs in saturated solutions is the apparent specific volume (φsp V ), which is calculated by means of Eq. (6) [43]: w3 þ w1þ2 1−ρ=ρ1þ2 ð6Þ φsp V ¼ w3 ρ
3 −1b,c φsp V / cm g
Cosolvent mixtured
Na·NAP
PC·HCl
Lys·Clon
Na·NAP
PC·HCl
Lys·Clon
0.9971 0.9802 0.9647 0.9492 0.9315 0.9119 0.8904 0.8673 0.8426 0.8152 0.7869
1.0619 1.0574 1.0559 1.0518 1.0402 1.0262 1.0099 0.9920 0.9736 0.9472 0.8947
1.1166 1.1114 1.1010 1.0889 1.0746 1.0588 1.0403 1.0135 0.9805 0.9321 0.8899
1.1442 1.1325 1.1250 1.1182 1.1058 1.0990 1.0840 1.0523 1.0026 0.9201 0.8384
0.690 0.684 0.699 0.707 0.712 0.710 0.712 0.706 0.696 0.677 0.633
0.829 0.827 0.828 0.828 0.828 0.827 0.822 0.817 0.808 0.795 0.732
0.719 0.724 0.729 0.737 0.744 0.746 0.745 0.739 0.717 0.695 0.647
a w1 is the mass fraction of methanol (1) in the methanol (1) + water (2) mixtures free of drug (3). b Standard uncertainties are u(T) = 0.05 K, u(p) = 2.2 kPa, u(w1) = 0.0005. Average standard uncertainty in density of the saturated solutions is u(ρ) = 0.0010 g cm−3. Average standard uncertainty in apparent specific volumes at saturation is u(φsp V ) = 0.004 cm3 g−1. c Na·NAP, PC·HCl, and Lys·Clon, are sodium naproxen, procaine hydrochloride, and lysine clonixinate, respectively. d Density values from Mikhail and Kimel [44].
Here, w3 and w1 + 2 are the mass fractions of the drug and the cosolvent mixture, respectively, and ρ and ρ1 + 2 are the densities of the saturated solution and the cosolvent mixture free of drug at 298.15 K, respectively. The density of the methanol (1) + water (2) cosolvent mixtures at 298.15 K was taken from the literature [44]. The density of the saturated solutions and the apparent specific volumes of the drugs at 298.15 K are presented in Table 4. Fig. 6 allows the visual comparison of densities for all the saturated solutions and the cosolvent mixtures free of drug. All the saturated solutions exhibit density values higher than those of the cosolvent mixtures free of drug indicating that all these drugs are more dense than the respective solvents. On the other hand, PC·HCl exhibits the highest apparent specific volume; whereas, Na·NAP and Lys·Clon exhibit similar specific volumes at saturation being them higher for Lys·Clon. These behaviors are similar to those reported for these drugs in propylene glycol (1) + water (2) mixtures [7]. If all the φsp V values are considered for every drug, except in neat methanol (8), the following average values are obtained: 0.699 (±0.013) cm3 g−1 for Na·NAP, 0.821 (±0.011) cm3 g−1 for PC·HCl, and 0.730
Table 3 The correlation coefficient (R), Fisher test value (F), the model constantsa for Jouyban-Acree model (±standard error) and mean percentage deviation (MPD) for back-calculated solubilities in molar and mole fraction units of pharmaceutical salts (3) in methanol (1) + water (2) mixtures at 298.15 K. Drugb
R
F
J0
J1
J2
MPD
162.186 (±52.573) 265.299 (±11.631) 1027.165 (±12.870)
326.718 (±121.222) 146.718 (±26.819) 515.249 (±29.676) Overall
2.4
Molar solubility Na·NAP
0.995
276
PC·HCl
N0.999
4035
Lys·Clon
N0.999
21,624
518.405 (±26.321) 451.162 (±5.823) 1098.921 (±6.443)
0.5 0.6 1.2
Mole fraction
Na·NAP
0.994
223
PC·HCl
0.999
2060
Lys·Clon
a a
N0.999
11,657
S0
S1
S2
557.066 (±31.493) 515.592 (±9.205) 1335.273 (±10.228)
182.634 (±62.904) 245.488 (±18.386) 1116.169 (±20.429)
357.826 (±145.042) 152.393 (±42.395) 304.129 (±47.104) Overall
All included model constants were statistically significant (p b 0.05). Na·NAP, PC·HCl, and Lys·Clon, are sodium naproxen, procaine hydrochloride, and lysine clonixinate, respectively.
2.9 0.9 0.9 1.6
M.M. Muñoz et al. / Journal of Molecular Liquids 220 (2016) 842–847
Fig. 6. Density of the saturated solutions and of the methanol (1) + water (2) mixtures free of drug (3) at 298.15 K. ○: Sodium naproxen; □: procaine hydrochloride; Δ: lysine clonixinate; ◊: methanol (1) + water (2) mixtures free of drug (3) [35]. Lines are the regular polynomial models describing the density behavior with the mixtures composition.
