Solubility of Dexamethasone in Supercritical ... - ACS Publications

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Solubility of Dexamethasone in Supercritical Carbon Dioxide with and without a Cosolvent Chuan Tang, Yi-Xin Guan,* Shan-Jing Yao, and Zi-Qiang Zhu Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China ABSTRACT: The solubility of dexamethasone, a synthetic glucocorticoid, in supercritical CO2 and together with 3.0 mol % ethanol as a cosolvent was measured at different temperatures (313.2, 318.2, and 323.2) K and pressures ranging from (10.0 to 25.0) MPa by a static analytical method. The obtained solubility of dexamethasone was between 1.19·10−6 and 1.52·10−6 in pure supercritical CO2 and between 1.97·10−6 and 2.98·10−6 in supercritical CO2 with a cosolvent. The experimental data in supercritical CO2 in the absence and presence of a cosolvent were correlated using four density-based semiempirical models, that is, Chrastil, Kumar and Johnston, Bartle, and Méndez-Santiago and Teja models. The results indicated that the Kumar and Johnston model gave a better correlated result than the other three with an average absolute relative deviation [AARD (%)] value lower than 2.15 %.

1. INTRODUCTION Supercritical fluids technology has been recognized as environmentally friendly and has gained great attention in many fields such as food,1 pharmaceutical,2 polymer processing,3 and the dyeing industry,4 etc. Compared with other supercritical fluids such as water, ethanol, and propane, supercritical carbon dioxide (SC-CO2) is the most commonly used because it is nontoxic, inert, nonflammable, and especially it is easy to attain to the critical point (Tc = 303.2 K, Pc = 7.38 MPa). Many processes including supercritical fluid extraction, supercritical fluid micronization, supercritical fluid drying, and supercritical solution impregnation have been proposed because of the superior performance of SC-CO2.5−8 Therein the solubility of a solid in supercritical fluids is one of the most important properties in the optimization and design of supercritical fluidbased processes. However, carbon dioxide has the limitation that it is not a good solvent for polar and high molecular compounds, owing to the lack of dipole polarity and the incapability for specific solvent−solute interactions. It has been found that the addition of a cosolvent to SC-CO2 can efficiently enhance its solvation power.9−12 Dexamethasone (Dex) is a synthetic glucocorticoid which exerts inhibitory effects on diverse inflammations, and is also used to guide the specific differentiation of mesenchymal stem cells into osteoblast cells in tissue engineering.13 However, the clinical use of Dex has some limits, that is, Dex of a high dose with about 96 mg may cause severe side effects.14 An alternative strategy would be a controlled- and sustained-release of Dex achieved by using a drug-loaded polymer matrix, and many combinations of Dex and the polymer based upon SC-CO2 processing have been successfully developed.15−17 Therefore, the knowledge of the solubility of Dex in SC-CO2 would be a prerequisite to carry out these processes. According to the molecular structure of Dex, the solubility of Dex in SC-CO2 is supposed to be quite small. Therefore, the © XXXX American Chemical Society

addition of a cosolvent to SC-CO2 would be a good choice to improve the dissolution of Dex in SC-CO2. At present, the solubility of Dex in SC-CO2 had been measured at (308.2, 318.2 and 328.2) K in the pressure range from (15.1 to 35.7) MPa,18 but the solubility of Dex in SC-CO2 with a cosolvent has not been reported yet. In this study, the solubility of Dex in SC-CO2 is determined at different temperatures (313.2, 318.2 and 323.2) K in the pressure range between (10.0 and 25.0) MPa together with a cosolvent concentration of 3.0 mol % ethanol to explore the practical application of Dex in supercritical-based processes. Then, the Chrastil equation,19 Kumar and Johnston equation,20 Bartle equation,21 MéndezSantiago and Teja equation22 are employed to correlate the solubility data, respectively, and the average absolute relative deviation [AARD (%)] among the four correlation models are discussed.

