Solubility and Partition Coefficients of 5-Fluorouracil in ScCO2 and

DOI: 10.1021/je400484u. Publication Date (Web): March 20, 2014. Copyright © 2014 American Chemical Society. *Tel: +86 411 87402439. E-mail: ...
1 downloads 0 Views 570KB Size
Download PDF
Article pubs.acs.org/jced

Solubility and Partition Coefficients of 5‑Fluorouracil in ScCO2 and ScCO2/Poly(L‑lactic acid) Shiping Zhan,*,† Qicheng Zhao,† Shuhua Chen,† Jingchang Wang,† Zhijun Liu,‡ and Chang Chen†,‡ †

College of Environmental and Chemical Engineering, Dalian University, Dalian 116622, China Institute of Fluid and Powder Engineering, Dalian University of Technology, Dalian 116023, China

‡

ABSTRACT: The solubility of a drug in supercritical carbon dioxide (ScCO2) is an important parameter for preparing the controlled release drug by supercritical fluid technology. In this work, a test technique of the flowing solubility is developed, and the test apparatus is set up based on an improved dynamic method. The solubility of 5fluorouracil (5-Fu) in ScCO2 with or without the cosolvent of ethanol is measured. The effects of the operating parameters including the pressure, the temperature, and the concentration of cosolvent on the solubility of 5-Fu in ScCO2 are investigated experimentally. The obtained solubility data are correlated by Chrastil and MendezSantiago and Teja models. The average absolute relative deviation (AARD) of the calculated value with the experimental ones is 3.52 % by the Chrastil model without cosolvent, and it is 14.6 % by the MendezSantiago and Teja model with cosolvent of ethanol. The results show that the addition of the ethanol as a cosolvent could significantly increase the solubility of 5-Fu in ScCO2. In addition, the partition coefficients K of 5-Fu between ScCO2 and poly(Llactic acid) (PLLA) are determined experimentally and correlated by Banchero’s empirical equation. The results show that the partition coefficient decreases with the increase of the pressure and increases with the increase of temperature. The calculated value of the partition coefficient K is well consonant with the experimental data, and the AARD is 14.7 %.

1. INTRODUCTION

measured detailedly and accurately in the process of producing the slow controlled release preparation by supercritical fluid. Some researchers carried on experimental studies7−9 and theoretical correlations10,11 on the solubility of small molecules in ScCO2. The solubility of 5-Fu in ScCO2 has been also measured by researchers,12,13 while the report about the solubility of 5-Fu with cosolvent in ScCO2 has not been seen yet. However, the solubility of drug in ScCO2 can be greatly enhanced with cosolvent.14 In general, the methods to measure solubility can be divided into two categories: static methods and dynamic ones. In a typical static method, the solute is put into an autoclave with a fixed volume, and ScCO2 is added. The pressure and temperature in the autoclave are adjusted to the predetermined values and kept for certain time until the saturated concentration of the solute in ScCO2 is reached. Finally the sample is taken out, and the solubility is analyzed. In a typical dynamic method, ScCO2 passes through a thermostatic bed at a constant speed under the certain temperature and pressure. The thermostatic bed must be long enough to make the solute reaches its saturation state in ScCO2. The concentration at the outlet of the thermostatic bed is detected, and the solubility of the solute in ScCO2 is determined. Each of these two methods has advantages as well as disadvantages. By the static method, the experimental equipment is simple and easy to be operated, but it needs a long time for the phase equilibrium to be

