Determination and Correlation of Dipyridamole p-Toluene Sulfonate

Article pubs.acs.org/jced

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

Determination and Correlation of Dipyridamole p‑Toluene Sulfonate Solubility in Seven Alcohol Solvents and Three Binary Solvents Mengya Li,†,‡ Shiyuan Liu,†,‡ Si Li,†,‡ Yang Yang,†,‡ Yingdan Cui,†,‡ and Junbo Gong*,†,‡,§ †

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

ABSTRACT: The solubility of dipyridamole p-toluene sulfonate in seven monosolvents (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, 2-butanol) and three different binary solvents (methanol + ethanol, methanol + 1-propanol, methanol + 1-butanol) was measured by a gravimetric method at temperatures ranging from 288.15 to 328.15 K. The experimental results indicate that the solubility of dipyridamole p-toluene sulfonate increases with increasing temperature while showing negative correlation with the mole fraction of organic solvents (ethanol, 1-propanol, 1-butanol) at a given temperature in binary solvents. The Apelblat model, the CNIBS/R-K model, and the modified version of Jouyban-Acree models (the Apel-JA equation) were used to correlate the experimental data, and the calculated results of above models were found to agree well with the experimental data.

1. INTRODUCTION Stroke, the third leading cause of death behind heart disease and cancer, is the most common cause of neurological disability in older individuals.1 There are more than 750 000 incident strokes occurring each year in the United States,2 of which 200 000 events are recurrent stroke following quietly high risks of an ischemic stroke (IS) or transient ischemic attack (TIA).3−5 As recurrent events are even more severe than index events, it results in an increasing possibility of dependency, disability, cognitive impairment and dementia, poor quality of life, and institutionalization.6,7 Fortunately, dipyridamole (DIP, 2,2′,2″,2‴- [ (4, 8-di-1piperidinylpyrimido [5,4-d]pyrimidine-2,6-diyl) dinitrilo ] tetrekis-), a thromboxane synthase inhibitor, has been clinically used for prevention of postoperative thromboembolic complication or reduction of the reoccurrence of transient ischemic attacks.8,9 Furthermore, the new pharmacological activities have been being constantly discovered since the DIP hit the market and was greatly accepted by the public because of low price, which will bring out a vast market prospect. At present, the purification and separation of dipyridamole ptoluene sulfonate (2, 2′, 2″, 2‴-[ (4,8-di-1-piperidinylpyrimido [5,4-d] pyrimidine-2, 6-diyl) dinitrilo ] tetrakis-, bis(4methylbenzenesulfonate)) and dipyridamole is the last process in the whole synthesis of dipyridamole, in which dipyridamole p-toluene sulfonate is an important medical intermediate.10,11 Thus, knowing its solubility data is of great significance for design of the subsequent process, and for the yield improvement. However, fewer researches focus on the solubility of this © XXXX American Chemical Society

important medical intermediate. Therefore, a quantitative and systematic analysis of the solubility of dipyridamole p-toluene sulfonate is reported. In this article, the solubility of dipyridamole p-toluene sulfonate in some industrial commonly used solvents was determined by a gravimetric method from 288.15 to 328.15 K (P = 0.1 MPa),12−16 including seven monosolvents (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, 2butanol) and binary solvent mixtures (methanol + ethanol, methanol + 1-propanol, methanol + 1-butanol). The Apelblat equation, CNIBS/R-K model and the combined version of the Jouyban-Acree model (Apel-JA) were used to correlate the experimental results. All of the models show satisfactory correlation results with the experimental values, and can help to understand the relationship between the solubility and temperature as well as solvent composition. All the results could be an auxiliary guide in separation and purification process of dipyridamole p-toluene sulfonate and dipyridamole.

2. EXPERIMENT 2.1. Materials. Dipyridamole p-toluene sulfonate (C38H56N8O10S2, Mw = 849.03, Figure 1) with a mass fraction purity higher than 99.0% was purchased from Qidong Dongyue Pharmaceutical Co., Ltd., China, which is an orange crystalline powder. The organic solvents (methanol, ethanol, 1-propanol, Received: September 15, 2017 Accepted: November 27, 2017

A

DOI: 10.1021/acs.jced.7b00825 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Figure 2. Comparison of X-ray powder diffraction patterns between the raw material and residual solids in seven monosolvents at 323.15 K.

Figure 1. Chemical structure of dipyridamole p-toluene sulfonate.