2. EXPERIMENTAL SECTION 2.1. Materials. Dexamethasone (Dex, 98% purity) was purchased from Xianju Pharmaceutical Co., Ltd. (Zhejiang, China), and ethanol (>99.7% purity) was purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Carbon dioxide (99.9% purity) was supplied by Hangzhou Jingong Gas Co. Ltd. (Zhejiang, China). 2.2. Equipment and Procedure. The solubility of Dex in SC-CO2 with and without a cosolvent was measured using a static high-pressure apparatus, as schematically shown in Figure 1. The apparatus comprises mainly an equilibrium vessel with a volume of 30 mL, and a sampling vessel with a volume of 1 mL connected to a sample trap. The equilibrium vessel was filled Received: April 13, 2014 Accepted: October 17, 2014

A

dx.doi.org/10.1021/je500345n | J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Table 1. Density Based Semi-empirical Models Used To Correlate the Experimental Solubility Data (y) of Dex in SC-CO2 with and without a Cosolvent models

Figure 1. Flow sheet of the solubility determination of Dex in SC-CO2 using the static method: (1) cooling bath, (2) high-pressure pump, (3) temperature transducer, (4 and 5) pressure transducer, (6) water bath, (7) equilibrium vessel, (8) sampling vessel, (9) microflow valve, (10) sample trap.

expressions

Chrastil19

⎛ A M ⎞ ln y = ⎜k − ln 2 ⎟ ln ρ1 + 0 + A1 M1 ⎠ T ⎝

Kumar and Johnston20

ln y = B0ρ1 +

B1 + B2 T C ln(yP) = C0ρ1 + 1 + C2 T

Bartle21 Méndez-Santiago and Teja22

with multilayer glass wool; Dex powder (about 1.0 to 1.1) g was preloaded between the layers of the glass wool. The sample trap was full of ethanol liquid to capture the Dex component that flowed out the sampling vessel along with the CO2. The temperature (T) of the equilibrium vessel was controlled using a water bath (accuracy ± 0.1 K); the pressure (P) was regulated via the high-pressure pump (accuracy ± 0.1 MPa). The experimental apparatus was previously used to measure the solubility of ibuprofen in SC-CO2, and the AARD (%) between ibuprofen solubility data obtained using the experimental apparatus and that in the literature23 is approximately 5.57%. In this experiment, CO2 flowing out the cylinder was cooled and pressurized, and then delivered to an equilibrium vessel (7). The equilibrium vessel was maintained at the preset experimental conditions for over 1 h to achieve the dissolution equilibrium of Dex in SC-CO2; afterward SC-CO2 saturated with Dex was allowed to pass to the sampling vessel (8) and kept for another 1 h to ensure a stable condition. The sampling vessel was slowly depressurized via a microflow valve (9), and the Dex was dissolved in ethanol in the sample trap (10). At the end of the experiment, the Dex that was retained in the sampling vessel, the lines between sampling vessel and the trap, along with that in the trap, was totally recovered and measured to determine the solubility of Dex. The amount of Dex was determined at 240 nm using a UV−vis spectrophotometer (Ultrospec 3300 pro, GE Healthcare). The calibration curve of Dex was fitted as eq 1, and the correlation coefficient R2 was 0.9996. A 240 = 39.3941 × Cdex

T ln(yP) = D0ρ1 + D1T + D2

solubility data of Dex in SC-CO2 with and without a cosolvent. The equations of the models are listed in Table 1. AARD (%) was used to compare the precision of the correlated models by using the following eq 2: AARD (%) =

100 n

n

∑ i=1

|ycal, i − yexp, i | yexp, i

(2)

where ycal is the calculated mole fraction of Dex; yexp is the experimental solubility of Dex; n is the number of the experimental data.

