Effect of Solvent Properties and Composition on the Solubility of

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Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Effect of Solvent Properties and Composition on the Solubility of Ganciclovir Form I Yüfang Wu,* Jiaqin Wu, Jiachao Wang, and Jiangwei Gao

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Department of Biological Sciences, XinZhou Teachers University, Xinzhou, Shanxi 034000, P. R. China ABSTRACT: Characterization of physical properties of polymorphs in pharmaceuticals is a very important aspect of drug development and manufacturing. This work is to improve the solubility and calculate dissolution thermodynamics of ganciclovir form I. An isothermal saturation method was applied to measure the solubility values of ganciclovir form I in some pure and mixed solvents at temperatures ranging from 278.15 to 318.15 K at atmospheric pressure. The solubility obtained a maximum value in pure 1-butanol and a minimum data in neat toluene. The obtained solubility data of ganciclovir form I in pure solvents were correlated with the modified Apelblat equation, the λh equation, and the NRTL model. Meanwhile, the Jouyban−Acree model was applied to simulate ganciclovir form I solubility in binary mixture compositions at various temperatures. The maximum value of the relative average deviation (RAD) was 3.04%, which indicates the experimental data was well consistent with the calculated ones. Apparent thermodynamic analysis indicated that the mixing process in pure solvent is a spontaneous and favorable process. Understanding some physical properties and thermodynamic properties of ganciclovir form I in different solvents is an important aspect of drug development.

1. INTRODUCTION Ganciclovir [9-(1,3-dihydroxy-2-propoxymethyl)guanine, CAS Registry Number: 82410-32-0] is an important acyclic guanine nucleoside analog having significant antiviral properties, being especially effective against viruses of the herpes family and a few other DNA viruses.1,2 Accordingly, many methods are reported in the literature for the production of ganciclovir.3−6 Its chemical structure is shown in Figure 1. The condensation

ganciclovir was heated and dissolved in a mixed solution of water and N,N-dimethylformamide and then cooled and crystallized.7 However, according to the reference, ganciclovir exhibits polymorphism and exists as anhydrous and hydrous forms.7,8 It was found that thorough research for the forms of ganciclovir was urgently required. The different crystalline forms of the drugs have different physical and biological properties, especially the insoluble substance. The U.S. Pharmacopeia reference standard (form I) of ganciclovir was investigated in this study. In this content, the solubility data of ganciclovir form I in methanol, ethanol, n-propanol, isopropanol, 1-butanol, acetonitrile, ethyl acetate, toluene, acetone, and (acetonitrile +1butanol) solvents was studied, and the effect of temperature, cosolvent percentage in mixed solvents, and molecular interactions on the dissolution process of ganciclovir form I was discussed as well. The solubility data are correlated and predicted by different thermodynamic models. In the following, the mixing Gibbs free energy in pure solvent of ganciclovir form I in the dissolution process is also reported.

Figure 1. Chemical structure of ganciclovir.

reaction as the starting reaction step was carried out with acetyl guanine and 1,3-dihalo-2-(acetoxymethoxy) propane or 1,3diacetoxy-2-(acetoxymethoxy) propane, and then the displacement reaction with acetate was applied to prepare triacetyl ganciclovir (raw materials containing 1,3-diacetoxy-2(acetoxymethoxy) propane could obtain it directly), finally obtained ganciclovir by hydrolysis reaction. However, ganciclovir prepared according to the above experimental method will contain 2′-monodehydroxy-2′-chloro ganciclovir impurities. Therefore, the research for the separation of ganciclovir has a high value of practical application. It could be concluded from the patent review that the crude product of © XXXX American Chemical Society

2. EXPERIMENTAL SECTION 2.1. Materials. Ganciclovir (form I) with a purity of 0.996 in mass fraction (which was determined by high-performance liquid phase chromatograph), methanol, ethanol, n-propanol, Received: November 14, 2018 Accepted: February 27, 2019

A

DOI: 10.1021/acs.jced.8b01080 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

isopropanol, 1-butanol, acetone, ethyl acetate, toluene, and acetonitrile was provided by Sinopharm Chemical Reagent Co., Ltd., China, and these solvents were analytical grade. The detailed information on solute and solvent is listed in Table 1. During the experiment, solute and solvent were used without further purification.

