Aniracetam Solubility in Pure and Binary Solvents: Effect of Molecular

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Aniracetam Solubility in Pure and Binary Solvents: Effect of Molecular Interaction and Analysis of Crystallized Products Danfeng Shao,* Zehui Yang,* and Guoquan Zhou

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School of Materials and Chemical Engineering, Ningbo University of Technology, Ningbo City, Zhejiang Provice 315211, P. R. China ABSTRACT: The aim of this work is to study the solubility of aniracetam and discuss the molecular interaction between solute and solvent in the dissolution process. This work would be important to optimize the crystallization and extraction process of aniracetam. The equilibrium data of aniracetam in seven pure solvents including methanol, ethanol, npropanol, isopropyl alcohol, acetone, toluene, ethyl acetate, and three binary mixtures were measured by using the isothermal saturation method from T = 273.15 to 318.15 K. The solubility of aniracetam in pure and mixed solvents increased with the increasing temperature. At a given temperature, the solubility of aniracetam in (acetone + alcohols) increased with increasing mass fraction of acetone. Moreover, it was greater in (acetone + methanol) than other mixed systems. The maximum solubility of aniracetam in pure solvents was obtained in acetone, and the order they follow from small to large is (n-propanol < isopropyl alcohol < ethanol < methanol < toluene < ethyl acetate < acetone). Two pure solvent models (modified Apelblat equation, λh equation) and two cosolvent models (CNIBS/R-K model and Jouyban−Acree model) were applied to analyze the obtained solubility data. The correlation showed the experiment data is very close to the calculated values and exhibit low values of RAD and RMSD. Infrared spectra recorded between crystallized products and raw material in the pure dry KBr matrix in pairs and Pearson correlation coefficient were used to quantify the degree of similarity. Furthermore, powder X-ray diffraction (PXRD) was applied before and after the experiments to analyze the crystal form of aniracetam studied in this work.

1. INTRODUCTION Aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone, CASRN 72432-10-1, its structure shown in Figure 1] is a chemical

prescription drug, because it has few side effects and the function of cognitive enhancement. According to the literature,10 the crude aniracetam is generally recrystallized from alcohol or its aqueous solutions. However, aniracetam when contacted with water is hydrolyzed throughout the PH range.10 The unwanted hydrolytic degradation of aniracetam makes the time of residence in the aqueous solution a crucial factor in the production of an aniracetam purification unit. In addition, the poor solubility of aniracetam in alcohol or its aqueous solutions and low crystallization rate are related to product revenue and product quality. Assembling the above reasons, in the interest of increasing the dissolving capacity of aniracetam and providing useful information for developing a purification process, seven pure and three mixed solvents have been evaluated. In our present study, the solubility values of aniracetam in pure acetone, toluene, ethyl acetate, methanol, ethanol, npropanol, iso-propyl alcohol, and their binary mixtures (acetone + methanol), (acetone + ethanol), and (acetone + isopropyl alcohol) were measured at different temperatures. Besides, two pure solvent models including the Apelblat equation and λh equation were applied to correlate the experimental data in seven pure solvents. The values in (acetone + methanol), (acetone + ethanol) and (acetone + isopropyl alcohol) were correlated by two cosolvent models

Figure 1. Chemical structure of aniracetam.

compound belonging to the racetam family, which was developed as a nootropic drug. It is a cognitively enhanced drug and exerts therapeutic effect in the treatment of sleep disorders and emotional disturbances such as anxiety, agitation and depressed mood, and abnormal behaviors such as cerebral infarction, Alzheimer’s disease, and Parkinson’s disease.1,2 Moreover, according to previous studies, aniracetam has the potential to inhibit desensitization on glutamatergic receptor,3 increase the excitability of post synaptic potentials,3 prolong the decay time of EPSC,4 and induct long-term potentiation in the hippocampus.5 So far the definitive mechanism of aniracetam has not yet been fully studied; however, according to some evidence, it is a reversible positive allosteric modulator of AMPA receptors.6 Meanwhile, aniracetam has been shown to treat cognitive dysfunction.7−9 In the USA, aniracetam is used as dietary supplement, while in Europe, it is sold as a © XXXX American Chemical Society

Received: January 8, 2018 Accepted: June 26, 2018

A

DOI: 10.1021/acs.jced.8b00023 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Table 1. Detailed Information on the Materials Used in the Work chemicals

CASRN

molar mass g·mol−1

source

mass fraction purity

analytical method

aniracetam methanol ethanol isopropyl alcohol acetone n-propanol toluene ethyl acetate

72432-10-1 67-56-1 64-17-5 67-63-0 67-64-1 71-23-8 108-88-3 141-78-6

219.24 32.04 46.07 60.10 58.08 60.10 92.14 88.11

Aladdin Chemical Co. Ltd. (China) Sinopharm Chemical Reagent Co., Ltd.,China

0.996 0.996 0.998 0.998 0.996 0.995 0.996 0.995

HPLCa GCb GC GC GC GC GC GC

a

High-performance liquid phase chromatograph. bGas chromatography.