5-Fluorouracil (5-Fu) is a common anticancer agent used in the treatment of solid tumors, such as colon cancer, rectal cancer, gastric cancer, breast cancer, ovarian cancer, chorionic carcinoma, squamous cell carcinoma of head and neck, skin cancer, liver cancer, bladder cancer, and so on.1 5-Fu preparation is often used as injection, but the 5-Fu preparation with high concentration could cause some side effects on gastrointestinal and bone; thus the application of 5-Fu has a great limitations.2 To overcome these limitations, the direction of the present research is to prepare 5-Fu into the slow controlled release preparations, which can effectively improve drug bioavailability and the patient’s adaptability.3 One of these preparations is a drug-loaded polymer.4 Producing the slow controlled release preparation by supercritical fluid process is an effective and safe method, especially for the drug-loaded polymer. The most typical supercritical fluid processes used currently are the rapid expansion of supercritical solutions (RESS) 5 and the antisolvent method of supercritical fluid.6 The solubility of 5Fu in supercritical carbon dioxide (ScCO2) and partition coefficients of 5-Fu between the ScCO2 and the poly(L-lactic acid) (PLLA) are crucial parameters for these processes to produce the drug-loaded polymer. The solubility of 5-Fu with or without cosolvent is always an important index for preparation of the drug-loaded polymer. The solubility of 5Fu in supercritical fluid refers to the saturation concentration of 5-Fu dissolved in supercritical fluids under certain temperatures and pressures. It is important that the solubility data are © 2014 American Chemical Society

Received: May 25, 2013 Accepted: March 11, 2014 Published: March 20, 2014 1158

dx.doi.org/10.1021/je400484u | J. Chem. Eng. Data 2014, 59, 1158−1164

Journal of Chemical & Engineering Data

Article

Figure 1. Schematic drawing of the flowing solubility test apparatus. 1, CO2 cylinder; 2, cylinder outlet valve; 3, CO2 filter; 4, 7, 9, 18, pressure gauge; 5, cooler; 6, plunger pump; 8, 13, 22, stop valves; 10, 15, temperature controller; 11, organic solution; 12, plunger pump; 14, high pressure vessel; 16, micrometering valve; 17, heater band; 19, primary absorber; 20, two stage absorber; 21, silica gel desiccator; 23, mass flowmeter; 24, flow integration meter.

prevented the insoluble drug from being carried out. The glass beads were conducive to a steady stream of the gas. Then, the autoclave was sealed. CO2 and cosolvent were pressed into the autoclave by the plunger pumps. The temperature in the highpressure autoclave was controlled by a constant temperature water bath. When the pressure and temperature in the autoclave reached their predetermined values, the valve (8) was closed, and the intake of CO2 was stopped. The pressure was held for a certain time until ScCO2 and 5-Fu reached equilibrium, then the trimmer valve (16) was opened. The CO2 carried 5-Fu slowly passed the multistage collector loaded with the dilute hydrochloric acid (0.1 mol/L) and the 5-Fu could be completely absorbed by the diluted hydrochloric acid. At the outlet of the collector, the amount of CO2 was measured with the mass flowmeter (accuracy 0.002 g·cm−3, YK-LK, Dalian Youke, China), and the total volume of CO2 was record with the flow totalizer. After 5-Fu had been absorbed for a certain time (about 10 min) in the collector, the fine-tuning valve (16) and a piston pump were closed. At the end of the experiment, the total volume of the dilute hydrochloric acid solution was measured in the collector, the concentration of 5-Fu in the dilute hydrochloric acid solution was analyzed using UV−vis spectrophotometer, and the amount of 5-Fu was calculated.

reached. In addition, the changes of the pressure caused by sampling would upset the equilibrium state reached. By the dynamic method, sampling does not affected the equilibrium state, but a long thermostatic bed has to be required in order to reach the equilibrium between ScCO2 and the solute. In this work, a flowing solubility test technique was developed, and the test apparatus was built based on an improved dynamic method. The test technique was a combination of the static method and the dynamic method, and it could take the advantages and overcome the disadvantages of both methods alone. The improved method is that the fluid was first maintained for a period of time and then flowed through at a low rate. The solubility of 5-Fu in ScCO2 was determined with or without the cosolvent. The density models of Chrastil and Mendez-Santiago and Teja were used to correlate the experimental data. The model parameters were determined, and the results were evaluated by average absolute relative deviation (AARD). In addition, the partition coefficients of 5-fluorouracil between the ScCO2 and PLLA were determined experimentally and correlated by Banchero’s empirical equation. The AARD of the calculation results with the experimental ones was examined.

