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Solubility of disodium cytidine 5′-monophosphate in different binary mixtures from 288.15 K to 313.15 K
Thermochimica Acta 565 (2013) 1–7
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Solubility of disodium cytidine 5 -monophosphate in different binary mixtures from 288.15 K to 313.15 K Jin Yu a,b , Tianle Ma b,c , An Li b,c , Xiaochun Chen a,b , Yong Chen a,b , Jingjing Xie a,b , Jinglan Wu a,b,∗ , Hanjie Ying a,b,c a
College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing, China National Engineering Technique Research Center for Biotechnology, Nanjing, China c State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing, China b
a r t i c l e
i n f o
Article history: Received 14 January 2013 Received in revised form 11 April 2013 Accepted 17 April 2013 Available online 1 May 2013 Keywords: Disodium cytidine 5 -monophosphate Solid–liquid equilibrium Solubility Binary solvent mixtures Solution thermodynamics
a b s t r a c t The solubility of disodium cytidine 5 -monophosphate (5 -CMPNa2 ) in methanol + water and ethanol + water binary mixtures was measured experimentally at the temperatures ranging from 288.15 to 313.15 K. The results showed that the solubility of 5 -CMPNa2 increased with the increasing of temperature and the mole fraction of water in different binary mixtures. The (CNIBS)/Redlich–Kister model and the semi-empirical Apelblat model were applied for the prediction of the experimental data. Both models could give satisfactory simulation results. In addition, the thermodynamic properties of the dissolution process such as Gibbs energy, enthalpy, and entropy were calculated using the van’t Hoff equation and the Gibbs equation. The results indicated that the dissolution process was endothermic. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Cytidine 5 -monophosphate (5 -CMP) is one of the four common ribonucleotides [1] which can be used as a taste enhancer as well as a substrate for the preparation of cytidine-5 -diphosphate choline (CDP-choline), cytidine triphosphate (CTP) and other medicinal derivatives. Its disodium salt is available called disodium cytidine 5 -monophosphate (5 -CMPNa2 ) (C9 H12 N3 Na2 O8 P, CAS registry no. 6757-06-8, molar mass: 367.16 g/mol). It is a high value-added product used as the milk additive. The molecular structure of 5 CMPNa2 is shown in Fig. 1. The preparation of 5 -CMPNa2 is widely investigated in the literatures [2,3]. However, there are few articles focus on the separation and crystallization of 5 -CMPNa2 . Mass crystallization from solution is a traditional technique and widely used in various areas such as the pharmaceutical, chemical and food industry for the production of particulates [4]. It plays an essential role in the achievement of highly pure products since crystallization is a solid–liquid separation process [5], in which a solute is transferred from the liquid solution to a pure solid crystalline phase [6]. Since 5 -CMPNa2 can be dissolved in water
∗ Corresponding author at: College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Xin mofan Road 5, Nanjing 210009, China. Tel.: +86 25 86990001; fax: +86 25 58139389. E-mail addresses: [email protected], [email protected] (J. Wu). 0040-6031/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.tca.2013.04.018
and is insoluble in organic solvents, the dilution crystallization [7] would be a best choice to gain the 5 -CMPNa2 crystal. This methodology has been successfully applied for the purification of other phosphoryl compounds [8,9] in our laboratory as well, i.e., cytidine5 -diphosphate choline (CDP-choline) and cytidine triphosphate (CTP). Good crystal morphology has been obtained. In this work, methanol and ethanol are selected as anti-solvent since they are inexpensive, easily removed from the solvents and can be dissolved in water in any proportion [8,10]. The thermodynamic equilibrium of 5 -CMPNa2 in the binary mixtures is therefore essential for the efficient design of the crystallization process. So far, in the literature, it has been found no detailed analysis concerning the influence of different binary solvent mixtures and temperature on the 5 -CMPNa2 solubility data. Consequently, as a preliminary experiment, the solubility of 5 CMPNa2 in methanol + water and ethanol + water binary mixtures was determined by an isothermal method [11] from the temperature of 288.15–313.15 K under atmospheric pressure (101.3 kPa). The effects of the different binary mixtures as well as temperatures on 5 -CMPNa2 solubility were investigated. Two models in terms of the (CNIBS)/Redlich–Kister model and the semi-empirical Apelblat model were used to simulate the solubility data and the model parameters. The thermodynamic properties of the dissolution process were discussed as well. The aim of this work is to provide the theoretical solubility data which could be later used in the 5 -CMPNa2 crystallization process.
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The following Eq. (2) is used to define the initial mole fraction composition of the solvent mixture (x20 ) and the results are listed in Table 1. x20 =
The CNIBS/Redlich–Kister model [13,14] was used to predict the experimental solubility data. The model equation is represented by Eq. (3) which describes the solubility data as a function of the mole fraction of water.
2. Experimental 2.1. Materials 5 -CMPNa2 with a mass fraction purity of greater than 0.99 was prepared by recrystallization. Methanol and ethanol used in the experiments were of analytical reagent grade. The mass fractions were 0.995 and 0.997 purchased from Shanghai Chemistry Reagent Co., China. 2.2. Apparatus and procedures The isothermal method was applied to measure the solubility of 5 -CMPNa2 in methanol + water and ethanol + water binary systems. An excess mass of 5 -CMPNa2 was added to a known mass of solvent with uncertainty of ±0.1 mg measured by an electronic balance (BS-124S, Sartorius, Germany). The experiments were carried out in a constant temperature water bath (type DC-2030, Shanghai Sunny Hengping Scientific Instrument Co. Ltd., China) with the desired temperature kept within ±0.05 K. A continuous stirring rate of 80 rpm was taken at least for 5 h to reach the solid–liquid equilibrium. This equilibrium time was established by measuring the concentration of 5 -CMPNa2 every 30 min until a constant value was achieved. The stirring was stopped after 5 h and the suspended solution was kept still for 1 h. After that, the supernatant solution was poured into the filter funnel to obtain the supernatant and remove the excess of solid. During the filtration process, the filter funnel and the filter tanks were kept at the experimental temperature. The solubility measurements were carried out at the temperatures of 288.15, 293.15, 298.15, 303.15, 308.15 and 313.15 K in order to obtain sufficient data used in the following model calculations. The concentrations of 5 -CMPNa2 were determined roughly by UV spectra at 280 nm (UV-2000, UNICO, USA) in the preliminary equilibrium-time experiments for the sake of convenience and quickness. The precise concentrations of 5 -CMPNa2 in the filtrate were analyzed at 280 nm by high performance liquid chromatography (Agilent 1100, USA), using a SepaxHP-C18 column (4.6 mm × 250 mm, 5 m, Sepax (Jiangsu) Technologies Inc., Changzhou, China). The mobile phase was 0.6% (V/V) phosphoric acid. The column temperature was 300.15 K and the flow rate was 1.0 ml/min. All the solubility experiments were performed in triplicates. The mean values were presented and used in the calculations. 3. Results and discussion 3.1. Solubility data The mole fraction solubility of 5 -CMPNa2 (x1 ) in different binary solvent mixtures could be obtained from Eq. (1) [12]. m1 /M1 m1 /M1 + m2 /M2 + m3 /M3
(2)
3.2. Mole fraction of solvent-dependent equilibrium
Fig. 1. Molecular structure of 5 -CMPNa2 .