Table 2. Experimental and Calculated Mole Fraction Solubility (xew,T × 102) of Aniracetam in Seven Pure Solvents at the Temperature Range from T = (273.15 to 318.15) K under 101.1 kPaa T/K

exp

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

1.914 2.361 2.967 3.694 4.521 5.366 6.259 7.302 8.498 9.836

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

0.0924 0.1097 0.1565 0.2146 0.2933 0.3869 0.4958 0.6271 0.7713 0.9555

Apelcalc acetone 1.912 2.410 2.995 3.672 4.445 5.317 6.290 7.362 8.531 9.792 ethanol 0.0810 0.1154 0.1608 0.2192 0.2927 0.3835 0.4936 0.6244 0.7775 0.9534

λhcalc

exp

1.983 2.433 2.965 3.592 4.326 5.182 6.178 7.330 8.660 10.19

1.497 1.702 2.004 2.415 2.852 3.327 3.845 4.481 5.132 5.812

0.0885 0.1199 0.1610 0.2140 0.2820 0.3686 0.4781 0.6161 0.7891 1.005

0.0462 0.0643 0.0968 0.1379 0.1950 0.2666 0.3580 0.4717 0.5919 0.7374

Apelcalc ethyl acetate 1.437 1.723 2.051 2.425 2.848 3.324 3.857 4.452 5.110 5.837 n-propanol 0.0416 0.0644 0.0963 0.1396 0.1965 0.2689 0.3586 0.4666 0.5933 0.7380

λhcalc

exp

1.470 1.740 2.050 2.406 2.814 3.282 3.818 4.432 5.136 5.945

1.014 1.162 1.356 1.624 1.944 2.309 2.693 3.113 3.575 4.081

0.0481 0.0686 0.0966 0.1345 0.1853 0.2527 0.3414 0.4573 0.6078 0.8020

Apelcalc

λhcalc

toluene 0.9650 0.9910 1.164 1.178 1.394 1.394 1.656 1.643 1.955 1.931 2.294 2.262 2.674 2.643 3.099 3.082 3.572 3.589 4.095 4.175 isopropyl alcohol 0.0716 0.0705 0.0757 0.0981 0.1001 0.1024 0.1371 0.1389 0.1371 0.1888 0.1885 0.1818 0.2518 0.2504 0.2390 0.3286 0.3263 0.3118 0.4178 0.4174 0.4036 0.5227 0.5246 0.5191 0.6470 0.6486 0.6637 0.7908 0.7895 0.8442

exp

Apelcalc

λhcalc

0.0951 0.1249 0.1853 0.2553 0.3534 0.474 0.6099 0.7746 0.9644 1.195

methanol 0.0891 0.1306 0.1864 0.2594 0.3523 0.4679 0.6084 0.7755 0.9701 1.192

0.0976 0.1350 0.1845 0.2497 0.3346 0.4444 0.5854 0.7652 0.9934 1.282

a

Standard uncertainties u are u(T) = 0.02 K, u (p) = 400 Pa; Relative standard uncertainty ur is ur(x) = 0.15.

having a type of Waters C18. The UV detector wavelength with 282 nm was employed. During the analysis, the column temperature was set to 303.15 K. Additionally, pure chromatographic grade methanol with the flow rate of 1 mL·min−1 served as mobile phase. The volume of injection was set at 20 μL. In this work, each experiment was repeated two times and the mean value of the results was taken as the final result. 2.3. Solubility Determination. In our research, the isothermal saturation method13 was employed to measure the aniracetam’s solubility values in seven pure and three binary solvents from T = 273.15 to 318.15 K under 101.3 kPa. It was similar to our previous method.14 Excessive amounts of aniracetam and 25 mL of solvent (the analytic balance was used to prepare mixed solvent of different composition in advance) were added into the jacketed glass vessel with magnetic stirrer. The temperature was controlled by a smart thermostatic water bath with circulating water, with a standard uncertainty of 0.02 K. At a certain temperature, the suspension was continuously stirred with a magnetic stirrer in the jacketed glass vessel for thorough mixing. A 2 mL injector with a 200 nm pore filter was used to take out about 0.5 mL of saturated liquid phase every hour to determine the

(CNIBS/R-K model and Jouyban−Acree model). To analyze the difference between crystallized products and raw material, the infrared spectra data of different samples in pure dry KBr was compared in pairs. Meanwhile the Pearson correlation coefficient, the standard statistical parameter,11,12 was employed to analyze the degree of similarity. Moreover, before and after the experiments, the crystal form for aniracetam was distinguished by PXRD. The solubility data obtained in this work can provide high research value for the crystallization process of aniracetam in industry.

