High-Pressure Phase Behavior of Poly(lactic-co-glycolic acid

Article pubs.acs.org/jced

High-Pressure Phase Behavior of Poly(lactic-co-glycolic acid), Dichloromethane, and Carbon Dioxide Ternary Mixture Systems Byeongheon Kim,† JungMin Gwon,† Taehyun Im,† Hun Yong Shin,‡ and Hwayong Kim*,† †

School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, 559 Gwanangno, Gwanak-gu, Seoul, 151-744, Korea ‡ Department of Chemical and Biological Engineering, Seoul National University of Science and Technology, 172, Gongneung 2-dong, Nowon-gu, Seoul, 139-743, Korea ABSTRACT: Phase behavior measurements of the (poly(lactic-co-glycolic acid) + dichloromethane + carbon dioxide) ternary system were taken using a variable-volume view cell at temperatures between 313.15 K and 363.15 K and at pressures up to 340 bar in poly(lactic-co-glycolic acid) weight fraction = 1.0 %, 2.0 %, and 3.0 %, respectively. To explain these systems, the hybrid equation of state (Peng−Robinson equation of state + SAFT equation of state) was applied with the van der Waals one-fluid mixing rule. The binary interaction parameters were obtained from the simplex method.

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INTRODUCTION Poly(lactic-co-glycolic acid) (PLGA) is one of the most attractive polymeric candidates among the available biodegradable polymers because of its remarkable properties and applications. The FDA-approved polymer PLGA is highly biocompatible and physically strong, and has been extensively studied for its characteristics and potentialities as a drug carrier.1 Recent research has suggested that PLGA can be used for sustained drug release through implantation. Furthermore, it is possible to regulate the overall physical properties of the polymer-drug by controlling the related factors such as polymer molecular weight, release interval, and ratio of glycolide to lactide.2 Because of these characteristics, PLGA has been researched for development and applications such as polymeric drug delivery devices, dental prosthetic devices, and synthetic bone scaffolding.3 Especially, processes involving supercritical fluids (SCFs) were mainly utilized for the fabrication and applications of PLGA, as modulating the thermal properties, particle size, porosity, bulk density, and residual solvent content of the polymer. Also, conformation, release, and cellular uptake of PLGA before and after SC-CO2 treatment was determined.4 Carbon dioxide (CO2) was used principally as a solvent in the SCF processes because of simple removal methods and environment-friendly benefits.5 However, CO2 can dissolve high molecular weight PLGA at high pressure (about 1500 bar). To dissolve PLGA easily, dichloromethane (DCM) was used as the solvent. DCM is an organic solvent, and has low toxicity compared with other hydrocarbon solvents and is used for the emulsion process of PLGA in order to prepare a single phase solution.1,6 For this reason, in determining the optimal condition for PLGA processes, the phase behavior of the PLGA + DCM + CO2 ternary system has important meaning. In this work, the phase separations were measured for the PLGA-DCM-CO2 ternary system in pressures up to 340 bar and temperatures © 2015 American Chemical Society

between 313.15 K and 363.15 K. The experimental data were correlated with the hybrid equation of state (EOS) to determine its applicability to such systems.7

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EXPERIMENTAL SECTION 1. Materials. PLGA (Mw, 196 000; polydispersity, 1.9) was obtained by the Korea Institute of Science and Technology (KIST) and used without pretreatment. The molecular weight and polydispersity of the PLGA were measured by GPC. Carbon dioxide (99.999 mol % minimum purity) was purchased from Korea Industrial Gases. Dichloromethane (99.8 mol % minimum purity) was purchased from Samchun Pure Chemical Co., Ltd. The carbon dioxide and dichloromethane were also used without further treatment. The properties of the pure materials are described in Table 1. 2. Apparatus and Procedures. Figure 1 shows a schematic diagram of the experimental apparatus used for determining the bubble and cloud points of the PLGA + DCM + CO2 ternary mixture systems. This experimental apparatus is the same equipment that was used in our previous work. Several types of mixture systems data obtained through this equipment were reported.8−11 Examination of the PLGA + DCM + CO2 systems was carried out through the following experimental procedures. A designated amount of PLGA was loaded into the cell to an accuracy of within ± 0.001 g, after which the DCM was put into the cell with injector to within ± 0.001 g. To remove any air within the cell, the cell was slowly purged twice with CO2 at room temperature. After the cell was purged, a designated amount of CO2 was injected into the cell using a high-pressure CO2 bomb to within ± 0.01 g. Received: March 9, 2015 Accepted: June 8, 2015 Published: June 18, 2015 2146

