Thermodynamic Study of Solubility for Imatinib Mesylate in Nine

Article pubs.acs.org/jced

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

Thermodynamic Study of Solubility for Imatinib Mesylate in Nine Monosolvents and Two Binary Solvent Mixtures from 278.15 to 318.15 K Xinyi Wang,†,‡,§,⊥ Dejiang Zhang,†,‡,§,⊥ Shiyuan Liu,†,‡,§ Yifu Chen,†,‡,§ Lina Jia,†,‡,§ and Songgu Wu*,†,‡,§

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†

National Engineering Research Center of Industry Crystallization Technology, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China ‡ Collaborative Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, China § Key Laboratory of Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China S Supporting Information *

ABSTRACT: The solubility of imatinib mesylate in nine monosolvents and two binary solvents was determined by the shaken flask method followed by UV composition analysis from 278.15 to 318.15 K at atmospheric pressure. The solubility increases with the increasing of temperature in all solvents we chose. Meanwhile, the dissolving capacity of imatinib mesylate ranks as methyl acetate < 2-propanol < acetonitrile < isobutanol < 1-butanol < tetrahydrofuran < 1-propanol < ethanol < methanol. The Apelblat model, λh equation, and nonrandom two-liquid (NRTL) model described the solubility data of imatinib mesylate in monosolvents; simultaneously, the Apelblat model, combined nearly ideal binary solvent/Redlich-Kister model, and NRTL model were employed in binary solvents. The results show a satisfactory correlation with the experimental data. Additionally, mixing thermodynamic properties of imatinib mesylate were calculated based on the NRTL model, which reveals the mixing process is spontaneous and exothermic.

1. INTRODUCTION Imatinib mesylate (C29H31N7O·CH4O3S, CAS registry no.: 220127-57-1, Figure 1) has been identified as a tyrosine kinase inhibitor that selectively inhibits the Abl tyrosine kinases1 and has outstanding activity against chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs).2,3 As the first protein kinase inhibitor approved for clinical use,4 imatinib mesylate shows a strong competitive advantage in tumor treatment.5 It has also been proven to be an efficient drug for the treatment of c-KIT mastocytosis and pulmonary arterial hypertension.2,6 Due to the remarkable efficacy, imatinib mesylate has attracted more and more attention.6,7 Imatinib mesylate commonly exists as two crystal forms, form α and form β. Form α is metastable at room temperature and unstable in the drug’s complex manufacturing process,1,8 while form β is more stable and also a commercial form. Thus, in this work, we mainly studied the stable form β. Owing to its ability to obtain high-quality products, crystallization is a widely applied technique in the pharmaceutical industry. The thermodynamic data, especially the solid−liquid phase equilibrium data, are significant for the crystallization process. There are many studies in previous works9−11 focusing on the synthesis of imatinib mesylate. However, no literature provides the solubility data of imatinib mesylate. In view of the importance of the thermodynamic data in manufacturing process, in current research, solubility of imatinib mesylate in © XXXX American Chemical Society

Figure 1. Chemical structure and unit cell structure of imatinib mesylate.

pure and mixed solvents which are all favorable in the manufacturing process12 was measured by the shaken flask method followed by UV composition analysis between 278.15 and 318.15 K. Additionally, the mixing thermodynamic properties during the dissolution process were investigated. These research data will provide guidance for solvent screening and operation conditions optimization.13 Received: June 29, 2018 Accepted: October 19, 2018

A

DOI: 10.1021/acs.jced.8b00551 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Table 1. Information on Chemicals Used in This Work chemical name

source

initial mass fraction purity

purification method

analysis method

imatinib mesylate methanol ethanol 1-propanol 2-propanol 1-butanol isobutanol acetonitrile tetrahydrofuran methyl acetate mefenamic acid

Nanjing Qike Chemical Co., Ltd. Yuanli Co., Ltd. Leigh Hanlon Pharmaceutical Chemical Co., Ltd. Leigh Hanlon Pharmaceutical Chemical Co., Ltd. Yuanli Co., Ltd. Yuanli Co., Ltd. Yuanli Co., Ltd. Leigh Hanlon Pharmaceutical Chemical Co., Ltd. Yuanli Co., Ltd. Yuanli Co., Ltd. Shanghai Aladdin Bio- Chem Co., Ltd.

≥0.990 ≥0.995 ≥0.995 ≥0.995 ≥0.995 ≥0.995 ≥0.995 ≥0.995 ≥0.995 ≥0.995 ≥0.990

recrystallized none none none none none none none none none none

HPLCa GCb GCb GCb GCb GCb GCb GCb GCb GCb HPLCa

a

High-performance liquid chromatography. bGas chromatograph analysis.

Figure 2. DSC and TG curves of imatinib mesylate. Figure 4. X-ray powder diffraction patterns of imatinib mesylate in different solvents at 318.15 K: (1) simulated from the reported singlecrystal structure, (2) prepared imatinib mesylate, (3) residual solids in methanol, (4) residual solids in ethanol, (5) residual solids in 1-propanol, (6) residual solids in 2-propanol, (7) residual solids in acetonitrile, (8) residual solids in tetrahydrofuran, (9) residual solids in 1-butanol, (10) residual solids in isobutanol, and (11) residual solids in methyl acetate.

at 323.15 K for 24 h. After filtering the solution, the precipitates were dried for 24 h for further examination. 2.2. Characterization. Powder X-ray diffraction (PXRD, D/MAX 2500 diffractometer, Rigaku, Japan) using Cu Kα radiation (1.541845 Å) was carried out to confirm the crystal form. All the samples, including the raw powder and the equilibrium solid phase, were scanned at a speed of 8° per minute at room temperature. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) (Model TGA/DSC, Mettler Toledo, Switzerland) calibrated by standard indium and zinc under a nitrogen atmosphere were used to determine the thermodynamic properties. Figure 2 depicts the results of characterization above. 2.3. Apparatus and Procedure. The solubility of imatinib mesylate in nine monosolvents (acetonitrile, tetrahydrofuran, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, and methyl acetate) and two binary solvents (methanol + ethanol and methanol + 2-propanol) was measured via shaken flask method followed by UV composition analysis. The UV

Figure 3. Absorbance versus concentration (mg·mL−1) calibration curve (measured at 287 nm).