2. EXPERIMENTAL SECTION 2.1. Materials. A white crystalline powder of aniracetam having a purity of 0.996 in mass fraction was purchased by Hubei Yuancheng Pharmaceutical Co., Ltd. (China). All solvents were analytical grade and used without additional purification and purchased from Sinopharm Chemical Reagent Co., Ltd., China. Detailed information was summarized and presented in Table 1. 2.2. Analysis Method of Solubility. Aniracetam’s purity was analyzed by high-performance liquid-phase chromatograph (HPLC). The separation column was a reverse phase column B

DOI: 10.1021/acs.jced.8b00023 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

C

0.3921 0.5004 0.6921 0.9124 1.198 1.525 1.881 2.302 2.781 3.343 0.2975 0.3589 0.4871 0.6431 0.8416 1.065 1.315 1.611 1.940 2.340 0.2298 0.3027 0.4064 0.5389 0.6961 0.8766 1.079 1.316 1.592 1.908

0.3004 0.4606 0.6863 0.8986 1.197 1.527 1.882 2.302 2.785 3.401 0.2670 0.3820 0.5212 0.6830 0.8560 1.046 1.276 1.523 1.826 2.135 0.2233 0.3064 0.3990 0.5092 0.6483 0.8099 0.9826 1.192 1.452 1.753