x1 =
m2 /M2 m2 /M2 + m3 /M3
(1)
where M is the molar weight and m is the mass. The subscripts 1, 2 and 3 refer to 5 - CMPNa2 , water and organic solvents.
ln x1 = x20 ln (x1 )2 + x30 ln (x1 )3 + x20 x30
n
sj (x20 − x30 )
j
(3)
j=0
where x20 and x30 are the initial mole fraction composition of the binary solvents without the solute existing in the solution. Sj is the model constant. j is a running exponent index. In pure solvent i, (x1 )i represents the mole fraction solubility of the solute, that is 5 CMPNa2 in this work. n could be equal to 0, 1, 2 or 3. The following Eq. (4) is obtained by selecting n = 2 and x30 = 1 − x20 . 2
3
ln x1 = B0 + B1 x20 + B2 (x20 ) + B3 (x20 ) + B4 (x20 )
4
(4)
where the constants B0 = ln (x1 )3 , B1 = ln (x1 )2 − ln (x1 )3 + S0 − S1 + S2 , B2 = − S0 + 3S1 − 3S2 , B3 = −2S1 + 6S2 and B4 = −4S2 . They are listed in Table 2. The percentage deviation ( (%D)) defined in Eq. (5) [15] was used to evaluate the agreement between the experimental data and the model predictions.
n exp (x1 − x1cal )/n exp x
(%D) = 100
i=1
exp
(5)
1
where x1 is the experimental data, x1cal is the calculated value from the model, and n is the number of the experimental data. The small discrepancy (see the percentage deviation ( (%D)) presented in Tables 1 and 2) indicates that the simulation curves calculated by the CNIBS/Redlich–Kister model fits the experimental data fairly well at different temperatures and mole fraction compositions of the binary solvents. It can be observed in Figs. 2 and 3 that the solubility value of 5 -CMPNa2 increased with the increasing mole fraction of water at any given temperature. This is due to the physical properties of 5 -CMPNa2 and water. It is well known that water is a polar solvent which has a high dielectric constant (78.5). The solute, 5 CMPNa2 belongs to a basic salt. The polar molecules of water can then solvate the Na+ and CMP2− ions because they can orient the appropriate partially charged portion of the molecule towards the ions in response to electrostatic attraction. This stabilizes the system and creates a hydration shell [16,17]. In addition, the amino group and hydroxyl groups existing in the CMP2− ions could be associated with water via hydrogen bonds, producing solvated ions as well. Hence, 5 -CMPNa2 possesses high solubility in water. The alcohols methanol and ethanol are polar protic solvents. According to Mullin [18], in polar protic solvents the solvent molecules interact by forming strong hydrogen bonds. In order to dissolve, the solute must break these bonds and replace them with bonds of similar strength. Theoretically, the amino group and hydroxyl groups could also be associated with alcohols to form hydrogen bonds. However, the strength was significantly weakened by the stereo-specific blockade by the large molecular configuration of 5 -CMPNa2 . Moreover, the alcohols (methanol and ethanol) have weak polarity (dielectric constants are 31.2 and 24.5,
J. Yu et al. / Thermochimica Acta 565 (2013) 1–7
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Table 1 The mole fraction solubility of 5 -CMPNa2 (x1 ) in water (2) + methanol (3) and water (2) + ethanol (3), at various initial mole fraction composition of binary solvent (x20 ) from 288.15 K to 313.15 K. x20 (mole fraction) Water(2) + methanol(3) T = 288.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 T = 293.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 T = 298.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 T = 303.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 T = 308.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 T = 313.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 Water(2) + ethanol(3) T = 288.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661 T = 293.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661 T = 298.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661
exp
104 x1
exp
exp
− x1cal )/x1
exp
(mole fraction)
102 (x1
0.87 1.59 3.60 5.92 9.19 11.67 29.69
± ± ± ± ± ± ±
0.03 0.02 0.01 0.05 0.04 0.07 0.02
−0.55 1.78 −3.22 2.02 1.47 −2.04 0.43
0.38 −2.09 1.05 0.41 −0.87 6.23 1.21
1.02 1.97 4.52 7.82 13.88 18.48 44.75
± ± ± ± ± ± ±
0.04 0.09 0.03 0.06 0.02 0.07 0.05
−0.55 1.76 −3.12 1.83 1.72 −2.21 0.45
−2.60 −0.61 0.88 2.26 3.09 5.81 2.76
1.28 2.50 5.64 9.90 19.26 27.42 62.44
± ± ± ± ± ± ±
0.02 0.04 0.03 0.03 0.07 0.04 0.09
−0.36 1.18 −2.24 1.60 0.55 −1.03 0.24
1.45 2.35 0.33 0.32 −0.77 −0.24 −2.73
1.56 3.12 6.90 12.37 27.82 42.79 94.82
± ± ± ± ± ± ±
0.02 0.03 0.05 0.03 0.06 0.04 0.07
−0.19 0.63 −1.20 0.91 0.20 −0.48 0.12
3.08 3.02 −1.64 −2.51 0.02 −0.63 0.92
1.73 3.60 8.71 16.27 39.35 65.65 135.94
± ± ± ± ± ± ±
0.05 0.02 0.02 0.07 0.06 0.01 0.08
0.20 −0.57 0.53 0.52 −2.42 2.01 −0.32
−3.78 −4.68 −0.19 0.26 −0.73 −2.02 −0.58
2.16 4.79 10.87 20.75 56.31 104.17 198.13
± ± ± ± ± ± ±
0.01 0.04 0.02 0.07 0.03 0.09 0.02
0.31 −0.86 0.64 1.20 −4.40 3.50 −0.56
1.02 1.26 0.44 0.34 0.29 0.70 0.18
0.12 0.34 1.20 2.79 7.83 12.45 22.01
± ± ± ± ± ± ±
0.02 0.04 0.03 0.05 0.07 0.02 0.03
0.03 −0.08 0.02 0.28 −0.84 0.71 −0.12
−0.69 −0.11 1.42 −1.47 −0.93 −3.55 −0.09
0.15 0.41 1.39 3.41 9.79 17.11 35.37
± ± ± ± ± ± ±
0.03 0.05 0.06 0.02 0.03 0.07 0.01
−0.13 0.58 −1.93 2.79 −3.05 1.81 −0.19
2.65 0.88 −0.44 0.52 −0.30 2.07 2.56
0.17 0.50 1.62 4.16 12.62 22.55 52.93
± ± ± ± ± ± ±
0.02 0.04 0.03 0.08 0.05 0.04 0.07
−0.35 1.34 −3.53 3.84 −2.07 0.47 0.13
−1.91 −1.67 −3.42 0.70 1.03 1.82 −1.08
(CNIBS)
102 (x1
exp
− x1cal )/x1
(Apelblat)
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J. Yu et al. / Thermochimica Acta 565 (2013) 1–7
Table 1 (Continued) exp
x20 (mole fraction)
104 x1
T = 303.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661 T = 308.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661 T = 313.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661
exp
exp
− x1cal )/x1
exp
(mole fraction)
102 (x1
102 (x1
0.22 0.63 2.13 5.22 16.45 29.56 81.69
± ± ± ± ± ± ±
0.05 0.02 0.04 0.01 0.03 0.07 0.02
−0.25 0.95 −2.26 2.13 −0.29 −0.56 0.22
−1.57 1.19 2.81 1.86 1.10 −0.47 −0.92
0.28 0.78 2.59 6.29 21.35 40.04 126.88
± ± ± ± ± ± ±
0.07 0.05 0.02 0.04 0.07 0.03 0.08
−0.18 0.65 −1.44 1.19 0.32 −0.78 0.21
1.92 −0.37 −0.52 −2.50 −1.46 −0.88 0.58
0.34 0.99 3.32 8.29 29.52 55.81 191.56
± ± ± ± ± ± ±
0.03 0.05 0.11 0.07 0.04 0.03 0.05
−0.28 1.00 −2.04 1.36 1.35 −1.87 0.43
−0.51 0.04 −0.07 0.66 0.35 0.29 −0.08
(CNIBS)
Table 2 Fitted parameters of CNIBS/Redlich–Kister model for 5 -CMPNa2 in binary solution at different temperatures.