(±0.016) cm3 g−1 for Lys·Clon. These values are slightly lower than those observed for the same drugs in propylene glycol (1) + water (2) mixtures [7]. The observed variations in φsp V values in methanol (1) + water (2) mixtures and neat water (2) are lower than 2.3% for all drugs. 4. Conclusions The drug solubility values presented in this report expand the physicochemical data about pharmaceutical salts in aqueous cosolvent mixtures. In this way, it could be stated that the dissolution process of these electrolyte drugs is clearly dependent on the mixtures composition. Furthermore, for practical purposes the following average apparent volumes at saturation could be considered in these mixtures: 0.699 (± 0.013) cm3 g− 1 for Na·NAP, 0.821 (± 0.011) cm3 g−1 for PC·HCl, and 0.730 (±0.016) cm3 g−1 for Lys·Clon. Acknowledgments We thank the Departments of Pharmacy and Physics of the Universidad Nacional de Colombia for facilitating the equipment and laboratories used. References [1] 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. [2] S.C. Sweetman, Martindale: The Complete Drug Reference, 36th ed. Pharmaceutical Press, London, 2009. [3] A. Jouyban, Handbook of Solubility Data for Pharmaceuticals, CRC Press, Boca Raton, FL, 2010. [4] D.R. Delgado, M.A. Ruidiaz, S.M. Gómez, M. Gantiva, F. Martínez, Thermodynamic study of the solubility of sodium naproxen in some ethanol + water mixtures, Quím. Nova 33 (2010) 1923–1927. [5] D.R. Delgado, E.F. Vargas, F. Martínez, Thermodynamic study of the solubility of procaine-HCl in some ethanol + water cosolvent mixtures, J. Chem. Eng. Data 55 (2010) 2900–2904. [6] R.A. Gutiérrez, D.R. Delgado, F. Martínez, Solution thermodynamics of lysine clonixinate in some ethanol + water mixtures, Lat. Am. J. Pharm. 31 (2012) 226–234. [7] D.M. Jiménez, Z.J. Cárdenas, F. Martínez, Solubility and apparent specific volume of some salt pharmaceutical salts in propylene glycol + water mixtures at 298.15 K, Chem. Eng. Commun. 203 (2016) 1013–1019. [8] D.R. Delgado, R. Sotomayor, D. Monterroza, C.P. Mora, E.F. Vargas, F. Martínez, Thermodynamics of mixing of sodium naproxen and procaine hydrochloride in ethanol + water cosolvent mixtures, Rev. Colomb. Cienc. Quím. Farm. 39 (2010) 132–148. [9] A.R. Holguín, D.R. Delgado, M.A. Ruidiaz, E.F. Vargas, F. Martínez, Apparent molar volumes of sodium naproxen in water at several concentrations and temperatures, Lat. Am. J. Pharm. 30 (2011) 619–623. [10] D.R. Torres, L.H. Blanco, F. Martínez, E.F. Vargas, Apparent molal volumes of lidocaine-HCl and procaine-HCl in aqueous solution as a function of temperature, J. Chem. Eng. Data 52 (2007) 1700–1703. [11] D.R. Delgado, A.F. Jiménez-Kairuz, R.H. Manzo, E.F. Vargas, F. Martínez, Apparent molar volumes of the anesthetics procaine-HCl and lidocaine-HCl in water at temperatures from 278.15 to 313.15 K, Rev. Colomb. Cienc. Quím. Farm. 39 (2010) 57–67. [12] D.R. Torres, L.H. Blanco, E.F. Vargas, F. Martínez, Calorimetric enthalpies of solution for lidocaine–HCl and procaine–HCl in water at 298.15 K, J. Chem. Eng. Data 54 (2009) 786–790.
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Jouyban, The importance of dielectric constant for solubility prediction in binary solvent mixture: electrolytes and zwitterions in water + ethanol, AAPS PharmSciTech 11 (2010) 1726–1729. [19] A.T. Florence, D. Atwood, Physicochemical Principles of Pharmacy, third ed. MacMillan Press Ltd., London, 1998. [20] M. Pudipeddi, A.T.M. Serajuddin, D.J.W. Grant, P.H. Stahl, Solubility and Dissolution of Weak Acids, Bases, and Salts, in: P.H. Stahl, C.G. Wermuth (Eds.), Handbook of Pharmaceutical Salts. Properties, Selection, and Use, IUPAC and Wiley-VCH, Zurich, 2002. [21] A.T. Serajuddin, Salt formation to improve drug solubility, Adv. Drug Deliv. Rev. 59 (2007) 603–616. [22] Z.J. Cárdenas, D.M. Jiménez, F. Martínez, Solubility and saturation apparent volume of propranolol·HCl in some binary aqueous cosolvent mixtures at 298.15 K, J. Chem. Eng. Data 60 (2015) 1520–1525. [23] M.M. Muñoz, C.J. Rodríguez, D.R. Delgado, M.Á. Peña, A. Jouyban, F. 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Rousseau, Solubility and pseudopolymorphic transitions in mixed solvents: sodium naproxen in methanol-water and ethanol-water solutions, Cryst. Growth Des. 10 (2010) 3802–3807. [29] Y.-S. Kim, J.R. Méndez del Río, R.W. Rousseau, Solubility and prediction of the heat of solution of sodium naproxen in aqueous solutions, J. Pharm. Sci. 94 (2005) 1941–1948. [30] Y. Marcus, The Properties of Solvents, John Wiley & Sons, Chichester, 1998. [31] Y. Marcus, Introduction to Liquid State Chemistry, John Wiley & Sons Ltd., London, 1977. [32] D.M. Jiménez, M.M. Muñoz, C.J. Rodríguez, Z.J. Cárdenas, F. Martínez, Solubility and preferential solvation of some non-steroidal anti-inflammatory drugs in methanol + water mixtures at 298.15 K, Phys. Chem. Liq. (2016), http://dx.doi. org/10.1080/00319104.2016.1140763. [33] A. Jouyban-Gharamaleki, L. Valaee, M. Barzegar-Jalali, B.J. Clark, W.E. 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Solubility and apparent specific volume at saturation of some pharmaceutical salts in methanol + water mixtures at 298.15 K María M. Muñoz a, María Á. Peña b, Ovidio A. Almanza c, Abolghasem Jouyban d,e, Fleming Martínez a,⁎, William E. Acree Jr. f a Grupo de Investigaciones Farmacéutico-Fisicoquímicas, Departamento de Farmacia, Facultad de Ciencias, Universidad Nacional de Colombia –Sede Bogotá, Cra. 30 No. 45-03, Bogotá D.C., Colombia b Departamento de Ciencias Biomédicas, Facultad de Farmacia, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain c Grupo de Física Aplicada, Departamento de Física, Facultad de Ciencias, Universidad Nacional de Colombia –Sede Bogotá, Cra. 30 No. 45-03, Bogotá D.C., Colombia d Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz 51664, Iran e Kimia Idea Pardaz Azarbayjan (KIPA) Science Based Company, Tabriz University of Medical Sciences, Tabriz 51664, Iran f Department of Chemistry, University of North Texas, Denton, TX 76203-5070, USA