0.4 exp

J−Acalc

R−Kcalc

0.2

J−Acalc

0.2320 0.3198 0.4260 0.5472 0.6967 0.8659 1.053 1.272 1.529 1.846

0.2900 0.3888 0.5091 0.6655 0.8478 1.040 1.261 1.520 1.836 2.165

0.3519 0.5172 0.7156 0.9273 1.215 1.529 1.887 2.296 2.744 3.323

R−Kcalc

0.3332 0.4734 0.6713 0.8758 1.127 1.410 1.750 2.125 2.539 3.082

0.4409 0.5769 0.7568 0.9917 1.293 1.599 1.940 2.362 2.896 3.448

0.6218 0.8029 1.024 1.371 1.780 2.287 2.874 3.568 4.319 5.237

exp

0.6

0.3755 0.4857 0.6403 0.8344 1.062 1.316 1.597 1.924 2.306 2.739

0.4686 0.5713 0.7579 0.9840 1.263 1.568 1.905 2.302 2.746 3.275

0.6290 0.7945 1.065 1.379 1.771 2.204 2.670 3.218 3.843 4.566

J−Acalc

0.3294 0.4625 0.6405 0.8253 1.060 1.331 1.646 2.004 2.419 2.929

0.4125 0.5615 0.7600 1.003 1.295 1.603 1.959 2.380 2.901 3.435

0.5508 0.7418 0.9993 1.342 1.756 2.271 2.836 3.514 4.282 5.227

R−Kcalc

0.6662 0.8255 1.069 1.304 1.630 2.016 2.460 2.945 3.475 4.111

0.6913 0.8717 1.160 1.507 1.914 2.374 2.906 3.558 4.249 5.057

0.8142 1.097 1.453 1.905 2.436 3.094 3.790 4.630 5.619 6.906

exp

0.8

0.6322 0.8028 1.039 1.329 1.667 2.031 2.427 2.890 3.427 4.035

0.7584 0.9338 1.210 1.544 1.942 2.366 2.826 3.367 3.980 4.690

0.9794 1.225 1.593 2.027 2.545 3.099 3.690 4.383 5.176 6.079

J−Acalc

0.6241 0.7925 1.040 1.295 1.627 2.020 2.476 2.973 3.521 4.196

0.7072 0.9043 1.195 1.530 1.939 2.383 2.896 3.504 4.192 4.983

0.8716 1.133 1.459 1.921 2.462 3.130 3.872 4.769 5.784 7.082

R−Kcalc

0.9267 1.155 1.464 1.836 2.282 2.804 3.385 4.029 4.776 5.657

1.075 1.375 1.774 2.191 2.699 3.234 3.850 4.528 5.321 6.255

1.243 1.603 1.992 2.523 3.168 3.881 4.713 5.701 6.772 8.157

exp

0.9

0.9723 1.220 1.558 1.971 2.447 2.949 3.487 4.118 4.846 5.667

1.099 1.357 1.734 2.189 2.720 3.275 3.871 4.570 5.367 6.276

1.303 1.620 2.073 2.611 3.239 3.897 4.596 5.415 6.352 7.411

J−Acalc

1.012 1.233 1.561 1.923 2.378 2.902 3.490 4.134 4.846 5.698

1.081 1.337 1.714 2.143 2.659 3.217 3.848 4.589 5.396 6.368

1.207 1.590 1.997 2.518 3.149 3.847 4.639 5.572 6.611 7.976

R−Kcalc

Standard uncertainties u are u(T) = 0.02 K, u(p) = 400 Pa; solvent mixtures were prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.003. w represents the mass fraction of acetone in mixed solvents of acetone + alcohols, Relative standard uncertainty ur is ur(x) = 0.15.

a

exp

Acetone (W) + Methanol (1 − W) 273.15 0.2224 0.2088 0.1995 278.15 0.3233 0.2700 0.2971 283.15 0.4347 0.3862 0.4207 288.15 0.5535 0.5198 0.5409 293.15 0.7234 0.7000 0.7171 298.15 0.8999 0.9135 0.9020 303.15 1.113 1.149 1.118 308.15 1.346 1.431 1.361 313.15 1.593 1.753 1.626 318.15 1.924 2.138 1.975 Acetone (W) + Ethanol (1 − W) 273.15 0.1996 0.1667 0.1899 278.15 0.2382 0.1995 0.2366 283.15 0.2985 0.2775 0.3041 288.15 0.3866 0.3734 0.3938 293.15 0.4980 0.4993 0.5019 298.15 0.6184 0.6451 0.6210 303.15 0.7532 0.8114 0.7586 308.15 0.9204 1.010 0.9199 313.15 1.106 1.229 1.100 318.15 1.328 1.502 1.314 Acetone (W) + Isopropyl Alcohol (1 − W) 273.15 0.1662 0.1228 0.1622 278.15 0.2062 0.1651 0.2011 283.15 0.2576 0.2262 0.2485 288.15 0.3248 0.3059 0.3127 293.15 0.4069 0.4018 0.3918 298.15 0.5028 0.5155 0.4856 303.15 0.6057 0.6453 0.5846 308.15 0.7239 0.7976 0.7002 313.15 0.8534 0.9767 0.8314 318.15 1.020 1.183 0.9942

T/K

Table 3. Experimental Mole Fraction Solubility (xew,T × 102) of Aniracetam in Acetone (W) + Methanol (1 − W), Acetone (W) + Ethanol (1 − W) and Acetone(W) + Isopropyl Alcohol (1 − W) Mixtures with Various Composition at the Temperature Range from T = (273.15 To 318.15) K under 101.1 kPaa

Journal of Chemical & Engineering Data Article

DOI: 10.1021/acs.jced.8b00023 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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equilibration time of the aniracetam solution, after which the content of liquid phase was analyzed by HPLC. The same amount of aniracetam in liquid phase analyzed by HPLC demonstrates that the aniracetam solution is in the state of dissolving equilibrium. The jacketed glass vessel with magnetic stirrer was stopped, once the aniracetam solution reaches the equilibrium state. The solution needs to be settled for at least 1 h before sampling, and then a 5 mL preheated or precooled injector with a filter (200 nm pore filter) was applied to take out the upper saturated liquid, and swiftly transfers into a preweighed volumetric flask with a rubber stopper. The analytic balance was used again to weigh the total amount of volumetric flask with a rubber stopper and the upper saturated liquid. After wards the volumetric flask with the upper saturated liquid was diluted with corresponding solvent to the lowest concave surface, and the content of solution was analyzed after shaking the mixture well. In seven pure solvents and three binary solvent mixtures, the measured solubility values of aniracetam (xw,T) in mole fraction were calculated by eq 1 and 2, respectively. xw , T =

m1/M1 m1/M1 + m2 /M 2

(1)

xw , T =

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

(2)

Figure 2. Mole fraction solubility (x) of aniracetam in selected solvents at different temperatures: ⧫, acetone; ☆, ethyl acetate; ★, toluene; ■, methanol; ●, ethanol;▲, isopropyl alcohol; ▼, npropanol.