exp
− x1cal )/x1
(Apelblat)
T/K
B0
Water(2) + methanol(3) 288.15 293.15 298.15 303.15 308.15 313.15
4.0 −4.2 −11.8 −21.4 −24.9 −39.6
−125 −61 −0.4 76 103 216
393 214 44 −169 −246 −557
−500 −283 −76 181 279 648
229 133 42 −71 −115 −274
1.64 1.66 1.03 0.53 0.94 1.64 (%D)/n = 1.24
Water(2) + ethanol(3) 288.15 293.15 298.15 303.15 308.15 313.15
−46.3 −45.7 −47.2 −43.1 −41.8 −43.9
200 198 208 177 172 184
−446 −439 −459 −370 −358 −383
467 455 470 362 347 368
−182 −174 −177 −129 −121 −127
0.30 1.50 1.67 0.95 0.68 1.19 (%D)/n = 1.05
B1
B2
Fig. 2. Mole fraction solubility of 5 -CMPNa2 (1) (x1 ) in methanol (3) + water (2) solvent mixture at various temperatures: () T = 288.15 K; () T = 293.15 K; () T = 298.15 K; (䊉) T = 303.15 K; () T = 308.15 K; () T = 313.15 K. The points represent the experimental data. Curves are calculated according with Eq. (4) using the Redlich–Kister model.
B3
B4
(%D)
Fig. 3. Mole fraction solubility of 5 -CMPNa2 (1) (x1 ) in ethanol (3) + water (2) solvent mixture at various temperatures: () T = 288.15 K; () T = 293.15 K; () T = 298.15 K; (䊉) T = 303.15 K; () T = 308.15 K; () T = 313.15 K. The points represent the experimental data. Curves are calculated according with Eq. (4) using the Redlich–Kister model.
J. Yu et al. / Thermochimica Acta 565 (2013) 1–7
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Table 3 Fitted parameters of Apelblat model for 5 -CMPNa2 for different temperature at various contents of organic solvent (x20 ).
x20 (mole fraction)
a
b
Water(2) + methanol(3) 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182
−37.4 −319.5 −83.6 −92.8 −129.5 −159.7 −135.7
−1485.9 10651.7 −1.8 −2.0 −2.9 −3.6 −3.1
5.9 48.3 13.4 15.1 21.6 27.0 22.9
2.05 2.33 0.75 1.02 0.96 2.61 1.39 (%D)/n = 1.59
Water(2) + ethanol(3) 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661
−343.9 −425.9 −652.5 −547.7 −746.8 −575.3 −153.3
11702.5 15362.1 25659.5 20901.9 29116.5 21008.2 −3.5
51.6 64.0 97.9 82.5 112.8 87.5 26.0
1.54 0.71 1.45 1.28 0.86 1.51 0.88 (%D)/n = 1.18
under 298.15 K, respectively), which makes it difficult for them to overcome electrostatic interaction between Na+ and CMP2− . As a result, 5 -CMPNa2 was insoluble in methanol and ethanol. Due to the weaker polarity of ethanol, the solubility of 5 -CMPNa2 was lower in ethanol + water than in methanol + water systems (comparison of Figs. 2 and 3). However, in the mixtures of water and alcohols, the hydroxyl group from water would associate with the alcohols via hydrogen bonds, more easily than that with 5 -CMPNa2 . Hence, the addition of alcohols in mixture solvents decreases the water molecules available for 5 -CMPNa2 , leading to the lower solubility of 5 -CMPNa2 . Consequently, methanol and ethanol demonstrated an anti-solvent effect for 5 -CMPNa2 , in which the solubility of 5 -CMPNa2 had the larger change in the ethanol + water system (Fig. 3), indicating that ethanol was an effective anti-solvent for 5 -CMPNa2 . 3.3. Temperature dependence of the mole fraction solubility of 5 -CMPNa2 The influence of temperatures on the solubility of 5 -CMPNa2 has been represented by the following semiempirical Apelblat model [19,20]. b ln x1 = a + + c ln T (6) T
c
(%D)
where a, b and c are the empirical constants of Apelblat model and listed in Table 3, together with the percentage deviations ( (%D)). The ratio of the calculated value (x1cal ) from the Apelblat model and exp the difference between the experimental solubility value (x1 ) and cal the calculated value (x1 ) are given in Table 1. 3.4. Thermodynamic properties of solutions According to van’t Hoff analysis [21], the apparent enthalpy change of solution could be related to the temperature and the solubility as following equation:
Hs =− R
∂ ln x1 ∂(1/T )
(7) p
Over a limited temperature interval (288.15–313.15 K) the heat capacity change of solution may be assumed to be constant. Hence, the values of Hs would be valid for the mean temperature (300.65 K) [22]. Thus, combined with the Apelblat model Eq. (6) the Hs can be calculated by Eq. (8). Hs = −R(b − cTmean )
(8)
According to Krug et al. [23], the Gibbs energy change for the dissolution process can be calculated as:
Fig. 4. Temperature dependence of solubility of 5 -CMPNa2 in methanol + water (a) and ethanol + water (b). (a) () x20 = 0.8182; (䊉) x20 = 0.7377; () x20 = 0.6923; () x20 = 0.6000; () x20 = 0.5295; () x20 = 0.4286; () x20 = 0.3600; (b) () x20 = 0.8661; (䊉) x20 = 0.8017; () x20 = 0.7639; () x20 = 0.6832; () x20 = 0.6179; () x20 = 0.5188; () x20 = 0.4471. The points represent the experimental data, and curves represent the results based on linear fitting.