DOI: 10.1021/acs.jced.5b00304 J. Chem. Eng. Data 2015, 60, 2146−2151

Journal of Chemical & Engineering Data

Article

Table 1. Properties of Pure Materials

Table 2. Parameters of the Materials for the Hybrid Equation of State Material

Parameters of macromolecule 11.7342 a0/(J·m3) b/(cm3/mol) 119.551 C 0.00039 m 4101.25 critical constants

poly(lactic-co-glycolic acid)

material dichloromethane carbon dioxide

TC/K 510.0a 304.12a

PC/bar 61.0a 73.74a

ω 0.199b 0.225a

a

Critical point for dichloromethane and critical point and acentric factor for carbon dioxide.15 bAcentric factor for dichloromethane.16

Figure 1. Schematic diagram of the variable volume view cell apparatus: (1) camera; (2) light source; (3) borescope; (4) thermocouple; (5) view cell; (6) magnetic stirrer; (7) air bath; (8) digital thermometer; (9) digital pressure transducer; (10) pressure gauge; (11) hand pump; (12) computer monitor.

surface and shown by an indicator (Hart Scientific, Inc., model 1502). The cell temperature was maintained to within ± 0.1 K during the phase separation. The phase behavior inside the cell was observed with a borescope (Olympus Corp., model R100038-00-50) and displayed on a monitor using a camera (Veltek international, Inc., model CVC5520). Thermodynamic Model. In this study, to correlate the experimental results, the hybrid equation of state (Peng− Robinson equation of state + SAFT equation of state) tailored for polymers in CO2 was applied. The main benefit of this hybrid equation of state is that it can be computationally efficient compared with previous polymer system equations of state, and does not require any properties of the polymer other than the molecular weight. Since only the molecular weight among the pure properties of PLGA could be used, we concluded that the hybrid equation of state would be appropriate for this system. The hybrid equation of state used the van der Waals one-fluid mixing rule involving three binary interaction parameter (kij). The compressibility factor of the hybrid equation of state was composed of three terms:

The mixture was then compressed using a pressure generator (High Pressure Equipment CO., model 62-6-10) until the mixtures reached a single phase at the predetermined experimental temperature. A magnetic stirring bar in the cell was used to maintain mixture equilibrium. After the mixture became a homogeneous single phase, the pressure in the cell was slowly decreased until the bubble or cloud point could be observed on the monitor. To obtain accurate results, this procedure was repeated until the pressure fluctuated within ± 0.3 bar, at which time the average of the last three pressures was determined as the phase transition pressure. The pressure of the solution was indirectly monitored by a digital pressure indicator (Red lion controls Inc., model PAXP0000) and transducer (Honeywell International Inc., model TJE, accuracy of 0.1 %). The temperature was measured with a PRT thermometer (HART Scientific, Inc., model 5622-32SR, accuracy of ± 0.045 K) placed to the 2147



Article

Table 3. Experimental Data for the PLGA(1) + Dichloromethane(2) + CO2(3) Systema polymer mass fraction (w1) = 1 % mass fractionb w2 = 0.698, w3 = 0.302

w2 = 0.660, w3 = 0.340

w2 = 0.593, w3 = 0.407

w2 = 0.548, w3 = 0.452

w2 = 0.497, w3 = 0.503

mass fractionb w2 = 0.698, w3 = 0.302

w2 = 0.633, w3 = 0.367

w2 = 0.599, w3 = 0.401

T/K 363.15 353.15 343.15 333.15 323.15 313.15 363.15 353.15 343.15 333.15 323.15 313.15 363.15 353.15 343.15 333.15 323.15 313.15 363.15 353.15 343.15 333.15 323.15 313.15 363.15 353.15 343.15 333.15 323.15 313.15 polymer mass