a r t i c l e
i n f o
Article history: Received 1 February 2016 Received in revised form 27 April 2016 Accepted 28 April 2016 Available online 22 May 2016 Keywords: Sodium naproxen Procaine hydrochloride Lysine clonixinate Methanol + water mixtures Solubility Cosolvency Apparent specific volume
a b s t r a c t Equilibrium solubility of sodium naproxen (Na·NAP), procaine hydrochloride (PC·HCl), and lysine clonixinate (Lys·Clon), was determined in methanol + water mixtures at 298.15 K. Mole fraction solubility of Na·NAP increases from neat water (x3 = 1.71 × 10−2) to reach a maximum in the mixture with w1 = 0.90 (x3 = 5.05 × 10−2); the solubility of PC·HCl increases from neat water (x3 = 9.68 × 10−2) to reach a maximum in the mixture with w1 = 0.20 (x3 = 0.1032); whereas, the solubility of Lys·Clon increases from neat water (x3 = 3.54 × 10−2) to reach a maximum in the mixture with w1 = 0.60 (x3 = 6.33 × 10−2). The generated solubility data are mathematically represented by using the Jouyban-Acree model with very good error level (average of 1.2% for molar solubilities). In addition, the apparent specific volumes at saturation of these drugs were also calculated in all the mixtures under study using the measured densities of the saturated solutions. In this way, the average apparent volumes at saturation in these mixtures could be considered as follows: 0.699 cm3 g−1 for Na·NAP, 0.821 cm3 g−1 for PC·HCl, and 0.730 cm3 g−1 for Lys·Clon. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Sodium naproxen (Na·NAP) and lysine clonixinate (Lys·Clon) are analgesic drugs commonly used in therapeutics, whereas, procaine hydrochloride (PC·HCl) is a local anesthetic drug used in current classical and alternative therapeutics [1,2]. Although these three pharmaceutical compounds are widely used in current therapeutics, the physicochemical data about their aqueous solutions is still not complete [1–3]. Nevertheless, the dissolution thermodynamic quantities of these drugs in ethanol (1) + water (2) mixtures [4–6] and propylene glycol (1) + water (2) mixtures [7] have been reported in the literature. In similar way, the thermodynamic properties of the hypothetical mixing processes of Na·NAP and PC·HCl in ethanol (1) + water (2) mixtures have also been reported [8]. Moreover, the apparent molar volumes of Na·NAP and PC·HCl in neat water at several concentrations and temperatures have also been reported [9–11]. Finally, other contributions to the physicochemical characterization of PC·HCl in neat water were reported previously, such as the calorimetric determination of ⁎ Corresponding author. E-mail address: [email protected] (F. Martínez).
http://dx.doi.org/10.1016/j.molliq.2016.04.116 0167-7322/© 2016 Elsevier B.V. All rights reserved.
the dissolution enthalpy and the calculation of the respective osmotic and activity coefficients at several concentrations [12,13]. On the other hand, as has already been mentioned in the literature, the solubility of electrolyte and non-electrolyte drugs in cosolvent mixtures is crucial in the pharmaceutical field because this knowledge is frequently used in purification methods, preformulation studies, and design of liquid dosage forms [14–16]. Thus, it is very important to systematically determine the solubility of pharmaceutical compounds such as drugs and excipients in mixed solvents. It is noteworthy that the systematic study of the solubility as a function of the dielectric constant (ε) of the solvent mixtures could allow the identification of maximum solubility peaks. The ε value of these maximum peaks is almost coincident with the “approximate dielectric requirement” of the drug and it normally occurs at a common range of ε values, despite of the cosolvent used in the aqueous mixtures, i.e. ethanol, propylene glycol, polyethylene glycol 400, or glycerol [17, 18]. In this way, taking into account the approximate dielectric requirement of the drug is advantageous during the design of homogeneous liquid dosage forms because it could reduce costs by diminishing the number of experiments required to obtain an adequate cosolvent mixture [7,19]. Moreover, the use of pharmaceutical salts is the most
M.M. Muñoz et al. / Journal of Molecular Liquids 220 (2016) 842–847
common and effective method to increase the solubility and dissolution rates of acidic and basic drugs in aqueous media [20,21]. The present research studied the solubility, density and apparent specific volume at saturation of Na·NAP, PC·HCl and Lys·Clon (solutes identified as component 3) in methanol (component 1) + water (component 2) mixtures at 298.15 K. This research is a continuation of that developed in propylene glycol (1) + water (2) mixtures at the same temperature [7]. Similar studies have been reported with propranolol hydrochloride in several cosolvent (1) + water (2) mixtures [22] and some structurally related sodium sulfonamides in propylene glycol (1) + water (2) mixtures [23]. It is important to note that methanol is not used to develop liquid pharmaceutical dosage forms owing its high toxicity but it is a very good model solvent for cosolvency studies and in some instances is used in drug purification procedures [24]. Otherwise, methanol is used in some microencapsulation techniques and also as the most common mobile phase in high performance liquid chromatography [25,26].