2. EXPERIMENTAL SECTION 2.1. Materials. Detailed information on chemicals used in this work is reported in Table 1. As the raw material is metastable form, recrystallization was used to transform it into stable form β.14 The raw material (8 g) was further purified by stirring in a 1:9 molar ratio of methanol/ethanol solvent (320 g) B



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Table 2. Experimental and Calculated Solubility of Imatinib Mesylate in Pure Solvents at Different Temperatures (p = 0.1 MPa)a temperature (K)

103 xexp

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.9124 1.1542 1.6715 2.3172 3.0803 4.1140 5.3270 6.7336 8.5961

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.0839 0.1308 0.1832 0.2457 0.3200 0.4167 0.5457 0.6782 0.8779

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.0339 0.0458 0.0628 0.0892 0.1178 0.1556 0.1994 0.2451 0.3040

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.0101 0.0118 0.0153 0.0203 0.0270 0.0354 0.0428 0.0534 0.0710

278.15 283.15 288.15 293.15 298.15

0.0169 0.0229 0.0299 0.0418 0.0579

103 xcal (Apelbat) methanol 0.8719 1.2218 1.6847 2.2881 3.0633 4.0460 5.2757 6.7960 8.6541 ethanol 0.0871 0.1259 0.1771 0.2430 0.3257 0.4270 0.5482 0.6902 0.8528 1-propanol 0.0330 0.0468 0.0649 0.0881 0.1173 0.1531 0.1962 0.2473 0.3067 2-propanol 0.0096 0.0123 0.0159 0.0204 0.0262 0.0336 0.0430 0.0552 0.0706 1-butanol 0.0165 0.0230 0.0315 0.0422 0.0556

103 xcal (λh)

103 xcal (NRTL)

temperature (K)

103 xexp

0.8883 1.2265 1.6744 2.2616 3.0237 4.0036 5.2519 6.8287 8.8035

0.8880 1.2267 1.6724 2.2589 3.0247 4.0052 5.2572 6.8416 8.7945

303.15 308.15 313.15 318.15

0.0751 0.0903 0.1110 0.1420

0.0920 0.1268 0.1729 0.2332 0.3115 0.4122 0.5405 0.7027 0.9063

0.0932 0.1267 0.1712 0.2300 0.3073 0.4080 0.5388 0.7075 0.9238

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.0146 0.0209 0.0273 0.0387 0.0522 0.0681 0.0844 0.1007 0.1360

0.0345 0.0472 0.0638 0.0855 0.1133 0.1488 0.1937 0.2502 0.3205

0.0352 0.0473 0.0632 0.0841 0.1114 0.1469 0.1927 0.2518 0.3274

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.0109 0.0127 0.0165 0.0219 0.0287 0.0370 0.0467 0.0574 0.0754

0.0092 0.0122 0.0160 0.0208 0.0268 0.0342 0.0434 0.0546 0.0682

0.0087 0.0117 0.0156 0.0205 0.0269 0.0348 0.0448 0.0571 0.0723

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.0290 0.0416 0.0552 0.0748 0.0943 0.1150 0.1520 0.2010 0.2388

0.0172 0.0232 0.0310 0.0411 0.0539

0.0176 0.0233 0.0307 0.0403 0.0528

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.0016 0.0019 0.0026 0.0034 0.0045 0.0057 0.0074 0.0095 0.0115

103 xcal (Apelbat) 1-butanol 0.0718 0.0913 0.1143 0.1408 isobutanol 0.0146 0.0206 0.0284 0.0385 0.0510 0.0663 0.0846 0.1063 0.1314 acetonitrile 0.0104 0.0133 0.0170 0.0219 0.0280 0.0359 0.0460 0.0590 0.0755 tetrahydrofuran 0.0297 0.0406 0.0546 0.0723 0.0944 0.1214 0.1541 0.1932 0.2394 methyl acetate 0.0015 0.0020 0.0026 0.0034 0.0044 0.0057 0.0073 0.0093 0.0118

103 xcal (λh)

103 xcal (NRTL)

0.0700 0.0903 0.1155 0.1466

0.0690 0.0897 0.1163 0.1502

0.0152 0.0207 0.0280 0.0373 0.0492 0.0645 0.0837 0.1077 0.1376

0.0151 0.0207 0.0280 0.0374 0.0494 0.0647 0.0839 0.1079 0.1375

0.0100 0.0132 0.0172 0.0224 0.0288 0.0367 0.0465 0.0584 0.0729

0.0093 0.0125 0.0167 0.0220 0.0288 0.0373 0.0480 0.0612 0.0775

0.0305 0.0408 0.0541 0.0711 0.0926 0.1196 0.1532 0.1947 0.2457

0.0311 0.0409 0.0535 0.0699 0.0909 0.1179 0.1525 0.1964 0.2520

0.0015 0.0020 0.0026 0.0034 0.0045 0.0057 0.0073 0.0093 0.0116

0.0014 0.0019 0.0026 0.0034 0.0045 0.0058 0.0074 0.0095 0.0120

a exp

x is the experimental solubility of imatinib mesylate in pure solvents; xcal (Apelbat), xcal (λh), and xcal (NRTL) are the calculated solubility by eqs 3, 4, and 8, respectively. The relative standard uncertainty of the solubility measurement is ur(x) = 0.027. The standard uncertainty of temperature is u(T) = 0.05 K. The relative uncertainty of pressure is ur(P) = 0.05.

The apparatus and procedure used in this research are similar to those in the previous work.16,17 First, a 50 mL conical flask with a given monosolvent or binary solvent of approximate 20 g was put into a thermostatic mechanical shaker (Tianjin Ounuo Instrument Co. Ltd., China) to control temperature. When the actual temperature of solvents reached the set temperature, excessive amount of imatinib mesylate was introduced. Then, the hermetic conical flasks in the thermostatic mechanical shaker were agitated for at least 18 h at a

method has been proven to be suitable for the concentration measurement of imatinib mesylate previously15 (see Supporting Information for the method verification.) The maximal absorption wavelength of imatinib mesylate is 287 nm experimentally, which is fundamentally consistent with the previous work.15 Before the measurement of solubility data, the calibration curves of imatinib mesylate in water and ethanol at room temperature were obtained using a UV-3010 spectrophotometer (HITACHI, Japan), and the results are shown in Figure 3. C



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solution. Supernatant of known weight was filtered via a preheated or precooled organic membrane (0.22 μm) and then diluted to the proper concentration with water or ethanol. After that, the concentration was measured. All of the masses were weighted by an analytical balance with an accuracy of 0.0001 g (AL204, Mettler Toledo, Switzerland). The experiments were carried out at least three times to make the results more credible. The solubility of imatinib mesylate was calculated using the equations below: A−b V a

ms =

x=

(1)

ms Ms ms Ms

m

+ ∑ Ml

(2)

l

where a and b are the slope and intercept of calibration curve; V is dilution volume; x is the mole fraction solubility of imatinib mesylate; A is the absorbance of diluted solution obtained from the UV spectrophotometer; Ms and Ml are the molar masses of imatinib mesylate and solvents; and ms and ml are the masses of imatinib mesylate and solvents, respectively.

3. THERMODYNAMIC MODELS The main objective of this work is to provide basic solid− liquid phase equilibrium data for the pharmaceutical industry. For the purpose of extension of the data we obtained, four classic thermodynamic models, the Apelblat model, λh equation, combined nearly ideal binary solvent/Redlich-Kister (CNIBS/R-K) model, and nonrandom two-liquid (NRTL) model, were applied to describe the experimental solubility data in monosolvents and mixed solvents. 3.1. Apelblat Model. The Apelblat model, as a frequently used semiempirical equation, was used to represent the solubility against temperature.18−20 The model can be applied in both monosolvents and mixed solvents. The expression is as follows: Figure 5. Experimental solubility data of imatinib mesylate in monosolvents at different temperatures from 278.15 to 318.15 K (p = 0.1 MPa).

ln x = A +

B + C ln(T /K) T /K

(3)

where T is the absolute temperature; x is the solubility of imatinib mesylate in solvents; and A, B, and C are semiempirical constants. The values of A and B are influenced by the nonidealities of the real solution in terms of the variation of activity coefficient. The value of C indicates how temperature affects fusion enthalpy.21

given temperature to confirm that it has enough time to reach the solid−liquid equilibrium, which was proved in preliminary experiment. Before determining the concentration, the stirring was suspended and the system was maintained at the given temperature to ensure the residual solid precipitate from the Table 3. Properties of Solvents Used in This Work solvent name

