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Sub-micrometric polymer particles formation by a supercritical assisted-atomization process
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JTICE-797; No. of Pages 10 Journal of the Taiwan Institute of Chemical Engineers xxx (2013) xxx–xxx
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Sub-micrometric polymer particles formation by a supercritical assisted-atomization process Hsien-Tsung Wu *, Ming-Wei Yang, Shih-Chang Huang Department of Chemical Engineering, Ming Chi University of Technology, 84 Gungjuan Rd., Taishan, New Taipei City 24301, Taiwan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 August 2013 Received in revised form 21 November 2013 Accepted 22 November 2013 Available online xxx
A supercritical assisted-atomization (SAA) process, using acetone and water solvents and supercritical carbon dioxide as the spraying medium, was used to prepare sub-micrometric particles of polymethyl methacrylate-co-ethyl acrylate (PMMA-co-EA) and chitosan hydrochloride (CH). The experimental results revealed that low polymer solution concentrations, high saturator temperatures, and an optimized carbon dioxide to polymer solution flow ratio effectively minimize the mean particle size. PMMA-co-EA and CH particle sizes ranged from 0.09 to 0.17 mm, and from 0.17 to 0.26 mm, respectively. Using the mixed-suspension, mixed-product-removal (MSMPR) population balance model, the precipitation kinetics parameters were determined from the particle size distributions of the polymer particles. The mass-weighted mean sizes of micronized PMMA-co-EA particles correlated well with the experimental factors. Primary nucleation was found dominant in SAA process and diffusion may govern particle growth. ß 2013 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.
Keywords: Supercritical assisted-atomization Sub-micrometric particles PMMA-co-EA Chitosan hydrochloride Precipitation kinetics
1. Introduction Conventional processes for polymer microparticle production include suspension cross-linking, phase separation, reverse micelles formation, solvent evaporation, spray-drying, ball-milling, and high-pressure homogenization. Such processes have several limitations. The use of organic solvents and difficult to separate surfactants, require post processing to reduce solvent residues below safety limits. There is potential for contamination by grinding media and possible adverse effects on chemical stability from shear force and high temperatures. Additionally, it can be difficult to reduce pliant materials particle sizes below a given limit, and these methods offer limited control over particle size and particle size distributions. Supercritical fluid-assisted methods may minimize or overcome such common problems. Reverchon et al. [1–3] successfully developed a supercritical assisted-atomization (SAA) process to produce micro- and nanometric particles of polymers, pharmaceutical compounds, catalysts, and superconductor precursors. The process is applicable to both aqueous and organic solvent systems. SAA involves two atomization steps: pneumatic atomization inducing from the pressure difference at the nozzle outlet, and decompressive atomization, generated by rapidly delivering CO2 inside the primary droplets. The evaporation of solvent and supersaturation of solute in liquid droplets then yields fine particles. The
* Corresponding author. Tel.: +886 2 2908 9899 4630; fax: +886 2 2908 3072. E-mail address: [email protected] (H.-T. Wu).
dimensions and morphologies of the resulting particles depend on droplet size, which in turn, is dependent on the solubilization of gas (e.g., CO2) in the liquid. Wu and Yang [4] micronized the PMMA particles using acetone in a SAA process. At an optimized CO2 to liquid flow ratio, the composition of CO2 in the feed stream was close to binary mixture bubble point (CO2 + acetone) at the saturator temperature. Thus, maximum solubilization of gas in the feed liquid solution produces fine particles. Additionally, the kinetic parameters for precipitation can be determined from the particle size distributions by applying population balance theory. Recently, a new SAA configuration operating under vacuum allowed the drying process to operate at low temperatures. The advantage of reducing temperatures in a precipitator could prevent the thermolabile materials from being damage [5] and avoid the coalescence of the materials exhibiting low glasstransition temperature and melting point [6]. In aqueous system, the decompressive atomization might inactivate because CO2 has poor solubility in aqueous solution (less than mole fraction 2% in water). However, Reverchon and Antonacci [7] micronized chitosan (CS) microparticles using SAA processes with 1% acetic acid aqueous, they produced CS particles with diameters ranging between 0.1 and 1.5 mm under excess of CO2 (a mass feed ratio R = 1.8). Successful formation of CS microparticles caused by large excess of gas that provides the necessary energy for liquid fragmentation and fine atomization [8]. An improved design of supercritical fluid assisted atomization with a hydrodynamic cavitation mixer (SAA-HCM) was developed to intensify the mixing between CO2 and the aqueous solution during the SAA process [9].
1876-1070/$ – see front matter ß 2013 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jtice.2013.11.010
Please cite this article in press as: Wu H-T, et al. Sub-micrometric polymer particles formation by a supercritical assisted-atomization process. J Taiwan Inst Chem Eng (2013), http://dx.doi.org/10.1016/j.jtice.2013.11.010
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Nomenclature B0 C dno d4;3 F CO2 F CO2 Fl G i KN kV L L¯ n no MT P R R2 TS xi
t rc rCO2
nucleation rate (no./s m3) mass concentration of polymer in the solution feed stream (mg/mL) arithmetic mean particle size (nm) mass-weighted mean particle size (nm) volume flow rate of CO2 at 276 K and 6.5 MPa (cm3/ min) (TS) volume flow rate of CO2 at the temperature in saturator and 6.5 MPa (cm3/min) volume flow rate of polymer solution (cm3/min) linear particle growth rate (nm/s) order of growth rate in nucleation kinetics equation (Eq. (1)) constant in nucleation kinetics equation (Eq. (1)) volumetric shape factor particle size (nm) arithmetic average size ranging from L1 to L2 (m) population density at size L (no./nm m3) population density of nuclei (no./nm m3) suspension density (kg/m3) pressure (MPa) the volume flow ratio of CO2 to polymer solution square of correlation coefficient the temperature in saturator (K) number of particles within a size range mean residence time of the mixed suspension (s) density of polymer particle (kg/m3) density of carbon dioxide (kg/m3)
superscripts calculated value calc experimental value expt
Polymethyl methacrylate-co-ethyl acrylate (PMMA-co-EA) latex can be produced as a water-based film, which can be used to control the dissolution or release of drug substances [10]. Chitosan hydrochloride (CH) is the chloride salt derivative of chitosan. A biopolymer of CH is used in novel dosage form design since water soluble at neutral and basic pH values [11,12], and is listed in the European Pharmacopeia [13]. The aim of this study is to investigate the use of PMMA-co-EA and CH with acetone and water solvents, respectively, in the SAAbased preparation of sub-micrometric particles for drug controlled release carriers. We studied the particle morphology and precipitation kinetics of the SAA-produced sub-micrometric polymer particles. Polymer precipitation experiments were conducted using various concentrations (C) of polymer solution, and various carbon dioxide to polymer solution flow ratios (R ¼ F CO2 =F l ) for a range of saturator temperatures (TS) from 313.2 K to 363.2 K. Product samples were analyzed using a field emission scanning electron microscope (FESEM). Particle size distributions and mean particle sizes were determined from FESEM image using image-processing software. In addition to determining favorable SAA conditions for smallparticle formation with narrowed particle size distribution, the mass-weighted mean sizes of micronized PMMA-co-EA and CH particles also correlated with the population balance theory. The correlated results and mechanisms of SAA precipitation kinetics of sub-micrometric polymer particles are discussed.