Chemicals Ganciclovir (form I) Methanol Ethanol n-Propanol Isopropanol Acetonitrile 1-Butanol Acetone Ethyl acetate Toluene

255.23 32.04 46.07 60.10 60.10 41.05 74.12 58.08 88.11 92.14

Source Sinopharm Chemical Reagent Co., Ltd.,China

mass fraction purity

Analytical method

0.996

HPLCa

0.996 0.995 0.996 0.997 0.995 0.996 0.995 0.995 0.996

GCb GC GC GC GC GC GC GC GC

m1/M1 m1/M1 + m2 /M 2

(1)

x w,T =

m1/M1 m1/M1 + m2 /M 2 + m3 /M3

(2)

where m1 stands for the mass of ganciclovir; m2 stands for the mass of methanol, ethanol, ethyl acetate, n-propanol, isopropanol, 1-butanol, toluene or acetone, and acetonitrile, and m3 stands for the mass of 1-butanol. M1, M2, and M3 are the corresponding molar mass.

Table 1. Detailed Information on the Materials Used in the Work Molar mass (g·mol−1)

x w,T =

3. RESULTS AND DISCUSSION 3.1. PXRD and Thermodynamic Properties Analysis. Characterization of polymorphs for ganciclovir is a very important aspect of its development and manufacturing. The PXRD results of excess solid in solvent and raw material are plotted in Figure 2. From Figure 2, it indicates that all excess

a

High-performance liquid phase chromatograph. bGas chromatography.

2.2. X-ray Powder Diffraction. The X-ray powder diffraction (XPRD) spectra of excess solid in solvent and raw material of ganciclovir were identified with a Bruker AXS D8 (Advance, Germany) instrument. During the experiment, the tube voltage was set at 40 kV, and current was 30 mA. Moreover, samples were determined by Cu Ka radiation (λ = 1.54184 nm); at room temperature and under atmospheric pressure, the data were collected at a scan speed of 5°·min−1 and from 5° to 80° (2-Theta). 2.3. Measurement of Ganciclovir Solubility. In this experiment, the solubility data of ganciclovir in ethanol, methanol, n-propanol, isopropanol, 1-butanol, acetone, ethyl acetate, toluene, and acetonitrile were determined by using the isothermal saturation method over a temperature range from (283.15 to 318.15) K under 101.3 kPa.9−11 The reliability of the method we used has been verified in our previous work.10 Excess solid was added into the jacketed vessel containing 25 mL of corresponding solvent prepared. The circulating water bath was used to control experimental temperature (with an accuracy of ±0.05 K). A reflux condenser was directly connected to the vessel to prevent solvent evaporation. The suspension was densely mixed by a magnetic agitator operating at 350 rpm speed, and continuously stirred for over 24 h to ensure the equilibrium of solutions at different temperatures. Then the stirring was stopped and permitted to settle for 2 h before sampling. After that a 5 mL preheated syringe connected with a filter (PTFE 0.2 um) was used to extract supernatant; then the corresponding weighing work was carried out, and finally the dilution and solute content were analyzed with HPLC. The detection parameters were as follows: a type of reverse phase column (LP-C18, 250 mm × 4.6 mm) and temperature was 303.15 K, the UV detector with wavelength of 254 nm, and chromatographic grade methanol as mobile phase with a flow rate of 1.0 mL·min−1. Each experiment was repeated three times. The solubility data of ganciclovir (xw,T) in pure solvents and mixed solvents were obtained by eqs 1 and 2, respectively.

Figure 2. PXRD patterns of ganciclovir form I in different solvents and raw material.

solid in solvent and raw material has the same characteristic peaks. Therefore, during solubility determination, there is no polymorph transformation or solvate formation. Moreover, based on the research work of Ruchira Maiti Sarbajna’s summarized,8 the patterns of ganciclovir form I exhibit characteristic patterns with prominent peaks at the following angular positions (8.4°, 12.5°, 16.9°, 18.1°, 19.0°, 21.1°, 25.5°, and 26.1°). The analysis results of Figure 2 show that the characteristic patterns with prominent peaks of raw material and the solids crystallized are exactly the same as the form I. In addition, there is an interesting experimental phenomenon through the interpretation of the literature.8 Results of thermodynamic analysis in ref 8 indicate that there is a solid− solid phase transition between the experimental temperature and the melting point. The Ganciclovir form I converts to form II at 500.97 K and then melts at 524.31 K without any weight loss. 3.2. Solubility of Ganciclovir Form I in Pure Solvents. Through the above experiments, the experimental and calculated solubility data of ganciclovir form I in methanol, ethanol, n-propanol, isopropanol, 1-butanol, acetone, ethyl acetate, toluene, and acetonitrile were generated and listed in Table 2. Moreover, Figure 3 intuitively expressed the relationship between temperature and solubility (the solubility increases with rising temperature); therefore, high purity target products can be obtained by cooling crystallization. In the pure solvents, the solubility data followed the sequence: 1-butanol > B



