Solubility of Trimethoprim in Selected Pure Solvents and (Water+

Dec 22, 2015 - ABSTRACT: Trimethoprim (TMP) is an important anti- bacterial synergist in human and veterinary medicine. In this work, the solubilities...
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Solubility of Trimethoprim in Selected Pure Solvents and (Water + Ethanol/2-Propanol) Mixed-Solvent Systems Dai-ping Yin, Meng-xi Liu, Hua-lin Fu,* Gang Shu, Jian-yu Zhou, Xue-yan Qing, and Wen-bin Wu Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of China ABSTRACT: Trimethoprim (TMP) is an important antibacterial synergist in human and veterinary medicine. In this work, the solubilities of TMP in five pure solvents (ethanol, water, ethyl acetate, acetonitrile, and 2-propanol) and two binary mixtures (ethanol + water and 2-propanol + water) were measured by an equilibrium method over the temperature range from (293.15 to 322.65) K under atmospheric pressure. The experimental results show that in the pure solvents the solubility of TMP increases with increasing temperature, and the solubility decreases in the following order: ethanol > acetonitrile > 2-propanol > ethyl acetate > water. In the mixed solvents, the solubility of TMP increases with increasing temperature and mass fraction of the organic solvent. The mole-fraction solubility of TMP was observed to be the highest in the mixed solvent 50% ethanol/2-propanol, and the lowest mole-fraction solubility of TMP was found in water. Three correlating models (the modified Apelblat equation, the λh equation, and the ideal model) were used to correlate the experimental solubility values in the pure solvents, and four models (the modified Apelblat equation, the λh equation, the ideal model, and the CNIBS/R-K model) were applied to correlate the experimental solubilities in the mixed solvents. All of these thermodynamic models gave satisfactory correlation results, with the modified Apelblat equation showing better fitting degree than the other three equations. Furthermore, the standard molar enthalpy of the TMP during the dissolving process (ΔH°sol) was also determined in this work, and the results show that the dissolution process is endothermic.

1. INTRODUCTION Trimethoprim (TMP, C14H18N4O3, CAS no. 738-70-5) is a white or off-white crystalline powder that is known to be a dihydropteroate synthase inhibitor.1 The chemical structure of TMP is given in Figure 1. According to previous biological

combination with sulfa drugs for the treatment of pulmonary infection and urinary tract infection.4,5 The solubility of drugs plays an important role in pharmaceutical and industrial processes, such as crystallization, isolation, and purification. In industrial manufacturing, the synthesis of TMP is a complex process, and potential impurities probably still remain in TMP.6,7 The purity of TMP is critical for its further application. In order to obtain high-purity products, it is necessary to apply solubility data to the industrial process. Meanwhile, the solubility property could guide the production of the pharmaceutical formulation. Previous studies have found that the aqueous solubility of TMP is poor. To solve this problem, some drug delivery approaches have been studied, such as the use of β-cyclodextrin8 or hydroxypropyl-βcyclodextrin.9 Compared with the development of formulations, the use of an organic solvent or cosolvent mixture is a simple way to increase the solubility of a drug. However, very few studies of the solubility of TMP in pure solvents or cosolvent mixtures have been reported. From a practical perspective, investigation of this question is highly expected because it could guarantee the process of isolation purification

Figure 1. Chemical structure of TMP.

studies,2,3 TMP can effectively inhibit the formation of the dihydrofolate reductase enzyme of bacteria but does not interfere with human dihydrofolate reductase. TMP is a synthetic broad-spectrum antimicrobial agent that is not only widely used in veterinary medicine for the treatment of disease caused by Gram-negative and Gram-positive microorganisms and coccidium but also used in human medicine in © XXXX American Chemical Society

Received: July 19, 2015 Accepted: December 10, 2015

A

DOI: 10.1021/acs.jced.5b00616 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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standard curve (Figure 2), and m represents the total mass of 1 mL of saturated solution. All of the experiments were repeated three times at each temperature in order to obtain a required mean value.

and formulation development more effectively. Accordingly, in this study an equilibrium method was employed to measure the solubilities of TMP in five pure solvents (ethanol, water, ethyl acetate, acetonitrile, and 2-propanol) and binary water + ethanol/2-propanol mixtures with different proportions over the temperature range from (293.15 to 322.65) K under atmospheric pressure (p = 0.1 MPa). The modified Apelblat equation, λh model, ideal model, and CNIBS/R-K model were used to correlate the experimental data, and the thermodynamic property ΔHsol ° was evaluated on the basis of the measured solubility data.