2. Experiment 2.1. Materials Polymethyl methacrylate-co-ethyl methacrylate (PMMA-coEA, ave. MW = 101 kg/mol) was purchased from Aldrich (USA), and chitosan hydrochloride (CH, 92% degree of deacetylation, MW = 60 kg/mol) was purchased from Charming & Beauty (Taiwan). HPLC grade acetone (99.9% purity) was purchased from Tedia, USA. A Millipore Milli-Q water purification system provided deionized water with a resistivity of 18 MV cm at 25 8C. Carbon dioxide (99.9% purity) and nitrogen (99.9% purity) gases were purchased from Yung-Ping Gas Co., Taiwan. These chemicals were used without further purification. 2.2. Apparatus and operation A schematic diagram of the supercritical assisted-atomization apparatus and operation procedure have been detailed elsewhere [4]. The apparatus comprises a saturator, a precipitator, a separator and feeding lines. The saturator is a 10 cm3 highpressure vessel, loaded with protruded stainless-steel packing to provide a large contact area between the liquid polymer solution and CO2. The solution obtained in the saturator was sprayed via a nozzle (I.D. 130 mm) into the precipitator. A metal frit (0.5 mm) mounted at the bottom of the outlet of the precipitator served to retain the polymer particles. Downstream the precipitator, a separator is used to recover solvent and gas at near atmospheric pressure. The three feeding lines contain the polymer solution, CO2 and N2. Two high-pressure liquid pumps were used to deliver CO2 and the polymer solution. The N2 flow was controlled using a mass controller from a cylinder, heated in an electric heat exchanger, and sent to the precipitator to assist in the liquid droplets’ evaporation. Briefly, the experimental procedure is described as follows. The saturator temperature (TS) and CO2 volume flow rate are pre-set. The precipitator temperatures are set to 333.2 K for acetone solvent, and 368.2 K for water solvent. After a steady state was achieved, the polymer solution was introduced into the saturator at a specified flow rate (most of the acetone solution and water solution flow rates were 5 ml/min and 2 ml/min, respectively). Polymer solution containing dissolved CO2 was sprayed through an injection nozzle to atomize the liquid as it entered the precipitator. As the atomized solution contacted the heated N2 (0.8 Nm3/h), the solvent evaporated from the droplets, resulting in supersaturation of the polymer particles. During this supercritical assisted-atomization process, the pressure in the saturator was held constant (approximately 6.5 0.3 MPa). Product samples were collected from the precipitator and observed using FESEM (model 6500, JEOL, Japan). The particle size distributions of samples and their mean values were determined using Sigma Scan Pro5 software. Approximately 1000 particles were counted on the FESEM micrographs taken for each run, to determinate the size distributions and mean values. All precipitation runs were performed at least twice for each set of experimental conditions. The obtained arithmetic mean particle size (dno ) and mass-weighted mean size expt (d4;3 ) could be reproduced to approximately 10%. The average yields of the PMMA-co-EA and CH polymer particle in SAA process were 80% and 70%, respectively. The loss was attributed to the adhesion quantity on the walls of the precipitator and inside the pores of the filter. Thermograms of polymer samples were obtained using a differential scanning calorimeter (DSC, Q-20, TA, USA). Samples (3–10 mg) were placed in aluminium pans, sealed, and heated under nitrogen from 25 to 150 8C at a heating rate of 10 8C/ min. The X-ray diffraction (XRD) patterns of product powders were recorded using an X’Pert Pro X-ray powder diffractometer
Please cite this article in press as: Wu H-T, et al. Sub-micrometric polymer particles formation by a supercritical assisted-atomization process. J Taiwan Inst Chem Eng (2013), http://dx.doi.org/10.1016/j.jtice.2013.11.010
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3
20
(PANalytical, Holland). The scanning region of the diffraction angle (2u) ranged from 158 to 608 at a scan rate of 0.028/s. 3. Results
16
12 P (MPa)
Caputo et al. [14] demonstrated that the droplet size of the SAA process is remarkably influenced by the sudden release of the supercritical carbon dioxide (scCO2) dissolved in the liquid. However, the solubility of scCO2 in liquids is dependent on the high-pressure vapor–liquid equilibrium (VLE) phase boundaries. The solvents used in this study were acetone and water. The VLE phase boundaries of CO2 + acetone have been reported elsewhere [4]. We obtained the VLE phase diagram for a carbon dioxide + water mixture (Fig. 1) from the Peng–Robinson equation, incorporating the one-parameter van der Waals one-fluid mixing rules. These equations have been used to fit experimental data at different temperatures from 323.2 K to 373.2 K in the literature [15,16]. The phase diagrams for the binary system (without polymer-containment) can be used to provide an approximately estimate of phase behavior of the solution mixtures in the saturator and to represent these as a qualitative relationship to facilitate the selection of suitable SAA operating conditions. The precipitation experiments were implemented at various concentrations (C) of polymer solution, saturator temperatures (TS), and volume flow ratios of CO2 to polymer solution (R ¼ F CO2 =F l ). The condition of CO2 volume flow was 276 K and 6.5 MPa. Tables 1 and 2 list the experimental conditions and results.
8
4
0 0
0.01
0.02
0.03
0.04
0.9
xco2
0.95
1
yco2
Fig. 1. VLE phase diagram for carbon dioxide + water: (*) T = 323.2 K, Bamberger et al. [15]; ( ) T = 323.2 K, Hou et al. [16]; (~) T = 333.2 K, Bamberger et al. [15]; (&) T = 353.2 K, Bamberger et al. [15]; (b) T = 373.2 K, Hou et al. [16].
Table 1 Experimental conditions and results of PMMA-co-EA particles. Run
CEA (mg/mL)
TS (K)
F CO2 (cm3/min)
R F CO2 =F l
dno (nm)a
d4;3 (nm)b
expt PDI d4;3 =dno
E1c E2c E3c E4c E5c E6c E7c E8 E9c E10c E11 E12 E13c E14c E15
1 5 10 30 10 10 10 10 10 10 10 10 10 10 10
353.2 353.2 353.2 353.2 333.2 313.2 353.2 353.2 333.2 333.2 333.2 333.2 313.2 313.2 313.2
6 6 6 6 6 6 4 8 8 8 8.4 8.4 8 8.4 8.4
1.2 1.2 1.2 1.2 1.2 1.2 0.8 1.6 1.6 2.0 2.4 2.8 2.0 2.4 2.8
86 2 121 2 135 4 167 5 146 3 154 4 146 2 146 4 142 2 139 3 148 3 161 4 140 3 140 3 157 4
106 2 165 7 208 15 273 18 228 17 240 11 220 10 230 17 195 12 184 3 215 2 226 5 201 2 190 6 210 3
1.2 1.4 1.5 1.6 1.6 1.6 1.5 1.6 1.4 1.3 1.5 1.4 1.4 1.4 1.3
a
d
i¼1 i , arithmetic mean size. N PN 4 d i¼1 i ¼ PN 3 , mass-weighted mean size.
dno ¼
expt b d4;3
PN
expt
d
i¼1 i
c
Data used in the MSMPR population balance model.
Table 2 Experimental conditions and results of CH particles. Run
CCH (mg/mL)
TS (K)
F CO2 (cm3/min)
R F CO2 =F l
dno (nm)a
d4;3 (nm)b
expt PDI d4;3 =dno
C1c C2c C3c C4c C5c C6c C7c C8c C9c C10c
1 2.5 5 7 2.5 2.5 2.5 1 1 1
353.2 353.2 353.2 353.2 313.2 333.2 363.2 353.2 353.2 353.2
3.6 3.6 3.6 3.6 3.6 3.6 3.6 2.0 2.8 4.8
1.8 1.8 1.8 1.8 1.8 1.8 1.8 1 1.4 2.4
170 3 188 14 238 9 264 24 238 22 197 16 193 6 182 9 170 7 174 8
249 12 376 34 456 31 575 35 459 44 457 23 426 27 378 29 289 6 362 30
1.5 2.0 1.9 2.2 1.9 2.3 2.2 2.1 1.7 2.1
PN
d
a
dno ¼
b
d4;3
c
Data used in the MSMPR population balance model.
expt
expt
i¼1 i , arithmetic mean size. N PN 4 d i ¼ Pi¼1 , mass-weighted mean size. N 3
d
i¼1 i
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100
Number fraction undersize
80
60
40
20
C = 1 mg/mL C = 5 mg/mL C = 10 mg/mL C = 30 mg/mL
0 0
100
200 300 Particles size (nm)
400
500
Fig. 3. The particle size distributions of the samples produced by SAA process at different concentrations (CEA) of polymer solution from 1 mg/mL to 30 mg/mL. (TS = 353.2 K, R = 1.2).
3.1. Effects of precipitation parameters on PMMA-co-EA particle size The effect of solute concentration on polymer particle size was obtained at polymer concentrations (CEA) in acetone in the range of 1–30 mg/mL, at saturator temperature TS = 353.2 K and a volume flow ratio (R) of 1.2 (Table 1, runs #E1–E4). The FESEM images of sample particles (Fig. 2) show the formation of spherical sub-micrometric particles. Fig. 3 shows that the particle size distribution (PSD) narrows with decreasing CEA. We measured polymer solution viscosity using a Rheometer (DVIII ULTRA, Brookfield, USA) at 20 8C. Fig. 4 shows that great viscosity of high concentration polymer solution might cause larger liquid droplets and increase the mean polymer particle size (d4;3 ) in SAA process. The similar results were reported in relevant SAA process [1–4,6,7,9].
250 0.9 220
190 0.6
160
→ 130
100
0.3 0
Fig. 2. FESEM images of PMMA-co-EA particles produced by SAA process at different concentrations (CEA) of polymer solution: (a) CEA = 5 mg/mL, (b) CEA = 10 mg/mL, (c) CEA = 30 mg/mL.
Viscosity (cp)
Mass-weighted mean particle size (nm)
1.2 280
10
20
C (mg/mL)
30
expt
Fig. 4. Mass-weighted mean particle size (*, d4;3 ) varying with concentration of calc polymer solution at Ts = 353.2 K, and R = 1.2; calculated value (&, d4;3 ) obtained from MSMPR population balance model. Viscosity (~) of different concentration of polymer solution at 20 8C and 100 s1.
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5
260 250
240
220
200
230
210
190 310
320
330
TS (K)
Fig. 5. Mass-weighted mean particle size (*,
340 expt d4;3 )
350
360
varying with saturator calc
temperature (Ts) at CEA = 10 mg/mL, and R = 1.2; calculated value (&, d4;3 ) obtained from MSMPR population balance model.