843
(mol dm−3) concentration scales, the density of the saturated solutions was determined by using a digital density meter with an accuracy of ± 0.0001 g cm−3 (DMA 45 Anton Paar, Austria) connected to a recirculating thermostatic bath at 298.15 ± 0.05 K (Neslab RTE 10 Digital One Thermo Electron Company, USA). Densities were also used to calculate the volumetric contribution of the drugs to the saturated solutions. 2.4. Calorimetric study Melting point and enthalpy of fusion of Na·NAP, Lys·Clon and PC·HCl as original samples were determined by DSC studies (TA Instruments DSC 2920, USA). Thermal analyses were performed at a heating rate of 10 K min−1 in a dynamic nitrogen atmosphere (10 cm3 min− 1). Nearly 7.0 mg of every drug was used in each case. The equipment was calibrated using Indium as standard. 2.5. X-ray diffraction analysis
2. Experimental section 2.1. Reagents and materials Sodium naproxen (Na·NAP, (+)-2-(6-Methoxy-2naphthyl)propionic acid sodium salt), lysine clonixinate (Lys·Clon, 2[(3-Chloro-2-methylphenyl)amino]nicotinic acid, L-lysine (1:1)), procaine hydrochloride (PC·HCl, 2-(Diethylamino)ethyl p-aminobenzoate monohydrochloride), methanol and distilled water with conductivity b2 μS cm−1, were used in this research. Molecular sieve (numbers 3 and 4, Merck, Germany) and Millipore Corp. Swinnex®-13 (USA) filter units were also used. Table 1 summarizes the characteristics of the compounds studied. 2.2. Solvent mixtures preparation All methanol (1) + water (2) solvent mixtures were prepared gravimetrically in quantities of 10.00 g by using an Ohaus Pioneer TM PA214 analytical balance with sensitivity ±0.1 mg. The mass fractions of methanol, w1, of the nine binary mixtures studied varied by w1 = 0.10 from w1 = 0.10 to w1 = 0.90 to cover the entire range of compositions. 2.3. Solubility determinations The procedures followed in this research were similar to those used previously to evaluate the solubility of acetaminophen in the same mixtures [27]. Briefly, an excess of drug was added to 5.00 g of each solvent mixture or neat solvent, in stoppered dark glass flasks. Solidliquid mixtures were placed in ultrasonic bath (Elma® E 60H Elmasonic, Germany) during 15 min followed by stirring in a thermostatic mechanical shaker (Julabo SW23, Germany) kept at 298.15 K for at least four days to reach the equilibrium. After this time the supernatant solutions were filtered at isothermal conditions (Millipore Corp. Swinnex®-13, USA) to ensure that they were free of particulate matter before sampling. Drug 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. All the solubility experiments were developed at least in triplicate and averaged. To make the equivalence between mole fraction (x3) and molarity
In order to identify the drugs' polymorphs employed in this research, the respective X-ray diffraction spectra were carried out on the original samples. The spectra were obtained by using a PANalytical X'Pert PRO diffractometer with Cu Kα1 radiation line (λ = 0.1540598 nm) and Bragg-Brentano geometry. It was operated in continuous mode between 2θ = 5° and 2θ = 90° and angle variation of 0.02° with detector data acquisition time of 60 s. 3. Results and discussion 3.1. Experimental solubility of the pharmaceutical salts Table 2 summarizes the experimental solubility of these drugs in all the methanol (1) + water (2) mixtures at 298.15 K, expressed in mole fraction (x3) and molarity (mol dm−3), respectively. In almost all cases the relative standard deviations were lower than 2.2%. Regarding the solubility of these drugs in neat water, our value for Na·NAP is in good agreement with those reported in the literature [4, 7,28,29]; in a similar way, a good agreement is also observed for PC·HCl [5,7]; nevertheless, no agreement is observed in the case of Lys·Clon with the value reported by Gutiérrez et al. [6] but a very good agreement is observed regarding the value reported by Jiménez et al. [7]. The high discrepancy between our value and that of ref. [6] for Lys·Clon could possibly be attributed