2. EXPERIMENTAL SECTION 2.1. Materials and Instrument. 5-Fluorouracil (5-Fu, pure > 98 %) was purchased from Shanghai Zhuo Rui Chemical Co. Ltd. (Shanghai, China). Anhydrous ethanol (analysis purity) was supplied by Tianjin Municipality Kemi’ou Chemical Reagent Co. Ltd. (Tianjin, China). CO2 (purity: 99.9 %) was purchased from Credit Co. (Dalian, China). The UV−vis spectrophotometer was supplied by Beijing Spectrum Analysis of General Instrument Co. (Beijing, China). 2.2. Apparatus and Procedure. Figure 1 shows a schematic diagram of the flowing solubility test apparatus which was built and used in this study. 5-Fu of 1 g (excess) was put in the high pressure autoclave of 500 mL, being circularly layered with the order of the glass wool, the glass beads, and the 5-Fu layer again and again until the 5-Fu layers were 4 to 6 deep. A sintered metal plate with the precision of 30 μm was placed at the bottom of the high pressure autoclave, which

3. RESULTS AND DISCUSSION 3.1. Correlation of Solubility Data. Two so-called semiempirical models of Chrastil15 and Mendez-Santiago and Teja16 were used to correlate the solubility data of 5-Fu in ScCO2 obtained in this study. The deviations of the experimentally measured solubility and the solubility given by each model were estimated by calculating the average absolute relative deviation (AARD) between the experimental and the calculated results using eq 1 AARD(%) =

100 N

∑

|y cal − y exp | |y exp |

(1)

Equation 2 was developed by Chrastil based on the hypothesis that a solute molecule associated with a number of solvent (ScCO2) molecules to form a solvate complex 1159

dx.doi.org/10.1021/je400484u | J. Chem. Eng. Data 2014, 59, 1158−1164

Journal of Chemical & Engineering Data

Article

α +β (2) T where y1 is the mole fraction of 5-Fu in ScCO2, k is the association number, ρf is the density of ScCO2 (mol·m−3), α is a function of the heat of dissolvent and heat of solute, and β is a function of the molecular weight of the solute and ScCO2. The values of k, α, and β in eq 2 can be obtained via linear regression. The model proposed by Mendez-Santiago and Teja is based on the theory of the dilute solution. This model demonstrates that all of the solubility data at different temperatures will coincide to a single line plotted according to eq 3

density of ScCO2, so that there is a pressure transition point (PTP). When the pressure is lower than PTP, the decrease of ScCO2 density would directly result in a decrease of the solubility with the increase of temperature. When the pressure is higher than PTP, the temperature becomes a main factor to effect on the vapor pressure of 5-Fu; thus the solubility increases with the increase of temperature. Table 1 gives a comparison between the measured solubility and the calculated one for 5-Fu in ScCO2.

y1 = k ln ρf +

⎛yP⎞ T ln⎜ 2std ⎟ = A + Bρf + CT + Dy3 ⎝P ⎠

Table 1. Comparison of the Measured Solubility of 5-Fu in ScCO2 with the Calculated onea

(3)

where y2 is the mole fraction of 5-Fu in ScCO2, y3 is the mole fraction of the cosolvent, P is the system pressure, Pstd is the standard pressure, and A, B, C, and D are the correlation constants. 3.2. Solubility of 5-Fu in ScCO2 without Cosolvent. Figure 2 shows the solubility of 5-Fu in ScCO2 without the

T/°C

P/MPa

ρ/g·L−1

40 40 40 40 45 45 45 45 55 55 55 55 AARD %

8 10 15 20 8 10 15 20 8 10 15 20

277.90 628.61 780.23 839.81 241.05 498.25 741.97 812.69 203.64 325.07 635.50 754.61

yexp·106 ycal·106, Chrastil 1.30 2.81 3.33 3.82 1.43 2.51 3.53 4.21 1.58 2.30 4.10 5.25

ycal·106, M-S T

1.33 2.77 3.36 3.58 1.36 2.60 3.72 4.03 1.55 2.35 4.28 5.00 3.52

1.16 3.23 3.68 3.40 1.30 2.55 3.98 4.27 1.82 2.19 4.18 4.69 8.72

a y is mole fraction. The standard uncertainties u are u(y) = 0.02·10−6, u(T) = 0.01 °C and u(P) = 0.01 MPa, and the combined expanded uncertainty Uc is Uc(ρ) = 0.1 g·L−1 (0.95 level of confidence).