Fig. 5 shows that the effect of the saturator temperature (TS) on polymer particle size for various saturator temperatures over the range of 313.2–353.2 K (Table 1, runs #E3, #E5 and #E6). For a polymer solution concentration of 10 mg/mL, and R = 1.2, mean particle size (d4;3 ) decreases with increasing saturator temperature. If the solution in the saturator forms a homogenous liquid phase, then the CO2 content of the solution is dependent on the volume flow ratio (R), and is limited by the VLE phase envelopes. From the VLE diagram for an acetone solution [4], the composition of CO2 in the saturated compressed-liquid (bubble point) increases with decreasing temperatures. For example, at a constant pressure (P = 6.5 MPa), the volume flow ratio (R) of 1.2 is close to the composition of CO2 in a saturated compressed-liquid (bubble point) at 353.2 K. At lower temperatures (e.g., 313.2 K and 333.2 K), the volume flow ratio (R = 1.2) remains in the compressed-liquid region. Therefore, for R = 1.2 over a saturator temperature range of 313.2–353.2 K, there are very little change in compositions of CO2 in the liquid solution. We attribute the decrease in PMMA-co-EA particles size that occurs with increasing temperature to the associated decrease in solution viscosity. The same trend was also reported in SAA-HCM process [9]. The mean particle sizes (d4;3 ) of micronized polymer particles that occur at different flow ratios (R) and saturator temperatures (TS) are shown in Fig. 6. The figure indicates that greater R values favor smaller particles, thus, there is an optimized R value for different saturator temperatures (e.g., R = 1.2 at TS = 353.2 K; R = 2.0 at TS = 333.2 K; R = 2.4 at TS = 313.2 K). Greater R-values mean that increases in the CO2 content of the polymer solution will enhance the secondary atomization (decompressive atomization). However, the composition of CO2 in solution is restricted by the VLE phase envelope. According to the VLE phase boundaries for different temperatures [4], the composition of CO2 in saturated compressed-liquids (bubble point) were approximately R = 1.2 (353.2 K), R = 1.6–2.0 (333.2 K) and R = 2.8 (313.2 K), respectively. These results are consistent with the optimized R values showed in Fig. 6 at 333.2 K and 353.2 K. Thus, the scCO2 dissolved in the liquid effectively minimizes the second droplet during atomization process, and then produced fine particles. This demonstrates that the influence of flow ratio (R) on the particles size can interact with
Mass-weighted mean particle size (nm)
Mass-weighted mean particle size (nm)
(a) 353.2 K
180 0.8
1.2
1.6
2
2.4
2.8
280 (b) 333.2 K 240
200
160
120 0.8
1.2
1.6
2
2.4
2.8
260 (c) 313.2 K 240
220
200
180 0.8
1.2
1.6
2
2.4
2.8
R = F CO2/Fl expt
Fig. 6. Mass-weighted mean particle size (*, d4;3 ) varying with volume flow rate ratio (R) at CEA = 10 mg/mL and saturator temperatures: (a) Ts = 353.2 K, (b) calc Ts = 333.2 K, (c) Ts = 313.2 K; calculated value (&, d4;3 ) obtained from MSMPR population balance model.
the phase behavior of mixtures in the saturator chamber. Additionally, the CO2 composition in solution is greater than the bubble point (i.e., greater than the optimized R values), the operating conditions probably fall into the vapor–liquid coexistence region (CO2-rich vapor and acetone-rich compressed-liquid phases). Precipitation of polymer in the saturator occurs because CO2 works as anti-solvent, acetone is soluble in CO2-rich vapor; this results in a greater concentration of polymer solution, and thus, larger particles sizes. Similarly, for a saturator temperature of 313.2 K, the mole fraction of CO2 in the saturated compressed-liquid is greater than 0.81; therefore, the optimized R-value of 2.4 for a saturator temperature of 313.2 K was slightly less than that for the 313.2 K bubble point at R = 2.8. The similar trends were also indicated in PMMA micronization using SAA process [3,4] and sodium cellulose sulfate micronization using SAA-HCM process [9]. 3.2. Effects of precipitation parameters on CH particle size According to the VLE phase diagram for mixture of CO2 + water (Fig. 1), CO2 has poor solubility with a mole fraction of less than
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Fig. 7. FESEM images of CH particles produced by SAA process at different concentrations (CCH) of polymer solution: (a) CCH = 1 mg/mL, (b) CCH = 2.5 mg/mL, (c) CCH = 5.0 mg/ mL, (d) CCH = 7.0 mg/mL.
0.02, thus, the saturator operating conditions are always in the vapor–liquid coexistence region. Thus, the effect of changes in the CO2 composition of the polymer solution on decompressive atomization should be minor. Nonetheless, the parameters influencing droplet size still include liquid viscosity, solute concentration, and the CO2 to liquid flow ratio. Thus, we investigated the effects of CH concentration (Table 2, runs #C1– C4), saturator temperature (runs #C2, #C5, #C6, and #C7), and volume flow ratio (runs #C1, #C8, #C9, and C10) on CH particle size. Fig. 7 shows FESEM images of CH particles produced by SAA process at different CH concentration (CCH) of solution, it formed discrete spherical sub-micrometric particles for all CCH values. PSDs obtained from FESEM images and image software were reported in Fig. 8 and illustrated the effect of solute concentration. When lower concentration solutions are processed, the particle size decreases and the distribution narrows. Similar results of chitosan particles were also showed in Reverchon’s work [7]. Fig. 9 shows the effects of varying SAA parameters on mean sizes (d4;3 ) of CH particles. Fig. 9(a and b) shows that d4;3 increases with increasing CH concentration in solution, and with decreasing saturator temperature; both of these effects can be attributed to
the viscosity of the solution. The mean particle size (d4;3 ) of micronized CH decreases with increasing volume flow ratio (Fig. 9c). A moderate excess of gas (R = 1.8) provides the energy necessary for liquid breakup and fine atomization in the SAA process of aqueous solution [7,8]. 3.3. Correlated results with the MSMPR population balance model This study applied mixed-suspension, mixed-product-removal (MSMPR) population balance theory and from product particle size distribution analyses to determine the precipitation kinetics parameters for nucleation and growth rate. Product particle size distributions of PMMA-co-EA and CH were converted to population densities (n, no./m3 nm) as described by Wu and Yang [4]. Representative population-density plots for PMMA-co-EA and CH are shown in Figs. 10 and 11, respectively. Reasonable nucleation rate B0 (no./m3 s) and growth rate G (nm/s) for sub-micrometric polymer particles were obtained from the population density plots (Tables 3 and 4). Runs #E1–E4 (Table 3) show a 30-fold variation in suspension density (MT) values calculated on a clear liquid volume basis [4], from 0.098 to 2.945 kg/m3, for the same mean residence time (t, s).
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7
600
100
80 400
60
300
(a) 40
20 C = 1.0 mg/mL C = 2.5 mg/mL C = 5.0 mg/mL C = 7.0 mg/mL
0 0
200
400
600
800
Particles size (nm) Fig. 8. The particle size distributions of the samples produced by SAA process at different concentrations (CCH) of CH solution from 1 mg/mL to 7 mg/mL. (TS = 353.2 K, R = 1.2).
Growth rate, G and the dominant particle size (Ld = 3Gt) increase with suspension density. The population density plots for runs #E1 through #E4 show different slopes (Fig. 10), suggesting that changing the suspension density of a system can provide control over the different size distribution, thus, primary nucleation may be dominant in the SAA process. Primary nucleation rates often exhibit a power-law kinetic expression [17]. Linear regression provided the best-fit for PMMA-co-EA particle sample as: B0 ¼ n0 G ¼ K N Gi ¼ expð32:76ÞG1:85
(1)
with a correlation coefficient (R2) of 0.97. Additionally, the expt experimental mass-weighted mean size (d4;3 ) of particles from the experimental PSD and the calculated mass-weighted mean size calc (d4;3 ) obtained from MSMPR population balance model, are given by Eqs. (2) and (3), respectively. P 4 expt xL d4;3 ¼ Pi i i 3 i xi Li calc d4;3
¼ 4Gt ¼
(2)
4iþ3 t i1 M T 6rC kV K N
!1
iþ3
(3)
where xi is the number of particles within the size range, Li is the mean size of each size range, and rC is density of polymer particle (1193 kg/m3 for PMMA-co-EA and 1479 kg/m3 for CH, Micromeritics, Accupyc 1340, USA). The volume shape factor kV equals p/ 6. Experimental d4;3 values for each run are listed in Table 1. Calculated values of d4;3 , obtained from Eq. (3), are listed in Table 3 and marked on Figs. 4–6. There is an average absolute deviation (AAD, %) 5.4% between experimental and calculated values of d4;3 across all of the experimental data presented in Table 3. The correlated results demonstrate that SAA precipitation experiments can be well-correlated with the MSMPR population balance model. Similar results are shown in Table 4 and Fig. 11 for submicrometric CH particles. For a constant mean residence time, suspension density, MT, varies from 0.068 to 0.474 kg/m3 (Table 4, runs #C1–C4). Growth rate increases with suspension density, and as with the PMMA-co-EA sample, the population density plots in
Mass-weighted mean particle size (nm)
Number fraction undersize
500
200 0
2
4
6
C (mg/mL)
8
520 480 440 400 360
(b) 320 310
320
330
340 TS (K)
350
360
370
440 400 360 320 280 240
(c)
200 0.8
1.2
1.6
2
2.4
R = F CO2/Fl expt
Fig. 9. Mass-weighted mean particle size (*, d4;3 ) varying with the process parameters of: (a) concentration of CH solution, at saturator temperature TS = 353.2 K, R = 1.8; (b) saturator temperature, at CCH = 2.5 mg/mL, R = 1.8; (c) calc volume flow ratio, at CCH = 1 mg/mL, TS = 353.2 K. Calculated value (&, d4;3 ) obtained from MSMPR population balance model.