to significant differences in quantification analytic techniques, saturation times, or even, polymorphic solid states, as described in the literature [3]. Contrary to this research and the one by Jiménez et al. [7], no ultrasonic treatment was applied when the Lys·Clon solubility was studied in ethanol (1) + water (2) mixtures [6]. As has been described, this vigorous acoustic treatment could affect the dissolution rate and, possibly, the equilibrium solubility of the drug, by modifying its solid crystal nature [7]. Unfortunately no calorimetric or spectroscopic characterizations on the solid bottom phases were developed to identify possible polymorphic transitions. Nevertheless, for further comparisons Figs. 1 and 2 depict DSC analyses and X-ray diffraction spectra of the original samples of every pharmaceutical salt studied in this research. If the mole fraction scale is considered, the solubility trends are almost similar for these three drugs. Thus, the solubility of Na·NAP increases from neat water (x3 = 1.71 × 10−2) to reach a maximum in
Table 1 Source and purities of the compounds used in this research. Compound
CAS
Formula
Molar mass / g mol−1
Source
Mass fraction purity
Sodium naproxen Procaine hydrochloride Lysine clonixinate Methanol Water
2615934-2 51-05-8 55837-30-4 67-56-1 7732-18-5
C14H13NaO3 C13H20N2O2·HCl C19H25ClN4O4 CH4O H2O
252.24 272.78 408.88 32.04 18.02
Zhejiang Weishi Biotech. Co., Ltd., China Xi'an Frankherb Biotech. Co., Ltd. China Hangzhou Dayangchem Co., Ltd., China Merck, Germany Obtained by distillation
0.99 0.99 0.99 0.998 N0.999
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M.M. Muñoz et al. / Journal of Molecular Liquids 220 (2016) 842–847
Table 2 Experimental solubility of the pharmaceutical salts (3) in methanol (1) + water (2) mixtures expressed in mole fraction and molarity at 298.15 K and local atmospheric pressure of 73.9 kPa. w1a,b 0.000d 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 1.000
mol dm−3b,c
100 x3b,c Na·NAP
PC·HCl
Lys·Clon
Na·NAP
PC·HCl
Lys·Clon
1.71 2.08 2.75 3.36 3.76 4.05 4.43 4.71 5.03 5.05 3.86
9.68 10.27 10.32 10.18 10.07 9.84 9.40 8.54 7.40 5.70 4.22
3.54 3.83 4.28 4.89 5.35 6.06 6.33 5.76 4.38 2.53 1.11
0.824 0.927 1.112 1.238 1.281 1.285 1.295 1.276 1.256 1.167 0.853
2.533 2.541 2.477 2.389 2.297 2.187 2.047 1.840 1.582 1.219 0.890
1.272 1.283 1.322 1.376 1.390 1.433 1.407 1.262 0.989 0.592 0.256
a w1 is the mass fraction of methanol (1) in the methanol (1) + water (2) mixtures free of drug (3). b Standard uncertainties are u(T) = 0.05 K, u(p) = 2.2 kPa, u(w1) = 0.0005. Average relative standard uncertainties in solubility, ur(x3) and ur(mol dm−3), are 0.022 (or 2.2%). c Na·NAP, PC·HCl, and Lys·Clon, are sodium naproxen, procaine hydrochloride, and lysine clonixinate, respectively. d Other reported molar solubility values in neat water are as follows: Na·NAP: 0.730 mol dm−3 [4] and 0.919 mol dm−3 [7], PC·HCl: 2.51 mol dm−3 [5] and 2.524 mol dm−3 [7], and Lys·Clon: 0.204 mol dm−3 [6] and 1.270 mol dm−3 [7].
the mixture with w1 = 0.90 (x3 = 5.05 × 10−2); the solubility of PC·HCl increases from neat water (x3 = 9.68 × 10−2) to reach a maximum in the mixture with w1 = 0.20 (x3 = 0.1032); whereas, the solubility of Lys·Clon increases from neat water (x3 = 3.54 × 10−2) to reach a maximum in the mixture with w1 = 0.60 (x3 = 6.33 × 10−2). Fig. 3 compares the mole fraction solubility of these drugs in methanol (1) + water (2), ethanol (1) + water (2) [4–6], and propylene glycol (1) + water (2) [7] mixtures at 298.15 K. For Na·NAP the mole fraction solubility decreases as: propylene glycol (1) + water (2) N methanol (1) + water (2) N ethanol (1) + water (2), which is almost coincident with the polarity decreasing of the respective cosolvents [17,30]. For PC·HCl the solubility decreases as: methanol (1) + water (2) N propylene glycol (1) + water (2) N ethanol (1) + water (2), except
Fig. 1. DSC analyses of pharmaceutical salts as original samples.
Fig. 2. X-ray diffraction spectra of pharmaceutical salts as original samples.