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Table 2. Experimental and Calculated Mole Fraction Solubility (104xew,T and 104xcalc w,T) of Ganciclovir Form I in Different Pure Solvents at the Temperature Range from T = (278.15 to 318.15) K under 101.1 kPaa solvent Methanol

Ethanol

n-Propanol

T/K

exp

calcApel

calcλh

calcNRTL

exp

calcApel

calcλh

calcNRTL

exp

calcApel

calcλh

calcNRTL

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.7335 0.7948 0.8720 0.9547 1.050 1.163 1.292 1.427 1.565 solvent

0.7285 0.7966 0.8731 0.9589 1.055 1.163 1.284 1.420 1.572

0.7130 0.7921 0.8776 0.9698 1.069 1.176 1.291 1.415 1.547

0.7339 0.7949 0.8689 0.9554 1.054 1.165 1.288 1.423 1.569

0.8996 0.9695 1.045 1.127 1.226 1.324 1.442 1.571 1.711

0.9003 0.9685 1.045 1.129 1.223 1.327 1.442 1.570 1.711

0.8842 0.9642 1.049 1.140 1.237 1.339 1.448 1.564 1.688

0.8999 0.9687 1.045 1.129 1.223 1.326 1.441 1.569 1.712

1.918 2.004 2.102 2.208 2.326 2.459 2.604 2.763 2.949

1.920 2.004 2.100 2.207 2.326 2.459 2.605 2.767 2.946

1.889 1.997 2.109 2.227 2.35 2.479 2.615 2.757 2.907

1.918 2.005 2.101 2.208 2.327 2.458 2.603 2.766 2.948

Isopropanol T/K

exp

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.6225 0.6817 0.7495 0.8289 0.9057 0.9915 1.072 1.165 1.270

Apel

calc

calc

0.6203 0.6844 0.753 0.8262 0.9043 0.9873 1.075 1.169 1.267

1-Butanol λh

NRTL

calc

0.6219 0.6849 0.7525 0.8249 0.9025 0.9856 1.074 1.169 1.271

0.6215 0.6835 0.7517 0.8255 0.9045 0.9884 1.077 1.169 1.266

exp 2.231 2.319 2.423 2.538 2.672 2.840 3.025 3.235 3.464

calc

calc

2.233 2.317 2.419 2.539 2.679 2.839 3.023 3.231 3.467 solvent

2.172 2.301 2.436 2.577 2.725 2.88 3.044 3.215 3.395

Acetone T/K 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

Apel

exp

calc −3

3.282e 4.257e−3 5.528e−3 7.224e−3 9.134e−3 1.121e−2 1.374e−2 1.671e−2 2.058e−2

−3

3.316e 4.332e−3 5.587e−3 7.12e−3 8.973e−3 1.119e−2 1.381e−2 1.689e−2 2.046e−2

Acetonitrile λh

Apel

calc

NRTL

2.232 2.317 2.42 2.54 2.679 2.839 3.022 3.23 3.469

exp

calc

−3

3.35e 4.327e−3 5.541e−3 7.037e−3 8.866e−3 1.109e−2 1.377e−2 1.698e−2 2.081e−2

NRTL

calc

−3

3.339e 4.318e−3 5.535e−3 7.035e−3 8.870e−3 1.110e−2 1.379e−2 1.701e−2 2.084e−2

Apel

exp

calc −3

2.414 e 3.205 e−3 4.540 e−3 5.962e−3 7.790e−3 9.973e−3 1.243e−2 1.545e−2 1.882e−2

−3

2.383 e 3.306 e−3 4.486e−3 5.961 e−3 7.768 e−3 9.937 e−3 1.249 e−2 1.545 e−2 1.881 e−2

calcNRTL

0.1240 0.1370 0.1509 0.1658 0.1819 0.1991 0.2175 0.2373 0.2584

0.1260 0.1366 0.1496 0.1646 0.1812 0.1991 0.2181 0.2381 0.2587

calc

0.1257 0.1375 0.1492 0.1635 0.1818 0.1994 0.2187 0.2373 0.2588

0.1247 0.1371 0.1506 0.1653 0.1813 0.1986 0.2173 0.2375 0.2594

Ethyl acetate λh

calcλh

Apel

Toluene λh

NRTL

calc

calc −3

2.506 e 3.346 e−3 4.422 e−3 5.789e−3 7.511e−3 9.663e−3 1.233e−2 1.562e−2 1.964e−2