2. EXPERIMENTAL SECTION 2.1. Materials. TMP with a mass-fraction purity of ≥0.999 was purchased from Wuhan Nuohui Pharmaceutical and Chemical Co., Ltd. All of the organic solvents were AR grade and used without further purification. More details about the reagents along with their CAS registry numbers are displayed in Table 1.

Figure 2. Standard curve for the dependence of the UV absorbance on the trimethoprim concentration.

Table 1. Provenance and Mass-Fraction Purities of the Materials Used material

source

trimethoprim

Wuhan Nuohui Pharmaceutical and Chemical Co., Ltd. Chengdu Kelong Chemical Reagent Co., Ltd. Tianjin Kermel Chemical Reagent Co., Ltd. Tianjin Kermel Chemical Reagent Co., Ltd. Tianjin Shentai Chemical Reagent Co., Ltd. double-distilled water prepared by our laboratory

ethanol

ethyl acetate acetonitrile 2-propanol water

purity/in mass fraction

CAS no.

purification method

99.9%

738-70-5

none

99.7%

64-17-5

none

99.5%

141-78-6

none

99.9%

75-05-8

none

99.7%

67-63-0

none

3. RESULTS AND DISCUSSION 3.1. Correlation Models. In our work, four widely used solid−liquid phase equilibrium models, the modified Apelblat equation, the λh equation, the ideal model, and the CNIBS/RK model, were employed to correlate and analyze the experimental data. Since the modified Apelblat equation, λh equation, ideal model can be used to express the relationship between solubility and temperature, they were applied to correlate the solubility data for both the pure solvents and the mixed solvents. The CNIBS/R-K model is employed to express the relationship between solubility and solvent composition, so here it was used only for the mixed solvents. 3.1.1. Modified Apelblat Equation. The modified Apelblat equation12−14 is a widely used semiempirical equation that assumes that the solution enthalpy changes linearly with temperature. The Apelblat equation is defined as follows: B ln xc(Ape) =A+ + C ln(T /K ) i (2) T /K

2.2. Apparatus and Procedure. The apparatus for the solubility measurements was similar to that in our previous work, which has been described in detail in the literature.10,11 Briefly, an excess amount of TMP and a known amount of pure solvent (ethanol, water, ethyl acetate, acetonitrile, or 2propanol) or a binary mixture of ethanol + water or 2-propanol + water (the mass fraction of the organic solvent in the mixed solvent was varied by 0.1 from 0 to 0.5) were added into an Erlenmeyer flask with a stopper for each measurement. Then the Erlenmeyer flasks were placed into a constant-temperature shaker for 24 h to allow the contents reach solid−liquid equilibrium. After the solutions reached solid−liquid equilibrium, 5 mL mixtures were picked and filtered using a microfiltration membrane (0.22 μm). Also, 2 mL of the filtrates were weighed, and their absorbance was measured using an ultraviolet spectrophotometer (WFZ UV-2000, Unico, China) at a wavelength of 271 nm. The saturated mole fraction of TMP in each solvent could be obtained from the following equation: x1 =

m1/M1 m1/M1 + (m − m1)/M 2

Where x(Ape) represents the calculated saturated mole fraction ci of TMP in each solvent, T is the absolute temperature, and A, B, and C are equation parameters. 3.1.2. λh Equation. The λh equation15,16 also can be used to explain the dissolution behavior of solid−liquid systems. The λh equation is shown as follows: ⎡ ⎞ ⎛ λ(1 − xc(iλh)) ⎤ ⎥ = λh⎜ 1 − 1 ⎟ ln⎢1 + ( h ) λ ⎢⎣ ⎥⎦ Tmi ⎠ ⎝T xci

(3)

x(λh) ci

where represents the calculated saturated mole fraction of TMP in each solvent, T is the absolute temperature, Tmi represents the melting point of the solute (Tmi = 474.15 K), and λ and h are the model adjustable parameters. 3.1.3. Ideal Model. The temperature dependence of the solubility of TMP in the selected solvents can be correlated using the following ideal solution equation:17

(1)

in which M1 and M2 represent the molecular weights of solute and solvent, respectively, m1 is the mass of the solute in 1 mL of saturated solution, which could be calculated according to the

ln xc(id) i = a + B

b T /K

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Table 2. Parameters of the Modified Apelblat Equation for TMP in the Selected Solvents parameters A

solvent ethanol water ethyl acetate acetonitrile 2-propanol

−668.032 −346.622 −603.658 −293.761 −383.560

W W W W W

= = = = =

10% 20% 30% 40% 50%

−652.353 −496.966 −532.714 −390.984 448.554

W W W W W

= = = = =

10% 20% 30% 40% 50%

20.009 3.841 845.815 885.083 601.153

B

C

Pure Solvents 26399.219 11860.258 23837.585 9615.605 12169.281 Ethanol + Water Mixtures 25704.117 19280.911 20715.272 14493.871 −24781.134 2-Propanol + Water Mixtures −5192.695 −3963.339 −44210.049 −45842.628 −31854.098