Figures 3 and 4 are the results of correlation of the experimental data by the models of Chrastil and Mendez-

Figure 2. Solubility of 5-Fu in ScCO2 under different pressures and temperatures.

cosolvent. Each experimental point is the average of at least three replicate measurements. The experimental results under the same conditions have good repeatability. The measured solubilities of 5-Fu in ScCO2 at 35 °C and 55 °C are in the same order of magnitude compared with the results measured by Guney using a dynamic method,13 and the trend of solubility change is consistent with the change of the solution density, which indicates that the measurement with the flowing solubility test apparatus has good reliability and accuracy. The solubility measured by Guney is smaller than the one measured by us, which may be attributed to that the improved dynamic method could make the solution have a higher saturation, and the solubility measured with the flowing solubility test apparatus may be closer to the real solubility than the one measured by dynamic method. It can be seen from Figure 2 that the solubility of 5-Fu in ScCO2 increases with the increase of pressure. This is mainly because the density of ScCO2 increases with the increase of pressure, which would lead to a reduction of the distance between the solute molecules and an enhancement of the intermolecular forces between the molecules of the solute (5Fu) and solvent (ScCO2). The effects of the temperature on the solubility are more complex, and it is a result of the competition between the vapor pressure of 5-Fu and the

Figure 3. ln y1 of 5-Fu with ln ρ at different temperatures.

Santiago and Teja (M-S T), respectively. Tables 2 and 3 are the values of model coefficients by Chrastil and M-S T, respectively. Each experimental point reported is the average of at least three replicate measurements. Table 1 gives the average relative deviation (AARD (%)) between the experimental results and the ones correlated by two models. It can be seen that the results correlated by the two models are quite good, and AARD (%) by Chrastil model and M-S T model is 3.52 % and 8.72 %, respectively. The two models are all suitable for correlation of solid solute with the lower solubility in ScCO2. 3.3. Solubility of 5-Fu in ScCO2 with the Cosolvent. Because CO2 belongs to nonpolar solvent and the solute is a polar material, the addition of polar cosolvent, such as ethanol, methanol, and so forth, can effectively change the polarity of 1160

dx.doi.org/10.1021/je400484u | J. Chem. Eng. Data 2014, 59, 1158−1164

Journal of Chemical & Engineering Data

Article

Figure 6. Solubility of 5-Fu in ScCO2 with ethanol as cosolvent at different temperatures.

Figure 4. Change of T ln(y2P/Pstd) with ρ at different temperatures.

the density of CO2 increases, and the solubility of ScCO2 is proportional to its density. In addition, the increase of the temperature can promote thermal motion of the solute molecular more effectively, so that the solubility increases with the increase of temperature. In the other hand, the increase of temperature can reduce the density of the solution, which results in a reduction of the solubility. Therefore, the influence of temperature is contradictory and finally depends on which one of these two opposite effects is dominant. As shown in Figure 6, the curve with cosolvent appears also a pressure transition point (PTP). By adjusting the operating pressure and temperature, the solubility of drug in the solvent can be controlled, so as to achieve the suitable loading of drug. Table 4 shows the results of the correlation using two kinds of equations on the solubility of 5-Fu in ScCO2. Table 5 shows the values of model coefficients with the cosolvent by M-S T. It can be seen that the average relative error is smaller by using the M-S T model than using the Chrastil model. This is because the M-S T model is a multivariate regression and contains the mole percent of the cosolvent. The amounts of the cosolvent have a direct expression on effect of the solubility in M-S T model, while the mole percent of the cosolvent in the Chrastil model is only considered indirectly through the density of the solution. The mole percent of the cosolvent is very important for the solubility of 5-Fu in ScCO2, so that the error of correlation by the Chrastil model is greater. Figures 7 and 8 are the results of the correlation by M-S T model on the experimental data under the different temperatures and concentrations. The results show that the experimental data can be well correlated using the M-S T model, and the AARD (%) is 14.6 %. According to the experimental results and theoretical analysis on the solubility of 5-Fu in ScCO2 with ethanol as a cosolvent, it can be realized that the average relative error is larger by the Chrastil model than by the M-S T model; therefore the correlation by M-S T model is more consistent with the experimental results.