2-propanol, 1-butanol, isobutanol, and 2-butanol) are of analytical reagent grade and were used without further treatment. More detailed information on the material is depicted in Table 1. Table 1. Sources and Mass Fraction Purity of Materials Used in the Experiments chemical

CAS

source

dipyridamole ptoluene sulfonate

49845-74-1

methanol

67-56-1

ethanol

64-17-5

Shandong Qidong Dongyue Pharmaceutical Co., Ltd., China Tianjin Jiangtian Co.,Ltd. Tianjin Jiangtian Co.,Ltd. Tianjin Jiangtian Co.,Ltd. Tianjin Jiangtian Co.,Ltd. Tianjin Jiangtian Co.,Ltd. Tianjin Jiangtian Co.,Ltd. Tianjin Jiangtian Co.,Ltd.

1-propanol

102910-31-6

2-propanol

67-63-0

1-butanol

71-36-3

isobutanol

78-83-1

2-butanol

78-92-2

mass fraction purity

analysis method

≥99.0%

HPLCa

≥99.5%

GCb

≥99.5%

GCb

≥99.5%

GC

b

≥99.5%

GCb

≥99.5%

GCb

≥99.5%

GCb

≥99.5%

GCb

Figure 3. Comparison of X-ray powder diffraction patterns between the raw material and residual solids in three binary solvents at 323.15 K: a, b, and c represent residual solids in (methanol + ethanol) at x2 = 0.20, 0.50, and 0.80, respectively; d, e, and f represent residual solids in (methanol + 1-propanol) at x2 = 0.20, 0.50, and 0.80, respectively; g, h, and i represent residual solids in (methanol + 1-butanol) at x2 = 0.2, 0.5, and 0.8, respectively.

amount of dipyridamole p-toluene sulfonate was added into 25 mL monosolvent or binary solvent mixture of known molar fraction composition in a 50 mL conical flask. The solution was stirred (200 rpm) for at least 12 h to reach the solid−liquid equilibrium using an air bath shaker with standard uncertainty u(T) = 0.1 K (type HNY-200R, Tianjin Honuor Instrument Co.Ltd., China). After that, the agitation was stopped and the solution was kept still for 2 h to ensure solid phase to precipitate to the bottom before sampling. The upper saturated solution was filtered with a preheated organic membrane filter (0.45 μm, Φ13 mm, Tianjin Jinteng Experimental Equipment Co., Ltd.) and transferred into a drying Petri dish which was weighed in advance. The Petri dish with saturated solution was weighted quickly and then put into a vacuum drying oven at 323.15 K for 36 h. The Petri dish with solutes was reweighed several times using an electronic balance (Mettler Toledo AB204-N, Switzerland) with standard uncertainty u(B) = 0.0001 g until the weight of Petri dish was constant. The same experiment was repeated three times to minimize the experiment errors. The mean value was used as the final result. According to the measured values, the mole fraction solubility of dipyridamole p-toluene sulfonate in the monosolvents can be calculated by eq 1 as follows:

a

High-performance liquid chromatography. bGas liquid chromatography. Both the analysis method and the mass fraction purity were provided by the suppliers.

2.2. Characterization. The X-ray power diffraction (PXRD) device (D/MAX 2500 diffractometer) was used for crystallinity test of the dipyridamole p-toluene sulfonate, which used Cu Kα radiation (1.5405 Å) and worked under 100 mA in current and 40 kV for voltage. The samples were scanned from 5° to 45° in 2θ with a scanning rate of 8 degree per minute at ambient conditions. In order to verify dipyridamole p-toluene sulfonate remained stable throughout the solid−liquid equilibrium experiments, excess samples were added at all temperatures and composition points to make suspensions. After stirring for 12 h, the sediments for each were removed to be characterized by PXRD in the same way. The residual patterns were compared with the raw material and shown in Figures 2 and 3. 2.3. Solubility Measurements. A gravimetric method described in detail in literature was used to determine the solubility of dipyridamole p-toluene sulfonate.12−16 An excess B


Journal of Chemical & Engineering Data x1 =

m1/M1 m1/M1 + m2 /M 2

Article

where x1 is the saturated mole fraction solubility of solute, x2 and x3 refer to the initial mole fraction of the binary solvents, meanwhile (x1)2 and (x1)3 represent the respective solubility values of solute in two different monosolvents. Si is a model parameter and N stands for the number of “curve-fit” parameters. In this work N equals 2, thus eq 5 can be rewritten as eq 6:

(1)

where x1 is the mole fraction solubility of dipyridamole ptoluene sulfonate and m1 and m2 represent the mass (g) of dipyridamole p-toluene sulfonate and monosolvent, respectively. M1 and M2 are the molar mass (g·mol−1) of solute and each of the alcohols selected, respectively. For binary mixed solvents, the mole fraction solubility of dipyridamole p-toluene sulfonate and the composition of mixed solvents can be expressed by following eqs 2 and 3, respectively: m1/M1 x1 = m1/M1 + m2 /M 2 + m3 /M3 x2 =

ln x1 = ln(x1)3 + x 2(ln(x1)2 − ln(x1)3 + S0 − S1 + S2) + x 22( −S0 + 3S1 − 5S2) + x 23( −2S1 + 8S2) + x 24( −4S2)

(6)

This equation could be further simplified as eq 7, which is called the variant of CNIBS/R-K model:

(2)

ln x1 = B0 + B1x 2 + B2 x 22 + B3x 23 + B4 x 24

m2 /M 2 m2 /M 2 + m3 /M3

(3)

where x1 is the mole fraction solubility of solute in mixed solvents, B0, B1, B2, B3, and B4 are constants of this model which could be worked out by the nonlinear least-squares analysis.25 3.3. Apel-JA Model. The Jouyban-Acree model is especially popular due to its ability to estimate the effect of both temperature and solvent composition of binary solvent mixtures on the solubility of solute.20,26 The model can be expressed by eq 8:

where x1 is the mole fraction solubility of dipyridamole ptoluene sulfonate, x2 is the initial mole fraction of methanol in binary solvents, and m1, m2, and m3 represent the mass (g) of dipyridamole p-toluene sulfonate, methanol, and the other organic solvent (ethanol, 1-propanol, 1-butanol), respectively. M1, M2, and M3 are the molar mass (g·mol−1) of solute and the two solvents in binary solvents selected.

N

3. THERMODYNAMIC MODELS The solubility of drugs could be well determined by experimental procedures and there are many thermodynamic models to act as a useful tools for a better understanding of solubility behavior of drugs by prediction or correlation.17 For example, the Apelblat model is always used to correlate solubility of a drug with temperature,18 and CNIBS/R-K model can be used to correlates the experimental solubility with solvent composition.19 What’s more, the combined version of the Jouyban-Acree model was used to express the relationship among solubility, solvent composition, and temperature.20 3.1. Apelblat Model. The Apelblat model has been widely used to evaluate the relationship between temperature and the mole fraction solubility of solute, and a mathematical representations for solubility were provided in many systems.21,22 It can be described as follows: B ln x1 = A + + C ln T (4) T where T represents the absolute temperature (K); x1 is the mole fraction of the solute at T; and A, B, and C are semiempirical constants. Values of A and B represent the variation in the solution activity coefficient, and can be regarded as an indication of the nonideality effect of solution on the solubility of solute. Constant C as a deviation of heat capacity ΔCp, reflects the effect of temperature on the fusion enthalpy. 3.2. CNIBS/R-K Model. The combined nearly ideal binary solvent/Redlich−Kister (CNIBS/R-K) model, studied the solid−liquid equilibrium of solute in mixed solvents, was proposed by Acree and Jouyban Gharamaleki that describes the relationship between experimental solubility value and various compositions in binary system.23,24 It could be expressed by eq 5 as follows:

ln x1 = x 2 ln(x1)2 + x3 ln(x1)3 + x 2x3 ∑ [Ji (x 2 − x3)i /T ] i=0

(8)

where Ji is a model constant; T is the absolute temperature (K); N refers to 0, 1, 2, and 3; and the other symbols denote the same meanings as in eq 5. The Jouyban-Acree model has been used in many recent reports by replacing the solute solubility (x1)i in a monosolvent i (i = 2, 3) with the corresponding values from the Apelblat model as shown bellow:

i=0

ln(x1)2 = A1 +

B1 + C1ln T T

(9)

ln(x1)3 = A 2 +

B2 + C2 ln T T

(10)

Thus, the substitution of eqs 9 and 10 into eq 8 followed by rearrangement yields eq 11. b1 + c 2 ln T + x 2(a1 − a 2) T x + (b1 + b2 + J0 − J1 + J2 ) 2 + ( −J0 + 3J1 − 5J2 ) T 2 3 (x 2 ) (x ) (x )4 + ( −2J1 + 8J2 ) 2 − 4J2 2 T T T

ln x1 = a1 +

+ (c1 − c 2)x 2 ln T

(11)