−3

2.493e 3.333e−3 4.411e−3 5.783e−3 7.513e−3 9.676e−3 1.236e−2 1.567e−2 1.971e−2

Apel

exp

calc −3

1.688 e 1.968 e−3 2.249 e−3 2.637e−3 3.034e−3 3.483e−3 3.934e−3 4.516e−3 5.185e−3

−3

1.693e 1.963e−3 2.271e−3 2.621e−3 3.016e−3 3.463e−3 3.966e−3 4.533e−3 5.168e−3

calcλh −3

1.676e 1.958e−3 2.276e−3 2.633e−3 3.032e−3 3.478e−3 3.975e−3 4.527e−3 5.137e−3

calcNRTL 1.689e−3 1.961e−3 2.271e−3 2.623e−3 3.020e−3 3.467e−3 3.97e−3 4.532e−3 5.16e−3

a

Standard uncertainties u are u(T) = 0.02 K, u(p) = 400 Pa; Relative standard uncertainty in mole fraction ur is ur(x) = 0.0250.

dissolves like”, so the solubility was higher in 1-butanol. However, the data in isopropanol is not consistent with this sequence; the main reason for this abnormal result is obviously that the hydroxyl group of the isopropanol molecule is located between two methyl groups; it hinders the interaction of the hydroxyl group of the isopropanol molecule with ganciclovir molecule. Meanwhile, the low solubility data in these solvents may be caused with the stronger solvent−solvent interaction; the minimum value of the solubility in pure solvents is in acetonitrile (1.257 × 10−5 at 278.15 K). Compared with acetonitrile, acetone, ethyl acetate, and toluene molecules, the hydroxyl group in the alcohol molecule is more likely to form hydrogen bond with the ganciclovir molecule. In addition, the solubility of solutes in acetonitrile, acetone, ethyl acetate, and toluene decreases with the decrease of polarity. Therefore, in the pure solvent studied, the effect of the hydrogen bond formed between the solvent and the solute molecules is the main effect on the solubility, compared with the polarity of the solvent. 3.3. Solubility Data of Ganciclovir Form I in Binary Solvent Mixtures. In this part, the experimental data and

Figure 3. Experimental and predicted solubility data of ganciclovir form I in pure solvent selected at different temperatures.

n-propanol > ethanol > methanol > isopropanol > acetonitrile > acetone > ethyl acetate > toluene. The polarity values are listed as methanol (76.2), ethanol (65.4), n-propanol (61.7), isopropanol (54.6), 1-butanol (60.2), acetone (35.5), ethyl acetate (23), toluene (9.9), acetonitrile (46.0).12 Obviously, the sequence in alcohols is contrary to the order of the solvent polarity. The result may be due to the formation of intramolecular hydrogen bonds, making the ganciclovir molecular polarity decrease. According to the rule of “like C



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Table 3. Experimental and Calculated Mole Fraction Solubility (104xew,T and 104xcalc w,T) of Ganciclovir Form I in Acetonitrile (w) + 1-Butanol (1 − w) Mixtures with Various Compositions at the Temperature Range from T = (278.15 to 318.15) K under 101.1 kPaa w 0.1

0.2

0.3

0.4

0.5

T/K

exp

calc

exp

calc

exp

calc

exp

calc

exp

calc

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

1.282 1.349 1.424 1.498 1.584 1.679 1.784 1.898 2.020

1.313 1.379 1.456 1.539 1.632 1.747 1.870 2.009 2.162

0.8382 0.8898 0.9509 1.017 1.087 1.160 1.244 1.331 1.447

0.8227 0.8719 0.9288 0.9894 1.0567 1.137 1.223 1.318 1.425

0.5739 0.6099 0.6451 0.6845 0.7280 0.7725 0.8218 0.8827 0.9420 w

0.5462 0.5836 0.6268 0.6723 0.7222 0.7810 0.8429 0.9110 0.9884

0.4165 0.4385 0.4611 0.4853 0.5106 0.5386 0.5692 0.6044 0.6449

0.3830 0.4122 0.4459 0.4812 0.5195 0.5640 0.6104 0.6609 0.7190

0.3176 0.3387 0.3633 0.3887 0.4151 0.4438 0.4731 0.5047 0.5384

0.2829 0.3063 0.3334 0.3617 0.3921 0.4271 0.4631 0.502 0.5472

0.6

0.7

0.8

0.9

T/K

exp

calc

exp

calc

exp

calc

exp

calc

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.2210 0.2342 0.2508 0.2690 0.2905 0.3143 0.3404 0.3711 0.4098