Fig. 11 show non-parallel lines. The best-fit for the CH particle sample was the power-law kinetic expression shown in Eq. (4): B0 ¼ expð31:80ÞG1:23
(4)
with an R2 value of 0.86. The experimental mass-weighted mean expt sizes (d4;3 ) calculated from Eq. (2) are listed in Table 2, and the calculated values of d4;3 , calculated from Eq. (3), are listed in Table 4 and marked on Fig. 9. There is an AAD of 10.8% between experimental and calculated values for d4;3 (Table 4). This error in the calculated CH particle may have arisen because the saturator operating conditions are permanently in the vapor–liquid coexistence region. The complexity of phase behavior that occurs in the saturator does not match the MSMPR crystallizer assumption of a well-mixed system. Fig. 12 shows Arrhenius plots of the polymer growth rates for experimental runs #E3, #E5, and #E6 for PMMA-co-EA, and runs #C2, #C5, #C6, and #C7 for CH. The activation energies of the PMMA-co-EA and CH particle growth are approximately 4.2 and 6.2 kJ/mol, respectively, suggesting that diffusion (activation
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38
32
ln n (no./m3 nm)
ln n (no./m 3 nm)
36
34
32
30
28
30
26 0
100
200 300 L (nm)
400
500
Fig. 10. Population density plots for the experimental run #E1 (~, MT = 0.098 kg/ m3, long dash line, R2 = 0.81), run #E2 (*, MT = 0.491 kg/m3, short dash line, R2 = 0.89), run #E3 (*, MT = 0.982 kg/m3, solid line, R2 = 0.92), and run #E4 ( , MT = 2.945 kg/m3, R2 = 0.94).
energy <20 kJ/mol), rather than surface integration (activation energy approximately 40–60 kJ/mol), controls the particle growth rate [18]. 3.4. Solid state characterization DSC analysis results for untreated and SAA processed polymers are shown in Fig. 13. The glass transition temperature (Tg) for PMMA-co-EA is 376.2 K (Fig. 13a, onset). The SAA processed PMMA-co-EA particles showed no obviously variation in Tg
0
200
400 L (nm)
600
800
Fig. 11. Population density plots for the experimental run #C1 (~, MT = 0.068 kg/ m3, long dash line, R2 = 0.89), run #C2 (*, MT = 0.169 kg/m3, short dash line, R2 = 0.90), run #C3 (*, MT = 0.338 kg/m3, solid line, R2 = 0.96), and run #C4 ( , MT = 0.474 kg/m3, R2 = 0.94).
compared with the raw polymer. Fig. 13(b) shows DSC results for untreated and SAA-processed CH samples. The first thermal event is a wide endothermic peak between 325 and 390 K, due to water evaporation. The second endothermic peak occurs at 475 K, although this endotherm is not sharp. Corrigan et al. [19] suggested that although chitosan has crystalline regions, the crystalline melting temperature might not be found because of the rigid-rod polymer backbone having strong inter- or intra-molecular hydrogen bonding, or both. Similar thermal behavior was reported for chitosan powder spray dried from a solution of acetic and
Table 3 Correlated results from the MSMPR population balance model for PMMA-co-EA particles. calc
Run
rCO2 (kg/m3)
MT (kg/m3)
1016 n0 (no./(m3 nm))
Gt (nm)
t (s)
G (nm/s)
1019 B0 (no./(m3 s))
d4;3 (nm)
E1 E2 E3 E4 E5 E6 E7 E9 E10 E13 E14
122 122 122 122 140 171 122 140 140 171 171
0.098 0.491 0.982 2.945 1.110 1.324 1.404 0.857 0.697 0.839 0.709
2.56 3.04 3.20 4.61 3.13 2.93 2.99 3.59 4.35 4.14 4.26
33.0 44.3 53.6 64.5 56.5 60.1 58.8 49.2 44.9 51.0 47.0
0.098 0.098 0.098 0.098 0.111 0.132 0.140 0.086 0.070 0.084 0.071
337 451 546 657 509 454 419 575 644 608 663
0.862 1.37 1.75 3.03 1.59 1.33 1.25 2.06 2.80 2.52 2.83
130 181 209 262 219 234 239 198 183 197 185
Table 4 Correlated results from the MSMPR population balance model for CH particles. calc
Run
rCO2 (kg/m3)
MT (kg/m3)
1014 n0 (no./(m3 nm))
Gt (nm)
t (s)
G (nm/s)
1017 B0 (no./(m3 s))
d4;3
C1 C2 C3 C4 C5 C6 C7 C8 C9 C10
122 122 122 122 171 140 115 122 122 122
0.068 0.169 0.338 0.474 0.231 0.192 0.160 0.116 0.085 0.052
3.44 3.64 4.18 4.04 3.83 3.19 3.01 2.73 3.89 3.39
85.7 100 117 124 107 103 104 98.0 83.0 74.4
0.068 0.068 0.068 0.068 0.092 0.077 0.064 0.116 0.085 0.052
1266 1481 1725 1834 1155 1345 1626 849 973 1441
4.36 5.39 7.22 7.41 4.42 4.28 4.90 2.32 3.79 4.89
323 401 473 512 439 417 395 378 346 299
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7.5
Intensity
ln G (nm/s)
7.1
6.7
raw CH
6.3
SAA CH 5.9 0.0027
0.0029
0.0031
0.0033
1/T S (K) Fig. 12. Arrhenius plots of particle’s growth (G) of: (*) CH; (*) PMMA-co-EA.
15
30
45
60
2θ Fig. 14. The XRD patterns of untreated CH sample and SAA-processed sample.
hydrochloric acid [19], and chitosan salt powders of chitosan acetate, chitosan lactate and chitosan citrate [20]. The slightly high temperature of second endothermic peak for SAA-processed CH may result from the inevitable dissociation of chitosan hydrochloride during the SAA process. In this case, the pH values for 1.0 wt% CH aqueous solutions of untreated and SAA-processed CH changed
(a) PMMA-co-EA
from 3.95 0.02 to 4.07 0.01, which illustrated the DSC result. Similar thermal behavior was reported for moist heat treatment of chitosan salt films made of chitosan citrate, chitosan formate, and chitosan lactate [21]. The XRD patterns of untreated CH and SAAprocessed CH samples shown in Fig. 14 indicate that the crystalline state of SAA-processed CH does not present any apparent differences to untreated CH.
Exo →
4. Conclusions
340
360
380 Temp. (K)
400
(b) CH
300
350
400
450
500
(K) Fig. 13. DSC thermograms of untreated sample (solid line) and SAA-processed sample (dash line) of: (a) PMMA-co-EA, (b) CH.
This study investigated the formation of sub-micrometric particles of PMMA-co-EA and CH produced by SAA process using acetone and water as solvents and supercritical carbon dioxide as a spraying medium. The experimental results reveal that lower concentrations of polymer solution, higher saturator temperatures, and optimized carbon dioxide to polymer solution flow ratios favored reduction in mean particle sizes. The MSMPR population balance equation is capable of representing the SAA precipitation kinetics under homogeneous conditions in the saturator. The mass-weighted mean size of micronized PMMAco-EA particles could correlate with the experimental factors by using the MSMPR population balance model. Despite the poor solubility of CO2 in water, sub-micrometric CH particles could be prepared under SAA conditions, using an excess amount of gas to provide the energy necessary for liquid disruption and fine atomization. Poor agreement between the MSMPR population balance model and experimental observation of CH particle sizes arise because the MSMPR assumption of a homogeneous mixture does not apply to the complex phase behavior in the saturator. XRD results revealed that the crystallinity of SAA-processed CH resembles that of untreated CH. Acknowledgement The authors gratefully acknowledge the financial support of the National Science Council, Taiwan, through grant no. NSC101-2221E131-040.
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References [1] Reverchon E. Supercritical-assisted atomization to produce micro- and/or nanoparticles of controlled size and distribution. Ind Eng Chem Res 2002;41:2405–11. [2] Reverchon E, Della Porta G. Micronization of antibiotics by supercriticalassisted atomization. J Supercrit Fluids 2003;26:243–52. [3] Reverchon E, Antonacci A. Polymer microparticles production by supercritical assisted atomization. J Supercrit Fluids 2007;39:444–52. [4] Wu HT, Yang MW. Precipitation kinetics of PMMA sub-micrometric particles with a supercritical assisted-atomization process. J Supercrit Fluids 2011;59:98–107. [5] Adami R, Liparoti S, Reverchon E. A new supercritical assisted atomization configuration, for the micronization of thermolabile compounds. Chem Eng J 2011;173:55–61. [6] Liparoti S, Adami R, Reverchon E. PEG micronization by supercritical assisted atomization, operated under reduced pressure. J Supercrit Fluids 2012;72:46–51. [7] Reverchon E, Antonacci A. Chitosan microparticles production by supercritical fluid processing. Ind Eng Chem Res 2006;45:5722–8. [8] Caputo G, Liparoti S, Adami R, Reverchon E. Use of supercritical CO2 and N2 as dissolved gases for the atomization of ethanol and water. Ind Eng Chem Res 2012;51:11803–08. [9] Wang Q, Guan YX, Yao SJ, Zhu ZQ. Microparticle formation of sodium cellulose sulfate using supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer. Chem Eng J 2010;159:220–9. [10] Cole G. Pharmaceutical coating technology. London: Taylor & Francis; 1995.