3. RESULTS AND DISCUSSION 3.1. Solubility of Dex in Pure SC-CO2. The experimental solubility data in pure SC-CO2 are presented in Table 2 and Table 2. Mole Fraction Solubility (y2) of Dex in Supercritical Carbon Dioxide Ta/K

Pb/MPa

ρc/g·L−1

y2d·106

313.2

10.0 12.0 15.0 20.0 25.0 10.0 12.0 15.0 20.0 25.0 10.0 12.0 15.0 20.0 25.0

628.6 717.8 780.2 839.8 879.5 498.3 657.7 742.0 812.7 857.1 384.3 584.7 699.8 784.3 834.2

1.21 1.26 1.34 1.39 1.41 1.21 1.26 1.36 1.41 1.46 1.19 1.24 1.35 1.46 1.52

318.2

(1)

where A240 was the absorbance of Dex solution and Cdex is the solution concentration in g/L. For the solubility experiments with the presence of ethanol as a cosolvent, 3.0 mol % of ethanol (ethanol/CO2 = 3:100) was previously added to the equilibrium vessel (accuracy ± 0.1 μL). The amount of CO2 used in each experiment was calculated by combining CO2 density data from the NIST Chemistry Webbook at different experimental conditions with the volume of the equilibrium vessel. Thus, the volume of ethanol added could be obtained. Between each experiment, the lines were washed using ethanol, and CO2 was used to flush the system for a period. 2.3. Correlation of the Experimental Solubility Data with Semiempirical Models. To predict the solubility in SC-CO2, there are usually two major approaches: one is the equation of state (EOS), and the other is a density-based semiempirical model. The density-based semiempirical model does not necessitate the solute properties which are usually unavailable. Therefore, the density-based semiempirical models are widely used in research and industry.24,25 In this work, density-based semiempirical models were used to correlate the

323.2

a

The standard uncertainty u for temperature u(T) is 0.1 K. bThe standard uncertainty u for pressure u(P) is 0.1 MPa. cρ is the density of pure CO2 at different experimental temperatures and pressures; the values are obtained from the NIST fluid property database. dThe relative standard uncertainty ur for the mole fraction solubility ur(y2) is 0.07.

Figure 2, and the solubility of Dex in SC-CO2 from the literature18 is also illustrated in Figure 2 for a reference. As shown in Table 2, the solubility of Dex obtained in this work is low. The solubility of Dex in pure SC-CO2 is in the range of 1.19·10−6 to 1.52·10−6, and the minimum and maximum solubility data were measured at 323.2 K, 10 MPa and 323.2 K, 25 MPa, respectively. Compared with Dex solubility data at B



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Table 3. Mole Fraction Solubility (y3) of Dex in Supercritical Carbon Dioxide with 3.0 mol % Ethanol as a Cosolvent and Cosolvent Effect (E) Ta/K

Pb/MPa

y3c·106

Ed

313.2

10 15 20 25 10 15 20 25 10 15 20 25

1.97 2.01 2.03 2.13 2.31 2.33 2.44 2.52 2.61 2.80 2.83 2.98

1.58

318.2

Figure 2. Experimental solubility data of Dex in SC-CO2 at different temperatures and pressures: ■, 313.2 K; ●, 318.2 K; ▲, 323.2 K; ○, data from ref 18. at 318.15 K.