Here m1 and m2 represents the mass of aniracetam and seven pure solvents, respectively. In addition, m3 is the mass of acetone. M1, M2, and M3 stand for the molar mass of aniracetam and corresponding solvent. 2.4. Infrared Spectroscopy and X-ray Diffraction Investigations. PerkinElmer spectrometer was applied to perform infrared spectroscopy (IR) analysis. About 2 mg of aniracetam and 200 mg of pure dry KBr were mixed and ground in agate mortar, after which the mixed sample was pelletized directly under pressure of about 10 bar. At room temperature, the IR absorption spectrum in the field frequency from 500 to 4000 cm−1 was measured and recorded. The crystal form of aniracetam before and after measurement was analyzed by X-ray powder diffraction (XPRD) and performed on the Rigaku D/max-2500 (Rigaku, Japan) with Cu Kα radiation (λ = 1.54184 nm). In addition, 40 kV and 30 mA were used as the voltage and current of tube, respectively; then the values from 10° to 80° (2-theta) at room temperature were collected.

Figure 3. Experimental and predicted solubility data of aniracetam in (a) acetone (w) + methanol (1 − w) mixed solutions; (b) acetone (w) + ethanol (1 − w) mixed solutions; (c) acetone (w) + isopropyl alcohol (1 − w) mixed solutions with various mass fractions at different temperatures: red dots, experimental values; surface, predicted values by the Jouyban−Acree model.

Table 4. Polarity and Hildebrand Solubility Parameters (δH) for the Selected Solventsa 103 δH (298 K)

3. RESULTS AND DISCUSSION 3.1. Temperature and Solvent Composition Effect on Solubility of Aniracetam. The experimental and calculated results for aniracetam in this work were presented in Table 2 and Table 3, and drawn in Figure 2 and Figure 3. As shown in those tables and figures, the solubility of aniracetam in seven pure and three mixed solvents increased with increasing temperature. At a given temperature, the order of solubility in pure solvents is acetone > ethyl acetate > toluene > methanol > ethanol > isopropyl alcohol > n-propanol. In addition, the data of aniracetam in (acetone + alcohols) increased with increasing mass fraction of acetone. Moreover, compared with other mixed systems, the solubility data of (acetone + methanol) mixed solution are the largest. 3.2. Solvent Properties Effect on Solubility of Aniracetam. It also can be seen from Tables 2, 3, and 4

a

solvent

polarity (water 100)

(J·m−3)1/2

acetone toluene isopropyl alcohol ethanol methanol ethyl acetate n-propanol

35.5 9.9 54.6 65.4 76.2 23 61.7

21.1 18.8 24.3 28.3 30.6 19.2 25.1

Taken from ref 15.

and Figures 2 and 3 that, in four pure alcohols, the sequence from high to low of solubility result is consistent with the trend for Hildebrand solubility parameters and the polarities except for isopropyl alcohol,15 which may be caused by the hydroxyl D

DOI: 10.1021/acs.jced.8b00023 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Table 5. Parameters of the Modified Apelblat Equation and λh Equation for Aniracetam in Four Pure Solvents λh

modified Apelblat solvent

A

B

C

102 RAD

104 RMSD

λ

h

102 RAD

104 RMSD

acetone ethyl acetate toluene methanol ethanol n-propanol isopropyl alcohol

136.28 23.64 26.73 297.18 230.73 392.93 246.51

−8820.97 −3498.27 −3723.23 −17596.54 −14467.03 −22302.07 −15087.63

−19.24 −2.688 −3.163 −42.74 −32.96 −56.88 −35.39

0.85 1.01 1.27 1.59 2.54 1.50 0.72

4.40 2.91 2.46 0.41 0.52 0.25 0.15

0.6142 0.2093 0.1519 0.2402 0.1548 0.2022 0.1262

4991.59 11520.73 16306.81 20404.67 29716.37 26589.64 36098.30

2.44 1.35 1.59 4.05 3.81 4.27 3.74

15.92 5.35 4.17 3.23 1.96 2.29 1.97

described as eqs 4 and 5, respectively, and the values are presented in Table 5. It can be concluded that the RMSD values are all smaller than 4.40 × 10−4 in the system of aniracetam + acetone, and the values of RAD are less than 2.54%. Hence the solubility values calculated by the modified Apelblat equation are close to the experimental data. N is the number of the experimental point of single pure solvent or the whole mixed solvent in eqs 4 and (5); xei and xci stand for the measured and correlated values, respectively. ÅÄÅ N ÑÉ1/2 ÅÅ ∑i = 1 (xie − xic)2 ÑÑÑ Å ÑÑ RMSD = ÅÅÅ ÑÑ ÅÅ ÑÑ N (4) ÅÇ ÑÖ