With the introduction of a constant term, eq 11 can be further simplified as eq 12: A2 x (x )2 + A3 ln T + A4 x 2 + A5 2 + A 6 2 T T T 3 4 (x ) (x ) + A 7 2 + A8 2 + A 9x 2 ln T (12) T T

ln x1 = A1 +

N

ln x1 = x 2 ln(x1)2 + x3 ln(x1)3 + x 2x3 ∑ Si(x 2 − x3)i

(7)

(5) C



Article

Table 2. Experimental (x1exp) and Calculated (x1cal) Mole Fraction Solubilities of Dipyridamole p-Toluene Sulfonate in Seven Monosolvents at Temperature T and Pressure P = 0.1 MPaa,b 104x1exp

T/K

methanol 15.40 18.38 24.04 27.82 30.83 37.29 44.32 53.24 65.11 ethanol 4.80 6.22 7.38 8.81 10.30 12.62 13.80 16.95 19.83 1-propanol 3.71 4.19 4.66 6.02 6.73 7.98 9.56 13.83 16.96 2-propanol 1.74 2.18 2.73 3.05 3.69 4.25 4.95

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

104x1cal (eq 4)

T/K

16.29 19.07 22.45 26.53 31.48 37.50 44.81 53.72 64.58

323.15 328.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

5.05 6.09 7.30 8.71 10.34 12.23 14.40 16.88 19.72

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

3.80 4.19 4.76 5.56 6.66 8.17 10.24 13.12 17.14

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

1.85 2.18 2.58 3.05 3.62 4.30 5.12

1 N

N

x i exp − x i cal x i exp

∑ i=1

6.10 7.28 2.03 2.47 3.00 3.62 4.34 5.19 6.17 7.32 8.63 2.42 2.95 3.53 4.19 4.90 5.68 6.50 7.38 8.29 1.14 1.49 1.91 2.40 2.97 3.62 4.33 5.12 5.97

the high crystallinity of dipyridamole p-toluene sulfonate used in this study. The patterns also revealed that the residual solids in selected solvents were all as same as that of raw material. As shown in Figures 2 and 3, it proved it that all the PXRD patterns of solid phase of solute have the same characteristic peaks. Therefore, it can be concluded that there was no degradation or crystal transformation during the entire experiment. 4.2. Solubility Data. The solubility of dipyridamole ptoluene sulfonate in the monosolvents and the binary solvents was measured by a gravimetric method from 288.15 to 328.15 K at atmosphere pressure (P = 0.1 MPa). The mole fraction solubilities of dipyridamole p-toluene sulfonate in the seven monosolvents are listed in Table 2 and graphically plotted in Figure S1. From which it can be learned that the solubility data in all of the seven monosolvents increases with the increasing temperature. By comparison of all experimental data, the solubility value of solute in methanol is the highest, followed by that in ethanol and 1-propanol. The solubility data of dipyridamole p-toluene sulfonate in 2-

(13)

∑i = 1 (x i cal − x i exp)2 N

2-propanol 6.22 7.27 1-butanol 2.08 2.32 3.10 3.70 4.37 5.22 5.98 7.28 8.76 isobutanol 2.49 2.87 3.34 4.21 5.20 5.90 6.09 7.35 8.40 2-butanol 1.22 1.49 1.80 2.31 3.01 3.84 4.27 5.00 6.02

x1exp is the experimental solubility; x1cal (eq 4) is the calculated solubility according to eqs 4. bThe standard uncertainty of T is u(T) = 0.1 K. The relative uncertainty of the solubility is ur(x1) = 0.01. The relative uncertainty of pressure is ur(P) = 0.05.

N

RMSD =

104x1cal (eq 4)

a

where Ai (i = 1−9) are the model parameters. The other symbols denote the same meanings as in eq 5. To assess the applicability and accuracy of the thermodynamic models, the average relative deviation (ARD) and the root-mean-square deviations (RMSD) are introduced by the following definitions ARD =

104x1exp

(14)

where N is the number of experimental measurement points, the xical stands for the mole fraction of calculated solubility of solute, and xiexp represents the experimental data.