0.2194 0.2389 0.2615 0.2849 0.3098 0.3383 0.3673 0.3983 0.4348

0.1792 0.1945 0.2095 0.2277 0.2478 0.2699 0.2908 0.3155 0.3420

0.1784 0.1951 0.2146 0.2347 0.2559 0.2799 0.3039 0.3295 0.3600

0.1717 0.1817 0.1943 0.2087 0.2244 0.2418 0.2627 0.2844 0.3100

0.1519 0.1667 0.1841 0.2019 0.2205 0.2414 0.2621 0.2839 0.3102

0.1422 0.1529 0.1656 0.1812 0.1964 0.2142 0.2324 0.2528 0.2732

0.1351 0.1488 0.1648 0.1812 0.1981 0.2169 0.2354 0.2545 0.2779

a

Standard uncertainties u are u(T) = 0.02 K, u(p) = 400 Pa; Relative standard uncertainty in mole fraction ur is ur(x) = 0.0280; Solvent mixtures were prepared by mixing different masses of the solvents with relative standard uncertainty ur (w) = 0.002. w represents the mass fraction of acetonitrile in mixed solvents of acetonitrile (w) + 1-butanol (1 − w).

maximum in pure 1-butanol at every temperature. At 278.15K, the mole fraction solubility of ganciclovir form I in pure acetonitrile and 1-butanol was enhanced from 1.257 × 10−5 to 2.231 × 10−4, an increase of 17.75-fold. The solubility data in the mixed solvent will be an important reference for the purification of ganciclovir form I in the industry. 3.4. Correlation of Ganciclovir Form I Solubility. In pure solvent, the solubility data were correlated by two semiempirical equations (the modified Apelblat model13,14 and the λh equation15) and the activity coefficient equation (NRTL model).16,17 Besides, in mixed mixtures, the results were correlated by the Jouyban−Acree model.18,19 3.4.1. Modified Apelblat Equation. The function of solubility data in mole fraction (x) and the absolute temperature (T) could be expressed with the modified Apelblat equation,13,14 which is a semiempirical equation and shown as eq 3.

calculated values of ganciclovir form I in binary solvent mixtures are summarized in Table 3. Figure 4 illustrates the

Figure 4. Experimental solubility data of ganciclovir form I in acetonitrile (w) + 1-butanol (1 − w) mixed solutions with various mass fractions at different temperatures. w is the composition of acetonitrile in mass fraction.

ln x = A +

B + C ln T T

(3)

where A, B, and C are the adjustable equation parameters and can be acquired by correlating the experimental solubility. 3.4.2. λh Equation. Another semiempirical equation used is the λh equation, which is used to describe the solid−liquid equilibrium behavior of ganciclovir form I as well, and expressed as eq 4.15 The λh equation has two parameters λ and h. ÄÅ É ij 1 ÅÅ λ(1 − x) ÑÑÑÑ 1 yzz lnÅÅÅ1 + ÑÑ = λhjjj − z jT x Tm zz{ ÅÅÇ ÑÑÖ (4) k

relationship between concentration, temperature, and solubility. It can be seen from that, when the mass fraction of acetonitrile is fixed, the solubility increases with increasing temperature. At certain temperature, the solubility in mixed solvents increases with increasing content of 1-butanol. In mixed solvent, when the initial mass fraction of 1-butanol increases to 0.6, the growth range of solubility increases. Eventually, the composition dependence of the solubility had a D



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Table 4. Parameters of the Modified Apelblat Equation, λh Equation, and NRTL Model for Ganciclovir Form I in Different Solvents along with the Values of Relative Average Deviation λh equation

Modified Apelblat equation

NRTL model

Solvent

A

B

C

100 RAD

104λ

10−6h

100 RAD

a12

b12/K

a21

b21/K

α

100 RAD

Methanol Ethanol n-Propanol Isopropanol 1-Butanol Acetonitrile Acetone Ethyl acetate Toluene

−121.82 −113.01 −113.48 −16.75 −161.42 −54.59 72.254 237.377 −59.773

3554.18 3408.53 3860.95 −1015.4 5973.69 559.05 −7252.86 −15054.75 −114.33

17.68 16.25 16.18 1.903 23.37 7.336 −10.856 −35.27 7.923

0.39 0.11 0.07 0.33 0.10 0.54 1.05 0.76 0.53

8.648 5.444 2.317 5.559 3.145 1.226 3.001 5.399 0.095

1.764 2.142 2.046 2.447 1.686 1.154 13.424 8.423 253.83

1.15 0.89 0.77 0.34 1.34 0.58 1.50 2.96 0.55

33.482 −2.111 −2.339 26.975 −1.618 35.310 1.479 1.645 −0.0004

−7814.38 −530.736 −457.020 −6104.09 −679.558 −8673.54 0.240 −0.407 −809.8

17.515 18.276 21.223 18.980 15.659 21.359 12.600 10.959 17.35

−5940.547 −1952.24 −3052.85 −6101.00 −1377.46 −6342.36 −2827.43 −2304.76 −2245.69