Table 3. Parameters of the λh Equation for TMP in the Selected Solvents

100.472 51.991 90.508 44.538 58.733

0.0235 0.0093 0.0065 0.0073 0.0229

97.669 74.383 79.990 58.906 −65.292

0.0272 0.0166 0.0174 0.0101 0.0166

−2.093 0.255 −123.763 −129.598 −87.911

λ

W W W W W

= = = = =

10% 20% 30% 40% 50%

W W W W W

= = = = =

10% 20% 30% 40% 50%

parameters

h

ARD

Pure Solvents 0.386 12803.132 0.005 907037.974 0.063 67732.622 0.078 53620.769 0.625 9869.941 Ethanol + Water Mixtures 0.021 226182.871 0.021 176120.683 0.087 46773.635 0.122 30803.046 0.383 11711.615 2-Propanol + Water Mixtures 0.028 165275.471 0.048 82798.607 0.519 10629.838 0.813 6701.377 0.411 11035.764

ethanol water ethyl acetate acetonitrile 2-propanol

solvent

0.0615 0.0222 0.0404 0.0222 0.0341

ethanol water ethyl acetate acetonitrile 2-propanol

0.0464 0.0374 0.0396 0.0293 0.0350

W W W W W

= = = = =

10% 20% 30% 40% 50%

0.0422 0.0203 0.0803 0.0636 0.0405 OARD = 0.0410

W W W W W

= = = = =

10% 20% 30% 40% 50%

where x(id) ci refers to the calculated saturated mole fraction of TMP in each solvent, T is the absolute temperature, and a and b are equation parameters. 3.1.4. CNIBS/R-K Model. The CNIBS/R−K model is suggested to describe solubility data in binary solvent systems and is defined as follows:18

a

b

Pure Solvents 8.071 −4503.857 3.235 −4130.881 5.396 −4000.826 5.945 −4083.263 11.667 −5895.623 Ethanol + Water Mixtures 4.888 −4336.853 3.578 −3597.781 5.559 −3887.910 5.406 −3624.197 9.191 −4698.896 2-Propanol + Water Mixtures 5.924 −4548.886 5.554 −4041.652 12.981 −6143.162 12.986 −5981.113 9.580 −4814.674

ARD 0.0462 0.0216 0.0339 0.0187 0.0323 0.0464 0.0324 0.0352 0.0243 0.0317 0.0414 0.0204 0.0560 0.0562 0.0371 OARD = 0.0356

saturated mole-fraction solubility of the solute in pure solvent i, the Si are the model constants, and N represents the number of curve-fitting parameters. For binary solvents with N = 2, replacing x03 with x03 = 1 − x02 allows eq 5 to be simplified to obtain eq 6: ln x1 = B0 + B1x 20 + B2 (x 20)2 + B3(x 20)3 + B4 (x 20)4

N

ln x1 = x 20 ln(x1)2 + x30 ln(x1)3 + x 20x30 ∑ Si(x 20 − x30)i

(6)

where B0, B1, B2, B3, and B4 are model constants that can be obtained by least-squares regression. In order to evaluate the accuracy and prediction ability of the correlation models, the average relative deviation (ARD) and overall average relative deviation (OARD) are employed. These are defined as follows:

i=0

(5)

x02

0.0412 0.0204 0.0272 0.0153 0.0179 OARD = 0.0186

Table 4. Parameters of the Ideal Model for TMP in the Selected Solvents

parameters solvent

ARD

x03

where and represent the initial mole fractions of the binary solvent calculated assuming that the solute was not present, x1 is the mole-fraction solubility of the solute, (x1)i represents the C

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Table 5. Parameters of the CNIBS/R-K Model for TMP in the Mixed Solvents parameters T/Ka

a

B0

B1

B2

293.15 298.45 303.45 308.15 312.95 318.65 322.65

−10.826 −10.826 −10.818 −10.811 −10.807 −10.801 −10.794

23.508 27.777 38.990 46.288 52.172 61.800 73.365

293.15 298.45 303.45 308.15 312.95 318.65 322.65

−10.861 −10.842 −10.836 −10.825 −10.820 −10.812 −10.806

38.519 51.459 57.217 62.150 66.915 76.036 87.815

B3

B4

Ethanol + Water Mixtures 37.625 −395.942 11.481 −362.056 −159.340 523.674 −244.202 884.620 −288.943 1008.277 −414.653 1613.247 −574.413 2405.258 2-Propanol + Water Mixtures −135.944 −4.654 −324.252 1043.697 −353.782 1097.509 −387.945 1244.870 −426.540 1409.261 −541.055 1960.876 −710.690 2829.980