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J. Yu et al. / Thermochimica Acta 565 (2013) 1–7
Table 4 Thermodynamic functions relative to solution process of 5 -CMPNa2 in various contents of organic solvent (x20 ) at 300.65 K. x20 (mole fraction) Water(2) + methanol(3) 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 Water(2) + ethanol(3) 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661
Hs (kJ/mol)
Gs (kJ/mol)
0.25 0.17 0.42 0.33 0.42 0.50 0.58
22.21 20.48 18.41 16.97 15.13 14.11 12.11
± ± ± ± ± ± ±
0.17 0.58 0.42 0.08 0.25 0.25 0.42
15.93 39.29 49.84 68.89 129.66 177.59 150.44
± ± ± ± ± ± ±
0.33 0.33 0.17 0.25 0.42 0.91 0.17
84.93 73.22 69.03 64.53 58.13 55.83 55.90
15.07 26.78 30.97 35.47 41.87 44.17 44.10
31.58 32.20 31.37 32.34 39.76 44.14 65.00
± ± ± ± ± ± ±
0.42 0.17 0.33 0.33 0.25 0.58 0.17
27.02 24.40 21.37 19.13 16.28 14.83 12.50
± ± ± ± ± ± ±
0.17 0.50 0.25 0.58 042 0.67 0.25
15.16 25.94 33.25 43.94 78.11 97.49 174.62
± ± ± ± ± ± ±
0.58 0.25 0.25 0.42 1.00 0.67 0.33
87.39 80.50 75.83 71.00 62.87 60.10 55.32
12.61 19.50 24.17 29.00 37.13 39.90 44.68
(9)
|Hs | |Hs | + |Tmean Ss |
(10)
|Tmean Ss | |Hs | + |Tmean Ss |
(11)
The calculated values of % H and % TS were listed in Table 4, which indicated that the enthalpy was the main contributing force to the Gibbs energy of the 5 -CMPNa2 dissolution process. 4. Conclusions The solubility of 5 -CMPNa2 in mixed systems was investigated from 288.15 to 313.15 K. The solubility values of 5 -CMPNa2 increased with the increasing of temperature and the mole fraction of water both in the water + methanol and the water + ethanol binary-solvent systems. The experimental solubility data were correlated by the CNIBS/Redlich–Kister model and the semi-empirical Apelblat model. The fitted parameters B0 , B1 , B2 , B3 , B4 of CNIBS model and a, b, c of Apelblat model at different temperatures According have been estimated and presented in the paper. to Table 2, the values of the sum of deviation ( (%D)/n) are 1.24 (water + methanol) and 1.05 (water + ethanol) for the CNIBS/Redlich–Kister model, whereas in Table 3, the values of the (%D)/n) are 1.59 (water + methanol) and sum of deviation ( 1.18 (water + ethanol) for Apelblat model. The results indicated that the experimental data were in good agreement with the prediction results with the two models. In addition, the discussion of Gibbs energy, enthalpy, and entropy for 5 -CMPNa2 in different binary mixtures indicated that the dissolution process was endothermic. Nomenclature
List of symbols A, a parameter parameter B, a
%TS
± ± ± ± ± ± ±
in which, the intercept can be obtained by plotting ln x1 versus (1/T − 1/Tmean ) [14] (shown in Fig. 4). The results of the calculated Gibbs energy, entropy and enthalpy of 5 -CMPNa2 are listed in Table 4. The positive values of Hs and Ss revealed that the dissolution of 5 -CMPNa2 in the mixtures was an entropy driven process. In order to quantitatively estimate the relative contribution to the Gibbs energy, enthalpy (% H ) and entropy (% TS ) calculated by Eqs. (10) and (11) are introduced [24].
%ςTS = 100
%H
27.00 32.29 33.40 37.68 54.11 67.50 57.34
Gs = −RTmean × intercept = Hs − Tmean Ss
%ςH = 100
Ss (J/mol/K)
C, c (%D) G H j m M n R S T x
parameter percentage deviation molar Gibbs free energy molar enthalpy running exponent index mass molar weight number of the experimental data gas constant entropy temperature mole fraction
Greek letter change Superscripts initial 0 ◦ standard molar calculated cal exp experimental Subscripts solute; parameter 1 2 water; parameter 3 organic solvent; parameter parameter 4 s solution Acknowledgements The work was supported in part by the Grant from the National Outstanding Youth Foundation of China (Grant No. 21025625), the PCSIRT, 12KJB530003, and the PAPD. We would like to acknowledge the financial support provided by the National High-Tech Research and Development Plan of China (863 Program, 2012AA021202) as well. References [1] G. Borodi, A. Hernanz, I. Bratu, M. Pop, R. Navarro, Hydrated sodium cytidine5 -monophosphate, Acta Crystallogr. 57 (2001) 514–516. [2] B. Noordam, J.G. Kortest, Production of 5 -ribonucleotides, WO2004067758 (2011). [3] T. Tanekawa, H., Takashima, T. Hachiya, Production of yeast extract containing flavoring, US4303680 (1981). [4] M. Kind, A. Mersmann, On supersaturation during mass crystallization from solution, Chem. Eng. Technol. 13 (1990) 50–62.