˜ os I, Miralles B, Acosta N, et al. Functional [11] Aranaz I, Mengı´bar M, Harris R, Pan characterization of chitin and chitosan. Curr Chem Biol 2009;3:203–30. [12] Kotze´ AF, Lueßen HL, de Leeuw BJ, de Boer AG, Verhoef JC, Junginger HE. Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). J Control Release 1998;51:35–46. [13] European Pharmacopeia; 2002;p. 1774–5. [14] Caputo G, Adami R, Reverchon E. Analysis of dissolved-gas atomization: supercritical CO2 dissolved in water. Ind Eng Chem Res 2010;49:9454–61. [15] Bamberger A, Sieder G, Maurer G. High-pressure (vapor–liquid) equilibrium in binary mixtures of (carbon dioxide–water or acetic acid) at temperatures from 313 to 353 K. J Supercrit Fluids 2000;17:97–110. [16] Hou SX, Maitland GC, Martin Trusler JP. Measurement and modeling of the phase behavior of the (carbon dioxide + water) mixture at temperatures from 298.15 K to 448.15 K. J Supercrit Fluids 2013;73:87–96. [17] Randolph AD, Larson MA. Theory of particulate processes. New York: Academic Press; 1971. [18] Mullin JW. Crystallization. 4th ed. Oxford: Butterworth-Heinemann; 2001. [19] Corrigan DO, Healy AM, Corrigan OI. Preparation and release of salbutamol from chitosan and chitosan co-spray dried compacts and multiparticulates. Eur J Pharm Biopharm 2006;62:295–305. [20] Cervera MF, Heina¨ma¨ki J, de la Paz N, Lo´pez O, Maunu SL, Virtanen T, et al. Effects of spray drying on physicochemical properties of chitosan acid salts. AAPS PharmSciTech 2011;12:637–49. [21] Ritthidej GC, Phaechamud T, Koizumi T. Moist heat treatment on physicochemical change of chitosan salt films. Int J Pharm 2002;232:11–22.
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Sub-micrometric polymer particles formation by a supercritical assisted-atomization process Hsien-Tsung Wu *, Ming-Wei Yang, Shih-Chang Huang Department of Chemical Engineering, Ming Chi University of Technology, 84 Gungjuan Rd., Taishan, New Taipei City 24301, Taiwan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 August 2013 Received in revised form 21 November 2013 Accepted 22 November 2013 Available online xxx
A supercritical assisted-atomization (SAA) process, using acetone and water solvents and supercritical carbon dioxide as the spraying medium, was used to prepare sub-micrometric particles of polymethyl methacrylate-co-ethyl acrylate (PMMA-co-EA) and chitosan hydrochloride (CH). The experimental results revealed that low polymer solution concentrations, high saturator temperatures, and an optimized carbon dioxide to polymer solution flow ratio effectively minimize the mean particle size. PMMA-co-EA and CH particle sizes ranged from 0.09 to 0.17 mm, and from 0.17 to 0.26 mm, respectively. Using the mixed-suspension, mixed-product-removal (MSMPR) population balance model, the precipitation kinetics parameters were determined from the particle size distributions of the polymer particles. The mass-weighted mean sizes of micronized PMMA-co-EA particles correlated well with the experimental factors. Primary nucleation was found dominant in SAA process and diffusion may govern particle growth. ß 2013 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.
Keywords: Supercritical assisted-atomization Sub-micrometric particles PMMA-co-EA Chitosan hydrochloride Precipitation kinetics
1. Introduction Conventional processes for polymer microparticle production include suspension cross-linking, phase separation, reverse micelles formation, solvent evaporation, spray-drying, ball-milling, and high-pressure homogenization. Such processes have several limitations. The use of organic solvents and difficult to separate surfactants, require post processing to reduce solvent residues below safety limits. There is potential for contamination by grinding media and possible adverse effects on chemical stability from shear force and high temperatures. Additionally, it can be difficult to reduce pliant materials particle sizes below a given limit, and these methods offer limited control over particle size and particle size distributions. Supercritical fluid-assisted methods may minimize or overcome such common problems. Reverchon et al. [1–3] successfully developed a supercritical assisted-atomization (SAA) process to produce micro- and nanometric particles of polymers, pharmaceutical compounds, catalysts, and superconductor precursors. The process is applicable to both aqueous and organic solvent systems. SAA involves two atomization steps: pneumatic atomization inducing from the pressure difference at the nozzle outlet, and decompressive atomization, generated by rapidly delivering CO2 inside the primary droplets. The evaporation of solvent and supersaturation of solute in liquid droplets then yields fine particles. The
* Corresponding author. Tel.: +886 2 2908 9899 4630; fax: +886 2 2908 3072. E-mail address: [email protected] (H.-T. Wu).
dimensions and morphologies of the resulting particles depend on droplet size, which in turn, is dependent on the solubilization of gas (e.g., CO2) in the liquid. Wu and Yang [4] micronized the PMMA particles using acetone in a SAA process. At an optimized CO2 to liquid flow ratio, the composition of CO2 in the feed stream was close to binary mixture bubble point (CO2 + acetone) at the saturator temperature. Thus, maximum solubilization of gas in the feed liquid solution produces fine particles. Additionally, the kinetic parameters for precipitation can be determined from the particle size distributions by applying population balance theory. Recently, a new SAA configuration operating under vacuum allowed the drying process to operate at low temperatures. The advantage of reducing temperatures in a precipitator could prevent the thermolabile materials from being damage [5] and avoid the coalescence of the materials exhibiting low glasstransition temperature and melting point [6]. In aqueous system, the decompressive atomization might inactivate because CO2 has poor solubility in aqueous solution (less than mole fraction 2% in water). However, Reverchon and Antonacci [7] micronized chitosan (CS) microparticles using SAA processes with 1% acetic acid aqueous, they produced CS particles with diameters ranging between 0.1 and 1.5 mm under excess of CO2 (a mass feed ratio R = 1.8). Successful formation of CS microparticles caused by large excess of gas that provides the necessary energy for liquid fragmentation and fine atomization [8]. An improved design of supercritical fluid assisted atomization with a hydrodynamic cavitation mixer (SAA-HCM) was developed to intensify the mixing between CO2 and the aqueous solution during the SAA process [9].
1876-1070/$ – see front matter ß 2013 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jtice.2013.11.010
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Nomenclature B0 C dno d4;3 F CO2 F CO2 Fl G i KN kV L L¯ n no MT P R R2 TS xi
t rc rCO2
nucleation rate (no./s m3) mass concentration of polymer in the solution feed stream (mg/mL) arithmetic mean particle size (nm) mass-weighted mean particle size (nm) volume flow rate of CO2 at 276 K and 6.5 MPa (cm3/ min) (TS) volume flow rate of CO2 at the temperature in saturator and 6.5 MPa (cm3/min) volume flow rate of polymer solution (cm3/min) linear particle growth rate (nm/s) order of growth rate in nucleation kinetics equation (Eq. (1)) constant in nucleation kinetics equation (Eq. (1)) volumetric shape factor particle size (nm) arithmetic average size ranging from L1 to L2 (m) population density at size L (no./nm m3) population density of nuclei (no./nm m3) suspension density (kg/m3) pressure (MPa) the volume flow ratio of CO2 to polymer solution square of correlation coefficient the temperature in saturator (K) number of particles within a size range mean residence time of the mixed suspension (s) density of polymer particle (kg/m3) density of carbon dioxide (kg/m3)
superscripts calculated value calc experimental value expt
Polymethyl methacrylate-co-ethyl acrylate (PMMA-co-EA) latex can be produced as a water-based film, which can be used to control the dissolution or release of drug substances [10]. Chitosan hydrochloride (CH) is the chloride salt derivative of chitosan. A biopolymer of CH is used in novel dosage form design since water soluble at neutral and basic pH values [11,12], and is listed in the European Pharmacopeia [13]. The aim of this study is to investigate the use of PMMA-co-EA and CH with acetone and water solvents, respectively, in the SAAbased preparation of sub-micrometric particles for drug controlled release carriers. We studied the particle morphology and precipitation kinetics of the SAA-produced sub-micrometric polymer particles. Polymer precipitation experiments were conducted using various concentrations (C) of polymer solution, and various carbon dioxide to polymer solution flow ratios (R ¼ F CO2 =F l ) for a range of saturator temperatures (TS) from 313.2 K to 363.2 K. Product samples were analyzed using a field emission scanning electron microscope (FESEM). Particle size distributions and mean particle sizes were determined from FESEM image using image-processing software. In addition to determining favorable SAA conditions for smallparticle formation with narrowed particle size distribution, the mass-weighted mean sizes of micronized PMMA-co-EA and CH particles also correlated with the population balance theory. The correlated results and mechanisms of SAA precipitation kinetics of sub-micrometric polymer particles are discussed.