323.2

318.15 K obtained from the work of Chim et al.,18 qualitative agreement was observed. The data measured in our work and in the work of Chim et al.18 were in the same order of magnitude, which confirmed the reliability of our work. For the isotherm of 318.2 K at 15.0 MPa, solubility values from this work and from ref 18 were nearly the same; and at the pressures of 20.0 MPa and 25.0 MPa, the solubility values from this work were a little higher than that from ref 18. From Figure 2, three isothermal curves intersected each other at the pressure region around (14.0 to 16.0) MPa, and this phenomenon was also pointed out by Chim et al.18 As expected, the Dex solubility increased with the elevation of pressure for each isotherm. Generally, the increase of pressure leads to the increase of the density of SC-CO2 which is beneficial to the interactions between the molecules of solute and solvent. The temperature affects the solubility of Dex in SC-CO2 in a complicated way. As the temperature increases the density of the solvent decreases, whereas the sublimation pressure of solute increases. At the lower pressures, the solubility of the solute is more sensitive to the solvent density than the solute vapor pressure, that is to say the solubility of the solute decreases with the increase of the temperature at the pressure below the crossover region. However, at the higher pressures, the effect of solute vapor pressure is dominant compared with that of solvent density, thus the solute solubility increases with the increase of temperature at the pressure above the crossover region. These two competitive effects on solute solubility result in the occurrence of crossover pressure region. Compared with prednisolone which has a similar steroid structure, Dex has a larger solubility according to the data measured in this work and literature.26 Taking into account the steroid ring structure, Dex has an additional fluorine atom connected to the 9-carbon atom and a methyl connected to 16-carbon atom; the difference in solubility between prednisolone and Dex is probably due to the C−F bond in Dex that provides a strong interaction with CO227 so as to enhance the solubility of Dex in SC-CO2. 3.2. Solubility of Dex in SC-CO2 with a Cosolvent. In preliminary experiments, the effect of ethanol concentration (1.0 mol %, 3.0 mol %, and 5.0 mol %) on the dissolution of Dex in SC-CO2 was studied, and the result showed that 3.0 mol % and 5.0 mol % of ethanol could improve the solubility of Dex in SC-CO2 effectively. Therefore, ethanol at a concentration of 3.0 mol % was selected as a cosolvent in this work. The operating pressures and temperatures as well as the concentration of the cosolvent should be carefully chosen so that the mixture of SC-CO2 and ethanol lies in the supercritical fluid region as a

1.76

1.97

a The standard uncertainty u for temperature u(T) is 0.1 K. bThe standard uncertainty u for pressure u(P) is 0.1 MPa. cThe relative standard uncertainty ur for the mole fraction solubility ur(y2) is 0.06. d The cosolvent effect (E) is the average value of the solubility of Dex in SC-CO2 with ethanol divided by that in pure SC-CO2 at different pressures with the same temperature.

single phase. The solubility of Dex with the cosolvent is expressed in terms of mole fraction (y3) and listed in Table 3 and Figure 3. To reveal solubility enhancement resulting from

Figure 3. Experimental solubility data of Dex in SC-CO2 with 3.0 mol % ethanol as a cosolvent at different temperatures and pressures: ■, 313.2 K; ●, 318.2 K; ▲, 323.2 K.

the addition of a cosolvent, herein the cosolvent effect (E) was introduced, which is defined as the ratio of the solubility obtained with a cosolvent to that in pure SC-CO2 at the same temperature, as shown in eq 3:

E=

∑P y3 (T , P) ∑P y2 (T , P)

(3)

From Table 3, the solubility of Dex in SC-CO2 with 3.0 mol % ethanol is in the range of 1.97·10−6 to 2.98·10−6. It can be seen that the solubility of Dex in SC-CO2 with ethanol was enhanced under all experimental conditions in this work, and the solubility of Dex increased with the elevation of pressure and temperature. An interesting phenomenon was that the crossover region was observed to disappear by adding the cosolvent of ethanol. E was relatively large at high temperatures indicating that the cosolvent effect was more significant. There were two possible reasons for the solubility enhancement by the cosolvent. The first reason was that both of ethanol and Dex were polar molecules, the addition of ethanol would increase the polarity of the system. Strong polar interactions C



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Table 4. Correlation Parameters for the Solubility of Dex in SC-CO2 with and without a Cosolvent pure SC-CO2 models Chrastil

Kumar and Johnston

Bartle

Méndez-Santiago and Teja

SC-CO2 with 3.0 mol % ethanol

correlation parameters

AARD (%)

correlation parameters

AARD (%)

k = 2.524 A0 = −828.691 A1 = −10.801 B0 = 0.559 B1 = −830.971 B2 = −11.313 C0 = 2.966 C1 = −3552.587 C2 = −1.733 D0 = 951.045 D1 = 0.466 D2 = −4258.029