group in the special positions of the isopropyl alcohol molecule. As compared with that with n-propanol, the formation of hydrogen bond between the hydroxyl group in the isopropyl alcohol molecule and in the aniracetam molecule is obviously weakened. Therefore, the solubility of aniracetam in isopropyl alcohol is greater than that in n-propanol. Furthermore, the same tendency can also be found in ethyl acetate, acetone, and toluene. The weak polarity of the aniracetam molecule may be the main reason for this phenomenon. The solubility of aniracetam in four pure alcohols is little relative to that in other solvents due to the strong polarities of the four alcohols. It seems that the aniracetam and solvents’ polarity has an effect on the order of solubility. The polarity of toluene is less than that of toluene and ethyl acetate together; however, the measured solubility value of aniracetam in toluene is also smaller than that of acetone or ethyl acetate. In general, a single reason cannot explain the too complicated dissolution behavior presented in Table 2. From Figure 1, we can see that there is a similar functional group (carbonyl or benzene ring) between acetone, ethyl acetate, toluene, and aniracetam. It conforms to the theory of “like dissolves like”. All those elements of acetone or ethyl acetate result in a stronger solute−solvent interaction and higher solubility against toluene. Regarding the four alcohols, the shorter is the carbon chain length, the greater is the dissolving capacity. Meanwhile, the order of the polarities with different compositions in the three mixed solvents is strictly consistent with the solubility data. From Tables 2 and 3 and Figures 2 and 3, we can obviously find that cooling crystallization and changing the solvent composition are suitable for the purification of aniracetam. 3.3. Solubility Correlation. To describe the dissolution behavior of aniracetam in selected solvents, two pure solvent models (modified Apelblat equation, λh equation) and two cosolvent models (CNIBS/R-K model and Jouyban−Acree model) were applied to analyze the obtained solubility data. The obtained equation parameters can provide data reference for aniracetam separation and purification process. The connection between the solubility of aniracetam in selected pure solvents and the temperature in Kelvin can be modeled by the modified Apelblat equation, eq 316−18 ln x = A +

B + C ln T T

RAD =

1 N

N

∑ i=1

xie − xic xie

(5)

As shown in eq 6, the Buchowski−Ksiazaczak λh model is also an alternative thermodynamic equation to express the relation of temperature to experimental solubility data.19 λ and h are the thermodynamic parameters of Buchowski− Ksiazaczak λh equation; moreover, in many common solid− liquid equilibrium systems, the experimental solubility data can be well correlated by those two thermodynamic parameters. In this work, this function was applied to express the relation of temperature to experimental solubility data. ÄÅ ÉÑ ÅÅi ij 1 λ(1 − x c) zyÑÑÑ 1 yzz j Å j z Å lnÅÅjj1 + z zzÑÑÑ = λhjjjj − c ÅÅÇk x Tm zz{ (6) {ÑÑÖ kT The parameter Tm stands for aniracetam’s melting temperature. The melting temperature of aniracetam is obtained from the literature (“DrugsSynonyms and Properties” Ashgate Publishing Co. (US) CAPLUS). The two equation parameters, λ and h can be obtained from eq 6 based on the experimental solubility data. They were also presented in Table 5. As shown in this table, the values of RMSD calculated by λh function are obviously larger than the values obtained from the modified Apelblat equation; however, they are less than 15.92 × 10−4. The RAD values calculated by λh equation are all less than 4.27%. Table 5 shows that the solubility data of aniracetam calculated by the two equations in seven solvents is very close to the measured values; moreover, comparing with the λh equation, the modified Apelblat equation is the more suitable function to express the dissolution behavior of aniracetam in the seven studied solvents. For binary mixtures, both the composition of mixed solvent and experimental temperature effect on the dissolution behavior of aniracetam is usually described by the Jouyban− Acree model20,21 In addition, at a given temperature, the

(3)

Here x is the experiment solubility data in mole fraction of aniracetam and T is the absolute temperature in Kelvin. Equation parameters A, B, and C can be regressed by the experimental solubility. On the basis of the measured solubility, a nonlinear method was used to obtain A, B, and C. Also the values of root-mean-square deviations (RMSD) together with the relative average deviations (RAD) are E

DOI: 10.1021/acs.jced.8b00023 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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showed the temperature effect on the solubility of aniracetam in three mixed systems. Combing the data shown in Figure 3 with the increasing temperature and the acetone composition in the binary solvents shows that aniracetam’s solubility increased. The calculated RMSD values are a little larger than those in the seven pure solvents; however, they are all less than 2.016 × 10−3. All the RAD values calculated with JouybanAcree model are no more than 4.61%. According to the refs 22 and 23, the commonly used and simplified CNIBS/R-K model can be expressed by the following function:

relation of composition of mixed solvents to the obtained solubility data can also be demonstrated by the CNIBS/R-K model.22,23 These two models are considered as the most appropriate models for binary solvent systems. The Jouyban−Acree model is described as eq 7. ln xw , T = w1 ln x1,T + w2 ln x 2, T +

w1w2 T

2

∑ Ji (w1 − w2)i i=0

(7)