Table 2. Values of Model Coefficients by the Chrastil Model solute

K

A

B

5-Fu

0.896

−2927.10

−9.22

Table 3. Values of Model Coefficients by the M-S T Model solute

A

B

C

D

5-Fu

−5.097

0.00111

0.00423

0

the solvent and increase the solubility of the solute in the solvent. In this study, with the ethanol as cosolvent, the solubility of 5-Fu was studied under the different cosolvent contents, pressures, and temperatures in ScCO2. Figure 5 shows the solubility of 5-Fu in ScCO2 with the different concentrations of ethanol as cosolvent under (10, 15,

Figure 5. Solubility of 5-Fu in ScCO2 with ethanol as cosolvent at different pressures.

and 20) MPa and 45 °C. It can be seen that the solubility of 5Fu in ScCO2 with ethanol increases as many as 2 orders of magnitude comparing to the one without the cosolvent. This is very beneficial to improve the solubility of the drug in ScCO2. The effect of cosolvent on the solubility is very complex, which is related to hydrogen bonding interaction, dipole force, and so forth. Because the polarity of the mixed solvent of CO2 and ethanol is higher than that of pure CO2, the interaction between 5-Fu and ScCO2 is less than the interaction between the drug and ethanol. After the addition of cosolvent, the solubility of 5-Fu in ScCO2 increases significantly. The solubility of 5-Fu in ScCO2 with ethanol as cosolvent under the different temperatures and pressures is presented in Figure 6. It can be seen that the solubility of 5-Fu in ScCO2 increases with the increase of the pressure, which is same as in the case without cosolvent. With the increase of the pressure,

4. PARTITION COEFFICIENT OF 5-FU BETWEEN SCCO2 AND POLYMER 5-Fu was used as a model drug, and poly(L-lactide) (PLLA) was used as a model polymer. Under a certain temperature, pressure, and the cosolvent concentration, the concentrations of the drug between ScCO2 and PLLA were determined,17 and the influences of the temperature, pressure, and cosolvent content on the partition coefficient were analyzed. In addition, the correlation calculations were conducted by an empirical model for experimental data of partition coefficient. 1161

dx.doi.org/10.1021/je400484u | J. Chem. Eng. Data 2014, 59, 1158−1164

Journal of Chemical & Engineering Data

Article

Table 4. Comparison between the Measured Solubility of 5-Fu in ScCO2 and the Calculated One with Ethanol as a Cosolventa T/°C

P/MPa

cosolvent/mol %

ρ/g·L−1

yexp·104

ycal·104, Chrastil

ycal·104, M-S T

40 40 40 40 50 50 50 50 45 45 45 45 45 45 45 45 45 45 45 45 AARD %

10 13 15 20 10 13 15 20 10 10 10 10 15 15 15 15 20 20 20 20

4 4 4 4 4 4 4 4 2 4 6 8 2 4 6 8 2 4 6 8

689.4 763.0 796.9 858.9 537.2 670.4 718.8 799.2 550 621.6 674.5 714.8 732.9 759 781.7 801.3 814.1 829.5 843.1 855

2.80 3.11 3.49 4.07 2.50 2.95 3.71 4.98 1.05 2.00 3.68 10.22 1.40 3.32 5.35 15.5 1.81 4.58 6.03 23.2 44.6 %