in mixtures with 0.30 ≤ w1 ≤ 0.60 where the solubility is higher in ethanol (1) + water (2) compared with propylene glycol (1) + water (2). For Lys·Clon, in mixtures with 0.00 ≤ w1 ≤ 0.60 the solubility is higher in methanol (1) + water (2) mixtures compared with propylene glycol (1) + water (2) mixtures, whereas, in the other compositions the behavior is inverse. For this last drug the lowest solubility is found in ethanol (1) + water (2) mixtures. It is noteworthy that the maximum solubility of all these drugs is obtained in a mixture, instead of neat water or neat methanol. This could be interpreted in terms of the behavior of a hydrophobic ion, because of the big size of the protonated or dissociated compound as has been exposed earlier [7,31]. On the other hand, Fig. 4 shows the molar solubility of these drugs as a function of the dielectric constant in methanol (1) + water (2), ethanol (1) + water (2) [4–6], and propylene glycol (1) + water (2) [7] mixtures at 298.15 K. Only Na·NAP and Lys·Clon exhibit clearly molar solubility maximum peaks in methanol (1) + water (2) mixtures. Thus, the ε value of the cosolvent mixture of maximum solubility (w1 = 0.60 and ε = 48.5 with C = 1.295 mol dm−3 for Na·NAP and w1 = 0.50 and ε = 52.9 with C = 1.433 mol dm−3 for Lys·Clon) could be considered as the “approximate dielectric requirement” for these two electrolyte drugs in methanol (1) + water (2) mixtures. Nevertheless, the maximum solubility of Na·NAP in ethanol (1) + water (2) mixtures is obtained in the mixture with w1 = 0.40 and ε = 53.5 (C = 1.016 mol dm−3) [4]; whereas, in propylene glycol (1) + water (2) mixtures it is obtained in the mixture with w1 = 0.80 and ε = 41.6 (C = 1.720 mol dm−3) [7]. In this way, the practical “approximate dielectric requirement” for this drug should be considered as a ε range from 42 to 53 as was indicated earlier [7]. Fig. 5 compares the logarithmic mole fraction solubility of Na·NAP and molecular naproxen in methanol (1) + water (2) mixtures at 298.15 K [32]. It is clear that the salt form of this drug is much more soluble than the respective molecular form. This is because of the strong ion-dipole interactions exhibited by the carboxylate group of Na·NAP mainly with water compared with the moderately strong hydrogen bonding exhibited by the carboxylic acid and ether groups of molecular naproxen with water and/or methanol [17]. A similar behavior was exhibited by these drugs in propylene glycol (1) + water (2) mixtures [7]. Better solubilization power
M.M. Muñoz et al. / Journal of Molecular Liquids 220 (2016) 842–847
Fig. 3. Solubility of pharmaceutical salts (3), expressed in mole fraction, in some cosolvent (1) + water (2) mixtures at 298.15 K. ○: methanol (1) + water (2) [This work]; □: ethanol (1) + water (2) [4–6]; Δ: propylene glycol (1) + water (2) [7]. Lines are the regular polynomial models describing the solubility behavior with the mixtures composition.
(solubility increase ratio against aqueous solubility) is observed for dissolving naproxen in comparison with Na·NAP. This could be due to better solvation of naproxen in the methanol-rich area. In the case of Na·NAP lower ionization is expected with decreasing the solvent ε values and the slight increase in the observed solubility of Na·NAP could be rationalized by solvation of its ion-pair. 3.2. Solubility (or density) correlations The solubility of solutes in mixed solvents could be mathematically represented by using a number of cosolvency models reported in the literature [33] among them, the Jouyban-Acree model is the most accurate one to represent the solubility of drugs in mixed solvents at various temperatures [34]. The general form of the model is presented as: lnC 3−ð1þ2Þ;T ¼ w1 lnC 3−1;T þ w2 lnC 3−2;T þ
2 w w X 1 2 J i ðw1 −w2 Þi T i¼0
ð1Þ
where w1 and w2 are the mass fractions of solvents 1 (methanol in this work) and 2 (water in this work), C3 − (1 + 2),T is the molar (mol dm−3) drug solubility in the methanol + water mixtures, C3 − 1,T is the molar drug solubility in neat methanol (component 1), C3 − 2,T is the molar drug solubility in neat water (component 2) at temperature T and Ji terms (expressed as K−1) are the model constants computed using a no intercept least square analysis [35]. All computations were carried out using SPSS Ver 11.5 software. One might reduce Eq. (1) in the form of the combined nearly ideal binary solvent/Redlich-Kister equation [36] at isothermal conditions as: 2 X Ai ðw1 −w2 Þi lnC 3−ð1þ2Þ ¼ w1 ln C 3−1 þ w2 ln C 3−2 þ ðw1 w2 Þ i¼0
ð2Þ
845
Fig. 4. Solubility of pharmaceutical salts (3), expressed in molarity, as a function of the dielectric constant in some cosolvent (1) + water (2) mixtures at 298.15 K. ○: methanol (1) + water (2) [This work]; □: ethanol (1) + water (2) [4–6]; Δ: propylene glycol (1) + water (2) [7]. Lines are the regular polynomial models describing the solubility behavior with the dielectric constant.
The main advantage that Eq. (1) has over Eq. (2) is that it represents both effects of solvent composition and temperature on solute solubility in binary solvent mixtures. The model thus could be used to predict the solubility in any solvent composition and temperature of interest using interpolation as has been shown in earlier works [37,38]. The experimental solubilities of the investigated drugs in methanol + water mixtures were fitted to Eq. (1) and the obtained model constants and other statistical parameters are listed in Table 3. Eq. (1) with the reported J terms for each drug is valid for calculating the solubility of the drug in methanol + water mixtures at various temperatures by employing the solubility data of the drug in methanol and water at T. The reported mean percentage deviation (MPD) values in Table 3 for the backcalculated solubility (or density) data of drugs are computed using: MPD ¼
100 X jCalculated−Observedj N Observed
ð3Þ
where N is the number of experimental data points. The overall MPD for back-calculated molar solubilities is 1.2%. The Jouyban-Acree model could be trained for representing the mole fraction solubility of drugs as: w w 1 2 ln x3−ð1þ2Þ ¼ w1 ln x3−1 þ w2 ln x3−2 þ T h i S0 þ S1 ðw1 −w2 Þ þ S2 ðw1 −w2 Þ2
ð4Þ
where x is the mole fraction solubility of the solute and the subscripts are defined the same as Eq. (1). The obtained model constants and the statistical parameters were reported in Table 3. Eq. (4) back-calculates the solubility of the investigated drugs in methanol + water mixtures with the overall MPD of 1.6%.