2. Experiment 2.1. Materials Polymethyl methacrylate-co-ethyl methacrylate (PMMA-coEA, ave. MW = 101 kg/mol) was purchased from Aldrich (USA), and chitosan hydrochloride (CH, 92% degree of deacetylation, MW = 60 kg/mol) was purchased from Charming & Beauty (Taiwan). HPLC grade acetone (99.9% purity) was purchased from Tedia, USA. A Millipore Milli-Q water purification system provided deionized water with a resistivity of 18 MV cm at 25 8C. Carbon dioxide (99.9% purity) and nitrogen (99.9% purity) gases were purchased from Yung-Ping Gas Co., Taiwan. These chemicals were used without further purification. 2.2. Apparatus and operation A schematic diagram of the supercritical assisted-atomization apparatus and operation procedure have been detailed elsewhere [4]. The apparatus comprises a saturator, a precipitator, a separator and feeding lines. The saturator is a 10 cm3 highpressure vessel, loaded with protruded stainless-steel packing to provide a large contact area between the liquid polymer solution and CO2. The solution obtained in the saturator was sprayed via a nozzle (I.D. 130 mm) into the precipitator. A metal frit (0.5 mm) mounted at the bottom of the outlet of the precipitator served to retain the polymer particles. Downstream the precipitator, a separator is used to recover solvent and gas at near atmospheric pressure. The three feeding lines contain the polymer solution, CO2 and N2. Two high-pressure liquid pumps were used to deliver CO2 and the polymer solution. The N2 flow was controlled using a mass controller from a cylinder, heated in an electric heat exchanger, and sent to the precipitator to assist in the liquid droplets’ evaporation. Briefly, the experimental procedure is described as follows. The saturator temperature (TS) and CO2 volume flow rate are pre-set. The precipitator temperatures are set to 333.2 K for acetone solvent, and 368.2 K for water solvent. After a steady state was achieved, the polymer solution was introduced into the saturator at a specified flow rate (most of the acetone solution and water solution flow rates were 5 ml/min and 2 ml/min, respectively). Polymer solution containing dissolved CO2 was sprayed through an injection nozzle to atomize the liquid as it entered the precipitator. As the atomized solution contacted the heated N2 (0.8 Nm3/h), the solvent evaporated from the droplets, resulting in supersaturation of the polymer particles. During this supercritical assisted-atomization process, the pressure in the saturator was held constant (approximately 6.5 0.3 MPa). Product samples were collected from the precipitator and observed using FESEM (model 6500, JEOL, Japan). The particle size distributions of samples and their mean values were determined using Sigma Scan Pro5 software. Approximately 1000 particles were counted on the FESEM micrographs taken for each run, to determinate the size distributions and mean values. All precipitation runs were performed at least twice for each set of experimental conditions. The obtained arithmetic mean particle size (dno ) and mass-weighted mean size expt (d4;3 ) could be reproduced to approximately 10%. The average yields of the PMMA-co-EA and CH polymer particle in SAA process were 80% and 70%, respectively. The loss was attributed to the adhesion quantity on the walls of the precipitator and inside the pores of the filter. Thermograms of polymer samples were obtained using a differential scanning calorimeter (DSC, Q-20, TA, USA). Samples (3–10 mg) were placed in aluminium pans, sealed, and heated under nitrogen from 25 to 150 8C at a heating rate of 10 8C/ min. The X-ray diffraction (XRD) patterns of product powders were recorded using an X’Pert Pro X-ray powder diffractometer
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3
20
(PANalytical, Holland). The scanning region of the diffraction angle (2u) ranged from 158 to 608 at a scan rate of 0.028/s. 3. Results
16
12 P (MPa)
Caputo et al. [14] demonstrated that the droplet size of the SAA process is remarkably influenced by the sudden release of the supercritical carbon dioxide (scCO2) dissolved in the liquid. However, the solubility of scCO2 in liquids is dependent on the high-pressure vapor–liquid equilibrium (VLE) phase boundaries. The solvents used in this study were acetone and water. The VLE phase boundaries of CO2 + acetone have been reported elsewhere [4]. We obtained the VLE phase diagram for a carbon dioxide + water mixture (Fig. 1) from the Peng–Robinson equation, incorporating the one-parameter van der Waals one-fluid mixing rules. These equations have been used to fit experimental data at different temperatures from 323.2 K to 373.2 K in the literature [15,16]. The phase diagrams for the binary system (without polymer-containment) can be used to provide an approximately estimate of phase behavior of the solution mixtures in the saturator and to represent these as a qualitative relationship to facilitate the selection of suitable SAA operating conditions. The precipitation experiments were implemented at various concentrations (C) of polymer solution, saturator temperatures (TS), and volume flow ratios of CO2 to polymer solution (R ¼ F CO2 =F l ). The condition of CO2 volume flow was 276 K and 6.5 MPa. Tables 1 and 2 list the experimental conditions and results.
8
4
0 0
0.01
0.02
0.03
0.04
0.9
xco2
0.95
1
yco2
Fig. 1. VLE phase diagram for carbon dioxide + water: (*) T = 323.2 K, Bamberger et al. [15]; ( ) T = 323.2 K, Hou et al. [16]; (~) T = 333.2 K, Bamberger et al. [15]; (&) T = 353.2 K, Bamberger et al. [15]; (b) T = 373.2 K, Hou et al. [16].
Table 1 Experimental conditions and results of PMMA-co-EA particles. Run
CEA (mg/mL)
TS (K)
F CO2 (cm3/min)
R F CO2 =F l
dno (nm)a
d4;3 (nm)b
expt PDI d4;3 =dno
E1c E2c E3c E4c E5c E6c E7c E8 E9c E10c E11 E12 E13c E14c E15
1 5 10 30 10 10 10 10 10 10 10 10 10 10 10
353.2 353.2 353.2 353.2 333.2 313.2 353.2 353.2 333.2 333.2 333.2 333.2 313.2 313.2 313.2
6 6 6 6 6 6 4 8 8 8 8.4 8.4 8 8.4 8.4
1.2 1.2 1.2 1.2 1.2 1.2 0.8 1.6 1.6 2.0 2.4 2.8 2.0 2.4 2.8
86 2 121 2 135 4 167 5 146 3 154 4 146 2 146 4 142 2 139 3 148 3 161 4 140 3 140 3 157 4
106 2 165 7 208 15 273 18 228 17 240 11 220 10 230 17 195 12 184 3 215 2 226 5 201 2 190 6 210 3
1.2 1.4 1.5 1.6 1.6 1.6 1.5 1.6 1.4 1.3 1.5 1.4 1.4 1.4 1.3
a
d
i¼1 i , arithmetic mean size. N PN 4 d i¼1 i ¼ PN 3 , mass-weighted mean size.
dno ¼
expt b d4;3
PN
expt
d
i¼1 i
c
Data used in the MSMPR population balance model.
Table 2 Experimental conditions and results of CH particles. Run
CCH (mg/mL)
TS (K)
F CO2 (cm3/min)
R F CO2 =F l
dno (nm)a
d4;3 (nm)b
expt PDI d4;3 =dno
C1c C2c C3c C4c C5c C6c C7c C8c C9c C10c
1 2.5 5 7 2.5 2.5 2.5 1 1 1
353.2 353.2 353.2 353.2 313.2 333.2 363.2 353.2 353.2 353.2
3.6 3.6 3.6 3.6 3.6 3.6 3.6 2.0 2.8 4.8
1.8 1.8 1.8 1.8 1.8 1.8 1.8 1 1.4 2.4
170 3 188 14 238 9 264 24 238 22 197 16 193 6 182 9 170 7 174 8
249 12 376 34 456 31 575 35 459 44 457 23 426 27 378 29 289 6 362 30
1.5 2.0 1.9 2.2 1.9 2.3 2.2 2.1 1.7 2.1
PN
d
a
dno ¼
b
d4;3
c
Data used in the MSMPR population balance model.
expt
expt
i¼1 i , arithmetic mean size. N PN 4 d i ¼ Pi¼1 , mass-weighted mean size. N 3
d
i¼1 i
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100
Number fraction undersize
80
60
40
20
C = 1 mg/mL C = 5 mg/mL C = 10 mg/mL C = 30 mg/mL
0 0
100
200 300 Particles size (nm)
400
500
Fig. 3. The particle size distributions of the samples produced by SAA process at different concentrations (CEA) of polymer solution from 1 mg/mL to 30 mg/mL. (TS = 353.2 K, R = 1.2).
3.1. Effects of precipitation parameters on PMMA-co-EA particle size The effect of solute concentration on polymer particle size was obtained at polymer concentrations (CEA) in acetone in the range of 1–30 mg/mL, at saturator temperature TS = 353.2 K and a volume flow ratio (R) of 1.2 (Table 1, runs #E1–E4). The FESEM images of sample particles (Fig. 2) show the formation of spherical sub-micrometric particles. Fig. 3 shows that the particle size distribution (PSD) narrows with decreasing CEA. We measured polymer solution viscosity using a Rheometer (DVIII ULTRA, Brookfield, USA) at 20 8C. Fig. 4 shows that great viscosity of high concentration polymer solution might cause larger liquid droplets and increase the mean polymer particle size (d4;3 ) in SAA process. The similar results were reported in relevant SAA process [1–4,6,7,9].
250 0.9 220
190 0.6
160
→ 130
100
0.3 0
Fig. 2. FESEM images of PMMA-co-EA particles produced by SAA process at different concentrations (CEA) of polymer solution: (a) CEA = 5 mg/mL, (b) CEA = 10 mg/mL, (c) CEA = 30 mg/mL.