J. Yu et al. / Thermochimica Acta 565 (2013) 1–7 [5] D. Widenski, A. Abbas, J. Romagnoli, Comparison of different solubility equations for modeling in cooling crystallization, Chem. Eng. Process. 49 (2010) 1284–1297. [6] A. Mersmann, M. Kind, Chemical engineering aspects of precipitation from solution, Chem. Eng. Technol. 11 (1988) 264–276. [7] Z.Q. Yu, P.S. Chow, R.B.H. Tan, Application of attenuated total reflectanceFourier transform infrared (ATR-FTIR) technique in the monitoring and control of anti-solvent crystallization, Ind. Eng. Chem. Res. 45 (2006) 438–444. [8] Z. Du, X. Huang, H. Ying, J. Xiong, H. Lv, X. Zhou, Solubility of cytidine 5 diphosphocholine sodium in water and different binary mixtures from 278.15 to 298.15 K, J. Chem. Eng. Data 55 (2009) 1000–1002. [9] Z. Du, Y. Hu, P. Wang, J. Zhou, J. Xiong, H. Ying, J. Bai, Conformers and hydrogen bonds in cytidine 5 -diphosphocholine sodium single crystals grown from a mixture of ethanol and water, J. Mol. Struct. 985 (2011) 227–232. [10] A.C. Ribeiro Neto, R.F. Pires, R.A. Malagoni, M.R. Franco Jr., Solubility of vitamin C in water, ethanol, propan-1-ol, water + ethanol, and water + propan-1-ol at 298.15 and 308.15 K, J. Chem. Eng. Data 55 (2009) 1718–1721. [11] A.I. Zvaigzne, W.E. Acree Jr., Solubility of anthracene in binary alkane + 3methyl-1-butanol solvent mixtures, J. Chem. Eng. Data 39 (1994) 708–710. [12] Q. Chen, Y. Wang, Y. Li, J. Wang, Solubility and metastable zone of cefoperazone sodium in acetone + water system, J. Chem. Eng. Data 54 (2009) 1123–1125. [13] W.E. Acree Jr., Mathematical representation of thermodynamic properties: part 2. Derivation of the combined nearly ideal binary solvent (NIBS)/Redlich–Kister mathematical representation from a two-body and three-body interactional mixing model, Thermochim. Acta 198 (1992) 71–79. [14] W.E. Acree Jr., A.I. Zvaigzne, Thermodynamic properties of nonelectrolyte solutions: part 4. Estimation and mathematical representation of solute activity
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Thermochimica Acta journal homepage: www.elsevier.com/locate/tca
Solubility of disodium cytidine 5 -monophosphate in different binary mixtures from 288.15 K to 313.15 K Jin Yu a,b , Tianle Ma b,c , An Li b,c , Xiaochun Chen a,b , Yong Chen a,b , Jingjing Xie a,b , Jinglan Wu a,b,∗ , Hanjie Ying a,b,c a
College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing, China National Engineering Technique Research Center for Biotechnology, Nanjing, China c State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing, China b
a r t i c l e
i n f o
Article history: Received 14 January 2013 Received in revised form 11 April 2013 Accepted 17 April 2013 Available online 1 May 2013 Keywords: Disodium cytidine 5 -monophosphate Solid–liquid equilibrium Solubility Binary solvent mixtures Solution thermodynamics
a b s t r a c t The solubility of disodium cytidine 5 -monophosphate (5 -CMPNa2 ) in methanol + water and ethanol + water binary mixtures was measured experimentally at the temperatures ranging from 288.15 to 313.15 K. The results showed that the solubility of 5 -CMPNa2 increased with the increasing of temperature and the mole fraction of water in different binary mixtures. The (CNIBS)/Redlich–Kister model and the semi-empirical Apelblat model were applied for the prediction of the experimental data. Both models could give satisfactory simulation results. In addition, the thermodynamic properties of the dissolution process such as Gibbs energy, enthalpy, and entropy were calculated using the van’t Hoff equation and the Gibbs equation. The results indicated that the dissolution process was endothermic. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Cytidine 5 -monophosphate (5 -CMP) is one of the four common ribonucleotides [1] which can be used as a taste enhancer as well as a substrate for the preparation of cytidine-5 -diphosphate choline (CDP-choline), cytidine triphosphate (CTP) and other medicinal derivatives. Its disodium salt is available called disodium cytidine 5 -monophosphate (5 -CMPNa2 ) (C9 H12 N3 Na2 O8 P, CAS registry no. 6757-06-8, molar mass: 367.16 g/mol). It is a high value-added product used as the milk additive. The molecular structure of 5 CMPNa2 is shown in Fig. 1. The preparation of 5 -CMPNa2 is widely investigated in the literatures [2,3]. However, there are few articles focus on the separation and crystallization of 5 -CMPNa2 . Mass crystallization from solution is a traditional technique and widely used in various areas such as the pharmaceutical, chemical and food industry for the production of particulates [4]. It plays an essential role in the achievement of highly pure products since crystallization is a solid–liquid separation process [5], in which a solute is transferred from the liquid solution to a pure solid crystalline phase [6]. Since 5 -CMPNa2 can be dissolved in water
∗ Corresponding author at: College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Xin mofan Road 5, Nanjing 210009, China. Tel.: +86 25 86990001; fax: +86 25 58139389. E-mail addresses: [email protected], [email protected] (J. Wu). 0040-6031/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.tca.2013.04.018
and is insoluble in organic solvents, the dilution crystallization [7] would be a best choice to gain the 5 -CMPNa2 crystal. This methodology has been successfully applied for the purification of other phosphoryl compounds [8,9] in our laboratory as well, i.e., cytidine5 -diphosphate choline (CDP-choline) and cytidine triphosphate (CTP). Good crystal morphology has been obtained. In this work, methanol and ethanol are selected as anti-solvent since they are inexpensive, easily removed from the solvents and can be dissolved in water in any proportion [8,10]. The thermodynamic equilibrium of 5 -CMPNa2 in the binary mixtures is therefore essential for the efficient design of the crystallization process. So far, in the literature, it has been found no detailed analysis concerning the influence of different binary solvent mixtures and temperature on the 5 -CMPNa2 solubility data. Consequently, as a preliminary experiment, the solubility of 5 CMPNa2 in methanol + water and ethanol + water binary mixtures was determined by an isothermal method [11] from the temperature of 288.15–313.15 K under atmospheric pressure (101.3 kPa). The effects of the different binary mixtures as well as temperatures on 5 -CMPNa2 solubility were investigated. Two models in terms of the (CNIBS)/Redlich–Kister model and the semi-empirical Apelblat model were used to simulate the solubility data and the model parameters. The thermodynamic properties of the dissolution process were discussed as well. The aim of this work is to provide the theoretical solubility data which could be later used in the 5 -CMPNa2 crystallization process.
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The following Eq. (2) is used to define the initial mole fraction composition of the solvent mixture (x20 ) and the results are listed in Table 1. x20 =
The CNIBS/Redlich–Kister model [13,14] was used to predict the experimental solubility data. The model equation is represented by Eq. (3) which describes the solubility data as a function of the mole fraction of water.