P/bar

transitionc

74.17 66.53 59.18 51.42 43.97 36.93 95.87 73.01 63.57 55.87 47.33 39.38 141.50 104.17 80.33 68.63 54.03 45.13 183.12 154.33 130.22 91.68 62.33 49.77 281.98 255.30 229.38 191.83 152.48 103.72 fraction (w1)

T/K

P/bar

363.15 353.15 343.15 333.15 323.15 313.15 363.15 353.15 343.15 333.15 323.15 313.15 363.15 353.15 343.15 333.15

79.54 70.08 62.17 54.49 46.18 39.24 103.46 85.91 73.09 63.11 52.79 44.33 153.07 116.82 82.01 70.84

BP BP BP BP BP BP CP CP BP BP BP BP CP CP CP BP BP BP CP CP CP CP BP BP CP CP CP CP CP CP =2%

transitionc BP BP BP BP BP BP CP CP CP BP BP BP CP CP CP CP

polymer mass fraction (w1) = 2 % standard uncertainty

mass fractionb

T/K

323.15 313.15 w2 = 0.557, 363.15 w3 = 0.443 353.15 343.15 333.15 323.15 313.15 w2 = 0.503 w3 = 0.497 363.15 353.15 343.15 333.15 323.15 313.15 polymer mass

0.0067 0.0267 0.0088 0.0233 0.0240 0.0173 0.0033 0.0115 0.0088 0.0145 0.0376 0.0033 0.0120 0.0058 0.0153 0.0100 0.0058 0.0033 0.0219 0.0145 0.0384 0.0033 0.0058 0.0321 0.0145 0.0260 0.0289 0.0115 0.0318 0.0088

mass fractionb w2 = 0.695, w3 = 0.305

w2 = 0.652, w3 = 0.348

w2 = 0.598, w3 = 0.402

standard uncertainty 0.0203 0.0120 0.0153 0.0058 0.0145 0.0033 0.0133 0.0173 0.0153 0.0203 0.0265 0.0176 0.0208 0.0058 0.0200 0.0173

w2 = 0.553, w3 = 0.447

w2 = 0.505, w3 = 0.495

P/bar

transitionc

56.82 BP 47.61 BP 223.72 CP 189.06 CP 145.78 CP 100.07 CP 66.46 BP 51.47 BP 316.29 CP 281.27 CP 244.10 CP 201.99 CP 162.46 CP 117.71 CP fraction (w1) = 3 %

standard uncertainty 0.0033 0.0088 0.0120 0.0088 0.0115 0.0167 0.0033 0.0291 0.0260 0.0267 0.0088 0.0173 0.0203 0.0033

T/K

P/bar

transitionc

standard uncertainty

363.15 353.15 343.15 333.15 323.15 313.15 363.15 353.15 343.15 333.15 323.15 313.15 363.15 353.15 343.15 333.15 323.15 313.15 363.15 353.15 343.15 333.15 323.15 313.15 363.15 353.15 343.15 333.15 323.15 313.15

83.35 73.95 64.41 57.08 49.29 41.48 126.68 90.38 69.15 60.98 50.97 42.15 181.47 143.63 92.67 75.48 57.57 50.30 243.88 204.48 163.63 120.93 72.38 54.47 337.65 300.03 259.33 216.48 171.72 122.33

CP BP BP BP BP BP CP CP CP BP BP BP CP CP CP CP BP BP CP CP CP CP CP BP CP CP CP CP CP CP

0.0088 0.0219 0.0000 0.0033 0.0058 0.0033 0.0153 0.0167 0.0088 0.0231 0.0133 0.0058 0.0203 0.0088 0.0120 0.0100 0.0058 0.0088 0.0260 0.0203 0.0367 0.0167 0.0033 0.0033 0.0176 0.0231 0.0145 0.0058 0.0167 0.0203