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M.M. Muñoz et al. / Journal of Molecular Liquids 220 (2016) 842–847 Table 4 Volumetric properties of the saturated solutions of pharmaceutical salts (3) in methanol (1) + water (2) mixtures at 298.15 K and local atmospheric pressure of 73.9 kPa. ρ / g cm−3b,c w1a,b
0.000 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 1.000
Fig. 5. Logarithmic mole fraction solubility of sodium naproxen (3, ○) and molecular naproxen (3, □) in methanol (1) + water (2) mixtures at 298.15 K. Lines are the regular polynomial models describing the solubility behavior with the mixtures composition.
The Jouyban-Acree model was also used to represent the density of mixed solvents and/or saturated solutions of drugs in the solvent mixtures as has been shown in earlier works [39–41]. One may train the model using the density data of solute free methanol + water mixtures at various temperatures and then to use it for prediction of the solute saturated solution in the solvent mixtures by employing the density values of the solute saturated solutions in the mono-solvents 1 (ρSat 1 , T) and 2 (ρSat 2 , T). When the model is trained using the density of solute free methanol + water mixtures reported in the second column of Table 4, the obtained equation with the model constants (± their standard errors) is: log ρ1þ2;T ¼ w1 log ρ1;T þ w2 log ρ2;T w1 w2 34:827ð0:275Þ þ 9:367ð0:548Þðw1 −w2 Þ þ 2 −6:001ð1:264Þðw1 −w2 Þ T
ð5Þ
which predicts the density of drug saturated solutions (ρ1 + 2 , T) Sat (replacing ρ1 , T and ρ2 , T with ρSat 1 , T and ρ1 , T) of the investigated drugs with the overall MPD of 3.0%. 3.3. Apparent specific volumes at saturation The volumetric properties of drugs and other components in aqueous solutions are relevant from several practical and theoretical points of view [42]. A relevant property of drugs in saturated solutions is the apparent specific volume (φsp V ), which is calculated by means of Eq. (6) [43]: w3 þ w1þ2 1−ρ=ρ1þ2 ð6Þ φsp V ¼ w3 ρ
3 −1b,c φsp V / cm g
Cosolvent mixtured
Na·NAP
PC·HCl
Lys·Clon
Na·NAP
PC·HCl
Lys·Clon
0.9971 0.9802 0.9647 0.9492 0.9315 0.9119 0.8904 0.8673 0.8426 0.8152 0.7869
1.0619 1.0574 1.0559 1.0518 1.0402 1.0262 1.0099 0.9920 0.9736 0.9472 0.8947
1.1166 1.1114 1.1010 1.0889 1.0746 1.0588 1.0403 1.0135 0.9805 0.9321 0.8899
1.1442 1.1325 1.1250 1.1182 1.1058 1.0990 1.0840 1.0523 1.0026 0.9201 0.8384
0.690 0.684 0.699 0.707 0.712 0.710 0.712 0.706 0.696 0.677 0.633
0.829 0.827 0.828 0.828 0.828 0.827 0.822 0.817 0.808 0.795 0.732
0.719 0.724 0.729 0.737 0.744 0.746 0.745 0.739 0.717 0.695 0.647
a w1 is the mass fraction of methanol (1) in the methanol (1) + water (2) mixtures free of drug (3). b Standard uncertainties are u(T) = 0.05 K, u(p) = 2.2 kPa, u(w1) = 0.0005. Average standard uncertainty in density of the saturated solutions is u(ρ) = 0.0010 g cm−3. Average standard uncertainty in apparent specific volumes at saturation is u(φsp V ) = 0.004 cm3 g−1. c Na·NAP, PC·HCl, and Lys·Clon, are sodium naproxen, procaine hydrochloride, and lysine clonixinate, respectively. d Density values from Mikhail and Kimel [44].
Here, w3 and w1 + 2 are the mass fractions of the drug and the cosolvent mixture, respectively, and ρ and ρ1 + 2 are the densities of the saturated solution and the cosolvent mixture free of drug at 298.15 K, respectively. The density of the methanol (1) + water (2) cosolvent mixtures at 298.15 K was taken from the literature [44]. The density of the saturated solutions and the apparent specific volumes of the drugs at 298.15 K are presented in Table 4. Fig. 6 allows the visual comparison of densities for all the saturated solutions and the cosolvent mixtures free of drug. All the saturated solutions exhibit density values higher than those of the cosolvent mixtures free of drug indicating that all these drugs are more dense than the respective solvents. On the other hand, PC·HCl exhibits the highest apparent specific volume; whereas, Na·NAP and Lys·Clon exhibit similar specific volumes at saturation being them higher for Lys·Clon. These behaviors are similar to those reported for these drugs in propylene glycol (1) + water (2) mixtures [7]. If all the φsp V values are considered for every drug, except in neat methanol (8), the following average values are obtained: 0.699 (±0.013) cm3 g−1 for Na·NAP, 0.821 (±0.011) cm3 g−1 for PC·HCl, and 0.730
Table 3 The correlation coefficient (R), Fisher test value (F), the model constantsa for Jouyban-Acree model (±standard error) and mean percentage deviation (MPD) for back-calculated solubilities in molar and mole fraction units of pharmaceutical salts (3) in methanol (1) + water (2) mixtures at 298.15 K. Drugb
R
F
J0
J1
J2
MPD
162.186 (±52.573) 265.299 (±11.631) 1027.165 (±12.870)
326.718 (±121.222) 146.718 (±26.819) 515.249 (±29.676) Overall
2.4
Molar solubility Na·NAP
0.995
276
PC·HCl
N0.999
4035
Lys·Clon
N0.999
21,624
518.405 (±26.321) 451.162 (±5.823) 1098.921 (±6.443)
0.5 0.6 1.2
Mole fraction
Na·NAP
0.994
223
PC·HCl
0.999
2060
Lys·Clon
a a
N0.999
11,657
S0
S1
S2
557.066 (±31.493) 515.592 (±9.205) 1335.273 (±10.228)
182.634 (±62.904) 245.488 (±18.386) 1116.169 (±20.429)
357.826 (±145.042) 152.393 (±42.395) 304.129 (±47.104) Overall
All included model constants were statistically significant (p b 0.05). Na·NAP, PC·HCl, and Lys·Clon, are sodium naproxen, procaine hydrochloride, and lysine clonixinate, respectively.