ARD

506.052 574.890 −878.133 −1374.839 −1482.199 −2439.642 −3724.998

0.0134 0.0123 0.0113 0.0313 0.0416 0.0601 0.0798

626.854 −1248.847 −1273.890 −1553.458 −1834.068 −2722.939 −4167.939

0.1132 0.0568 0.0403 0.0074 0.0079 0.0320 0.0494 OARD = 0.0398

The standard uncertainty in the temperature is u(T) = 0.05 K.

Table 6. Mole-Fraction Solubilities of TMP (xi) in the Pure Solvents over the Temperature Range from (293.15 to 322.65) K at p = 0.1 MPaa 104·xci 104·xi

T/K 293.15 298.45 303.45 308.15 312.95 318.65 322.65

7.0974 9.1973 11.1738 13.4110 17.3243 22.6190 30.4341

293.15 298.45 303.45 308.15 312.95 318.65 322.65

2.7627 3.3184 3.9780 4.8134 6.0567 7.7341 9.6573

293.15 298.45 303.45 308.15 312.95 318.65 322.65

2.2656 2.9368 4.3376 5.4346 7.6374 10.6434 14.1064

eq 2 Ethanol 7.2714 8.8907 10.9882 13.6557 17.3421 23.5162 29.4880 Ethyl Acetate 2.7671 3.3052 3.9876 4.8363 5.9812 7.8440 9.5966 2-Propanol 2.2352 3.0633 4.1514 5.5539 7.5128 10.8172 14.0183

eq 3

104·xci T/K

eq 4

104·xi

6.1983 8.3644 10.9927 14.0991 18.0421 23.9534 29.0547

6.8077 8.9431 11.4678 14.3811 17.9950 23.2785 27.7367

293.15 298.45 303.45 308.15 312.95 318.65 322.65

0.1996 0.2485 0.3018 0.3676 0.4682 0.6053 0.7143

2.4596 3.1872 4.0375 5.0088 6.2029 7.9334 9.3837

2.6076 3.3228 4.1441 5.0671 6.1836 7.7725 9.0816

293.15 298.45 303.45 308.15 312.95 318.65 322.65

3.5038 4.3660 5.3432 6.6419 8.0883 10.2581 12.6618

2.0244 2.9422 4.1367 5.6416 7.6709 10.9172 13.8821

2.1507 3.0739 4.2564 5.7245 7.6768 10.7531 13.5254

eq 2 Water 0.1995 0.2469 0.3043 0.3728 0.4614 0.5987 0.7219 Acetonitrile 3.5108 4.3552 5.3681 6.5647 8.0971 10.4416 12.5196

eq 3

eq 4

0.1868 0.2418 0.3061 0.3795 0.4697 0.6003 0.7097

0.1928 0.2477 0.3111 0.3829 0.4703 0.5955 0.6994

3.3080 4.2717 5.3941 6.6725 8.2396 10.5040 12.3966

3.4097 4.3666 5.4708 6.7171 8.2309 10.3947 12.1844

a The standard uncertainties u are u(T) = 0.05 K and u(p) = 0.5 kPa, and the relative standard uncertainty in the measured mole-fraction solubilities is 2%.

ARD =

1 N

OARD =

N

∑ i=1

1 M

xi − xci xi

where xi is the measured value, xci represents the calculated solubility value (obtained from eq 2 , 3, 4 or 6), N is the number of experimental points, and M is the number of investigated solvents. The optimized parameters of the correlation models along with the ARDs and OARDs are listed in Tables 2−5. The calculated solubility data for TMP obtained using the modified Apelblat model, the λh equation,

(7)

M

∑ ARDi i=1

(8) D

DOI: 10.1021/acs.jced.5b00616 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Table 7. Mole-Fraction Solubilities of TMP (xi) in Ethanol + Water Mixtures over the Temperature Range from (293.15 to 322.65) K at p = 0.1 MPaa

Table 8. Mole-Fraction Solubilities of TMP (xi) in 2Propanol + Water Mixtures over the Temperature Range from (293.15 to 322.65) K at p = 0.1 MPaa