4. RESULTS AND DISCUSSION 4.1. X-ray Powder Diffraction Analysis. The X-ray powder diffraction (PXRD) patterns verified the identity and D



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Table 3. Experimental (x1exp) and Calculated (x1cal) Mole Fraction Solubilities of Dipyridamole p-Toluene Sulfonate in Methanol (x2) + Ethanol (1-x2) at Temperature T and Pressure P = 0.1 MPaa,b x2

104x1exp

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

5.73 6.26 7.01 8.41 8.92 10.10 11.24 12.93 13.99

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

6.73 7.31 8.59 10.14 10.59 12.08 13.82 15.03 16.22

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

8.10 9.02 10.69 11.67 12.66 13.37 15.66 16.89 20.11

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

10.08 11.38 12.65 13.42 14.24 15.35 17.52 20.26 23.08

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80

11.94 13.31 14.04 15.91 17.24 19.43 21.31 23.88

104x1cal (eq 4) T 5.67 6.14 7.12 8.50 8.96 10.11 11.41 12.89 14.08 T 6.85 7.55 8.62 9.95 10.56 11.74 13.31 14.87 16.47 T 8.23 9.17 10.33 11.64 12.43 13.69 15.57 17.29 19.38 T 9.81 11.01 12.28 13.60 14.62 16.03 18.27 20.26 22.93 T 11.63 13.07 14.48 15.87 17.18 18.85 21.51 23.90

104x1cal (eq 7)

104x1cal (eq 12)

x2

104x1exp

5.60 6.38 7.18 8.06 9.04 10.14 11.37 12.72 14.10

5.72 6.40 7.13 7.93 8.83 9.87 11.11 12.59 14.41

0.90

27.14

6.71 7.50 8.52 9.70 10.98 12.28 13.58 14.91 16.41

6.92 7.71 8.55 9.46 10.49 11.68 13.08 14.76 16.80

8.25 9.31 10.39 11.49 12.62 13.84 15.29 17.18 19.89

8.31 9.23 10.20 11.26 12.44 13.81 15.42 17.35 19.68

10.26 11.46 12.42 13.32 14.33 15.64 17.45 19.94 23.32

9.89 10.97 12.11 13.35 14.74 16.33 18.21 20.45 23.16

11.79 13.11 14.42 15.80 17.36 19.17 21.35 23.97

11.68 12.96 14.30 15.77 17.42 19.31 21.52 24.17

= 288.15 K

= 293.15 K

= 298.15 K

= 303.15 K

= 308.15 K

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

13.77 15.40 16.71 18.61 20.83 23.08 26.05 28.64 31.71

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

15.28 17.50 19.36 21.38 23.09 26.07 30.28 34.20 39.67

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

18.87 20.28 23.01 25.09 27.55 31.21 35.75 40.69 45.77

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

21.91 23.94 26.20 29.24 32.77 37.17 41.81 48.86 57.74

104x1cal (eq 4) T 27.25 T 13.70 15.36 16.94 18.51 20.17 22.26 25.38 28.38 32.53 T 16.04 17.87 19.68 21.55 23.66 26.36 30.02 33.90 38.99 T 18.69 20.61 22.70 25.08 27.73 31.32 35.58 40.73 46.91 T 21.66 23.55 26.01 29.15 32.47 37.33 42.25 49.17 56.63

104x1cal (eq 7)

104x1cal (eq 12)

= 308.15 K 27.12

27.37

13.71 15.11 16.83 18.79 20.92 23.20 25.66 28.51 32.11

13.70 15.22 16.83 18.58 20.55 22.81 25.46 28.63 32.45

15.69 17.48 19.19 21.07 23.36 26.28 29.97 34.46 39.49

15.96 17.78 19.71 21.83 24.20 26.94 30.15 33.98 38.61

18.71 20.55 22.64 25.06 27.93 31.35 35.45 40.37 46.23

18.48 20.66 23.00 25.56 28.46 31.79 35.72 40.41 46.07

21.97 24.10 26.37 29.07 32.48 36.85 42.41 49.22 57.08

21.26 23.89 26.72 29.86 33.40 37.51 42.34 48.12 55.13

= 313.15 K

= 318.15 K

= 323.15 K

= 328.15 K

a

x1exp is the experimental solubility; x1cal (eq 4), x1cal (eq 7), and x1cal (eq 12) are the calculated solubility according to eqs 4, 7, and 12, respectively. bThe standard uncertainty of T is u(T) = 0.1 K. The relative uncertainty of the solubility is ur(x1) = 0.01. The relative uncertainty of pressure is ur(P) = 0.05. The relative uncertainty of the initial mass fraction of methanol in the binary solvents is ur(x2) = 0.002.

with high polarity and it can be more soluble in methanol followed by that in ethanol and 1-propanol, which is corresponding with the order of the dielectric constant above, while this case was not found for the others four alcohols. The reason may lie in the fact that the solubility is also determined by the mutual competition of interactions between the solute− solvent and solvent−solvent. There are > NH+ as well as  OH groups in the structure of solute molecule, which can act as hydrogen-bonding donors when the OH groups in alcohol

propanol and three butanols are quite approximate and ten times lower than that in methanol. According to the general rule of “like dissolves like”,27,28 greater solubility can be achieved when the polarity of solvent is close to that of the solute. Dielectric constant is a good index for polarity of solvents.29 The sequence of the dielectric constant of the seven monosolvents from high to low can be ranked as methanol > ethanol >1-propanol >2-propanol >1-butanol > isobutanol >2butanol.30 The dipyridamole p-toluene sulfonate is a compound E