πa

∑αb

∑βc

dielectric constantd

cohesive energy densitye

viscosityf

methanol ethanol 1-propanol 2-propanol 1-butanol isobutanol acetonitrile tetrahydrofuran methyl acetate

0.60 0.54 0.52 0.48 0.47 0.40 0.75 0.58 0.60

0.43 0.37 0.37 0.33 0.37 0.33 0.07 0.00 0.00

0.47 0.48 0.48 0.56 0.48 0.56 0.32 0.48 0.45

32.61 24.85 20.52 19.26 17.33 15.94 35.69 7.43 6.86

858 676 595 562 543 524 581 361 372

0.54 1.07 1.95 2.04 2.54 3.10 0.37 0.46 0.36

a Polarity/dipolarity of the solvent. bSummation of the hydrogen bond donor propensities of the solvent. cSummation of the hydrogen bond acceptor propensities of the solvent. dDielectric constant. eCohesive energy density in the unit of J·cm−3. fViscosity of the solvent at 298.15 K in the unit of mPa·s.

D



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Table 4. Parameters of Apelblat Model for Imatinib Mesylate in Pure Solvents solvent

A

B

C

ARD (%)

104RMSD


106.5103 310.7806 243.4212 −181.0106 217.1768 240.0612 −191.7905 130.4763 −81.8489

−9307.6727 −18450.6695 −15410.3751 3813.5885 −14118.8024 −15239.9173 4314.1295 −10132.4196 −768.0721

−14.2306 −45.0938 −35.2404 27.6728 31.5256 −34.8973 29.2822 −18.5623 12.6536

1.9008 2.3731 1.6566 2.9217 2.5166 2.3153 2.5180 2.2477 2.2072

0.5248 0.1115 0.0212 0.0101 0.0200 0.0271 0.0083 0.0377 0.0015

Table 5. Parameters of λh Equation for Imatinib Mesylate in Pure Solvents solvent

102 λ

10−5 h

ARD (%)

104 RMSD


236.8928 23.4245 7.1330 0.8594 2.6490 2.8660 0.9027 3.8689 0.1664

0.02146 0.21580 0.68977 5.12643 1.78628 1.69890 4.86322 1.19085 27.16609

2.3591 3.8781 3.2698 3.4521 3.2838 3.4625 2.8193 2.9215 2.2771

1.0124 0.1527 0.0720 0.0126 0.0326 0.0310 0.0107 0.0402 0.0012

ln x = B0 + B1xA0 + B2 (xA0 )2 + B3(xA0 )3 + B4 (xA0 )4

where B0, B1, B2, B3, and B4 are all parameters of the model. 3.4. NRTL Model. Based on the concept of local composition proposed by Wilson, Renon and Prausnitz developed the NRTL model to describe solubility data in nonideal solution.26 Prausnitz et al. commented that the solubility can be calculated according to the formula below after simplification:27 ln xi =

ln γi =

ln x =

XA +

XB +

xA0x B0

∑ i=0

Si(xA0

−

x B0)i

(7)

(Gjixj + Gkixk)(τjiGjixj + τkiGkixk)

+

+

(xi + xjGji + xkGki)2 [τijGijxj2 + GijGkjxjxk(τij − τkj)] (xj + xiGij + xkGkj)2

[τijGik xk2 + Gik Gjk xjxk(τik − τjk)] (xk + xiGik + xjGjk )2

N

x B0 ln

ΔfusH ijj 1 1 yz − zzz − ln γi jjj R k Tm T z{

where ΔfusH refers to the fusion enthalpy of solute, and γi represents activity coefficient of component i in real solution. In monosolvents and binary solvents, the activity coefficient γi can be obtained using eq 8 and eq 9, respectively:26,28 ÅÄÅ ÑÉÑ Å ÑÑ τjiGji2 τijGij2 2Å Å ÑÑ ln γi = xj ÅÅÅ + 2 2Ñ ÑÑ ÅÅ (xi + Gjixj) ( x + G x ) ÑÑÖ j ij i (8) ÅÇ

3.2. λh Equation. According to the classical theory of solid−liquid equilibrium, λh equation could also be cited to fit solubility data. It presents the relationship between solubility and temperature.22 The expression is shown below: ÉÑ ÄÅ ÄÅ É ÅÅ 1 λ(1 − x) ÑÑÑÑ 1 ÑÑÑ ÅÅÅ Å ÑÑ lnÅÅ1 + ÑÑ = λ hÅÅÅ − ÅÅÇ ÑÑÖ ÅÅÇ T x Tm ÑÑÑÖ (4) where h and λ represent the parameters of λh equation, and Tm is melting point of solute which was obtained via DSC detection in this work. 3.3. CNIBS/R-K Model. The CNIBS/R-K model was employed to describe the relationship between proportion of binary solvent mixtures and isothermal solubility.23,24 It can be expressed by eq 5: xA0 ln

(6)

(9)

where Gji, Gij, Gik, Gki, Gjk, Gkj, τji, τij, τki, τik, τkj, and τjk are parameters of NRTL model. They can be expressed as below:

(5)

where N is the number of the solvents; x0A and x0B are the initial mole fraction of organic solvents, which are calculated assuming solute is not present; XA and XB are the mole fraction of solute in monosolvents, respectively; and Si is the model constant. In binary solvents, the equation can be modified to eq 6:24,25

Gij = exp( −αijτij) τij =

gij − gjj RT

=

(10)

Δgij (11)

RT

Table 6. Parameters of NRTL Model for Imatinib Mesylate in Pure Solvents solvent

α12

10−4 Δg12

10−4 Δg21

ARD (%)

105 RMSD


0.3400 0.0001 0.0001 0.0511 0.0001 0.0564 0.0514 0.0001 0.0436

−0.5523 −63.7565 −71.2931 9.6400 −75.8013 10.2911 9.5808 −75.2187 11.2580

0.0931 64.9133 73.1195 −1.2283 78.0874 −1.0411 −1.2319 77.3331 −1.0098

2.3018 4.8785 3.9351 3.7436 4.4245 3.2192 3.4595 3.6555 2.2805

8.6810 2.0362 0.8418 0.1552 0.4253 0.2891 0.1598 0.5221 0.0187

E



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Table 7. Experimental and Calculated Solubility of Imatinib Mesylate in Binary Solvent (Methanol + Ethanol) at Different Temperatures (p = 0.1 MPa)a x0A

103 xexp

103 xcal (Apelblat)

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.0839 0.1231 0.1422 0.1783 0.2112 0.2642 0.3289 0.4143 0.5071 0.6722 0.9124

0.0871 0.1241 0.1401 0.1755 0.2047 0.2631 0.3310 0.4233 0.5318 0.6896 0.8719

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.1308 0.1692 0.1981 0.2461 0.2841 0.3678 0.4771 0.5951 0.7830 0.9593 1.1491

0.1259 0.1685 0.2027 0.2533 0.3074 0.3816 0.4855 0.5995 0.7281 0.9219 1.2218

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.1832 0.2231 0.2778 0.3489 0.4537 0.5426 0.7082 0.8681 0.9968 1.2280 1.6683