104·xci T/K

104·xi

293.15 298.45 303.45 308.15 312.95 318.65 322.65

0.5390 0.6181 0.8101 1.0049 1.2193 1.5737 2.1053

293.15 298.45 303.45 308.15 312.95 318.65 322.65

1.7409 2.1246 2.4376 2.8779 3.6295 4.4143 5.4340

293.15 298.45 303.45 308.15 312.95 318.65 322.65

4.7343 5.8145 6.6731 8.1021 10.5340 12.9933 15.9044

293.15 298.45 303.45 308.15 312.95 318.65 322.65

9.8269 11.8826 14.2804 16.7458 20.4228 25.1932 31.0276

293.15 298.45 303.45 308.15 312.95 318.65 322.65

10.2766 14.1010 18.4048 24.1201 29.4410 37.4646 45.8780

eq 2 W 0.5320 0.6452 0.7909 0.9750 1.2274 1.6464 2.0482 W 1.7586 2.0737 2.4613 2.9295 3.5426 4.5059 5.3826 W 4.7546 5.6831 6.8401 8.2567 10.1384 13.1454 15.9266 W 9.8933 11.8144 14.1231 16.8554 20.3634 25.7523 30.5530 W 10.2778 14.3147 19.0040 24.2086 30.2947 38.4338 44.6371

eq 3 = 10% 0.4622 0.6145 0.7969 1.0098 1.2770 1.6728 2.0109 = 20% 1.6073 2.0222 2.4941 3.0202 3.6522 4.5461 5.2797 = 30% 4.3130 5.5297 6.9372 8.5308 10.4732 13.2629 15.5823 = 40% 9.1862 11.5554 14.2485 17.2492 20.8522 25.9448 30.1202 = 50% 11.1821 14.6793 18.8139 23.5867 29.5111 38.1831 45.5120

104·xci eq 4

T/K

eq 6

104·xi

0.4990 0.6489 0.8245 1.0253 1.2723 1.6302 1.9299

0.5489 0.6285 0.7978 0.9631 1.1525 1.4507 1.8900

293.15 298.45 303.45 308.15 312.95 318.65 322.65

0.6522 0.9505 1.1851 1.4647 1.7330 2.2427 2.9721

1.6748 2.0827 2.5403 3.0439 3.6408 4.4721 5.1440

1.6931 2.0709 2.4953 3.0712 3.9565 4.9996 6.4086

293.15 298.45 303.45 308.15 312.95 318.65 322.65

2.7018 3.2538 4.3322 5.2812 6.3899 7.7882 9.5073

4.5117 5.7098 7.0769 8.6043 10.4414 13.0398 15.1692

4.8342 5.9274 6.5571 7.7167 9.8741 11.8348 14.0534

293.15 298.45 303.45 308.15 312.95 318.65 322.65

3.2704 4.8156 7.1709 10.5256 13.9891 17.9273 21.5176

9.5182 11.8550 14.4811 17.3745 20.8092 25.5990 29.4754

9.7520 11.7991 14.3725 17.0479 20.9130 26.0711 32.4680

293.15 298.45 303.45 308.15 312.95 318.65 322.65

5.4997 8.7677 12.4960 17.6234 23.1336 29.3049 36.5479

10.7274 14.2599 18.4834 23.4074 29.5752 38.6876 46.4481

10.2879 14.1153 18.3879 24.0586 29.3412 37.2817 45.5813

293.15 298.45 303.45 308.15 312.95 318.65 322.65

9.9836 14.2760 19.8816 25.0133 30.4277 38.2346 46.5431

eq 2 W 0.6810 0.8984 1.1557 1.4529 1.8215 2.3601 2.8141 W 2.6585 3.3954 4.2438 5.1996 6.3585 8.0119 9.3774 W 3.1733 5.0296 7.3881 10.1735 13.5627 18.1817 21.6828 W 5.5178 8.6962 12.6876 17.3382 22.9089 30.3447 35.8539 W 10.0615 14.3419 19.3218 24.8075 31.1197 39.3232 45.3519

eq 3 = 10% 0.6644 0.8811 1.1397 1.4410 1.8182 2.3758 2.8511 = 20% 2.6627 3.3971 4.2431 5.1970 6.3554 8.0126 9.3859 = 30% 3.9485 5.5155 7.4798 9.8710 12.9926 17.8150 22.0870 = 40% 6.7364 9.3718 12.6624 16.6537 21.8455 29.8344 36.8862 = 50% 11.2733 14.8408 19.0696 23.9626 30.0497 38.9809 46.5441