Standard uncertainties u are u(T) = ± 0.0816 K, u(P) = ± 0.2919 bar, and u(w) = ± 0.0265g.17−19 bw1 (PLGA), w2 (dichloromethane), and w3 (CO2) are mass fractions; w2 and w3 are calculated on a polymer-free basis. cBP, bubble-point; CP, cloud point. a

Z = Z PR + Zassoc + Zchain

The compressibility factor from the Peng−Robinson equation of state was determined from the following cubic equation:12

(1)

These terms imply PR-EOS, weakly polar, or association interactions, and polymer intrachain correlations, respectively. In this work, the first and third terms were applied for nonpolar polymers, and the first two terms were utilized for CO2 and DCM.

2 Z PR − (1 − B)Z PR + (A − 3B2 − 2B)Z PR

− (AB − B2 − B3) = 0 2148

(2) DOI: 10.1021/acs.jced.5b00304 J. Chem. Eng. Data 2015, 60, 2146−2151


Article

Figure 2. P−T isopleths of the PLGA (mass fraction = 1.0 %) + dichloromethane + CO2 system at different CO2 mass fractions: ■, 0.503; △, 0.452; ▼, 0.407; ○, 0.340; ●, 0.302. The symbols represent experimental data and the lines represent the calculated data using the hybrid EOS.



Figure 5. Effect of CO2 mass fraction in constant PLGA mass fraction (w = 2.0 %) on the phase separation pressure at various temperatures: □, 313.15 K; ■, 323.15 K; Δ, 333.15 K; ▼, 343.15 K; ○, 353.15 K; ●, 363.15 K.

where A and B rely on pressure, temperature, and the energy parameters. A=

aP R2T 2

(3)

B=

bP RT

(4)

The mixture parameters a and b are calculated by the van der Waals one-fluid mixing rule. a=

∑ ∑ xixjaij i

b=

j

∑ xibi i

aij =

aiaj (1 − kij)

(5)

(6)

Figure 6. Effect of dichloromethane mass fraction in constant PLGA mass fraction (w = 2.0 %) on the phase separation pressure at various temperature: □, 313.15 K; ■, 323.15 K; △, 333.15 K; ▼, 343.15 K; ○, 353.15 K; ●, 363.15 K.

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pair distribution function for segments of component i as follows: giihs(dii)

⎡ dii ⎤2 3dii ζ2 ζ22 1 = + + 2⎢ ⎥ 2 ⎣ 2 ⎦ (1 − ζ3)3 1 − ζ3 2 (1 − ζ3) (11)

where ζk =

πNA ρ ∑ Ximidiik 6 i

(12)

The parameters (ai0, Ci, bi, mi) were estimated from experimental data by regression, as shown in Table 2.

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RESULT AND DISCUSSION Table 3 shows the phase transition for the PLGA + DCM + CO2 system at temperatures ranging from 313.15 K to 363.15 K at intervals of 10 K, with pressures up to 340 bar. Figures 2 to 4 present the P−T isopleth diagrams of the phase separation pressures at mass fractions of PLGA = 1.0 %, 2.0 %, and 3.0 %, respectively. The bubble points are defined by the L−V and the cloud points are defined by the L−L phase transition. The bubble points (L−V phase transition) occurred at low temperature range with relatively low CO2 mass fraction. As the CO2 mass fraction and temperature increased, cloud points (L−L phase transition) frequently occurred with dramatically high phase transition pressure compared with that of the bubble points. Figures 5 and 6 illustrate the effects of the CO2 mass fraction and DCM mass fraction under various conditions. In Figure 5, as the CO2 mass fraction increased, the phase separation pressure increased at constant temperature. Whereas, in Figure 6 as the DCM mass fraction increased, the phase separation pressure decreased at constant temperature. These phenomena indicate DCM is a good solvent, but CO2 behaves as an antisolvent. Figure 7 shows the comparison of our data (PLGA = 2.0 %) with the Gwon group’s data for the poly(D-lactic acid)(PDLA) = 2 % + DCM + CO2 ternary system.8 Despite the difference in polymer molecular weight, ours are measured in much higher pressure region compared with their findings at any temperature. According to the Hansen solubility parameter theory, which explains what kind of solvent can dissolve polymer well, poly(lactic acid) (PLA) dissolved in dichloromethane more than poly(glycolic acid) (PGA).13,14 As PLGA is a copolymer of PLA and PGA, PLGA is less soluble than PDLA in dichloromethane according to this tendency. The solubility of PLGA is relatively lower than that of PDLA for the same reason. Comparisons of the experimental data with the correlation results calculated by the hybrid EOS model are presented in Figures 2−4. The hybrid EOS was calculated according to the molecular weight and critical properties of the polymer (TC, PC), and the acentric factor (ω) of DCM and CO2. The optimal values of the three binary parameters and polymer parameters were determined by minimizing the following objective function (OBF) and the absolute average deviation of pressure (AADP):