0.1771 0.2260 0.2835 0.3521 0.4388 0.5338 0.6858 0.8267 0.9841 1.2302 1.6847

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.2457 0.3089 0.4031 0.4878 0.6372 0.7664 0.9791 1.1481 1.3070 1.6412 2.3092

0.2430 0.2996 0.3839 0.4725 0.5974 0.7217 0.9348 1.1116 1.3140 1.6386 2.2881

0 0.1 0.2 0.3 0.4 0.5

0.3200 0.4061 0.5019 0.6221 0.7911 0.9511

0.3257 0.3929 0.5044 0.6135 0.7781 0.9452

103 xcal (CNIBS/R-K)

T = 278.15 K 0.0896 0.1141 0.1430 0.1771 0.2175 0.2662 0.3270 0.4060 0.5143 0.6710 0.9122 T = 283.15 K 0.1344 0.1644 0.1984 0.2400 0.2946 0.3687 0.4694 0.6036 0.7730 0.9660 1.1474 T = 288.15 K 0.1922 0.2155 0.2674 0.3469 0.4509 0.5726 0.7037 0.8420 1.0036 1.2374 1.6648 T = 293.15 K 0.2586 0.2996 0.3796 0.4957 0.6401 0.7992 0.9598 1.1237 1.3233 1.6453 2.3066 T = 298.15 K 0.3299 0.3951 0.4940 0.6258 0.7870 0.9727

103 xcal (NRTL) 0.0932 0.1313 0.1577 0.1914 0.2345 0.2897 0.3601 0.4486 0.5563 0.6779 0.8880 0.1267 0.1730 0.2080 0.2527 0.3101 0.3839 0.4785 0.5988 0.7470 0.9203 1.2267 0.1712 0.2266 0.2727 0.3317 0.4075 0.5056 0.6319 0.7940 0.9981 1.2416 1.6724 0.2300 0.2951 0.3555 0.4329 0.5326 0.6620 0.8296 1.0470 1.3243 1.6612 2.2589 0.3073 0.3823 0.4611 0.5622 0.6927 0.8628

x0A

103 xexp

103 xcal (Apelblat)

0.6 0.7 0.8 0.9 1

1.1831 1.4433 1.7427 2.2103 3.0783

1.2326 1.4597 1.7344 2.1785 3.0633

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.4167 0.4948 0.6462 0.7694 0.9453 1.1701 1.5481 1.8192 2.2412 2.8069 4.0992

0.4270 0.5099 0.6442 0.7722 0.9720 1.2014 1.5752 1.8745 2.2644 2.8908 4.0460

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.5457 0.6352 0.7831 0.9171 1.1377 1.4513 1.9421 2.3090 2.8194 3.7912 5.2981

0.5482 0.6553 0.8009 0.9440 1.1678 1.4847 1.9548 2.3571 2.9259 3.8286 5.2757

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.6782 0.8362 0.9792 1.1331 1.3225 1.7412 2.4054 2.8632 3.7231 5.1053 6.7282

0.6902 0.8344 0.9711 1.1228 1.3524 1.7870 2.3597 2.9060 3.7437 5.0607 6.7960

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.8779 1.0731 1.1525 1.3080 1.5647 2.1785 2.7753 3.6392 4.8927 6.7250 8.5961

0.8528 1.0531 1.1499 1.3015 1.5131 2.0978 2.7753 3.5164 4.7454 6.6760 8.6541


T = 298.15 K 1.1816 1.4251 1.7415 2.2216 3.0749 T = 303.15 K 0.4386 0.4870 0.5964 0.7621 0.9765 1.2273 1.5032 1.8130 2.2118 2.8476 4.0887 T = 308.15 K 0.5634 0.6190 0.7421 0.9299 1.1803 1.4900 1.8572 2.3013 2.8829 3.7589 5.3027 T = 313.15 K 0.6994 0.8048 0.9489 1.1441 1.4078 1.7640 2.2476 2.9072 3.8085 5.0427 6.7406 T = 318.15 K 0.9006 1.0136 1.1555 1.3543 1.6466 2.0811 2.7257 3.6636 4.9702 6.6618 8.6104

103 xcal (NRTL) 1.0845 1.3732 1.7445 2.2046 3.0247 0.4080 0.4928 0.5949 0.7263 0.8965 1.1186 1.4081 1.7901 2.2841 2.9075 4.0052 0.5388 0.6318 0.7636 0.9336 1.1541 1.4421 1.8188 2.3188 2.9719 3.7954 5.2572 0.7075 0.8058 0.9752 1.1938 1.4788 1.8503 2.3365 2.9871 3.8337 4.9098 6.8416 0.9238 1.0227 1.2397 1.5199 1.8850 2.3598 2.9901 3.8213 4.9083 6.2993 8.7945

a exp

x is the experimental solubility of imatinib mesylate in binary solvent (methanol + ethanol); xcal (Apelbat), xcal (CNIBS/R-K). and xcal (NRTL) are the calculated solubility by eqs 3, 6, and 9, respectively. The relative standard uncertainty of the solubility measurement is ur(x) = 0.052. The relative standard uncertainty of the initial mole fraction of methanol x0A is ur(x0A) = 0.006. The standard uncertainty of temperature is u(T) = 0.05 K. The relative uncertainty of pressure is ur (P) = 0.05. F



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Table 8. Experimental and Calculated Solubility of Imatinib Mesylate in Binary Solvent (Methanol + 2-Propanol) at Different Temperatures (p = 0.1 MPa)a x0A

103 xexp

103 xcal (Apelbat)

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.0101 0.0149 0.0171 0.0290 0.0512 0.0840 0.1383 0.2152 0.3458 0.5423 0.9124

0.0096 0.0146 0.0173 0.0287 0.0511 0.0863 0.1394 0.2177 0.3530 0.5308 0.8719

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.0118 0.0178 0.0232 0.0377 0.0660 0.1146 0.1784 0.2860 0.4618 0.6941 1.1493

0.0123 0.0183 0.0230 0.0380 0.0660 0.1103 0.1781 0.2824 0.4518 0.7114 1.2218

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.0153 0.0229 0.0299 0.0487 0.0840 0.1378 0.2273 0.3641 0.5815 0.9389 1.6681

0.0159 0.0230 0.0304 0.0496 0.0837 0.1378 0.2224 0.3561 0.5702 0.9378 1.6847

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.0203 0.0287 0.0411 0.0654 0.1020 0.1702 0.2679 0.4252 0.6998 1.1895 2.3089

0.0204 0.0288 0.0399 0.0639 0.1042 0.1685 0.2719 0.4375 0.7100 1.2173 2.2881

0 0.1 0.2 0.3 0.4 0.5

0.0270 0.0365 0.0523 0.0807 0.1283 0.2032

0.0262 0.0360 0.0523 0.0812 0.1276 0.2020


T = 278.15 K 0.0107 0.0129 0.0187 0.0299 0.0500 0.0838 0.1372 0.2187 0.3427 0.5435 0.9123 T = 283.15 K 0.0141 0.0161 0.0231 0.0376 0.0645 0.1104 0.1834 0.2919 0.4510 0.6995 1.1485 T = 288.15 K 0.0174 0.0206 0.0299 0.0485 0.0821 0.1388 0.2286 0.3654 0.5780 0.9408 1.6678 T = 293.15 K 0.0222 0.0277 0.0403 0.0636 0.1035 0.1682 0.2697 0.4290 0.6938 1.1923 2.3085 T = 298.15 K 0.0258 0.0360 0.0535 0.0823 0.1288 0.2034