2.39 3.40 3.95 5.12 1.67 3.60 4.59 6.63 1.41 2.16 2.86 3.50 3.82 4.31 4.78 5.21 5.50 5.87 6.22 6.53 14.6 %

2.80 3.28 3.45 3.69 2.13 3.43 3.88 4.55 0.74 2.08 5.17 11.87 1.59 3.33 6.83 13.75 2.00 3.91 7.58 14.52

a y is mole fraction. Standard uncertainties u are u(y) = 0.02·10−4, u(ycosolvent) = 0.02, u(T) = 0.01 °C, and u(P) = 0.01 MPa, and the combined expanded uncertainty Uc is Uc(ρ) = 1.0 g·L−1 (0.95 level of confidence).

Table 5. Values of Model Coefficients with the Cosolvent by the M-S T Model solute

A

B

C

D

5-Fu

−7.837

0.00191

0.0142

8.899

Figure 8. Change of T ln(y2P/Pstd) with ρ under 318.15 K and 15 MPa at different cosolvent concentrations.

Figure 7. Change of T ln(y2P/Pstd) with ρ in the presence of ethanol (4 % mol) at different temperatures.

The partition coefficient K of drug between ScCO2 and PLLA was defined by eq 4 K=

wip wif

(4)

wpi

where is the mass percent content of the drug in the PLLA, wfi is the mass percent content of the drug in the ScCO2 at the corresponding conditions. 4.1. Correlation Model of Partition Coefficient. Determining partition coefficients of drug between ScCO2 and PLLA by experimental methods is very time-consuming and laborious. Obviously, it is necessary to establish a correlative model of experimental data to predict results of

Figure 9. Partition coefficients of 5-Fu under different pressures and temperatures.

the partition coefficient within a certain range. Because the three-phase system contains both small molecular, such as CO2, the solid drugs, and cosolvent, and the macromolecular polymer, a theoretical study on the phase equilibrium is very 1162

dx.doi.org/10.1021/je400484u | J. Chem. Eng. Data 2014, 59, 1158−1164

Journal of Chemical & Engineering Data

Article

Table 6. Partition Coefficients of 5-Fu between ScCO2 and PLLA Obtained from Experiments and Calculations T/°C

P/MPa

5-Fu·103 mg·mg−1 (polymer)

5-Fu·106 mg·mg−1(ScCO2)

Kexp·10−3

Kcal·10−3

40 40 40 50 50 50 60 60 60 AARD %

10 15 20 10 15 20 10 15 20

4.15 3.21 1.89 5.36 4.51 3.39 11.0 9.48 6.77

1.43 1.70 1.95 1.19 1.97 2.25 1.25 2.24 2.72

2.90 1.89 0.97 4.50 2.29 1.51 8.80 4.23 2.49 14.7 %

2.43 1.51 1.27 5.61 2.27 1.78 8.76 3.53 2.50

with the experimental data, and the average relative deviation (AARD) is 14.7 %, which illustrate that it is feasible using the Banchero model to correlate the partition coefficients. With eq 4, the partition coefficient of 5-Fu between ScCO2 and PLLA after the addition of ethanol was calculated, and some results are shown in Table 8. Under the constant pressure and temperature, the partition coefficient increases first and then decreases with the increase of the ethanol content, which is mainly due to the increase rate of 5-Fu content in the PLLA particle, which is less than the rate of it in ScCO2. When the ethanol content is smaller, the ethanol increases the interaction between 5-Fu and PLLA. With the increase of ethanol content, the great change of the solvent polarity would cause a great increase of the interaction between 5-Fu and the solvent.