2. Experimental 2.1. Materials 5 -CMPNa2 with a mass fraction purity of greater than 0.99 was prepared by recrystallization. Methanol and ethanol used in the experiments were of analytical reagent grade. The mass fractions were 0.995 and 0.997 purchased from Shanghai Chemistry Reagent Co., China. 2.2. Apparatus and procedures The isothermal method was applied to measure the solubility of 5 -CMPNa2 in methanol + water and ethanol + water binary systems. An excess mass of 5 -CMPNa2 was added to a known mass of solvent with uncertainty of ±0.1 mg measured by an electronic balance (BS-124S, Sartorius, Germany). The experiments were carried out in a constant temperature water bath (type DC-2030, Shanghai Sunny Hengping Scientific Instrument Co. Ltd., China) with the desired temperature kept within ±0.05 K. A continuous stirring rate of 80 rpm was taken at least for 5 h to reach the solid–liquid equilibrium. This equilibrium time was established by measuring the concentration of 5 -CMPNa2 every 30 min until a constant value was achieved. The stirring was stopped after 5 h and the suspended solution was kept still for 1 h. After that, the supernatant solution was poured into the filter funnel to obtain the supernatant and remove the excess of solid. During the filtration process, the filter funnel and the filter tanks were kept at the experimental temperature. The solubility measurements were carried out at the temperatures of 288.15, 293.15, 298.15, 303.15, 308.15 and 313.15 K in order to obtain sufficient data used in the following model calculations. The concentrations of 5 -CMPNa2 were determined roughly by UV spectra at 280 nm (UV-2000, UNICO, USA) in the preliminary equilibrium-time experiments for the sake of convenience and quickness. The precise concentrations of 5 -CMPNa2 in the filtrate were analyzed at 280 nm by high performance liquid chromatography (Agilent 1100, USA), using a SepaxHP-C18 column (4.6 mm × 250 mm, 5 m, Sepax (Jiangsu) Technologies Inc., Changzhou, China). The mobile phase was 0.6% (V/V) phosphoric acid. The column temperature was 300.15 K and the flow rate was 1.0 ml/min. All the solubility experiments were performed in triplicates. The mean values were presented and used in the calculations. 3. Results and discussion 3.1. Solubility data The mole fraction solubility of 5 -CMPNa2 (x1 ) in different binary solvent mixtures could be obtained from Eq. (1) [12]. m1 /M1 m1 /M1 + m2 /M2 + m3 /M3
(2)
3.2. Mole fraction of solvent-dependent equilibrium
Fig. 1. Molecular structure of 5 -CMPNa2 .
x1 =
m2 /M2 m2 /M2 + m3 /M3
(1)
where M is the molar weight and m is the mass. The subscripts 1, 2 and 3 refer to 5 - CMPNa2 , water and organic solvents.
ln x1 = x20 ln (x1 )2 + x30 ln (x1 )3 + x20 x30
n
sj (x20 − x30 )
j
(3)
j=0
where x20 and x30 are the initial mole fraction composition of the binary solvents without the solute existing in the solution. Sj is the model constant. j is a running exponent index. In pure solvent i, (x1 )i represents the mole fraction solubility of the solute, that is 5 CMPNa2 in this work. n could be equal to 0, 1, 2 or 3. The following Eq. (4) is obtained by selecting n = 2 and x30 = 1 − x20 . 2
3
ln x1 = B0 + B1 x20 + B2 (x20 ) + B3 (x20 ) + B4 (x20 )
4
(4)
where the constants B0 = ln (x1 )3 , B1 = ln (x1 )2 − ln (x1 )3 + S0 − S1 + S2 , B2 = − S0 + 3S1 − 3S2 , B3 = −2S1 + 6S2 and B4 = −4S2 . They are listed in Table 2. The percentage deviation ( (%D)) defined in Eq. (5) [15] was used to evaluate the agreement between the experimental data and the model predictions.
n exp (x1 − x1cal )/n exp x
(%D) = 100
i=1
exp
(5)
1
where x1 is the experimental data, x1cal is the calculated value from the model, and n is the number of the experimental data. The small discrepancy (see the percentage deviation ( (%D)) presented in Tables 1 and 2) indicates that the simulation curves calculated by the CNIBS/Redlich–Kister model fits the experimental data fairly well at different temperatures and mole fraction compositions of the binary solvents. It can be observed in Figs. 2 and 3 that the solubility value of 5 -CMPNa2 increased with the increasing mole fraction of water at any given temperature. This is due to the physical properties of 5 -CMPNa2 and water. It is well known that water is a polar solvent which has a high dielectric constant (78.5). The solute, 5 CMPNa2 belongs to a basic salt. The polar molecules of water can then solvate the Na+ and CMP2− ions because they can orient the appropriate partially charged portion of the molecule towards the ions in response to electrostatic attraction. This stabilizes the system and creates a hydration shell [16,17]. In addition, the amino group and hydroxyl groups existing in the CMP2− ions could be associated with water via hydrogen bonds, producing solvated ions as well. Hence, 5 -CMPNa2 possesses high solubility in water. The alcohols methanol and ethanol are polar protic solvents. According to Mullin [18], in polar protic solvents the solvent molecules interact by forming strong hydrogen bonds. In order to dissolve, the solute must break these bonds and replace them with bonds of similar strength. Theoretically, the amino group and hydroxyl groups could also be associated with alcohols to form hydrogen bonds. However, the strength was significantly weakened by the stereo-specific blockade by the large molecular configuration of 5 -CMPNa2 . Moreover, the alcohols (methanol and ethanol) have weak polarity (dielectric constants are 31.2 and 24.5,
J. Yu et al. / Thermochimica Acta 565 (2013) 1–7
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Table 1 The mole fraction solubility of 5 -CMPNa2 (x1 ) in water (2) + methanol (3) and water (2) + ethanol (3), at various initial mole fraction composition of binary solvent (x20 ) from 288.15 K to 313.15 K. x20 (mole fraction) Water(2) + methanol(3) T = 288.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 T = 293.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 T = 298.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 T = 303.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 T = 308.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 T = 313.15 ± 0.05 K 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 Water(2) + ethanol(3) T = 288.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661 T = 293.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661 T = 298.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661
exp
104 x1
exp
exp
− x1cal )/x1
exp
(mole fraction)
102 (x1
0.87 1.59 3.60 5.92 9.19 11.67 29.69
± ± ± ± ± ± ±
0.03 0.02 0.01 0.05 0.04 0.07 0.02
−0.55 1.78 −3.22 2.02 1.47 −2.04 0.43
0.38 −2.09 1.05 0.41 −0.87 6.23 1.21
1.02 1.97 4.52 7.82 13.88 18.48 44.75
± ± ± ± ± ± ±
0.04 0.09 0.03 0.06 0.02 0.07 0.05
−0.55 1.76 −3.12 1.83 1.72 −2.21 0.45