103 xcal (NRTL) 0.0087 0.0127 0.0199 0.0317 0.0512 0.0834 0.1368 0.2244 0.3697 0.6383 0.8880 0.0117 0.0167 0.0258 0.0405 0.0644 0.1035 0.1678 0.2733 0.4506 0.7903 1.2267 0.0156 0.0217 0.0331 0.0512 0.0804 0.1279 0.2052 0.3324 0.5493 0.9767 1.6724 0.0205 0.0279 0.0420 0.0643 0.0999 0.1572 0.2503 0.4039 0.6694 1.2075 2.2589 0.0269 0.0355 0.0530 0.0802 0.1234 0.1924

x0A

103 xexp

103 xcal (Apelbat)

0.6 0.7 0.8 0.9 1

0.3275 0.5265 0.8810 1.5801 3.0782

0.3259 0.5245 0.8728 1.5571 3.0633

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.0354 0.0451 0.0690 0.1015 0.1569 0.2333 0.3846 0.6221 1.0504 2.0107 4.0991

0.0336 0.0448 0.0680 0.1019 0.1539 0.2377 0.3832 0.6145 1.0602 1.9643 4.0460

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.0428 0.0561 0.0870 0.1273 0.1806 0.2705 0.4433 0.6981 1.2695 2.4812 5.2980

0.0430 0.0556 0.0881 0.1264 0.1828 0.2749 0.4427 0.7045 1.2733 2.4459 5.2757

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.0534 0.0680 0.1081 0.1555 0.2165 0.3106 0.4892 0.7867 1.4806 2.9310 6.7282

0.0552 0.0688 0.1136 0.1550 0.2141 0.3127 0.5030 0.7915 1.5130 3.0082 6.7960

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0.0710 0.0849 0.1523 0.1872 0.2456 0.3573 0.5742 0.8787 1.8193 3.6705 8.5961

0.0706 0.0850 0.1458 0.1882 0.2474 0.3502 0.5626 0.8724 1.7798 3.6568 8.6541


T = 298.15 K 0.3243 0.5262 0.8845 1.5782 3.0785 T = 303.15 K 0.0304 0.0467 0.0703 0.1050 0.1572 0.2391 0.3745 0.6134 1.0676 2.0032 4.1001 T = 308.15 K 0.0389 0.0595 0.0874 0.1265 0.1838 0.2743 0.4275 0.7089 1.2690 2.4800 5.2982 T = 313.15 K 0.0539 0.0747 0.1046 0.1479 0.2129 0.3153 0.4885 0.8069 1.4559 2.9404 6.7271 T = 318.15 K 0.0729 0.0996 0.1336 0.1799 0.2487 0.3601 0.5578 0.9415 1.7594 3.6910 8.5938

103 xcal (NRTL) 0.3042 0.4895 0.8143 1.4878 3.0247 0.0348 0.0449 0.0662 0.0994 0.1515 0.2345 0.3687 0.5923 0.9902 1.8312 4.0052 0.0448 0.0562 0.0823 0.1224 0.1851 0.2846 0.4456 0.7158 1.2017 2.2511 5.2572 0.0571 0.0698 0.1015 0.1498 0.2250 0.3441 0.5371 0.8632 1.4573 2.7661 6.8416 0.0723 0.0862 0.1243 0.1824 0.2723 0.4145 0.6453 1.0389 1.7608 3.3778 8.7945

a exp

x is the experimental solubility of imatinib mesylate in binary solvent (methanol + 2-propanol); xcal (Apelbat), xcal (CNIBS/R-K), and xcal (NRTL) are the calculated solubility by eqs 3, 6, and 9, respectively. The relative standard uncertainty of the solubility measurement is ur(x) = 0.065. The relative standard uncertainty of the initial mole fraction of methanol x0A is ur(x0A) = 0.008. The standard uncertainty of temperature is u(T) = 0.05 K. The relative uncertainty of pressure is ur (P) = 0.05. G



αij = αji

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(12)

where α is an empirical parameter depending on different systems between 0 and 1, and g is a parameter reflecting the cross interaction energy between components i and j. In this work, Apelblat and NRTL models were selected for correlation of solubility in both monosolvents and binary solvent mixtures, while λh equation is only for pure solvents, and CNIBS/R-K model is only for binary solvents. To evaluate the fitting effect of the models above, we defined the average relative deviation (ARD) and the root-mean-square deviation (RMSD) as follows: N

ARD =

x exp − x cal 1 ∑ i exp i N i=1 xi

ÄÅ ÉÑ1/2 N ÅÅ 1 ÑÑ ÅÅ exp cal 2 Ñ (xi − xi ) ÑÑÑ RMSD = ÅÅ ∑ ÅÅ N − 1 ÑÑ ÑÖ i=1 ÅÇ

(13) Figure 6. Experimental solubility x of imatinib mesylate versus initial mole fraction of methanol (x0A) in the binary solvent (methanol + ethanol) at different temperatures from 278.15 to 318.15 K (p = 0.1 MPa).

(14)

where the superscript exp and cal represent the experimental value and calculated data, respectively, and N represents the number of solubility data points.

4. RESULTS AND DISCUSSION 4.1. Thermal Analysis (DSC/TGA). The melting properties of imatinib mesylate were determined by DSC and TGA, shown in Figure 2. The thermal analysis was performed at the heating rate of 10 K·min−1 under a dynamic nitrogen atmosphere whose flowing rate is 50 mL·min−1. A negligible weight loss can be observed up to 543.15 K. There is a clear exothermic peak attributed to the melt of the sample. The onset temperature (Tonset) is 488.32 K (the expanded uncertainty is U = 0.5 K, 0.95 of confidence for uncertainty), regarded as melting point (Tm). At the same time, the fusion enthalpy (ΔfusH) is 112.03 J·g−1 (the expanded uncertainty is U = 5.45 J·g−1, 0.95 of confidence for uncertainty). The experimental data we obtained are consistent with the research reported before.1,29 4.2. X-ray Powder Diffraction Analysis. The raw powder and residual solid in distinct conditions were collected for PXRD testing. A comparison of the results obtained from experimental data and simulated from the reported singlecrystal structure29 verifies that the β form of imatinib mesylate is stable during the whole solubility measurement process and that there is no polymorphic transformation. A part of diffraction result was taken as an example and is shown in Figure 4. 4.3. Solubility Data. 4.3.1. Solubility in Pure Solvents. Table 2 reveals the measured mole fraction solubility data in nine monosolvents (acetonitrile, tetrahydrofuran, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, and methyl acetate) between 278.15 and 318.15 K, which are graphically shown in Figure 5. It is illustrated that the sequence of solubility at the same temperature is methyl acetate < 2-propanol < acetonitrile < isobutanol < 1-butanol < tetrahydrofuran < 1-propanol < ethanol < methanol. All the experimental data increase apparently with the increasing temperature, and the slope of the solubility also increases, which indicates cooling should be a suitable crystallization method for imatinib mesylate. Solvent properties were collected to explain the effect of solvent on solubility, shown in Table 3.30,31 There is a wellknown empirical rule named “like dissolves like”32 to describe dissolution phenomenon. Because polarity is suitable for