eq 4

eq 6

0.6819 0.8983 1.1547 1.4514 1.8202 2.3607 2.8177

0.7672 1.0314 1.2558 1.4805 1.7135 2.1423 2.7692

2.6581 3.3955 4.2443 5.2004 6.3592 8.0118 9.3761

2.1305 2.8874 3.9801 5.1995 6.4966 8.3281 10.5428

3.4417 4.9933 7.0095 9.5452 12.9592 18.4110 23.3817

3.8729 5.2431 7.6169 10.6432 13.8251 17.0921 19.9909

6.0075 8.6307 12.0076 16.2187 21.8428 30.7456 38.8010

5.1881 8.5142 12.2386 17.5561 23.2279 29.7913 37.4878

10.6585 14.2680 18.6125 23.7084 30.1287 39.6734 47.8465

10.0612 14.3317 19.9367 25.0262 30.4112 38.1513 46.3866

a The standard uncertainties u are u(T) = 0.05 K and u(p) = 0.5 kPa, and the relative standard uncertainty in the measured mole-fraction solubilities is 2%.

a The standard uncertainties u are u(T) = 0.05 K and u(p) = 0.5 kPa, and the relative standard uncertainty in the measured mole-fraction solubilities is 2%.

the ideal model, and the CNIBS/R-K model are given in Tables 6−8. From Tables 6−8, it is obvious that the correlation results with the modified Apelblat equation, λh model, ideal model, and CNIBS/R-K model almost exactly follow the experimental data. Furthermore, Tables 2−5 show that the ARDs of all four equations are very low, with none of the values exceeding 0.0615. These results indicate that eq 2, eq 3, eq 4, and eq 6 are suitable for correlating the solubilities of TMP in the selected solvents. However, the modified Apelblat equation shows more accuracy for this dissolution system, as the maximum ARD and OARD of the modified Apelblat equation are 0.0412 and

0.0186, respectively, which are smaller than those of the other three equations. 3.2. Solubilities in the Selected Solvents. The solubility data for TMP in the five pure solvents (ethanol, water, ethyl acetate, acetonitrile, and 2-propanol) from (298.15 to 333.15) K at atmospheric pressure (0.1 MPa) are displayed in Table 6, where T represents the absolute temperature and xi and xci are the experimental and calculated solubility values, respectively. More visually, the x/T curves for TMP in different pure solvents are shown in Figure 3. Besides, we compared the molefraction solubilities of TMP in this experiment with the literature values.19 The comparison results are shown in Figure 4, from which we can see that the solubilities in 2-propanol E

DOI: 10.1021/acs.jced.5b00616 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Figure 3. Mole-fraction solubilities (xi) of TMP in the selected pure solvents over the temperature range from (293.15 to 322.65) K: red ●, ethanol; green ■, acetonitrile; blue ◆, 2-propanol; purple ▲, ethyl acetate; ◇, water.

Figure 6. Mole-fraction solubilities of TMP (xi) in water + 2-propanol mixed-solvent systems over the temperature range from (293.15 to 322.65) K: red ■, 50% 2-propanol; green ▼, 40% 2-propanol; blue ▲, 30% 2-propanol; orange ●, 20% 2-propanol; pink ■, 10% 2-propanol.

Figure 4. Comparison between experimental values and those from ref 12: ▲, experimental 2-propanol; ●, literature 2-propanol; ◆, experimental ethanol; ■, literature ethanol. Figure 7. Van’t Hoff plots of ln xi vs 1/T for TMP in the pure solvents: red ●, ethanol; green ■, acetonitrile; blue ◆, 2-propanol; purple ▲, ethyl acetate; ◇, water.

Figure 5. Mole-fraction solubilities of TMP (xi) in water + ethanol mixed-solvent systems over the temperature range from (293.15 to 322.65) K: red ■, 50% ethanol; green ▼, 40% ethanol; blue ▲, 30% ethanol; orange ●, 20% ethanol; pink ■, 10% ethanol.

Figure 8. Van’t Hoff plots of ln xi vs 1/T for TMP in the mixed solvents: red ■, 10% ethanol; red □, 10% 2-propanol; green ×, 20% ethanol; green +, 20% 2-propanol; blue ▲, 30% ethanol; blue △, 30% 2-propanol; orange ●, 40% ethanol; orange ○, 40% 2-propanol; pink ◆, 50% ethanol; pink ◇, 50% 2-propanol.

obtained in this work are in good agreement with literature. However, some discrepancy exists between our solubility values in ethanol and those of the reference. We consider that the main reason for the discrepancy is the difference in the methods used. Our method has been reported many times to

include the work of Feng et al.20 and Shao et al.21 Besides, the solubility measurements were repeated three times at each F