Here w1 and w2 are the composition of solvents 1 and 2 in mass fraction in binary mixed solvents, respectively; xw,T is the aniracetam’s solubility in three mixed solvents in mole fraction; x1,T and x2,T represent the aniracetam’s solubility in studied pure solvent in mole fraction; T is the absolute temperature; Ji is the regressed parameters of the Jouyban−Acree model. The obtained model parameters were given in Table 6, and Figure 3

ln x = B0 + B1x 2 + B2 x 22 + B3x 23 + +B4 x 24

Here x represents aniracetam’s solubility in mole fraction; x2 stands the initial percentage of content of acetone in mole fraction in binary solvent mixtures; B0 to B4 are model parameters. Those five thermodynamic model parameters are given in Table 7. The calculated RMSD values are a little smaller than those in the Jouyban−Acree model; the RAD values in (acetone + methanol) at 273.15 K are a little large. However, other data are within 5% of the range. 3.4. Infrared Spectroscopy and X-ray Diffraction Analysis. For contrastive analysis the difference between all these crystallized products and raw material, their infrared spectra recorded, and XRD data were compared comprehen-

Table 6. Parameters of the Jouyban−Acree Model for Aniracetam in Three Mixed Solvents

acetone + methanol acetone + ethanol acetone + isopropyl alcohol

J0

J1

J1

102 RAD

104 RMSD

182.34 −116.38 −235.71

−364.03 −431.72 −472.88

−229.35 −472.55 −694.26

4.15 3.32 4.61

20.16 8.13 8.50

(8)

Table 7. Parameters of the Cnibs/R-K Model for Aniracetam in Three Mixed Solvents T/K

B0

Acetone + Methanol 273.15 −6.929 278.15 −6.661 283.15 −6.281 288.15 −5.964 293.15 −5.643 298.15 −5.353 303.15 −5.102 308.15 −4.865 313.15 −4.649 318.15 −4.436 Acetone + Ethanol 273.15 −6.975 278.15 −6.814 283.15 −6.465 288.15 −6.149 293.15 −5.834 298.15 −5.556 303.15 −5.308 308.15 −5.071 313.15 −4.863 318.15 −4.648 Acetone + Isopropyl Alcohol 273.15 −7.236 278.15 −6.921 283.15 −6.585 288.15 −6.265 293.15 −5.977 298.15 −5.711 303.15 −5.471 308.15 −5.247 313.15 −5.035 318.15 −4.835

B2

B3

B4

102 RAD

104 RMSD

7.065 8.975 8.625 7.634 7.147 6.278 5.779 5.221 4.676 4.449

−10.97 −19.13 −18.26 −13.84 −12.20 −8.577 −6.674 −4.431 −2.190 −1.468

9.602 21.00 19.53 13.03 10.76 5.608 3.051 −0.004 −3.100 −3.790

−2.723 −7.925 −7.140 −4.152 −3.159 −0.880 0.178 1.467 2.804 2.932

7.45 4.95 1.67 1.33 0.81 0.49 0.90 1.30 1.57 1.62

4.28 3.61 1.58 1.73 1.68 2.01 4.50 7.61 9.23 10.38

5.726 5.881 4.679 3.961 3.155 2.497 2.027 1.589 1.199 0.868

−10.41 −8.53 −3.902 −1.045 1.718 3.660 4.985 6.220 7.881 8.553

10.58 6.207 0.065 −3.980 −7.490 −9.659 −11.03 −12.28 −14.63 −15.03

−2.888 −0.489 2.115 3.921 5.359 6.135 6.552 6.917 7.949 7.935

3.51 1.77 1.80 1.50 0.76 0.35 0.50 0.61 0.65 0.99

1.62 2.09 2.93 2.41 1.97 0.87 1.03 3.29 3.83 5.65

5.946 4.144 2.433 1.373 0.664 0.187 −0.357 −0.821 −1.305 −1.580

−12.14 −3.223 3.996 8.080 10.70 12.09 13.77 15.38 17.27 18.36

12.52 −0.995 −10.89 −16.62 −20.05 −21.46 −23.18 −25.15 −27.75 −29.20

−3.072 3.226 7.500 10.12 11.55 11.96 12.45 13.21 14.35 14.92

3.79 3.26 3.94 3.62 3.47 3.15 3.24 3.05 2.42 2.41

4.22 3.90 5.06 5.08 5.90 6.33 7.38 8.00 7.09 8.23

B1

F

DOI: 10.1021/acs.jced.8b00023 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Figure 4. IR spectra in KBr pellets (on left) and their correlation trajectories by Pearson correlation coefficient (on right): (a) recrystallization by acetone (red) against raw material (blue); (b) recrystallization by ethyl acetate (green) against raw material (pink); (c) recrystallization by toluene (blue) against raw material (gray); (d) recrystallization by methanol (red) against raw material (black); (e) recrystallization by ethanol (orange) against raw material (blue) ; (f) recrystallization by isopropyl alcohol (navy blue) against raw material (light blue); (g) recrystallization by npropanol (blue) against raw material (green).