Article

Table 4. Experimental (x1exp) and Calculated (x1cal) Mole Fraction Solubilities of Dipyridamole p-Toluene Sulfonate in Methanol (x2) + 1-Propanol (1-x2) at Temperature T and Pressure P = 0.1 MPaa,b x2

104x1exp

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

4.12 4.29 5.17 5.99 7.37 8.87 10.03 12.18 13.53

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

4.60 5.14 5.90 7.03 8.50 10.30 11.98 14.27 16.49

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

5.51 6.10 7.13 8.34 10.09 11.77 13.97 16.62 19.19

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

6.22 7.08 8.47 9.93 12.14 13.92 16.33 19.72 22.96

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80

7.55 8.51 10.38 11.62 13.72 16.46 19.30 23.03

104x1cal (eq 4) T 4.09 4.31 5.04 5.98 7.38 8.93 10.22 12.37 13.86 T 4.66 5.09 6.02 7.03 8.56 10.20 11.79 14.16 16.13 T 5.40 6.05 7.20 8.33 10.02 11.81 13.74 16.43 18.97 T 6.35 7.24 8.62 9.91 11.82 13.84 16.20 19.32 22.50 T 7.58 8.71 10.33 11.86 14.05 16.40 19.28 22.99

104x1cal (eq 7)

104x1cal (eq 12)

x2

104x1exp

3.95 4.41 5.13 6.10 7.31 8.73 10.30 11.95 13.64

4.01 4.51 5.21 6.10 7.23 8.59 10.19 12.00 13.98

0.90

27.06

4.56 5.14 5.97 7.07 8.47 10.16 12.13 14.27 16.44

4.61 5.21 6.02 7.07 8.39 9.99 11.87 14.02 16.36

5.32 6.12 7.16 8.45 10.01 11.84 13.96 16.44 19.38

5.37 6.08 7.04 8.29 9.84 11.73 13.95 16.49 19.27

6.34 7.16 8.38 9.97 11.88 14.08 16.58 19.47 23.01

6.35 7.20 8.34 9.81 11.65 13.89 16.52 19.53 22.83

7.62 8.72 10.06 11.71 13.77 16.33 19.43 23.04

7.61 8.62 9.98 11.73 13.92 16.57 19.70 23.26

= 288.15 K

= 293.15 K

= 298.15 K

= 303.15 K

= 308.15 K

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

9.28 10.71 12.31 14.36 16.70 19.56 22.47 27.08 31.39

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

11.02 13.07 15.46 17.26 20.01 22.93 27.63 32.90 38.75

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

14.46 15.93 18.27 21.34 25.28 30.33 35.25 41.77 48.56

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

16.98 18.85 20.76 24.91 29.52 35.09 42.04 51.83 60.20

104x1cal (eq 4) T 26.92 T 9.16 10.54 12.39 14.25 16.81 19.63 23.16 27.68 32.47 T 11.21 12.82 14.87 17.20 20.24 23.72 28.06 33.67 39.43 T 13.87 15.67 17.85 20.84 24.51 28.93 34.26 41.35 48.22 T 17.35 19.22 21.44 25.34 29.85 35.57 42.13 51.25 59.33

104x1cal (eq 7)

104x1cal (eq 12)

= 308.15 K 26.99

27.18

9.25 10.70 12.37 14.35 16.68 19.46 22.78 26.77 31.54

9.21 10.42 12.05 14.15 16.76 19.92 23.64 27.87 32.51

11.35 13.21 15.10 17.25 19.89 23.27 27.57 32.83 38.73

11.27 12.74 14.70 17.21 20.33 24.11 28.53 33.56 39.06

14.57 16.07 18.27 21.27 25.17 30.01 35.70 41.95 48.16

13.94 15.71 18.07 21.10 24.84 29.36 34.63 40.61 47.12

17.45 18.86 21.08 24.38 29.01 35.18 42.88 51.59 59.88

17.39 19.53 22.39 26.04 30.55 35.96 42.25 49.35 57.05

= 313.15 K

= 318.15 K

= 323.15 K

= 328.15 K

a


solvents act as hydrogen-bonding acceptors. Therefore, hydrogen bonds can be formed between the solute and solvent molecules. Besides, the steric effect and van der Waals force should also be taken into consideration: the molecular size of dipyridamole p-toluene sulfonate is relatively large due to its functional group with ring structure, when interact with alcohols with longer carbon chain such as other three butanols, the steric effect may act as a more important role compared with hydrogen bonds, which causes a lower solubility of solute