Table 7. Constants in Banchero Model (Equation 5) A

b

c

4.28·106

−1.783·103

−2.89·10−3

difficult. The aim of this work was to select a suitable correlation model of the partition coefficient and determine the model parameters. The experimental data of partition coefficients on 5-Fu between ScCO2 and PLLA was correlated with the empirical equation proposed by Banchero et al.18 as eq 5 b + cρ (5) T where K is the partition coefficient; T is the operating temperature (K); ρ is the density of the fluid (kg·m−3); a, b, and c are the constants obtained from the regression of the experimental data. Because the solubility of the drug in ScCO2 was very small, the solution density could be replaced with the one of pure ScCO2 in the calculation. The density of ScCO2 was calculated by the PR equation.19 4.2. Partition of 5-Fu between ScCO2 and PLLA. Under temperatures of (40, 50, and 60) °C and pressures of (10, 15, and 20) MPa, the partition coefficients K of 5-Fu between ScCO2 and PLLA are determined. The results are shown in Figure 9 and Table 6. From Figure 9 it can be seen that the partition coefficient K decreases gradually with the increase of pressure under isothermal conditions, which is mainly due to the solubility of 5-Fu in ScCO2 increases with the increase of the pressure and the amount of 5-Fu loaded in the PLLA decreases with the increase of pressure. Under isobaric conditions, the partition coefficient K increases with the increase of temperature. The trend of the increase is relatively slow in the higher pressure range, while at lower pressure it is more remarkable. Table 6 also gives the partition coefficient of 5-Fu between ScCO2 and PLLA obtained from the calculation using Banchero model (eq 5), in which the constants are shown in Table 7. The calculation value of the partition coefficient K is well consonant ln K = ln a +

5. CONCLUSIONS In this work, a flowing solubility test technique was developed and the test apparatus was set up based on an improved dynamic method. The solubility of 5-fluorouracil (5-Fu) in ScCO2 with or without the cosolvent of ethanol was measured, and the partition coefficients K of 5-Fu between ScCO2 and PLLA were determined. The effects of operating parameters including the pressure, the temperature, and the concentration of cosolvent on the solubility of 5-Fu in ScCO2 were investigated experimentally. The experimental results showed that the content of the cosolvent, pressure, temperature, and density of the solution were important factors to influence the solubility of 5-Fu in ScCO2. The solubility of the 5-Fu was measured under different operating conditions, and the experimental data were correlated by the Chrastil model and the Mendez-Santiago and Teja model. The AARD of the calculation results with the experimental ones without the cosolvent was 3.52 % by Chrastil model, while the AARD with the cosolvent of ethanol was 14.6 % by the Mendez-Santiago and Teja model. Under different operating conditions, the partition coefficients of the 5-Fu between the ScCO2 and PLLA were determined experimentally and correlated by Banchero’s empirical equation. The results showed that the partition coefficients of the 5-Fu between the ScCO2 and PLLA

Table 8. Partition Coefficients of 5-Fu between ScCO2 and PLLA with Ethanol as Cosolvent T/°C

P/MPa

cosolvent/mol %

5-Fu·102 mg·mg−1(polymer)

5-Fu·104 mg·mg−1(ScCO2)

partition coefficient K·10−2

50 50 50 50 50

15 15 15 15 15

1 2 3 4 5

1.26 3.66 5.74 6.27 5.32

0.51 0.83 1.25 1.93 3.29

2.47 4.41 4.59 3.25 1.62

1163

dx.doi.org/10.1021/je400484u | J. Chem. Eng. Data 2014, 59, 1158−1164

Journal of Chemical & Engineering Data

Article

application by combining supercritical antisolvent and supercritical solvent impregnation processes. Ind. Eng. Chem. Res. 2013, 52, 2852− 2857. (18) Ferri, A.; Banchero, M.; Manna, L. Dye uptake and partition ratio of disperse dyes between a PET yarn and supercritical carbon dioxide. J. Supercrit. Fluids 2006, 37, 107−114. (19) Baigui, B.; Yanru, W.; Jun, S. Parameters for the PR and SRK equations of state. Fluid Phase Equilib. 1992, 78, 331−334.

decreased with the increases of the pressure and increased with the increase of the temperature. The calculate value of the partition coefficient by Banchero’s empirical equation was well consonant with the experimental data, and the AARD was 14.7 %.

■

AUTHOR INFORMATION

Corresponding Author

*Tel: +86 411 87402439. E-mail: [email protected]. Funding

This research is supported by the National Natural Science Foundation of China (no.: 21176032). Notes

The authors declare no competing financial interest.