sively and systematically. Furthermore, the degree of similarity of infrared spectrum data was quantified by the Pearson correlation coefficient (R).22,23 ∑ XY −

R=

(∑ X

2

−

2 (∑ X ) N

According to the results of Figure 5, we can know that there is no phase transformation before and after the experiment.

4. CONCLUSION The isothermal dissolution equilibrium method was applied to measure the solubility values of aniracetam from T = 273.15 to 318.15 K under atmospheric pressure in seven pure and three binary mixtures solvents with various compositions. In pure solvents, the order of solubility from high to low is the sequence of acetone > ethyl acetate > toluene > methanol > ethanol > isopropyl alcohol > n-propanol. In mixed solvents, the measured solubility of aniracetam in (acetone + methanol), (acetone + ethanol), and (acetone + isopropyl alcohol) increased with the content increase of acetone at the same temperature. The influence of aniracetam dissolution behavior upon temperature, solvent type, and solvent composition was correlated by two pure solvent models (modified Apelblat equation, λh equation) and two cosolvent models (CNIBS/RK model and Jouyban−Acree model). The calculated data of RAD and RMSD were no more than 4.95% and 2.16 × 10−3, respectively, except for the system of (acetone + methanol) with the CNIBS/R-K model at 273.15 K. As compared with the experimental data, the predictions of the four thermodynamic models give a satisfactory result. The spectra of raw material and crystallized products are exactly similar. From this work, isopropyl alcohol or n-propanol was selected as a poor solvent and acetone as a good solvent to isolate aniracetam.

∑X∑Y N

)(∑ Y

2

−

2 (∑ Y ) N

)

(9)

Here N denotes the value for infrared spectra; X and Y denote the raw material and crystallized product values, respectively. If the two infrared spectra recorded are exactly the same, the Pearson correlation coefficient obtained should equal 1. The comparison itself is illustrated in Figure 4. The obtained Pearson correlation coefficients in seven pure solvents are almost equal to 1; the spectra of raw material and crystallized products indicate a significant sameness. Figure 5 presents the PXRD patterns of crystallized products from different solvents and raw material. From Figure 5, before and after experiment, the characteristic peak of PXRD patterns is exactly the same.

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Figure 5. PXRD patterns of aniracetam in different solvents and raw material.

Danfeng Shao: 0000-0001-7934-089X G

DOI: 10.1021/acs.jced.8b00023 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Funding

magnesium-dl-aspartate, and magnesium-l-lactate in water. J. Chem. Thermodyn. 2002, 34, 1127−1136. (18) 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. (19) 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. (20) Jouyban, A.; Fakhree, M. A. A.; Acree, W. E., Jr. Comment on “Measurement and correlation of solubilities of (z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid in different pure solvents and binary mixtures of water + (ethanol, methanol, or glycol). J. Chem. Eng. Data 2012, 57, 1344−1346. (21) Eghrary, S. H.; Zarghami, R.; Martinez, F.; Jouyban, A. Solubility of 2-butyl-3-benzofuranyl 4-(2-(diethylamino)ethoxy)-3,5diiodophenyl ketone hydrochloride (amiodarone HCl) in ethanol + water and n-methyl-2-pyrrolidone + water mixtures at various temperatures. J. Chem. Eng. Data 2012, 57, 1544−1550. (22) Jouyban, A.; Martinez, F.; Acree, W. E. Further calculations on solubility of 3-amino-1-adamantanol in ethanol + water binary solvent mixtures at various temperatures. J. Mol. Liq. 2016, 219, 211−215. (23) Jouyban, A.; Clark, B. J. Describing solubility of polymorphs in mixed solvents by CNIBS/R-K equation. Pharmazie 2003, 57, 861− 862.

The research is supported by China National Key Research and invention program of the 13th Five-Year Plan (No.2017YFD0200707). The authors also want to give thanks to the Ministry of Education Scientific Research Foundation (No.XM20131225085213994) as well as Zhejiang Province Public Technology Project (No.2013C31G2290019) and Ningbo Natural Science Foundation (No.2013A610094). Notes

The authors declare no competing financial interest.

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DOI: 10.1021/acs.jced.8b00023 J. Chem. Eng. Data XXXX, XXX, XXX−XXX