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molecules is weaker than that between the solute and 2propanol molecules. The solubilities of TMP in water + ethanol and water + 2propanol mixtures are given in Tables 7 and 8, respectively, and the corresponding solubility curves are shown in Figures 5 and 6. We found that the solubility of TMP in the mixtures increases with increasing temperature and mass fraction of the organic solvent. Besides, the solubilities of TMP in the binary water + ethanol/2-propanol mixed solvents are far higher than that in water, even when the mass fraction of ethanol/2propanol is 10%. This phenomenon may be explained by the possible interaction between water and the alcohol. We all know that the water and ethanol or 2-propanol are miscible in any proportion as a result of the intermolecular hydrogen bonds formed between them. The introduction of the alcohol is able to disrupt the self-association of water, thereby reducing the ability of water to squeeze out hydrophobic compounds. Hence, the solubility of TMP increases remarkably with the addition of ethanol or 2-propanol in the mixed solvents. In addition, when the mass fraction of ethanol or 2-propanol is ≥40%, the solubility of TMP in the mixed solvent is greater than that in pure ethanol. One plausible explanation is the principle of “like dissolves like”. With the addition of ethanol or 2-propanol, the polarity in water is changed. The closer the polarities of the solute and solvent are, the greater the solubility is. 3.3. Thermodynamic Parameters for Trimethoprim Dissolution. The standard molar enthalpy ΔH°sol of the TMP during the dissolving process in different solvents can be obtained using eq 9, which is deduced from the van’t Hoff equation:23

Table 9. Values of the Standard Thermodynamic Parameter ΔH°sol for the Process of Dissolution ΔH°sol/kJ·mol−1

solvent Pure Solvents ethanol water ethyl acetate acetonitrile 2-propanol

37.45 34.34 33.26 33.95 49.02 Ethanol + Water Mixtures

W W W W W

= = = = =

10% 20% 30% 40% 50%

W W W W W

= = = = =

10% 20% 30% 40% 50%

36.29 30.22 32.68 30.51 39.62 2-Propanol + Water Mixtures 38.19 33.79 51.53 50.12 40.23

temperature in order to obtain a required mean value. In addition, the method for the solubility measurement has been used in our previous work and obtained accurate data.22 Therefore, we are sure that our values are acceptable. From Table 6 and Figure 3 we can clearly see that the solubility of TMP is a function of temperature and increases with increasing temperature, but the rate of increase differs in different solvents. Furthermore, among the pure solvents, TMP has the lowest solubility in water, as the mole-fraction solubility (xi) of TMP in water is only 0.7143 × 10−4 even in the case of T = 322.15 K, which could be explained by this reason: the hydrophobic group (aromatic ring) in TMP makes the hydrophobic interaction a key factor that determines the solubility of TMP in water. The order of the solubilities in the organic solvents is ethanol > acetonitrile > 2-propanol > ethyl acetate. However, this sequence is not completely consistent with the polarity order, as it is well-known that the polarity of the organic solvents follows the order acetonitrile > ethanol > 2-propanol > ethyl acetate. Thus, the polarity of the solvent is not the sole reason for the solubility behavior. Intermolecular interactions and hydrogen bonding between the solvent molecules and TMP may potentially affect the solubility. The protic solvents (ethanol and 2-propanol) own a hydroxyl group (−OH), which makes it possible for them to form hydrogen bonds with the amino group (−NH2) existing in TMP, facilitating dissolution of the solute. Compared with that in ethanol, the solubility of TMP in 2-propanol is lower, which may be the result of its longer hydrocarbon chain. Further analysis of the chemical structures of the solvents showed that an unsaturated triple bond between the carbon and nitrogen atoms (−CN) exists in the molecular structure of acetonitrile, which can be used as an electron donor, so an intermolecular hydrogen bond also can be formed between acetonitrile and TMP. This may explain why the solubility of TMP in acetonitrile is little higher than that in 2-propanol. Similarly, in the case of ethyl acetate, the O atom in the carbonyl group of ethyl acetate forms a hydrogen bond with the H atom of the amino group (−NH2) in TMP. However, the hydrogen bonding between the solute and ethyl acetate

⎛ ∂ ln x ⎞ ° = −R × ⎜ ΔHsol ⎟ ⎝ ∂(1/T ) ⎠

(9)

in which x is the mole fraction of the solute in the saturated solution, R represents the gas constant (8.314 J·mol−1·K−1), and T is the experimental absolute temperature. The value of ΔH°sol can thus be calculated from the slope of the line for ln x plotted versus 1/T. The corresponding curves are shown in Figures 7 and 8, and the results are given in Table 9, from which we can see that all of the ΔH°sol values are positive, suggesting that the dissolution of TMP in the selected solvents is endothermic. Furthermore, the positive values of ΔHsol ° for TMP dissolution are probably due to the weaker molecular interactions between the solute and the solvent molecules compared with the solvent−solvent and solute−solute interactions.