0.2 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.2

0.22 0.11 0.04 0.30 0.11 0.33 1.46 2.92 0.51

where λ and h are adjustable equation parameters and Tm denotes the melting temperature of ganciclovir form I in Kelvin. 3.4.3. NRTL Model. According to previous references,8 ganciclovir form I has a phase transition between the experimental temperature and the melting point. Previously reported in the references,16,17 before solid fusion, if there is a solid−solid phase transition, for the temperatures below that of the phase transition the effect of phase transformation when calculating the activity coefficient of ganciclovir form I with the activity coefficient equation must be considered (NRTL model). Therefore, the solubility of ganciclovir form I in organic solvents can be simplified as eq 5. −ln xi =

where aij and bij are adjustable model parameters related to energy interaction between the component i and component j. The two parameters are independent upon temperature and composition. 3.4.4. Jouyban−Acree Model. In mixed solvents, the results were correlated by the Jouyban−Acree model (the most accurate model among the available cosolvency models) and shown in the following equation.18,19 2

ln x w,T = w1 ln x1,T + w2 ln x 2,T +

(11)

where xw,T is the solubility of ganciclovir form I, x1,T and x2,T are the mole fraction solubility of ganciclovir form I in pure solvent, T is temperature in Kelvin, w1 is the mass fraction of acetonitrile in mixed solvents, and w2 is the mass fraction of 1butanol in mixed solvents, Ji are the Jouyban−Acree model parameters. The solubility data were correlated by a thermodynamic model with the least-squares method. Moreover, the deviations between calculated values and experimental ones were evaluated and presented in Tables 2 and 3. The parameters obtained of each model were given in Tables 4 and 5. In this

ΔfusH jij 1 1 yzz ΔHtr − jjj z+ R k T /K Tm/K zz{ R

ij 1 1 yzz jj jj T /K − T /K zzz + ln γi tr k {

(5)

According to ref 8, the ganciclovir form I converted into form II at 500.97 K, the enthalpy of transition is 7.73 kJ·mol−1, the heat of fusion is 49.46 kJ·mol−1 and the melting point is 524.31 K. γi represents the activity coefficient of ganciclovir form I, which can be obtained from the NRTL model: ÄÅ ÉÑ N N N ∑ j = 1 τjiGjixj ∑i = 1 xiτijGij ÑÑÑÑ xjGij ÅÅÅÅ ÅÅτij − ÑÑ ln γi = +∑ N N N ÅÅ ∑i = 1 Gijxi ∑i = 1 Gijxi ÑÑÑÑ j = 1 ∑i = 1 Gijxi Å ÅÇ Ö

Table 5. Parameters of the Jouyban−Acree Model along with Values of Relative Average Deviation for Ganciclovir Form I in Acetonitrile (w) + 1-Butanol (1 − w) Mixtures acetonitrile (w) + 1-butanol (1 − w) J0 J1 J2 102RAD

(6)

Gji = exp( −αjiτji)

(7)

αij = αji

(8)

τij =

gij − gjj RT

=

(9)

RAD =

Δgij are adjustable parameters relating to energy interaction and independent of temperature. α is a parameter in relation to the nonrandomness of a solution, which is usually in the range from (0.2 to 0.47). Assuming that the binary cross-interaction parameters τij are a linear relationship with temperature, it can be expressed as eq 10. τij = aij +

ij |x c − x e | yz 1 ∑ jjjj w,T e w,T zzzz N x w,T k {

(12)

where the number of experimental data points was expressed with N. The relative average deviations (RAD) are all no larger than 3.04 × 10−2, which indicates that these four models were suitable to describe the solubility of ganciclovir form I in selected pure and mixed solvents. 3.5. Apparent Thermodynamic Analysis in Pure Solvents. According to the Lewis−Randall rule in which the

bij T

−697.74 52.37 −14.22 3.04

work, the relative average deviations (RAD, as shown in eq 12) were calculated and tabulated in Tables 4 and 5, respectively.