Viscosity (cp)
Mass-weighted mean particle size (nm)
1.2 280
10
20
C (mg/mL)
30
expt
Fig. 4. Mass-weighted mean particle size (*, d4;3 ) varying with concentration of calc polymer solution at Ts = 353.2 K, and R = 1.2; calculated value (&, d4;3 ) obtained from MSMPR population balance model. Viscosity (~) of different concentration of polymer solution at 20 8C and 100 s1.
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5
260 250
240
220
200
230
210
190 310
320
330
TS (K)
Fig. 5. Mass-weighted mean particle size (*,
340 expt d4;3 )
350
360
varying with saturator calc
temperature (Ts) at CEA = 10 mg/mL, and R = 1.2; calculated value (&, d4;3 ) obtained from MSMPR population balance model.
Fig. 5 shows that the effect of the saturator temperature (TS) on polymer particle size for various saturator temperatures over the range of 313.2–353.2 K (Table 1, runs #E3, #E5 and #E6). For a polymer solution concentration of 10 mg/mL, and R = 1.2, mean particle size (d4;3 ) decreases with increasing saturator temperature. If the solution in the saturator forms a homogenous liquid phase, then the CO2 content of the solution is dependent on the volume flow ratio (R), and is limited by the VLE phase envelopes. From the VLE diagram for an acetone solution [4], the composition of CO2 in the saturated compressed-liquid (bubble point) increases with decreasing temperatures. For example, at a constant pressure (P = 6.5 MPa), the volume flow ratio (R) of 1.2 is close to the composition of CO2 in a saturated compressed-liquid (bubble point) at 353.2 K. At lower temperatures (e.g., 313.2 K and 333.2 K), the volume flow ratio (R = 1.2) remains in the compressed-liquid region. Therefore, for R = 1.2 over a saturator temperature range of 313.2–353.2 K, there are very little change in compositions of CO2 in the liquid solution. We attribute the decrease in PMMA-co-EA particles size that occurs with increasing temperature to the associated decrease in solution viscosity. The same trend was also reported in SAA-HCM process [9]. The mean particle sizes (d4;3 ) of micronized polymer particles that occur at different flow ratios (R) and saturator temperatures (TS) are shown in Fig. 6. The figure indicates that greater R values favor smaller particles, thus, there is an optimized R value for different saturator temperatures (e.g., R = 1.2 at TS = 353.2 K; R = 2.0 at TS = 333.2 K; R = 2.4 at TS = 313.2 K). Greater R-values mean that increases in the CO2 content of the polymer solution will enhance the secondary atomization (decompressive atomization). However, the composition of CO2 in solution is restricted by the VLE phase envelope. According to the VLE phase boundaries for different temperatures [4], the composition of CO2 in saturated compressed-liquids (bubble point) were approximately R = 1.2 (353.2 K), R = 1.6–2.0 (333.2 K) and R = 2.8 (313.2 K), respectively. These results are consistent with the optimized R values showed in Fig. 6 at 333.2 K and 353.2 K. Thus, the scCO2 dissolved in the liquid effectively minimizes the second droplet during atomization process, and then produced fine particles. This demonstrates that the influence of flow ratio (R) on the particles size can interact with
Mass-weighted mean particle size (nm)
Mass-weighted mean particle size (nm)
(a) 353.2 K
180 0.8
1.2
1.6
2
2.4
2.8
280 (b) 333.2 K 240
200
160
120 0.8
1.2
1.6
2
2.4
2.8
260 (c) 313.2 K 240
220
200
180 0.8
1.2
1.6
2
2.4
2.8
R = F CO2/Fl expt
Fig. 6. Mass-weighted mean particle size (*, d4;3 ) varying with volume flow rate ratio (R) at CEA = 10 mg/mL and saturator temperatures: (a) Ts = 353.2 K, (b) calc Ts = 333.2 K, (c) Ts = 313.2 K; calculated value (&, d4;3 ) obtained from MSMPR population balance model.
the phase behavior of mixtures in the saturator chamber. Additionally, the CO2 composition in solution is greater than the bubble point (i.e., greater than the optimized R values), the operating conditions probably fall into the vapor–liquid coexistence region (CO2-rich vapor and acetone-rich compressed-liquid phases). Precipitation of polymer in the saturator occurs because CO2 works as anti-solvent, acetone is soluble in CO2-rich vapor; this results in a greater concentration of polymer solution, and thus, larger particles sizes. Similarly, for a saturator temperature of 313.2 K, the mole fraction of CO2 in the saturated compressed-liquid is greater than 0.81; therefore, the optimized R-value of 2.4 for a saturator temperature of 313.2 K was slightly less than that for the 313.2 K bubble point at R = 2.8. The similar trends were also indicated in PMMA micronization using SAA process [3,4] and sodium cellulose sulfate micronization using SAA-HCM process [9]. 3.2. Effects of precipitation parameters on CH particle size According to the VLE phase diagram for mixture of CO2 + water (Fig. 1), CO2 has poor solubility with a mole fraction of less than
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Fig. 7. FESEM images of CH particles produced by SAA process at different concentrations (CCH) of polymer solution: (a) CCH = 1 mg/mL, (b) CCH = 2.5 mg/mL, (c) CCH = 5.0 mg/ mL, (d) CCH = 7.0 mg/mL.
0.02, thus, the saturator operating conditions are always in the vapor–liquid coexistence region. Thus, the effect of changes in the CO2 composition of the polymer solution on decompressive atomization should be minor. Nonetheless, the parameters influencing droplet size still include liquid viscosity, solute concentration, and the CO2 to liquid flow ratio. Thus, we investigated the effects of CH concentration (Table 2, runs #C1– C4), saturator temperature (runs #C2, #C5, #C6, and #C7), and volume flow ratio (runs #C1, #C8, #C9, and C10) on CH particle size. Fig. 7 shows FESEM images of CH particles produced by SAA process at different CH concentration (CCH) of solution, it formed discrete spherical sub-micrometric particles for all CCH values. PSDs obtained from FESEM images and image software were reported in Fig. 8 and illustrated the effect of solute concentration. When lower concentration solutions are processed, the particle size decreases and the distribution narrows. Similar results of chitosan particles were also showed in Reverchon’s work [7]. Fig. 9 shows the effects of varying SAA parameters on mean sizes (d4;3 ) of CH particles. Fig. 9(a and b) shows that d4;3 increases with increasing CH concentration in solution, and with decreasing saturator temperature; both of these effects can be attributed to
the viscosity of the solution. The mean particle size (d4;3 ) of micronized CH decreases with increasing volume flow ratio (Fig. 9c). A moderate excess of gas (R = 1.8) provides the energy necessary for liquid breakup and fine atomization in the SAA process of aqueous solution [7,8]. 3.3. Correlated results with the MSMPR population balance model This study applied mixed-suspension, mixed-product-removal (MSMPR) population balance theory and from product particle size distribution analyses to determine the precipitation kinetics parameters for nucleation and growth rate. Product particle size distributions of PMMA-co-EA and CH were converted to population densities (n, no./m3 nm) as described by Wu and Yang [4]. Representative population-density plots for PMMA-co-EA and CH are shown in Figs. 10 and 11, respectively. Reasonable nucleation rate B0 (no./m3 s) and growth rate G (nm/s) for sub-micrometric polymer particles were obtained from the population density plots (Tables 3 and 4). Runs #E1–E4 (Table 3) show a 30-fold variation in suspension density (MT) values calculated on a clear liquid volume basis [4], from 0.098 to 2.945 kg/m3, for the same mean residence time (t, s).
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7
600
100
80 400
60
300
(a) 40
20 C = 1.0 mg/mL C = 2.5 mg/mL C = 5.0 mg/mL C = 7.0 mg/mL
0 0
200
400
600
800
Particles size (nm) Fig. 8. The particle size distributions of the samples produced by SAA process at different concentrations (CCH) of CH solution from 1 mg/mL to 7 mg/mL. (TS = 353.2 K, R = 1.2).