Figure 7. Comparison of the phase separation pressures between PLGA (mass fraction = 2 %) + dichloromethane + CO2 system and poly(D-lactic acid) (mass fraction = 2 %) + dichloromethane + CO2 system: solid circle symbols represent our data and transparent triangle symbols represent data from Gwon and co-workers:8 ●, PLGA + DCM + CO2 system; △, PDLA + DCM + CO2 system.

Table 4. Calculation Results with the Hybrid Equation of State mass fraction of PLGA

k12

k13

k23

AADP/%

1.0 % 2.0 % 3.0 %

−0.02519 −0.01355 0.01389

0.38993 0.16668 0.11967

−0.16833 −0.10019 0.01756

3.69 2.99 3.32

The acentric factor (ω) and critical constants (TC, PC) are necessary for calculating the compressibility factor. The solvent parameters are shown in Table 2. However, the acentric factor and critical constant of the polymer cannot typically be measured. The parameters for the PR-EOS of the PLGA were determined by the following equation:

ai = ai0 exp(CiT )

(8)

where ai0, Ci and excluded volume (bi) parameter are obtained by regression of the experimental results. The compressibility factor for the association is given by ⎛ 1 1 ⎞ ∂X S Zassoc = ρ ∑ ⎜ S − ⎟ ⎝X 2 ⎠ ∂ρ S

(9)

S

where X represents the mole fraction of the molecules not bonded at site S, ρ represents the number density of molecules, and the summation indicates a sum over all associating sites on the molecule. The compressibility factor for the chain connectivity of the polymer can be determined from the following equation: Zchain =

∑ i

ζ3 xi(1 − mi) ⎡ 3 diiζ2 ⎢ + hs 2 (1 − ζ3)2 gii (dii) ⎣ (1 − ζ3)2

2 2 3 dii ζ2 ζ3 ⎤ ⎥ + + + 2 (1 − ζ3)4 ⎦ (1 − ζ3)3 (1 − ζ3)2

3diiζ2ζ3

N

dii2ζ22

OBF =

∑ i=1

(10)

Piexp − Pical Piexp

(13)

N

where xi represents the mole fraction of chains of component i, dii indicates the effective molecular diameter, mi is the number of segments in a chain of component i and ζ represents the reduced density. The parameter mi is calculated from the experimental data. The parameter gii represents the radial

AADP (%) =

∑i = 1 |(Piexp − Pical)/Piexp| N

× 100

(14)

where Pexp is the experimental pressure and Pcal is the pressure calculated by the hybrid EOS at the experimental value. N is the 2150