Figure 7. Experimental solubility x of imatinib mesylate versus initial mole fraction of methanol (x0A) in the binary solvent (methanol + 2-propanol) at different temperatures from 278.15 to 318.15 K (p = 0.1 MPa).

judgment with dielectric constant,33 the order of the polarity of the nine monosolvents is methyl acetate < tetrahydrofuran < isobutanol < 1-butanol < 2-propanol < 1-propanol < ethanol < methanol < acetonitrile. As imatinib mesylate is a polar compound, the principle above seems to accord well with the results in short chain alcohols. However, this rule does not apply to the other solvents. The reason may lie in that dissolution is a complex process and cannot be described clearly with only one parameter. The formation of hydrogen bonds may be another vital factor that affects solubility. There are many hydrogen bond donors and receptors in imatinib mesylate (Figure 1), which may increase the potential for hydrogen bond formation, thereby influencing the capacity of dissolution. The higher polarity in company with the greater hydrogen bond donor propensities may cause the apparently higher solubility of imatinib mesylate in methanol than in other studied solvents. Additionally, the steric effect is also a factor that cannot be ignored. Imatinib mesylate is a relatively large molecule because of its functional group with ring structure; when interacting with the solvents with larger molecular weight, the steric effect may play an important role compared with hydrogen bonds. Further, cohesive energy density, van der Waals force, and other factors can also affect the solubility. H



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summarized in Tables 7 and 8 and plotted in Figures 6 and 7. In methanol + ethanol binary mixed solvent, the solubility of imatinib mesylate increases with the proportion of methanol at a constant temperature. That is to say, there is no cosolvency34 phenomenon in the mixture systems we measured, indicating antisolvent crystallization is suitable in these mixture systems for imatinib mesylate. Meanwhile, what can be observed is the solubility is also enhanced with temperature at a given fraction of methanol, which is similar to the phenomenon in pure solvents. Likewise, the solubility in the binary solvent (methanol + 2-propanol) also fits the analysis above. As Figures 6 and 7 show, the solubility increases strongly with the fraction of methanol. That is probably because methanol significantly enhances the polarity of solvent and highly improves the interaction between solute and solvent. The Apelblat model, CNIBS/R-K model, and NRTL model were applied to obtain the fitting curves based on the experimental solubility data in two binary solvents. The results of correlation are given in Tables 7 and 8; meanwhile, Tables 9−11

Table 9. Parameters of Apelblat Model for Imatinib Mesylate in Binary Solvents x0A

A

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

41.8008 477.8396 549.9617 804.4382 517.4110 544.9579 331.3590 52.6783 −170.4677

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

−106.1112 −84.9813 111.2287 223.6503 307.7581 313.4787 414.7791 130.2510 145.9481

B

C

methanol + ethanol −6230.3413 −5.0453 −25518.1411 −70.1776 −28520.3690 −81.0342 −39802.9773 −119.0146 −27192.4621 −76.0270 −28498.4804 −80.0464 −18989.4221 −48.1251 −6742.2037 −6.3925 3022.6476 27.0641 methanol + 2-propanol 934.7133 16.2776 −682.5752 13.5867 −8897.7043 −15.9374 −13300.2009 −32.9977 −16679.4782 −45.6898 −16902.4516 −46.4787 −21365.8874 −61.5471 −9142.4969 −18.7150 −10401.2386 −20.6275

ARD (%)

104 RMSD

1.9003 1.6438 1.6252 3.7181 2.6180 2.0655 2.4418 2.5056 1.5383

0.1278 0.1016 0.1253 0.3108 0.4033 0.3158 0.5666 0.6884 0.4411

1.1770 2..0515 0.9560 0.9305 1.5938 1.1622 1.2664 1.5719 1.6952

0.0047 0.0308 0.0086 0.0189 0.0391 0.0681 0.0708 0.1992 0.3755

Table 11. Parameters of NRTL Model for Imatinib Mesylate in Two Binary Mixed Solvents

The Apelblat model, λh equation, and NRTL model were adopted to reflect the relationship of temperature and solubility data in nine monosolvents. Table 2 summarizes the correlated solubility data and the values of ARD; RMSD and the model parameters can be found from Tables 4−6. The values of ARD are all less than 4.0%, indicating the relatively ideal fitting effect, especially for the Apelblat model. 4.3.2. Solubility in Binary Solvents. In the pharmaceuticals industry, mixed solvents are frequently used in crystallization to obtain the high-quality product such as targeted crystal habit and desired polymorphic forms. In this work, we chose two binary solvents to test the solubility of imatinib mesylate. Methanol, as the solubility of imatinib mesylate is highest among these solvents in this work, was selected to be the good solvent. The experimental data in binary solvents are

parameters

methanol + ethanol

methanol + 2-propanol

10−5 Δg12 10−5 Δg13 10−5 Δg21 10−5 Δg23 10−5 Δg31 10−5 Δg32 α12 α13 α23 ARD (%) 104 RMSD

−0.1949 0.6405 0.1706 0.0207 −0.3953 −0.0137 0.0440 0.0240 0.8800 5.8519 0.9813

−0.0947 1.4086 0.0979 0.0592 −0.1037 −0.0102 0.2100 0.0448 0.6800 5.9349 0.6052

summarize the values of ARD, RMSD, and the model parameters. From the tables, it is shown that the calculated solubility by the three models is in good agreement with experimental solubility in binary solvents.

Table 10. Parameters of CNIBS/R-K Model for Imatinib Mesylate in Binary Solvents temperature (K)

B0

B1

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−9.3201 −8.9147 −8.5570 −8.2604 −8.0166 −7.7320 −7.4816 −7.2653 −7.0124

2.4935 2.1624 0.4004 0.7831 1.4555 0.3271 0.3302 1.2758 1.1844

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−11.4463 −11.1730 −10.9614 −10.7156 −10.5663 −10.4018 −10.1535 −9.8283 −9.5264

0.7138 −0.1243 0.3815 1.1637 2.9258 4.4175 4.5106 3.2174 3.2818

B2

B3

methanol + ethanol −0.8324 0.1457 −1.8664 4.4662 8.7211 −13.6549 8.2733 −14.4306 4.1750 −7.6438 8.4746 −13.4789 7.1036 −10.3000 1.3263 −0.3595 −0.3931 4.0570 methanol + 2-propanol 13.5227 −17.0771 16.9750 −21.4651 15.3654 −20.0751 12.0614 −16.5777 4.7893 −6.5882 −1.4128 1.3929 −3.1322 4.1039 0.5702 −0.8474 −2.0303 3.8342 I

B4

ARD (%)

105 RMSD

0.5166 −2.6165 6.6985 7.5726 4.2574 6.9282 5.1300 0.0433 −2.5708

2.1212 1.5704 2.1929 2.3766 1.1691 2.7223 2.4296 2.7742 2.4351

0.5339 0.6809 1.4162 1.7913 1.1194 3.4651 4.2524 6.9628 5.9721

7.2924 9.0241 8.9044 8.0145 3.6791 0.5397 −0.5245 1.9504 −0.2323

3.4219 3.9417 2.5938 2.0902 1.1032 2.8778 2.2371 2.4467 4.7352

0.1819 0.4831 0.1810 0.2763 0.1780 0.7775 0.6484 1.1232 2.9769



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Table 12. Mixing Thermodynamic Properties of the Solution with the Pure Solvents at Different Temperaturesa temperature (K)