2.25

k = 2.285 A0 = −3404.758 A1 = −2.198 B0 = 0.169 B1 = −3409.695 B2 = −2.338 C0 = 2.472 C1 = −5889.214 C2 = 6.585 D0 = 792.898 D1 = 8.457 D2 = −6489.850

2.27

1.55

11.74

11.56

and hydrogen bonding between ethanol and Dex could cause the enhancement of the solubility,9 this may be the dominant effect on the solubility. Second, when the cosolvent was introduced into the system, the density of the mixture increased, and the solubility of Dex increased subsequently. Moreover, at high temperatures, the interaction between cosolvent and Dex molecule was strengthened due to the molecular thermal motion, and the solubility enhancement by the cosolvent was more significant at high temperature. 3.3. Correlation of Solubility Data Using Different Models. The experimental data of Dex in SC-CO2 with and without a cosolvent were correlated with four density based semiempirical models: Chrastil, Kumar and Johnston, Bartle, Méndez-Santiago and Teja models using linear least-square method. The results are summarized in Table 4. In the correlation of solubility data of Dex in pure SC-CO2, the values of AARD (%) are all less than 11.74 %; most importantly, the AARD (%) of Kumar and Johnston model is 1.55 %, which is the best regression among the four models. The correlated results are shown in Figure 4. The models could not well describe the increase of the solubility that is verified for each isotherm with the increase of the pressure. Some researchers28 also attempted a temperature-dependent model such as the Sparks model,25 but the improvement was not significant. Because the Sparks model has five adjustable parameters, the application of different sets of parameters for each isotherm would need a large number of experimental data. Considering the experimental data measured in this study, the presented models, especially the Kumar and Johnston model, can describe approximately the solubility data dependence on density and temperature using only one set of adjustable parameters with acceptable accuracy. From Figure 4, it should be noted that the accuracy of the models to correlate experimental data at lower density was relatively low. The reason was that the density of the fluid varied more sensitively with a slight change of the pressure at a lower pressure range and the same result was also proposed in the literature.18 Some useful information could also be gained from the parameters of the models in Table 4. For the Chrastil model, k is an association constant denoting that a Dex molecule is approximately associated with two to three CO2 molecules to form the complex. The parameter A0 in the Chrastil model could be utilized to count the total heat of solute (ΔHtotal), and the parameter C1 in the Bartle model could be used to estimate the heat of sublimation (ΔHsub). Thus, the heat of solvation (ΔHsol) can be calculated according to eq 4. The values of

2.15

11.73

11.58

Figure 4. Solubility of Dex (y2) in pure SC-CO2 correlated using density-based semiempirical models: (a) Chrastil model, (b) Kumar and Johnston model, (c) Bartle model, (d) Méndez-Santiago and Teja model for the isotherms at ■, 313.2 K; ●, 318.2 K; ▲, 323.2 K. Lines represent the results obtained from different models. Dots represent experimental data. D



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(10.0 to 25.0) MPa. The crossover pressure region for the binary system was (14.0 to 16.0) MPa. Ethanol at a concentration of 3.0 mol % as a cosolvent could promote the dissolution of Dex in SC-CO2. Four density-based semiempirical models including Chrastil, Kumar and Johnston, Bartle, Méndez-Santiago and Teja were used to correlate the solubility of Dex in SC-CO2 with and without a cosolvent, and the Kumar and Johnston model gave a better correlated result than the other three.

■

AUTHOR INFORMATION

Corresponding Author

*Tel.: +86-571-87951982. Fax: +86-571-87951982. E-mail: [email protected]. Funding

This work was financially supported by National Natural Science Foundation of China. Notes

The authors declare no competing financial interest.

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REFERENCES

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Figure 5. Solubility of Dex (y3) in SC-CO2 with 3.0 mol % ethanol as cosolvent correlated using density based semiempirical models: (a) Chrastil model, (b) Kumar and Johnston model, (c) Bartle model, (d) Méndez-Santiago and Teja model for the isotherms at ■, 313.2 K; ●, 318.2 K; ▲ 323.2 K. Lines represent the results obtained from different models. Dots represent experimental data.