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(7) Shin, H. Y.; Wu, J. Equation of State for the Phase Behavior of Carbon Dioxide−Polymer SystemsInd. Eng. Chem. Res. 2010, 49, 7678− 7684. (8) Jungmin, G.; Kim, S. H.; Shin, H. Y.; Kim, H. Phase Behavior of Poly (D-lactic acid), Dichloromethane, and Carbon Dioxide Ternary Mixture Systems at High Pressure. J. Chem. Eng. Data 2014, 59, 2144− 2149. (9) Bae, W.; Kwon, S.; Byun, H.-S.; Kim, H. Phase Behavior of the Poly(vinyl pyrrolidone) + N-Vinyl-2-pyrrolidone + Carbon Dioxide System. J. Supercrit. Fluids 2004, 30, 127−137. (10) Cho, D. W.; Shin, M. S.; Shin, J.; Bae, W.; Kim, H. High-Pressure Phase Behavior of Methyl Lactate and Ethyl Lactate in Supercritical Carbon Dioxide. J. Chem. Eng. Data 2011, 56, 3561−3566. (11) Shin, J.; Lee, Y. W.; Kim, H.; Bae, W. High-Pressure Phase Behavior of Carbon Dioxide + Heptadecafluorodecyl Acrylate + Poly(heptadecafluorodecyl acrylate) System. J. Chem. Eng. Data 2006, 51, 1571−1575. (12) Peng, D.-Y.; Robinson, D. B. A New Two-Constant Equation of State. Ind. Eng. Chem. Fundam. 1976, 15, 59−64. (13) Brandrup, J.; Immergut, E. H.; Grulke, E. A. Polymer Handbook; 4th ed.; Wiley-Interscience: 1999. (14) Liu, J.; Xiao, Y.; Allen, C. Polymer-Drug Compatibility: A Guide to the Development of Delivery Systems for the Anticancer Agent, Ellipticine. J. Pharm. Sci. 2003, 93, 132−143. (15) Poling, B. E.; Prausnitz, J. M.; O’Connell, J. P. The Properties of Gases and Liquids, 5th ed.; McGraw-Hill Book Company: New York, 2000. (16) Haynes, W. M.; Lide, D. R. CRC Handbook of Chemistry and Physics, 91st ed.; CRC Press: Boca Raton, FL, 2010. (17) Analytical Methods Committee Uncertainty of Measurement: Implications of Its Use in Analytical Science. Analyst 1995, 120, 2303− 2308. (18) Chirico, R. D.; Frenkel, M.; Diky, V. V.; Marsh, K. N.; Wilhoit, R. C. ThermoMLAn XML-Based Approach for Storage and Exchange of Experimental and Critically Evaluated Thermophysical and Thermochemical Property Data. 2. Uncertainties. J. Chem. Eng. Data 2003, 48, 1344−1359. (19) Salahinejad, M.; Aflaki, F. Uncertainty Measurement of Weighing Results from an Electronic Analytical Balance. Meas. Sci. Rev. 2007, 7, 67−75.

number of experimental data points. The simplex method was used to obtain the optimized parameters for the objective function. The AADP (%) and the binary interaction parameters, kij, for the PLGA + DCM + CO2 systems are summarized in Table 4. The absolute average deviation of pressure between the experimental data and the correlation results was determined to be from 3 % to 4 %. Thus, we concluded that the hybrid EOS model was a reasonably satisfactory polymer−solvent−gas system model for the PLGA + DCM + CO2 systems.

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CONCLUSION We measured the phase separation pressures at temperatures between 313.15 K and 363.15 K and pressures of up to 340 bar for the poly(lactic-co-glycolic acid) + dichloromethane + CO2 ternary system. The phase separation pressures (bubble and cloud points) were found to be dependent on the mass fraction of PLGA, CO2/DCM mass ratio, and temperature. Above all things, we conclude the CO2 mass fraction is the decisive factor in the phase separation pressure. According to increments of CO2 mass fraction, the L−L transition (cloud point) occurred quickly. As the mass proportion of DCM increased, on the contrary, the transition pressure was decreased because of the increment of solvent polarity. That effect caused the phase transition to occur in lower pressures. The correlation results by the hybrid equation of state with one-fluid mixing rules are in good agreement with the experimental results (AADP/% = 3.69 (1.0 wt %), 2.99 (2.0 wt %), and 3.32 (3.0 wt %)).

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +82-2-880-7406. Fax: +82-2-888-6695. E-mail: [email protected]. Funding

This work was supported by the Korea Government (MEST) (NRF-2012M1A2A2671789). Notes

The authors declare no competing financial interest.

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REFERENCES

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High-Pressure Phase Behavior of Poly(lactic-co-glycolic acid

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