Δgij RT

w1w2 ∑ J (w1 − w2)i T i=0 i

(10) E



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ethyl acetate > toluene. In (acetonitrile + isopropanol) binary mixtures, solubility data was positively associated with temperature, while negatively associated with the mass fraction of acetonitrile. The solubility data of ganciclovir form I was correlated with these four thermodynamic models, and RAD values were no larger than 3.04 × 10 −2 . Apparent thermodynamic functions were all negative, which showed that the mixing process in pure solvent is a spontaneous and favorable process. Moreover, 1-butanol is a good solvent in the preparation of high purity crystals.

standard states are the actual states of the pure components, the mixing properties of solution can be calculated. For an ideal solution, the mixing Gibbs free energy in pure solvent is expressed as20,21 Δmix Gid = RT (x1 ln x1 + x 2 ln x 2)

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where x1 is the mole solubility of solute, and x2 is the mole fraction of corresponding solvent. For nonideal solution, it can be obtained with eq 14 Δmix G = GE + Δmix Gid

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The superscript id is the ideal state, and the excess mixing properties can be described as eq 15.22 GE = RT (x1 ln γ1 + x 2 ln γ2)

*Y.F. Wu. Tel: +86 350 3339210. E-mail address: [email protected].

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ORCID

Table 6 lists the thermodynamic properties of the mixing process for ganciclovir form I in methanol, ethanol, n-propanol,

Yüfang Wu: 0000-0001-9169-4340 Notes

Table 6. Calculated Values of Ganciclovir Form I in Different Pure Solvents for the Mixing Gibbs Free Energy (ΔmixG/J·mol−1) T/K

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The project was supported by College Students’ Science and Technology Innovation Project of XinZhou Teachers University, China (201707).

solvents Methanol

Ethanol

n-Propanol

Isopropanol

−2.1248 −2.2619 −2.4366 −2.6203 −2.8295 −3.0744 −3.3483 −3.6259 −3.8996

−2.7086 −2.8774 −3.057 −3.2493 −3.4808 −3.7035 −3.9703 −4.2567 −4.5615

−5.6785 −5.8459 −6.04 −6.2488 −6.4818 −6.745 −7.0293 −7.3381 −7.7004

−1.803 −1.9405 −2.0956 −2.2741 −2.4395 −2.62 −2.7804 −2.9625 −3.1628

Acetonitrile

Acetone

Toluene

−0.3642 −0.3911 −0.4172 −0.4491 −0.4897 −0.5271 −0.567 −0.6036 −0.645

−0.0135 −0.016 −0.0186 −0.0222 −0.026 −0.0304 −0.0348 −0.0406 −0.0473

Ethyl acetate −0.007 −0.0092 −0.0127 −0.0163 −0.021 −0.0263 −0.0323 −0.0394 −0.0472

AUTHOR INFORMATION

Corresponding Author

1Butanol −6.6304 −6.7833 −6.9737 −7.1866 −7.4406 −7.7706 −8.1301 −8.5362 −8.9712

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REFERENCES

(1) Battiwalla, M.; Wu, Y. Y.; Bajwa, R. P. S.; Radovic, M.; Almyroudis, N. G.; Segal, B. H.; Wallace, P. K.; Nakamura, R.; Padmanabhan, S.; Hahn, T.; McCarthy, P. L., Jr. Ganciclovir inhibits lymphocyte proliferation by impairing DNA synthesis. Biol. Blood Marrow Transplant. 2007, 13, 765−770. (2) Bowden, R. A.; Digel, J.; Reed, E. C.; Meyers, J. D. Immunosuppressive effects of ganciclovir on in vitro lymphocyte responses. J. Infect. Dis. 1987, 156, 899−903. (3) Zhang, X. S. A preparation method for ganciclovir. CN Patent, 105,524,065, Apr. 27, 2016. (4) Liu, J.; Barrio, J. R.; Satyamurthy, N. Efficient synthesis of 9-(4[18F] fluoro-3-hydroxymethylbutyl) guanine ([18F] FHBG) and 9[(3-[18F] fluoro-1-hydroxy-2-propoxy) methyl] guanine ([18F] FHPG). J. Fluorine Chem. 2017, 201, 24−42. (5) Babu, J. S.; Chandra, R. P.; Khanduri, C. H.; Kumar, Y. Process for the preparation of ganciclovir intermediate n2-acetyl-9-(1,3diacetoxy-2-propoxymethyl) guanine. US Patent 2005,0176,956, Aug. 11, 2005. (6) Arzeno, H. B.; Humphreys, E. R.; Wong, J. W.; Christopher, R. Process for the preparation of ganciclovir derivatives. EP Patent 0885,224, Dec. 18, 2002. (7) Chen, A.; Jun, Y.; Chen, Z. Y.; Li, M. H. Refining method of ganciclovir. CN Patent, 102,643,277A, Aug. 22, 2012. (8) Sarbajna, R. M.; Preetam, A.; Devi, A. S.; Suryanarayana, M. V.; Madhuresh, S.; Debashish, D. Studies on crystal modifications of ganciclovir. Mol. Cryst. Liq. Cryst. 2011, 537, 141−154. (9) Shakeel, F.; Iqbal, M.; Ezzeldin, E.; Nazrul, H. Thermodynamics of solubility of ibrutinib in ethanol + water cosolvent mixtures at different temperatures. J. Mol. Liq. 2015, 209, 461−464. (10) Wu, Y. F.; Di, Y. C.; Zhang, X. L.; Zhang, Y. T. Solubility determination and thermodynamic modeling of 3-methyl-4-nitrobenzoic acid in twelve organic solvents from T=(283.15 to 318.15) K and mixing properties of solutions. J. Chem. Thermodyn. 2016, 102, 257−269. (11) Ha, E. S.; Lee, Y. R.; Kim, M. S. Solubility of dronedarone hydrochloride in six pure solvents at the range of 298.15 to 323.15 K. J. Mol. Liq. 2016, 216, 360−363. (12) Smallwood, I. M. Handbook of organic solvent properties; Amoled: London, 1996.