in butanols. Additionally, although the sulfonate group and benzene rings of dipyridamole p-toluene sulfonate cannot form hydrogen bonds, they would contribute to van der Waals force between molecules. Thus, in this study, the solubility behavior of solute is affected by several factors together. The solubility results of dipyridamole p-toluene sulfonate in three binary solvents are listed in Tables 3, 4, and 5 and graphically displayed in Figures S2−S4. It can be observed that the solubility of solute in binary solvent mixtures increases with F



Article

Table 5. Experimental (x1exp) and Calculated (x1cal) Mole Fraction Solubilities of Dipyridamole p-Toluene Sulfonate in Methanol (x2) + 1-Butanol (1-x2) at Temperature T and Pressure P = 0.1 MPaa,b x2

104x1exp

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

3.01 4.23 5.04 6.52 7.71 9.07 11.07 13.15 14.40

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

4.50 5.56 6.53 8.18 9.38 11.21 13.09 15.55 17.03

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

5.36 6.89 8.13 9.56 11.43 13.23 16.12 19.12 21.11

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

6.79 7.26 9.92 11.90 13.18 15.17 18.75 21.87 23.93

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80

7.07 8.10 10.29 12.75 14.35 16.68 20.76 24.32

104x1cal (eq 4) T 3.26 4.48 5.25 6.71 7.99 9.38 11.24 13.32 14.62 T 4.16 5.32 6.44 8.06 9.34 10.96 13.24 15.67 17.17 T 5.14 6.24 7.75 9.53 10.85 12.74 15.52 18.37 20.18 T 6.18 7.24 9.14 11.08 12.52 14.75 18.08 21.45 23.74 T 7.23 8.31 10.58 12.69 14.37 17.00 20.95 24.97

104x1cal (eq 7)

104x1cal (eq 12)

x2

104x1exp

3.06 4.11 5.20 6.37 7.70 9.26 11.04 12.94 14.58

3.34 4.38 5.35 6.35 7.52 8.99 10.88 13.12 15.38

0.90

27.71

4.08 5.49 6.81 8.10 9.50 11.14 13.11 15.30 17.31

4.06 5.30 6.45 7.62 8.98 10.70 12.89 15.49 18.09

5.06 6.68 8.22 9.76 11.44 13.45 15.88 18.72 21.64

4.86 6.32 7.67 9.04 10.63 12.64 15.18 18.20 21.21

5.99 7.89 9.73 11.56 13.50 15.70 18.30 21.33 24.61

5.74 7.44 9.02 10.62 12.48 14.82 17.79 21.30 24.80

6.57 8.50 10.37 12.30 14.50 17.15 20.39 24.16

6.68 8.65 10.49 12.36 14.54 17.27 20.72 24.82

= 288.15 K

= 293.15 K

= 298.15 K

= 303.15 K

= 308.15 K

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

7.92 8.79 11.39 13.97 15.66 18.76 23.22 28.61 32.73

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

8.51 10.71 13.00 15.05 17.86 22.00 27.32 33.59 38.35

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

9.69 11.96 14.95 17.39 20.71 25.68 31.73 38.08 44.13

0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

11.82 13.38 16.81 20.10 24.92 29.33 36.68 45.30 56.01

104x1cal (eq 4) T 27.94 T 8.25 9.44 12.04 14.33 16.40 19.51 24.15 28.98 32.91 T 9.20 10.62 13.48 15.98 18.62 22.31 27.71 33.52 38.78 T 10.02 11.84 14.87 17.58 21.03 25.42 31.65 38.66 45.72 T 10.68 13.10 16.17 19.13 23.65 28.86 35.99 44.46 53.90

104x1cal (eq 7)

104x1cal (eq 12)