ΔmixG (J·mol−1)

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−27.35 −34.03 −48.16 −65.09 −84.93 −110.59 −140.01 −174.25 −217.76

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−2.54 −3.84 −5.25 −6.89 −8.79 −11.21 −14.36 −17.52 −22.16

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1.08 −1.35 −1.81 −2.50 −3.23 −4.17 −5.23 −6.32 −7.69

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−0.31 −0.37 −0.47 −0.60 −0.77 −0.96 −1.14 −1.39 −1.79

278.15 283.15 288.15 293.15 298.15

−0.51 −0.67 −0.86 −1.17 −1.58

ΔmixH (J·mol−1) methanol −19.65 −24.19 −34.29 −46.32 −60.30 −78.42 −99.01 −122.82 −153.19 ethanol −2.04 −3.10 −4.22 −5.51 −7.00 −8.88 −11.32 −13.72 −17.31 1-propanol −0.96 −1.19 −1.58 −2.17 −2.78 −3.57 −4.44 −5.29 −6.37 2-propanol −0.27 −0.32 −0.41 −0.54 −0.71 −0.90 −1.08 −1.35 −1.79 1-butanol −0.47 −0.62 −0.79 −1.06 −1.42

103 ΔmixS (J·mol−1·K−1)

temperature (K)

27.66 34.73 48.11 64.02 82.61 106.12 133.03 164.23 202.97

303.15 308.15 313.15 318.15

ΔmixG (J·mol−1)

1-butanol −1.79 −2.08 −2.47 −3.06 isobutanol −0.44 −0.34 −0.61 −0.49 −0.79 −0.64 −1.09 −0.91 −1.43 −1.24 −1.83 −1.62 −2.22 −2.02 −2.61 −2.42 −3.42 −3.28 acetonitrile −0.33 −0.28 −0.37 −0.32 −0.49 −0.43 −0.64 −0.58 −0.80 −0.74 −0.97 −0.91 −1.21 −1.15 −1.44 −1.40 −1.90 −1.90 tetrahydrofuran −0.88 −0.84 −1.22 −1.17 −1.59 −1.50 −2.10 −1.97 −2.59 −2.41 −3.11 −2.85 −4.00 −3.65 −5.16 −4.68 −6.03 −5.39 methyl acetate −0.05 −0.04 −0.06 −0.05 −0.07 −0.07 −0.10 −0.09 −0.12 −0.11 −0.15 −0.14 −0.20 −0.19 −0.24 −0.24 −0.29 −0.29 −2.01 −2.38 −2.87 −3.59

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

1.80 2.62 3.55 4.68 6.02 7.70 9.83 12.15 15.27

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.43 0.59 0.81 1.12 1.50 1.99 2.59 3.28 4.14

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.17 0.18 0.20 0.21 0.21 0.19 0.17 0.12 0.01

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.12 0.19 0.27 0.38 0.54

ΔmixH (J·mol−1)

103 ΔmixS (J·mol−1·K−1) 0.73 0.97 1.27 1.66 0.37 0.45 0.52 0.60 0.66 0.68 0.66 0.60 0.44 0.18 0.19 0.21 0.22 0.22 0.21 0.18 0.14 0.01 0.13 0.19 0.29 0.42 0.61 0.86 1.16 1.54 2.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.02 0.01

The expanded uncertainties are U(ΔmixH) = 0.065 ΔmixH, U(ΔmixS) = 0.066 ΔmixS, U(ΔmixG) = 0.056 ΔmixG (0.95 level of confidence).

a

where M = G, H, and S, and ΔmixM refers to mixing thermodynamic properties of real solution; The superscript E means the excess properties; the superscript id represents mixing thermodynamic properties of an ideal solution. For ideal solution, the thermodynamic properties can be obtained according to the Lewis−Randall rule:37

4.4. Mixing Thermodynamic Properties Analysis. Thermodynamic properties reflect the interaction between solute and solvent in nonideal solutions during mixing process. Due to the usefulness of these data for production, it is necessary to clarify the mixing thermodynamic properties whose initial state is regarded to be at the time of mixing the three components, including the mixing Gibbs energy (ΔmixG), mixing enthalpy (ΔmixH), and the mixing entropy (ΔmixS). These mixing thermodynamic properties can be expressed as follows:35,36 Δmix M = Δmix M id + ME

N

Δmix Gid = RT ∑ xi ln xi i

(16)

N

Δmix Sid = − R∑ xi ln xi

(15)

i

J

(17) DOI: 10.1021/acs.jced.8b00551 J. Chem. Eng. Data XXXX, XXX, XXX−XXX


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Table 13. Mixing Thermodynamic Properties of the Solution with the Binary Solvent (Methanol + Ethanol)a ΔmixG (kJ·mol−1)

temperature (K)

Δmix H (kJ·mol−1)

ΔmixS (J·mol−1·K−1)

temperature (K)

ΔmixG (kJ·mol−1)

x0A = 0.1 −0.79 −0.81 −0.82 −0.84 −0.85 −0.86 −0.88 −0.90 −0.91

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1.23 −1.25 −1.27 −1.29 −1.31 −1.34 −1.36 −1.38 −1.40

−0.11 −0.11 −0.12 −0.12 −0.12 −0.12 −0.12 −0.13 −0.13

2.44 2.45 2.45 2.45 2.45 2.46 2.46 2.46 2.46

−0.20 −0.20 −0.20 −0.20 −0.20 −0.20 −0.20 −0.21 −0.21

3.71 3.71 3.72 3.73 3.73 3.74 3.74 3.74 3.75

−1.51 −1.53 −1.56 −1.58 −1.61 −1.63 −1.66 −1.69 −1.71

−0.26 −0.26 −0.26 −0.26 −0.26 −0.26 −0.26 −0.26 −0.26

4.49 4.50 4.51 4.52 4.53 4.54 4.55 4.56 4.56

−1.67 −1.69 −1.72 −1.75 −1.78 −1.80 −1.83 −1.86 −1.89

−0.29 −0.29 −0.29 −0.29 −0.29 −0.29 −0.29 −0.29 −0.29

4.94 4.95 4.97 4.98 4.99 5.00 5.01 5.03 5.04

−1.72 −1.74 −1.77 −1.80 −1.83

−0.30 −0.30 −0.29 −0.29 −0.29

5.09 5.11 5.12 5.14 5.15

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1.66 −1.69 −1.72 −1.75 −1.78 −1.81 −1.84 −1.88 −1.91

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1.51 −1.53 −1.56 −1.59 −1.62 −1.65 −1.68 −1.71 −1.75

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1.23 −1.25 −1.28 −1.30 −1.33 −1.36 −1.39 −1.43 −1.47

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−0.80 −0.82 −0.84 −0.86 −0.88 −0.91 −0.95 −0.99 −1.04