−2.60 −0.61 0.88 2.26 3.09 5.81 2.76
1.28 2.50 5.64 9.90 19.26 27.42 62.44
± ± ± ± ± ± ±
0.02 0.04 0.03 0.03 0.07 0.04 0.09
−0.36 1.18 −2.24 1.60 0.55 −1.03 0.24
1.45 2.35 0.33 0.32 −0.77 −0.24 −2.73
1.56 3.12 6.90 12.37 27.82 42.79 94.82
± ± ± ± ± ± ±
0.02 0.03 0.05 0.03 0.06 0.04 0.07
−0.19 0.63 −1.20 0.91 0.20 −0.48 0.12
3.08 3.02 −1.64 −2.51 0.02 −0.63 0.92
1.73 3.60 8.71 16.27 39.35 65.65 135.94
± ± ± ± ± ± ±
0.05 0.02 0.02 0.07 0.06 0.01 0.08
0.20 −0.57 0.53 0.52 −2.42 2.01 −0.32
−3.78 −4.68 −0.19 0.26 −0.73 −2.02 −0.58
2.16 4.79 10.87 20.75 56.31 104.17 198.13
± ± ± ± ± ± ±
0.01 0.04 0.02 0.07 0.03 0.09 0.02
0.31 −0.86 0.64 1.20 −4.40 3.50 −0.56
1.02 1.26 0.44 0.34 0.29 0.70 0.18
0.12 0.34 1.20 2.79 7.83 12.45 22.01
± ± ± ± ± ± ±
0.02 0.04 0.03 0.05 0.07 0.02 0.03
0.03 −0.08 0.02 0.28 −0.84 0.71 −0.12
−0.69 −0.11 1.42 −1.47 −0.93 −3.55 −0.09
0.15 0.41 1.39 3.41 9.79 17.11 35.37
± ± ± ± ± ± ±
0.03 0.05 0.06 0.02 0.03 0.07 0.01
−0.13 0.58 −1.93 2.79 −3.05 1.81 −0.19
2.65 0.88 −0.44 0.52 −0.30 2.07 2.56
0.17 0.50 1.62 4.16 12.62 22.55 52.93
± ± ± ± ± ± ±
0.02 0.04 0.03 0.08 0.05 0.04 0.07
−0.35 1.34 −3.53 3.84 −2.07 0.47 0.13
−1.91 −1.67 −3.42 0.70 1.03 1.82 −1.08
(CNIBS)
102 (x1
exp
− x1cal )/x1
(Apelblat)
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Table 1 (Continued) exp
x20 (mole fraction)
104 x1
T = 303.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661 T = 308.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661 T = 313.15 ± 0.05 K 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661
exp
exp
− x1cal )/x1
exp
(mole fraction)
102 (x1
102 (x1
0.22 0.63 2.13 5.22 16.45 29.56 81.69
± ± ± ± ± ± ±
0.05 0.02 0.04 0.01 0.03 0.07 0.02
−0.25 0.95 −2.26 2.13 −0.29 −0.56 0.22
−1.57 1.19 2.81 1.86 1.10 −0.47 −0.92
0.28 0.78 2.59 6.29 21.35 40.04 126.88
± ± ± ± ± ± ±
0.07 0.05 0.02 0.04 0.07 0.03 0.08
−0.18 0.65 −1.44 1.19 0.32 −0.78 0.21
1.92 −0.37 −0.52 −2.50 −1.46 −0.88 0.58
0.34 0.99 3.32 8.29 29.52 55.81 191.56
± ± ± ± ± ± ±
0.03 0.05 0.11 0.07 0.04 0.03 0.05
−0.28 1.00 −2.04 1.36 1.35 −1.87 0.43
−0.51 0.04 −0.07 0.66 0.35 0.29 −0.08
(CNIBS)
Table 2 Fitted parameters of CNIBS/Redlich–Kister model for 5 -CMPNa2 in binary solution at different temperatures.
exp
− x1cal )/x1
(Apelblat)
T/K
B0
Water(2) + methanol(3) 288.15 293.15 298.15 303.15 308.15 313.15
4.0 −4.2 −11.8 −21.4 −24.9 −39.6
−125 −61 −0.4 76 103 216
393 214 44 −169 −246 −557
−500 −283 −76 181 279 648
229 133 42 −71 −115 −274
1.64 1.66 1.03 0.53 0.94 1.64 (%D)/n = 1.24
Water(2) + ethanol(3) 288.15 293.15 298.15 303.15 308.15 313.15
−46.3 −45.7 −47.2 −43.1 −41.8 −43.9
200 198 208 177 172 184
−446 −439 −459 −370 −358 −383
467 455 470 362 347 368
−182 −174 −177 −129 −121 −127
0.30 1.50 1.67 0.95 0.68 1.19 (%D)/n = 1.05
B1
B2
Fig. 2. Mole fraction solubility of 5 -CMPNa2 (1) (x1 ) in methanol (3) + water (2) solvent mixture at various temperatures: () T = 288.15 K; () T = 293.15 K; () T = 298.15 K; (䊉) T = 303.15 K; () T = 308.15 K; () T = 313.15 K. The points represent the experimental data. Curves are calculated according with Eq. (4) using the Redlich–Kister model.
B3
B4
(%D)
Fig. 3. Mole fraction solubility of 5 -CMPNa2 (1) (x1 ) in ethanol (3) + water (2) solvent mixture at various temperatures: () T = 288.15 K; () T = 293.15 K; () T = 298.15 K; (䊉) T = 303.15 K; () T = 308.15 K; () T = 313.15 K. The points represent the experimental data. Curves are calculated according with Eq. (4) using the Redlich–Kister model.
J. Yu et al. / Thermochimica Acta 565 (2013) 1–7
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Table 3 Fitted parameters of Apelblat model for 5 -CMPNa2 for different temperature at various contents of organic solvent (x20 ).
x20 (mole fraction)
a
b
Water(2) + methanol(3) 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182
−37.4 −319.5 −83.6 −92.8 −129.5 −159.7 −135.7
−1485.9 10651.7 −1.8 −2.0 −2.9 −3.6 −3.1
5.9 48.3 13.4 15.1 21.6 27.0 22.9
2.05 2.33 0.75 1.02 0.96 2.61 1.39 (%D)/n = 1.59
Water(2) + ethanol(3) 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661
−343.9 −425.9 −652.5 −547.7 −746.8 −575.3 −153.3
11702.5 15362.1 25659.5 20901.9 29116.5 21008.2 −3.5
51.6 64.0 97.9 82.5 112.8 87.5 26.0
1.54 0.71 1.45 1.28 0.86 1.51 0.88 (%D)/n = 1.18
under 298.15 K, respectively), which makes it difficult for them to overcome electrostatic interaction between Na+ and CMP2− . As a result, 5 -CMPNa2 was insoluble in methanol and ethanol. Due to the weaker polarity of ethanol, the solubility of 5 -CMPNa2 was lower in ethanol + water than in methanol + water systems (comparison of Figs. 2 and 3). However, in the mixtures of water and alcohols, the hydroxyl group from water would associate with the alcohols via hydrogen bonds, more easily than that with 5 -CMPNa2 . Hence, the addition of alcohols in mixture solvents decreases the water molecules available for 5 -CMPNa2 , leading to the lower solubility of 5 -CMPNa2 . Consequently, methanol and ethanol demonstrated an anti-solvent effect for 5 -CMPNa2 , in which the solubility of 5 -CMPNa2 had the larger change in the ethanol + water system (Fig. 3), indicating that ethanol was an effective anti-solvent for 5 -CMPNa2 . 3.3. Temperature dependence of the mole fraction solubility of 5 -CMPNa2 The influence of temperatures on the solubility of 5 -CMPNa2 has been represented by the following semiempirical Apelblat model [19,20]. b ln x1 = a + + c ln T (6) T
c
(%D)
where a, b and c are the empirical constants of Apelblat model and listed in Table 3, together with the percentage deviations ( (%D)). The ratio of the calculated value (x1cal ) from the Apelblat model and exp the difference between the experimental solubility value (x1 ) and cal the calculated value (x1 ) are given in Table 1. 3.4. Thermodynamic properties of solutions According to van’t Hoff analysis [21], the apparent enthalpy change of solution could be related to the temperature and the solubility as following equation:
Hs =− R
∂ ln x1 ∂(1/T )
(7) p
Over a limited temperature interval (288.15–313.15 K) the heat capacity change of solution may be assumed to be constant. Hence, the values of Hs would be valid for the mean temperature (300.65 K) [22]. Thus, combined with the Apelblat model Eq. (6) the Hs can be calculated by Eq. (8). Hs = −R(b − cTmean )
(8)
According to Krug et al. [23], the Gibbs energy change for the dissolution process can be calculated as:
Fig. 4. Temperature dependence of solubility of 5 -CMPNa2 in methanol + water (a) and ethanol + water (b). (a) () x20 = 0.8182; (䊉) x20 = 0.7377; () x20 = 0.6923; () x20 = 0.6000; () x20 = 0.5295; () x20 = 0.4286; () x20 = 0.3600; (b) () x20 = 0.8661; (䊉) x20 = 0.8017; () x20 = 0.7639; () x20 = 0.6832; () x20 = 0.6179; () x20 = 0.5188; () x20 = 0.4471. The points represent the experimental data, and curves represent the results based on linear fitting.