−0.0049 −0.0056 −0.0064 −0.0073 −0.0083 −0.0093 −0.0103 −0.0116 −0.0131

isopropanol, 1-butanol, and acetonitrile, respectively. It was observed that the values of ΔmixG are all negative, suggesting that the mixing process in pure solvent is a spontaneous and favorable process. The ΔmixG values were recorded in the range of (−0.3643 to −8.616 J·mol−1). Moreover, in six pure solvents, it followed the sequence toluene > ethyl acetate > acetone > acetonitrile > isopropanol > methanol > ethanol > npropanol >1-butanol. It is contrary to the order of solubility at the studied temperature.

4. CONCLUSION In pure and binary mixed solvents, the solubility data of ganciclovir form I was obtained experimentally. The results increased with increasing temperature. In the pure solvents, the solubility followed the sequence 1-butanol > n-propanol > ethanol > methanol > isopropanol > acetonitrile > acetone > F



Article

(13) Apelblat, A.; Manzurola, E. Solubilities of o-acetylsalicylic, 4aminosalicylic, 3,5-dinitrosalicylic, and p-toluic acid, and magnesiumDL-aspartate in water from T = (278 to 348) K. J. Chem. Thermodyn. 1999, 31, 85−91. (14) Apelblat, A.; Manzurola, E. Solubilities of L-aspartic, DLaspartic, DL-glutamic, p-hydroxybenzoic, o-anistic, p-anisic, and itaconic acids in water from T = 278K to T = 345K. J. Chem. Thermodyn. 1997, 29, 1527−1533. (15) Buchowski, H.; Ksiazczak, A.; Pietrzyk, S. Solvent activity along a saturation line and solubility of hydrogen-bonding solids. J. Phys. Chem. 1980, 84, 975−979. (16) Domańska, U.; Bogelłukasik, E. Solubility of benzimidazoles in alcohols. J. Chem. Eng. Data 2003, 48, 951−956. (17) Choi, P. B.; Mclaughlin, E. Effect of a phase transition on the solubility of a solid. AIChE J. 1983, 29, 150−153. (18) Wu, Y. F.; Qin, Y. N.; Bai, L.; Kang, Y.; Zhang, Y. T. Determination and thermodynamic modelling for 4-nitropyrazole solubility in (methanol + water), (ethanol + water) and (acetonitrile + water) binary solvent mixtures from T=(278.15 to 318.15) K. J. Chem. Thermodyn. 2016, 103, 276−284. (19) Jouyban, A. Solubility prediction of drugs in water-polyethylene glycol 400 mixtures using Jouyban-acree model. Chem. Pharm. Bull. 2006, 54, 1561−1566. (20) Zhang, Z.; Li, Z. F.; Wang, Y.; Li, C.; Yu, B.; Zheng, X. C.; Jiang, L.; Gong, J. B. Determination and correlation of solubility and thermodynamic properties of L-methionine in binary solvents of water + (methanol, ethanol, acetone). J. Chem. Thermodyn. 2016, 96, 82− 92. (21) Yao, G. B.; Li, Z. H.; Xia, Z. X.; Yao, Q. C. Solubility of Nphenylanthranilic acid in nine organic solvents from T = (283.15 to 318.15) K: Determination and modeling. J. Chem. Thermodyn. 2016, 103, 218−227. (22) Kondepudi, D. K. Introduction to modern thermodynamics; Wiley: Chichester, 2008.

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