−0.29 −0.29 −0.30 −0.30

5.17 5.18 5.19 5.20

−0.29 −0.28 −0.28 −0.28 −0.28 −0.28 −0.29 −0.29 −0.29

4.96 4.98 4.99 5.01 5.03 5.04 5.05 5.06 5.08

−0.25 −0.25 −0.25 −0.25 −0.25 −0.25 −0.26 −0.26 −0.28

4.51 4.53 4.55 4.57 4.58 4.60 4.61 4.63 4.64

−0.20 −0.20 −0.20 −0.20 −0.21 −0.21 −0.22 −0.23 −0.25

3.70 3.72 3.74 3.76 3.77 3.79 3.80 3.82 3.83

−0.13 −0.13 −0.14 −0.14 −0.15 −0.16 −0.18 −0.21 −0.24

2.41 2.42 2.43 2.45 2.46 2.47 2.48 2.50 2.51

x0A = 0.8

x0A = 0.9

x0A = 0.5 278.15 283.15 288.15 293.15 298.15

−1.86 −1.89 −1.92 −1.96

x0A = 0.7

x0A = 0.4 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

303.15 308.15 313.15 318.15

x0A = 0.6

x0A = 0.3 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15


x0A = 0.5

x0A = 0.2 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15



a

Δmix H id = 0

The mixing thermodynamic properties of imatinib mesylate in nine monosolvents and two binary solvents were obtained by fitting with the NRTL model. Tables 12−14 summarize the results above. It is shown that the values of mixing Gibbs energy and mixing enthalpy are all negative, while the values of the mixing entropy are all positive. That means the mixing process is spontaneous and exothermic in selected solvents.39 Simultaneously, the positive mixing entropy indicates this process is entropy increment. It is noticed that the sequence of the mixing Gibbs energy of imatinib mesylate in nine monosolvents is methanol < ethanol < 1-propanol < tetrahydrofuran < 1-butanol < isobutanol < acetonitrile < 2-propanol < methyl acetate at a constant temperature, which is contrary to the

(18)

and we can calculate the excess properties according to formula below:38 N

GE = RT ∑ xi ln γi i

N i ∂lnγi yz zz HE = − RT 2∑ xijjjj z k ∂T { P , x i

SE =

HE − GE T

(19)

(20) (21) K



Article

Table 14. Mixing Thermodynamic Properties of the Solution with the Binary Solvent (Methanol + 2-Propanol)a temperature (K)




temperature (K)


x0A = 0.1 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−0.74 −0.76 −0.77 −0.78 −0.79 −0.80 −0.81 −0.82 −0.83

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1.13 −1.15 −1.16 −1.18 −1.19 −1.21 −1.22 −1.24 −1.25

−0.16 −0.16 −0.16 −0.16 −0.15 −0.15 −0.15 −0.15 −0.15

2.11 2.11 2.12 2.12 2.12 2.13 2.13 2.14 2.14

−0.28 −0.28 −0.28 −0.28 −0.27 −0.27 −0.27 −0.26 −0.26

3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12

−0.38 −0.37 −0.37 −0.36 −0.36 −0.35 −0.35 −0.34 −0.34

3.52 3.54 3.55 3.57 3.58 3.60 3.61 3.63 3.64

−0.43 −0.43 −0.42 −0.41 −0.41 −0.40 −0.39 −0.38 −0.38

3.69 3.71 3.73 3.76 3.78 3.80 3.82 3.84 3.86

−0.45 −0.44 −0.43 −0.42 −0.41

3.62 3.65 3.68 3.71 3.74

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

−1.46 −1.48 −1.50 −1.51 −1.53 −1.55 −1.57 −1.59 −1.61

278.15 283.15 288.15 293.15 298.15

−1.46 −1.47 −1.49 −1.51 −1.53

−1.55 −1.56 −1.58 −1.60

−0.40 −0.39 −0.38 −0.38

3.77 3.79 3.82 3.85

−0.42 −0.41 −0.40 −0.39 −0.38 −0.37 −0.36 −0.35 −0.34

3.36 3.39 3.43 3.47 3.50 3.54 3.58 3.61 3.64

−0.35 −0.33 −0.32 −0.31 −0.30 −0.29 −0.27 −0.26 −0.25

2.94 2.99 3.03 3.08 3.12 3.16 3.20 3.24 3.28

−0.21 −0.20 −0.19 −0.18 −0.17 −0.16 −0.16 −0.15 −0.15

2.42 2.47 2.51 2.56 2.59 2.63 2.66 2.69 2.72

−0.03 −0.03 −0.03 −0.03 −0.04 −0.05 −0.06 −0.07 −0.09

1.77 1.80 1.82 1.83 1.84 1.84 1.84 1.84 1.82

x0A = 0.6 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1.36 −1.37 −1.39 −1.41 −1.42 −1.44 −1.46 −1.48 −1.49

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1.17 −1.18 −1.20 −1.21 −1.23 −1.24 −1.26 −1.28 −1.29

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−0.89 −0.90 −0.91 −0.93 −0.95 −0.96 −0.98 −1.00 −1.02

x0A = 0.7

x0A = 0.3 −1.36 −1.37 −1.39 −1.41 −1.43 −1.44 −1.46 −1.48 −1.50


x0A = 0.5

x0A = 0.2

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15


x0A = 0.8

x0A = 0.4

x0A = 0.9 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

x0A = 0.5

−0.53 −0.54 −0.55 −0.57 −0.59 −0.61 −0.63 −0.65 −0.67


a

order of solubility. Likewise, the values of mixing Gibbs energy decrease as the temperature increases at a given composition of solvents, including pure solvents and binary solvents. Further, the lower mixing Gibbs energy leads to the higher solubility when the solvent composition is constant.

by UV composition analysis in the temperature range of 278.15 to 318.15 K at atmospheric pressure. It was found that the solubility in all studied systems increases with the increasing temperature, and the dissolving capacity at a given temperature is in the order of methyl acetate < 2-propanol < acetonitrile < isobutanol < 1-butanol < tetrahydrofuran < 1-propanol < ethanol < methanol. Afterward, the Apelblat model, λh equation, CNIBS/R-K model, and NRTL model were applied to correlate with the solubility data. The fitted values generally have a good correspondence with the experimental data. Finally, the mixing thermodynamic properties of imatinib mesylate were calculated based on the NRTL model. The

5. CONCLUSION Solubility of imatinib mesylate in acetonitrile, tetrahydrofuran, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, methyl acetate, methanol + ethanol, and methanol + 2-propanol was measured by the shaken flask method followed L



Article

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mixing Gibbs energy and mixing enthalpy are all negative, which suggests the mixing process is spontaneous and endothermic. Furthermore, the mixing entropy is all positive, which reveals that the mixing is a process of entropy increment. On the basis of the results above, the experimental and thermodynamic values are helpful for the crystallization and purification of imatinib mesylate.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.8b00551.

■

UV method verification (PDF)

AUTHOR INFORMATION

Corresponding Author

*Tel.: 86-22-27405754; Fax: +86-22-27374971; E-mail: [email protected]. ORCID

Yifu Chen: 0000-0003-4674-5705 Songgu Wu: 0000-0003-4329-4654 Author Contributions ⊥

X.W. and D.Z. contributed equally.

Funding

The authors are grateful for the financial support of National Natural Science Foundation of China (Grants NNSFC 21676179 and NNSFC 91634117) and the Major National Science and Technology Projects (Grant 2017ZX07402003 and 2017ZX09101001). Notes

The authors declare no competing financial interest.

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REFERENCES

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N


Thermodynamic Study of Solubility for Imatinib Mesylate in Nine

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