4. CONCLUSION In our study, the solubilities of TMP in five pure solvents and two mixed-solvent systems (ethanol + water and 2-propanol + water) from (293.15 to 322.65) K have been investigated and discussed, and from the solubility data we can draw the following conclusions: (1) The dissolution process is related to the temperature. With increasing temperature, the solubilities of TMP in the selected solvents increase, but the increments with temperature vary for different solvents. For the (water + ethanol/2-propanol) mixed-solvent systems, the solubility of TMP depends not only on the temperature but also on the mass fraction of the organic solvent. G

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(13) Jiang, L. K.; Wang, L. S.; Du, C. J.; Sun, G. Q.; Qi, C. M. Measurement and correlation of the solubilities of tetra (5, 5-dimethyl1, 3-dioxaphosphorinanyl-2-oxy) neopentane in different pure solvents. Fluid Phase Equilib. 2014, 367, 117−124. (14) Zhi, W.; Hu, Y.; Yang, W.; Kai, Y.; Cao, Z. Measurement and correlation of solubility of d-sorbitol in different solvents. J. Mol. Liq. 2013, 187, 201−205. (15) MAO, Z.; SUN, X.; LUAN, X.; WANG, Y.; LIU, G. Measurement and Correlation of Solubilities of Adipic Acid in Different Solvents. Chin. J. Chem. Eng. 2009, 17, 473−477. (16) Bhesaniya, K. D.; Nandha, K.; Baluja, S. Measurement, correlation and dissolution thermodynamics of biological active chalcone in organic solvents at different temperatures. J. Chem. Thermodyn. 2014, 74, 32−38. (17) Shakeel, F.; Haq, N.; Siddiqui, N. A.; Alanazi, F. K.; Alsarra, I. A. Thermodynamics of the solubility of reserpine in {{2-(2ethoxyethoxy)ethanol+water}} mixed solvent systems at different temperatures. J. Chem. Thermodyn. 2015, 85, 57−60. (18) Wang, H.; Qin, Y.; Han, D.; Li, X.; Wang, Y.; Du, S.; Zhang, D.; Gong, J. Determination and correlation of solubility of thiamine nitrate in water+ethanol mixtures and aqueous solution with different pH values from 278.15K to 303.15K. Fluid Phase Equilib. 2015, 400, 53− 61. (19) Li, Q.; Li, Z.; Wang, S. Solubility of Trimethoprim (TMP) in Different Organic Solvents from (278 to 333) K. J. Chem. Eng. Data 2008, 53 (1), 286−287. (20) Feng, Y.; Dai, H.; Gao, W.; Huang, Y.; Tang, W.; Zhang, C.; Luo, H.; Yuan, Y.; Chen, L.; Li, Y. Measurement and Correlation of Solubility of Tetraphenyl Piperazine-1,4-diyldiphosphonate in Mixed Solvents. J. Chem. Eng. Data 2015, 60 (3), 561−567. (21) Shao, X.; Ge, H.; Li, Z.; Ren, C.; Wang, J. Solubility of methylphosphonic acid in selected organic solvents. Fluid Phase Equilib. 2015, 390, 7−13. (22) Liu, M.; Yin, D.; Fu, H.; Zhang, Y.; Liu, M.; Zhou, J.; Qing, X.; Wu, W. Solid−liquid equilibrium of azithromycin in water+1,2propanediol solutions from (289.35 to 319.15) K. J. Mol. Liq. 2014, 199, 51−56. (23) Wang, Q.; Fang, W.; Li, Y.; Xiao, H.; Wang, Z. Measurement and correlation of solubility of N-chlorobenzenesulfonamide sodium and N-chloro-4-toluenesulfonamide sodium in binary ethanol+propan2-ol mixtures from 278.00K to 323.00K. Fluid Phase Equilib. 2013, 345, 11−17.

(2) The experimental data for TMP in each solvent could be well-correlated by the modified Apelblat equation, the λh model, the ideal model, and the CNIBS/R-K model, but the modified Apelblat equation is more suitable for correlating the solubility data for TMP in the selected solvents with a smaller OARD. (3) The values of ΔHsol ° demonstrate that the dissolving process is endothermic. (4) The experimental data and the correlation equations in our study could be applied to industrial production, and the thermodynamic parameters could be used in the relative process. The (water + ethanol/2-propanol) mixed-solvent systems are better than the pure solvents for the sake of economy.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +86-0835-2885614. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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REFERENCES

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DOI: 10.1021/acs.jced.5b00616 J. Chem. Eng. Data XXXX, XXX, XXX−XXX