■

REFERENCES

(1) Casale, F.; Canaparo, R.; Serpe, L. Plasma concentrations of 5fluorouracil and its metabolites in colon cancer patients. Pharm. Res. 1967, 50, 173−179. (2) Pisanelli, G. C.; Wilt, C. L.; Pinedo, H. M. Antitumour activity, toxicity and inhibition of thymidylate synthase of prolonged administration of 5-fluorouracil in mice. Eur. J. Cancer 1995, 31, l517−1525. (3) Wang, Y. L.; Wang, Y. P.; Yang, J. The application of a supercritical anti-solvent process for sustained drug delivery. Powder Technol. 2006, 164, 94−102. (4) Viviana, P. C.; Mara, E. M. B.; Catarina, M. M. D.; Carmen, A. L.; Angel, C.; Maria, H. G. Anti-glaucoma drug-loaded contact lenses prepared using supercritical solvent impregnation. J. Supercrit. Fluids 2010, 53, 165−173. (5) Mishima, K.; Matsuyama, K.; Tanabe, D. Microencapsulation of proteins by rapid expansion of supercritical solution with a nonsolvent. AIChE J. 2000, 46, 857−865. (6) Lee, L. Y.; Wang, C. H.; Smith, K. A. Supercritical antisolvent production of biodegradable micro- and nanoparticles for controlled delivery of pacitaxel. J. Controlled Release 2008, 125, 96−106. (7) Hassan, S. G.; Mohammad, K. Solubility of trioctylamine in supercritical carbon dioxide. J. Supercrit. Fluids 2008, 44, 148−154. (8) Mohammad, H.; Yadollah, Y.; Mostafa, K. Solubility of some statin drugs in supercritical carbon dioxide and representing the solute solubility data with several density-based correlations. J. Supercrit. Fluids 2007, 41, 187−194. (9) Li, Z. Y.; Meng, T. Y.; Zhang, X. D. Experimental Research on Dyeing Poly(ethylene terephthalate) Fibers with Disperse Blue 60 in Supercritical Carbon Dioxide. J. Chem. Eng. Chin. Univ. 2006, 20, 203− 207. (10) Li, J. L.; Jin, J. S.; Zhang, Z. T. Solubility of pToluenesulfonamide in Pure and Modified Supercritical Carbon Dioxide. J. Chem. Eng. Data 2009, 54, 1142−1146. (11) Su, C. S.; Chen, Y. P. Correlation for the solubilities of pharmaceutical compounds in supercritical carbon dioxide. Fluid Phase Equilib. 2007, 254, 167−173. (12) Guney, O.; Akgerman, A. Solubilities of 5-Fluorouracil and βEstradiol in Supercritical Carbon Dioxide. J. Chem. Eng. Data 2000, 45, 1049−1052. (13) Suleiman, D.; Estevez, L. A.; Pulido, J. C. Solubility of AntiInflammatory, Anti-Cancer, and Anti-HIV Drugs in Supercritical Carbon Dioxide. J. Chem. Eng. Data 2005, 50, 1234−1241. (14) Li, J. L.; Jin, J. S.; Zhang, Z. T.; Wang, Y. B. Measurement and correlation of solubility of benzamide in supercritical carbon dioxide with and without cosolvent. Fluid Phase Equilib. 2011, 307, 11−15. (15) Chrastil, J. Solubility of solids and liquids in supercritical gases. J. Phys. Chem. 1982, 86, 3016−3021. (16) Teja, A. S.; Mendez-Santiago, J. The solubility of solids in supercritical fluids. Fluid Phase Equilib. 1999, 158−160, 501−510. (17) Zhan, S. P.; Chen, C.; Wang, W. J.; Zhao, Q. C.; Liu, Z. J. Preparing 5-Fu-loaded PLLA microparticles for controlled release 1164

dx.doi.org/10.1021/je400484u | J. Chem. Eng. Data 2014, 59, 1158−1164