2.9 0.9 0.9 1.6
M.M. Muñoz et al. / Journal of Molecular Liquids 220 (2016) 842–847
Fig. 6. Density of the saturated solutions and of the methanol (1) + water (2) mixtures free of drug (3) at 298.15 K. ○: Sodium naproxen; □: procaine hydrochloride; Δ: lysine clonixinate; ◊: methanol (1) + water (2) mixtures free of drug (3) [35]. Lines are the regular polynomial models describing the density behavior with the mixtures composition.
(±0.016) cm3 g−1 for Lys·Clon. These values are slightly lower than those observed for the same drugs in propylene glycol (1) + water (2) mixtures [7]. The observed variations in φsp V values in methanol (1) + water (2) mixtures and neat water (2) are lower than 2.3% for all drugs. 4. Conclusions The drug solubility values presented in this report expand the physicochemical data about pharmaceutical salts in aqueous cosolvent mixtures. In this way, it could be stated that the dissolution process of these electrolyte drugs is clearly dependent on the mixtures composition. Furthermore, for practical purposes the following average apparent volumes at saturation could be considered in these mixtures: 0.699 (± 0.013) cm3 g− 1 for Na·NAP, 0.821 (± 0.011) cm3 g−1 for PC·HCl, and 0.730 (±0.016) cm3 g−1 for Lys·Clon. Acknowledgments We thank the Departments of Pharmacy and Physics of the Universidad Nacional de Colombia for facilitating the equipment and laboratories used. References [1] 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. [2] S.C. Sweetman, Martindale: The Complete Drug Reference, 36th ed. Pharmaceutical Press, London, 2009. [3] A. Jouyban, Handbook of Solubility Data for Pharmaceuticals, CRC Press, Boca Raton, FL, 2010. [4] D.R. Delgado, M.A. Ruidiaz, S.M. Gómez, M. Gantiva, F. Martínez, Thermodynamic study of the solubility of sodium naproxen in some ethanol + water mixtures, Quím. Nova 33 (2010) 1923–1927. [5] D.R. Delgado, E.F. Vargas, F. Martínez, Thermodynamic study of the solubility of procaine-HCl in some ethanol + water cosolvent mixtures, J. Chem. Eng. Data 55 (2010) 2900–2904. [6] R.A. Gutiérrez, D.R. Delgado, F. Martínez, Solution thermodynamics of lysine clonixinate in some ethanol + water mixtures, Lat. Am. J. Pharm. 31 (2012) 226–234. [7] D.M. Jiménez, Z.J. Cárdenas, F. Martínez, Solubility and apparent specific volume of some salt pharmaceutical salts in propylene glycol + water mixtures at 298.15 K, Chem. Eng. Commun. 203 (2016) 1013–1019. [8] D.R. Delgado, R. Sotomayor, D. Monterroza, C.P. Mora, E.F. Vargas, F. Martínez, Thermodynamics of mixing of sodium naproxen and procaine hydrochloride in ethanol + water cosolvent mixtures, Rev. Colomb. Cienc. Quím. Farm. 39 (2010) 132–148. [9] A.R. Holguín, D.R. Delgado, M.A. Ruidiaz, E.F. Vargas, F. Martínez, Apparent molar volumes of sodium naproxen in water at several concentrations and temperatures, Lat. Am. J. Pharm. 30 (2011) 619–623. [10] D.R. Torres, L.H. Blanco, F. Martínez, E.F. Vargas, Apparent molal volumes of lidocaine-HCl and procaine-HCl in aqueous solution as a function of temperature, J. Chem. Eng. Data 52 (2007) 1700–1703. [11] D.R. Delgado, A.F. Jiménez-Kairuz, R.H. Manzo, E.F. Vargas, F. Martínez, Apparent molar volumes of the anesthetics procaine-HCl and lidocaine-HCl in water at temperatures from 278.15 to 313.15 K, Rev. Colomb. Cienc. Quím. Farm. 39 (2010) 57–67. [12] D.R. Torres, L.H. Blanco, E.F. Vargas, F. Martínez, Calorimetric enthalpies of solution for lidocaine–HCl and procaine–HCl in water at 298.15 K, J. Chem. Eng. Data 54 (2009) 786–790.
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