= 308.15 K 27.97

28.92

7.42 9.38 11.31 13.42 15.93 19.13 23.18 28.05 33.18

7.68 9.95 12.08 14.26 16.80 19.99 24.02 28.81 33.64

8.38 10.53 12.74 15.24 18.28 22.15 27.05 32.92 39.12

8.72 11.32 13.77 16.31 19.27 23.00 27.71 33.33 39.03

9.53 11.83 14.49 17.62 21.35 25.82 31.19 37.56 44.91

9.80 12.74 15.57 18.51 21.96 26.30 31.82 38.41 45.18

11.73 14.03 16.69 19.98 24.21 29.73 36.83 45.60 55.55

10.89 14.21 17.44 20.85 24.86 29.92 36.37 44.12 52.16

= 313.15 K

= 318.15 K

= 323.15 K

= 328.15 K

a


increasing temperature at constant solvent compositions. Besides, at a certain temperature, the solubility of solute is positive with mole fraction of methanol. Hence, the organic solvents (ethanol, 1-propanol, 1-butanol) can play as an antisolvents in the separation and purification process of dipyridamole p-toluene sulfonate. The dissolving capacity of solute in the binary solvent mixtures could be ranked as (methanol + ethanol) > (methanol + 1-propanol) > (methanol + 1-butanol), which it is almost in accordance with the

mentioned order of polarity of solvents. And as discussed above, in addition to the polarity of the selected solvents, there are other complex influencing factors in solutions, such as hydrogen bonds, van der Waals force, and so on. 4.3. Data Correlation. In this study, the Apelblat equation, CNIBS/R-K equation, and the combined version of the Jouyban-Acree model (Apel-JA model) were correlated by the experimental solubility data of dipyridamole p-toluene sulfonate by the MATLAB (MATLAB R2014a) program. The G



■

experimental data and the modeling solubility data are given in Tables 2−5 and the parameters along with the ARD and RMSD of three models are summarized in Tables S1−S4. As can be observed, the experimental solubility data shows good agreement with the calculated results by using the three eqs (eqs 4, 7, 12) above, of which the maximum ARD values of the correlating models are 6.28% (Apelblat model), 3.24% (CNIBS/R-K), and 4.90% (Apel-JA), respectively. Similarly, the maximum RMSD values are 10.12 × 10−5 (Apelblat model), 5.24 × 10−5 (CNIBS/R-K), 11.44 × 10−5 (Apel-JA), respectively. Hence, it can be concluded that the solubility as a function of temperature is correlated well with the Apelblat model. Meanwhile, it shows good correlation with the CNIBS/ R-K model as a function of solvent composition in the binary solvent mixtures. As a function of both temperature and the mole fraction of organic solvent, the Apel-JA model can still give good correlation results with satisfactory accuracy. The experimental values and those from the correlation models in this article can be used as basic data and acceptable models in the industrial separation and purification process, in which dipyridamole p-toluene sulfonate manufactures the dipyridamole.

AUTHOR INFORMATION

Corresponding Author

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

Junbo Gong: 0000-0002-3376-3296 Funding

The authors are grateful to the financial support of National Natural Science Foundation of China (NNSFC 81361140344 and NNSFC 21376164), National 863 Program (2015AA021002), Major Science and Technology Program for Water Pollution Control and Treatment (NO.2015ZX07202-013), and Tianjin Science and Technology Project (15JCZDJC33200). Notes

The authors declare no competing financial interest.

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5. CONCLUSIONS In this work, the solubility data of dipyridamole p-toluene sulfonate was measured in seven monosolvents and three binary systems at a wide temperature range (288.15 to 328.15 K) at 0.1 MPa. It can be concluded from the experimental results that the solubility value of solute depends both on the temperature and solvent composition. The solubility of solute in all selected solvent systems increases with increasing temperature, and in three binary solvent mixtures, it is also positive with the mole fraction of methanol at a certain temperature. The dissolution behavior of dipyridamole ptoluene sulfonate in monosolvents and binary solvents was found to follow the “like dissolves like” rule and also influenced by other factors including intermolecular interactions, van der Waals force, and steric effect. The measured data was correlated by the Apelblat equation, CNIBS/R-K model, and the Apel-JA model, respectively, which corresponding results show an overall good agreement with the experimental data. Compared with other methods, the CNIBS/R-K equation can provide a more accurate and reliable prediction of the solubility in the binary solvents. Ultimately, it can be concluded that the experimental data presented in this study could be useful for designing and operating crystallization processes of dipyridamole p-toluene sulfonate and dipyridamole in industry.

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Article

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.7b00825. Calculated parameters with the average relative deviation (ARD) and the root-mean-square deviations (RMSD) of three models (Apelblat model, CNIBS/R-K model, the Apel-JA model) and the graphical figures of the mole fraction solubilities of dipyridamole p-toluene sulfonate in the seven monosolvents and three binary solvents (PDF) H



Article

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Determination and Correlation of Dipyridamole p-Toluene Sulfonate

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