Growth rate, G and the dominant particle size (Ld = 3Gt) increase with suspension density. The population density plots for runs #E1 through #E4 show different slopes (Fig. 10), suggesting that changing the suspension density of a system can provide control over the different size distribution, thus, primary nucleation may be dominant in the SAA process. Primary nucleation rates often exhibit a power-law kinetic expression [17]. Linear regression provided the best-fit for PMMA-co-EA particle sample as: B0 ¼ n0 G ¼ K N Gi ¼ expð32:76ÞG1:85
(1)
with a correlation coefficient (R2) of 0.97. Additionally, the expt experimental mass-weighted mean size (d4;3 ) of particles from the experimental PSD and the calculated mass-weighted mean size calc (d4;3 ) obtained from MSMPR population balance model, are given by Eqs. (2) and (3), respectively. P 4 expt xL d4;3 ¼ Pi i i 3 i xi Li calc d4;3
¼ 4Gt ¼
(2)
4iþ3 t i1 M T 6rC kV K N
!1
iþ3
(3)
where xi is the number of particles within the size range, Li is the mean size of each size range, and rC is density of polymer particle (1193 kg/m3 for PMMA-co-EA and 1479 kg/m3 for CH, Micromeritics, Accupyc 1340, USA). The volume shape factor kV equals p/ 6. Experimental d4;3 values for each run are listed in Table 1. Calculated values of d4;3 , obtained from Eq. (3), are listed in Table 3 and marked on Figs. 4–6. There is an average absolute deviation (AAD, %) 5.4% between experimental and calculated values of d4;3 across all of the experimental data presented in Table 3. The correlated results demonstrate that SAA precipitation experiments can be well-correlated with the MSMPR population balance model. Similar results are shown in Table 4 and Fig. 11 for submicrometric CH particles. For a constant mean residence time, suspension density, MT, varies from 0.068 to 0.474 kg/m3 (Table 4, runs #C1–C4). Growth rate increases with suspension density, and as with the PMMA-co-EA sample, the population density plots in
Mass-weighted mean particle size (nm)
Number fraction undersize
500
200 0
2
4
6
C (mg/mL)
8
520 480 440 400 360
(b) 320 310
320
330
340 TS (K)
350
360
370
440 400 360 320 280 240
(c)
200 0.8
1.2
1.6
2
2.4
R = F CO2/Fl expt
Fig. 9. Mass-weighted mean particle size (*, d4;3 ) varying with the process parameters of: (a) concentration of CH solution, at saturator temperature TS = 353.2 K, R = 1.8; (b) saturator temperature, at CCH = 2.5 mg/mL, R = 1.8; (c) calc volume flow ratio, at CCH = 1 mg/mL, TS = 353.2 K. Calculated value (&, d4;3 ) obtained from MSMPR population balance model.
Fig. 11 show non-parallel lines. The best-fit for the CH particle sample was the power-law kinetic expression shown in Eq. (4): B0 ¼ expð31:80ÞG1:23
(4)
with an R2 value of 0.86. The experimental mass-weighted mean expt sizes (d4;3 ) calculated from Eq. (2) are listed in Table 2, and the calculated values of d4;3 , calculated from Eq. (3), are listed in Table 4 and marked on Fig. 9. There is an AAD of 10.8% between experimental and calculated values for d4;3 (Table 4). This error in the calculated CH particle may have arisen because the saturator operating conditions are permanently in the vapor–liquid coexistence region. The complexity of phase behavior that occurs in the saturator does not match the MSMPR crystallizer assumption of a well-mixed system. Fig. 12 shows Arrhenius plots of the polymer growth rates for experimental runs #E3, #E5, and #E6 for PMMA-co-EA, and runs #C2, #C5, #C6, and #C7 for CH. The activation energies of the PMMA-co-EA and CH particle growth are approximately 4.2 and 6.2 kJ/mol, respectively, suggesting that diffusion (activation
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38
32
ln n (no./m3 nm)
ln n (no./m 3 nm)
36
34
32
30
28
30
26 0
100
200 300 L (nm)
400
500
Fig. 10. Population density plots for the experimental run #E1 (~, MT = 0.098 kg/ m3, long dash line, R2 = 0.81), run #E2 (*, MT = 0.491 kg/m3, short dash line, R2 = 0.89), run #E3 (*, MT = 0.982 kg/m3, solid line, R2 = 0.92), and run #E4 ( , MT = 2.945 kg/m3, R2 = 0.94).
energy <20 kJ/mol), rather than surface integration (activation energy approximately 40–60 kJ/mol), controls the particle growth rate [18]. 3.4. Solid state characterization DSC analysis results for untreated and SAA processed polymers are shown in Fig. 13. The glass transition temperature (Tg) for PMMA-co-EA is 376.2 K (Fig. 13a, onset). The SAA processed PMMA-co-EA particles showed no obviously variation in Tg
0
200
400 L (nm)
600
800
Fig. 11. Population density plots for the experimental run #C1 (~, MT = 0.068 kg/ m3, long dash line, R2 = 0.89), run #C2 (*, MT = 0.169 kg/m3, short dash line, R2 = 0.90), run #C3 (*, MT = 0.338 kg/m3, solid line, R2 = 0.96), and run #C4 ( , MT = 0.474 kg/m3, R2 = 0.94).
compared with the raw polymer. Fig. 13(b) shows DSC results for untreated and SAA-processed CH samples. The first thermal event is a wide endothermic peak between 325 and 390 K, due to water evaporation. The second endothermic peak occurs at 475 K, although this endotherm is not sharp. Corrigan et al. [19] suggested that although chitosan has crystalline regions, the crystalline melting temperature might not be found because of the rigid-rod polymer backbone having strong inter- or intra-molecular hydrogen bonding, or both. Similar thermal behavior was reported for chitosan powder spray dried from a solution of acetic and
Table 3 Correlated results from the MSMPR population balance model for PMMA-co-EA particles. calc
Run
rCO2 (kg/m3)
MT (kg/m3)
1016 n0 (no./(m3 nm))
Gt (nm)
t (s)
G (nm/s)
1019 B0 (no./(m3 s))
d4;3 (nm)
E1 E2 E3 E4 E5 E6 E7 E9 E10 E13 E14
122 122 122 122 140 171 122 140 140 171 171
0.098 0.491 0.982 2.945 1.110 1.324 1.404 0.857 0.697 0.839 0.709
2.56 3.04 3.20 4.61 3.13 2.93 2.99 3.59 4.35 4.14 4.26
33.0 44.3 53.6 64.5 56.5 60.1 58.8 49.2 44.9 51.0 47.0
0.098 0.098 0.098 0.098 0.111 0.132 0.140 0.086 0.070 0.084 0.071
337 451 546 657 509 454 419 575 644 608 663
0.862 1.37 1.75 3.03 1.59 1.33 1.25 2.06 2.80 2.52 2.83
130 181 209 262 219 234 239 198 183 197 185
Table 4 Correlated results from the MSMPR population balance model for CH particles. calc
Run
rCO2 (kg/m3)
MT (kg/m3)
1014 n0 (no./(m3 nm))
Gt (nm)
t (s)
G (nm/s)
1017 B0 (no./(m3 s))
d4;3
C1 C2 C3 C4 C5 C6 C7 C8 C9 C10
122 122 122 122 171 140 115 122 122 122
0.068 0.169 0.338 0.474 0.231 0.192 0.160 0.116 0.085 0.052
3.44 3.64 4.18 4.04 3.83 3.19 3.01 2.73 3.89 3.39
85.7 100 117 124 107 103 104 98.0 83.0 74.4
0.068 0.068 0.068 0.068 0.092 0.077 0.064 0.116 0.085 0.052
1266 1481 1725 1834 1155 1345 1626 849 973 1441
4.36 5.39 7.22 7.41 4.42 4.28 4.90 2.32 3.79 4.89
323 401 473 512 439 417 395 378 346 299
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7.5
Intensity
ln G (nm/s)
7.1
6.7
raw CH
6.3
SAA CH 5.9 0.0027
0.0029
0.0031
0.0033
1/T S (K) Fig. 12. Arrhenius plots of particle’s growth (G) of: (*) CH; (*) PMMA-co-EA.
15
30
45
60
2θ Fig. 14. The XRD patterns of untreated CH sample and SAA-processed sample.
hydrochloric acid [19], and chitosan salt powders of chitosan acetate, chitosan lactate and chitosan citrate [20]. The slightly high temperature of second endothermic peak for SAA-processed CH may result from the inevitable dissociation of chitosan hydrochloride during the SAA process. In this case, the pH values for 1.0 wt% CH aqueous solutions of untreated and SAA-processed CH changed
(a) PMMA-co-EA
from 3.95 0.02 to 4.07 0.01, which illustrated the DSC result. Similar thermal behavior was reported for moist heat treatment of chitosan salt films made of chitosan citrate, chitosan formate, and chitosan lactate [21]. The XRD patterns of untreated CH and SAAprocessed CH samples shown in Fig. 14 indicate that the crystalline state of SAA-processed CH does not present any apparent differences to untreated CH.
Exo →
4. Conclusions
340
360
380 Temp. (K)
400
(b) CH
300
350
400
450
500
(K) Fig. 13. DSC thermograms of untreated sample (solid line) and SAA-processed sample (dash line) of: (a) PMMA-co-EA, (b) CH.
This study investigated the formation of sub-micrometric particles of PMMA-co-EA and CH produced by SAA process using acetone and water as solvents and supercritical carbon dioxide as a spraying medium. The experimental results reveal that lower concentrations of polymer solution, higher saturator temperatures, and optimized carbon dioxide to polymer solution flow ratios favored reduction in mean particle sizes. The MSMPR population balance equation is capable of representing the SAA precipitation kinetics under homogeneous conditions in the saturator. The mass-weighted mean size of micronized PMMAco-EA particles could correlate with the experimental factors by using the MSMPR population balance model. Despite the poor solubility of CO2 in water, sub-micrometric CH particles could be prepared under SAA conditions, using an excess amount of gas to provide the energy necessary for liquid disruption and fine atomization. Poor agreement between the MSMPR population balance model and experimental observation of CH particle sizes arise because the MSMPR assumption of a homogeneous mixture does not apply to the complex phase behavior in the saturator. XRD results revealed that the crystallinity of SAA-processed CH resembles that of untreated CH. Acknowledgement The authors gratefully acknowledge the financial support of the National Science Council, Taiwan, through grant no. NSC101-2221E131-040.
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