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Table 4 Thermodynamic functions relative to solution process of 5 -CMPNa2 in various contents of organic solvent (x20 ) at 300.65 K. x20 (mole fraction) Water(2) + methanol(3) 0.3600 0.4286 0.5295 0.6000 0.6923 0.7377 0.8182 Water(2) + ethanol(3) 0.4471 0.5188 0.6179 0.6832 0.7639 0.8017 0.8661
Hs (kJ/mol)
Gs (kJ/mol)
0.25 0.17 0.42 0.33 0.42 0.50 0.58
22.21 20.48 18.41 16.97 15.13 14.11 12.11
± ± ± ± ± ± ±
0.17 0.58 0.42 0.08 0.25 0.25 0.42
15.93 39.29 49.84 68.89 129.66 177.59 150.44
± ± ± ± ± ± ±
0.33 0.33 0.17 0.25 0.42 0.91 0.17
84.93 73.22 69.03 64.53 58.13 55.83 55.90
15.07 26.78 30.97 35.47 41.87 44.17 44.10
31.58 32.20 31.37 32.34 39.76 44.14 65.00
± ± ± ± ± ± ±
0.42 0.17 0.33 0.33 0.25 0.58 0.17
27.02 24.40 21.37 19.13 16.28 14.83 12.50
± ± ± ± ± ± ±
0.17 0.50 0.25 0.58 042 0.67 0.25
15.16 25.94 33.25 43.94 78.11 97.49 174.62
± ± ± ± ± ± ±
0.58 0.25 0.25 0.42 1.00 0.67 0.33
87.39 80.50 75.83 71.00 62.87 60.10 55.32
12.61 19.50 24.17 29.00 37.13 39.90 44.68
(9)
|Hs | |Hs | + |Tmean Ss |
(10)
|Tmean Ss | |Hs | + |Tmean Ss |
(11)
The calculated values of % H and % TS were listed in Table 4, which indicated that the enthalpy was the main contributing force to the Gibbs energy of the 5 -CMPNa2 dissolution process. 4. Conclusions The solubility of 5 -CMPNa2 in mixed systems was investigated from 288.15 to 313.15 K. The solubility values of 5 -CMPNa2 increased with the increasing of temperature and the mole fraction of water both in the water + methanol and the water + ethanol binary-solvent systems. The experimental solubility data were correlated by the CNIBS/Redlich–Kister model and the semi-empirical Apelblat model. The fitted parameters B0 , B1 , B2 , B3 , B4 of CNIBS model and a, b, c of Apelblat model at different temperatures According have been estimated and presented in the paper. to Table 2, the values of the sum of deviation ( (%D)/n) are 1.24 (water + methanol) and 1.05 (water + ethanol) for the CNIBS/Redlich–Kister model, whereas in Table 3, the values of the (%D)/n) are 1.59 (water + methanol) and sum of deviation ( 1.18 (water + ethanol) for Apelblat model. The results indicated that the experimental data were in good agreement with the prediction results with the two models. In addition, the discussion of Gibbs energy, enthalpy, and entropy for 5 -CMPNa2 in different binary mixtures indicated that the dissolution process was endothermic. Nomenclature
List of symbols A, a parameter parameter B, a
%TS
± ± ± ± ± ± ±
in which, the intercept can be obtained by plotting ln x1 versus (1/T − 1/Tmean ) [14] (shown in Fig. 4). The results of the calculated Gibbs energy, entropy and enthalpy of 5 -CMPNa2 are listed in Table 4. The positive values of Hs and Ss revealed that the dissolution of 5 -CMPNa2 in the mixtures was an entropy driven process. In order to quantitatively estimate the relative contribution to the Gibbs energy, enthalpy (% H ) and entropy (% TS ) calculated by Eqs. (10) and (11) are introduced [24].
%ςTS = 100
%H
27.00 32.29 33.40 37.68 54.11 67.50 57.34
Gs = −RTmean × intercept = Hs − Tmean Ss
%ςH = 100
Ss (J/mol/K)
C, c (%D) G H j m M n R S T x
parameter percentage deviation molar Gibbs free energy molar enthalpy running exponent index mass molar weight number of the experimental data gas constant entropy temperature mole fraction
Greek letter change Superscripts initial 0 ◦ standard molar calculated cal exp experimental Subscripts solute; parameter 1 2 water; parameter 3 organic solvent; parameter parameter 4 s solution Acknowledgements The work was supported in part by the Grant from the National Outstanding Youth Foundation of China (Grant No. 21025625), the PCSIRT, 12KJB530003, and the PAPD. We would like to acknowledge the financial support provided by the National High-Tech Research and Development Plan of China (863 Program, 2012AA021202) as well. References [1] G. Borodi, A. Hernanz, I. Bratu, M. Pop, R. Navarro, Hydrated sodium cytidine5 -monophosphate, Acta Crystallogr. 57 (2001) 514–516. [2] B. Noordam, J.G. Kortest, Production of 5 -ribonucleotides, WO2004067758 (2011). [3] T. Tanekawa, H., Takashima, T. Hachiya, Production of yeast extract containing flavoring, US4303680 (1981). [4] M. Kind, A. Mersmann, On supersaturation during mass crystallization from solution, Chem. Eng. Technol. 13 (1990) 50–62.
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