ΔHtotal, ΔHsub, and ΔHsol of Dex were −6.890 kJ/mol, 29.536 kJ/mol, and −36.426 kJ/mol, respectively. ΔHtotal ΔHsol + ΔHsub = (4) R R In the correlation of solubility data of Dex in SC-CO2 with 3.0 mol % ethanol, the minimum AARD (%) is 2.15 % when Kumar and Johnston model was used. The correlated results are illustrated in Figure 5. Correlation results suggest that the solubility of Dex in SC-CO2 with and without a cosolvent would be better correlated by Kumar and Johnston models.

4. CONCLUSIONS The solubility of Dex in SC-CO2 with and without ethanol as a cosolvent was experimentally measured using a static analytical method at (313.2, 318.2 and 323.2) K and pressure range from E



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(16) Duarte, A. R. C.; Mano, J. F.; Reis, R. L. Preparation of chitosan scaffolds loaded with dexamethasone for tissue engineering applications using supercritical fluid technology. Eur. Polym. J. 2009, 45, 141−148. (17) Duarte, A. R. C.; Mano, J. F.; Reis, R. L. Dexamethasone-loaded scaffolds prepared by supercritical-assisted phase inversion. Acta Biomater. 2009, 5, 2054−2062. (18) Chim, R. B.; de Matos, M. B. C.; Braga, M. E. M.; Dias, A. M. A.; de Sousa, H. C. Solubility of dexamethasone in supercritical carbon dioxide. J. Chem. Eng. Data 2012, 57, 3756−3760. (19) Chrastil, J. Solubility of solids and liquids in supercritical gases. J. Phys. Chem. 1982, 86, 3016−3021. (20) Kumar, S. K.; Johnston, K. P. Modelling the solubility of solids in supercritical fluids with density as the independent variable. J. Supercrit. Fluids 1988, 1, 15−22. (21) Bartle, K. D.; Clifford, A. A.; Jafar, S. A.; Shilstone, G. F. Solubilities of solids and liquids of low volatility in supercritical carbon dioxide. J. Phys. Chem. Ref. Data 1991, 20, 714−728. (22) Méndez-Santiago, J.; Teja, A. S. The solubility of solids in supercritical fluids. Fluid Phase Equilib. 1999, 158−160, 501−510. (23) Mirzajanzadeh, M.; Zabihi, F.; Ardjmand, M. Measurement and correlation of ibuprofen in supercritical carbon dioxide using stryjek and vera EOS. Iran. J. Chem. Eng. 2010, 7, 43. (24) Yeoh, H. S.; Chong, G. H.; Mohd Azahan, N.; Abdul Rahman, R.; Choong, T. S. Y. Solubility measurement method and mathematical modeling in supercritical fluids. Eng. J. 2013, 17, 67−78. (25) Sparks, D. L.; Hernandez, R.; Estévez, L. A. Evaluation of density-based models for the solubility of solids in supercritical carbon dioxide and formulation of a new model. Chem. Eng. Sci. 2008, 63, 4292−4301. (26) Dean, J. R.; Kane, M.; Khundker, S.; Dowle, C.; Tranter, R. L.; Jones, P. Estimation and determination of steroid solubility in supercritical carbon dioxide. Analyst 1995, 120, 2153−2157. (27) Davies, O. R.; Lewis, A. L.; Whitaker, M. J.; Tai, H.; Shakesheff, K. M.; Howdle, S. M. Applications of supercritical CO2 in the fabrication of polymer systems for drug delivery and tissue engineering. Adv. Drug Delivery Rev. 2008, 60, 373−387. (28) Chim, R.; Marceneiro, S.; Braga, M. E. M.; Dias, A. M. A.; de Sousa, H. C. Solubility of norfloxacin and ofloxacin in supercritical carbon dioxide. Fluid Phase Equilib. 2012, 331, 6−11.

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