Langmuir 2001, 17, 5435-5439
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New Approach To Produce Monosized Polymer Microcapsules by the Solute Co-diffusion Method Jin-Woong Kim,† Sung-A Cho,‡ Hak-Hee Kang,† Sang-Hoon Han,† Ih-Seop Chang,† Ok-Sub Lee,† and Kyung-Do Suh*,‡ Cosmetics Research Institute, Pacific Corporation R&D Center, 314-1 Bora-ri, Kiheung-eup, Yongin-si, Kyounggi-do 449-900, Korea, and Department of Chemical Engineering, College of Engineering, Hanyang University, Seoul 133-791, Korea Received November 28, 2000. In Final Form: June 4, 2001 This study introduces a new approach for producing highly monosized polymer microcapsules. The technique employs an impressive process in which the solute, dissolved freely in a solvent, is diffused uniformly into the preexisting monosized polymer particles in the form of a fine emulsion. The solvent is then eliminated, resulting consequently in solute-loaded polymer microcapsules. We named it a solute co-diffusion method, SCM. The loading efficiency of the solute was predicted successfully by a thermodynamic equation. In the experiment, the indomethacin-loaded poly(methyl methacrylate) microparticles were produced via SCM. From our results, SCM is expected to expand significantly the drug-loading technology in related fields.
Introduction Microencapsulation is a very useful technique for altering the properties of capsulated materials. The technology can be used to control release characteristics, improve their stability by protecting them from environmental stimuli, and also convert liquids into solids.1,2 Therefore, there have been intensive studies on the production of polymer microcapsules in the fields of pharmaceuticals, agriculture, paper coatings, paints, and cosmetics.1,3 Polymer microcapsules are prepared by employing several processes such as coacervation phase separation, interfacial polymerization, solvent evaporation, spray coating, multiorifice centrifugal process, and air suspension.4-10 Because each of those processes has its advantages and disadvantages, no one is suitable for all substances. Therefore, the process selected depends on the desired size of the encapsulated product and the physiochemical properties of both the substance to be capsulated and the coating material. Usually, the size and size distribution of the polymer microcapsules are influenced by the method of encapsulation and the process parameters used.11 Because the size * To whom correspondence should be addressed. Phone: 82-02-2290-0526; fax: 82-02-2295-2102; e-mail: kdsuh@ hanyang.ac.kr. † Pacific Corporation R&D Center. ‡ Hanyang University. (1) Arshady, R., Ed. Microspheres Microcapsules & Liposomes; Citus Books: London, 1999. (2) El-Nokaly, M. A., Piatt, D. M., Charpentier, B. M., Eds. Polymeric Delivery Systems: Properties and Applications; ACS Symposium Series 520; American Chemical Society: Washington, DC, 1993. (3) Park, K. N., Mrsny, R. J., Eds. Controlled Drug Delivery: Designing Technologies for the Future; American Chemical Society: Washington, DC, 2000. (4) Loftsson, T.; Frioriksdottir, H. Int. J. Pharm. 1990, 62, 243. (5) Loftsson, T.; Olafsdottir, B. J.; Baldvinsdottir, J. Int. J. Pharm. 1992, 79, 107. (6) Rainsford, K. D. Drug Invest. 1990, 2, 3. (7) Backkenfeld, T.; Muller, B. W.; Kolter, K. Int. J. Pharm. 1991, 74, 85. (8) Backkenfeld, T.; Muller, B. W.; Wiese, M.; Seydel, K. Pharm. Res. 1990, 7, 484. (9) Bettinetti, G. P.; Mura, P.; Liguori, A.; Bramanti, G. Farmaco 1989, 44, 196. (10) Loftsson, T.; Bodor, N. Acta Pharm. Nord. 1989, 1, 185.
and size distribution of the microcapsules are crucial to the release rate of the capsulated substance, an accurate preliminary characterization of the size distribution is required. Therefore, monosized polymer microcapsules are ideal for all of the applications. In the present study, we are proposing a useful method to produce effectively the monosized polymer microcapsules. The concept is constructed from the fact that the solute/solvent mixture in the form of a fine emulsion is diffused uniformly into the preexisting monosized polymer particles.12-15 Finally, the solvent is eliminated from the suspended droplets composed of solute, solvent, and polymer. We named this process a solute co-diffusion method (SCM). In SCM, the size and size distribution of the microcapsules are predetermined by the characteristics of the preexisting polymer particles. We consider the effectiveness of SCM on the production of polymer microcapsules theoretically and experimentally. Thermodynamic Consideration The system used for SCM is composed of monosized polymer particles, a slightly water-soluble solvent, a waterinsoluble solute dissolved freely in the solvent, and water containing a small amount of surfactants. Basically, the assumption is that there is only transportation of solvent molecules into the preexisting polymer particles and no transportation of the solvent out of the polymer phase. The solute behaves like a solvent, diffusing into the polymer phase during the diffusion process. Partial molar free energy, ∆G h *, of the solvent in the cross-linked polymer particles during diffusion is composed of the following three contributions:
∆G h * ) ∆G h m + ∆G h t + ∆G h el
(1)
h t, and ∆G h el are the respective contributions where ∆G h m, ∆G (11) Donbrow, D. N. In Topics in Pharmaceutical Science; Breimer, D. D., Speiser, P., Eds.; Elsevier Science B.V.: Amsterdam, 1987. (12) Thomson, B.; Rudin, A.; Lajoie, G. J. Appl. Polym. Sci. 1996, 59, 2009. (13) Sheu, H. R.; El-Aasser, M. S.; Vanderhoff, J. W. J. Polym. Sci., Part A: Polym. Chem. 1990, 28, 629. (14) Kim, J. W.; Suh, K. D. Polymer 2000, 41, 6181. (15) Kim, J. W.; Suh, K. D. Macromol. Chem. Phys. 2001, 202, 621.
10.1021/la001654o CCC: $20.00 © 2001 American Chemical Society Published on Web 08/09/2001
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Kim et al.
[
Table 1. Standard Recipe for the Dispersion Polymerization of PMMA Particlesa ingredient
L-PMMA (g)b
X-PMMA (g)c
MMA PDAd PVP K-30 aerosol-OTe AIBN methanol
1.00
0.97 0.03 0.40 0.04 0.01 8.55
0.40 0.04 0.01 8.55
a 55 °C, 24 h, 40 rpm. b Linear PMMA. c Cross-linked PMMA. Pluronic L64 diacrylate was a useful cross-linker in DPM. e Di2-ethylhexyl ester of sodium sulfosuccinic acid (aerosol-OT, American Cyanamid).
d
of solvent-polymer mixing force, polymer network elasticretractile force, and particle-water interfacial tension force. The partial molar free energy change by the absorption of slightly water-soluble molecules developed by Morton et al. is depicted as follows:16
[
(
]
)
2V h Sγ 1 ∆G h ) RT ln φS + 1 - φP + φP2χ + jP rRT
(2)
where φS is the volume fraction of the slightly water-soluble molecule, φP is the volume fraction of the polymer, jP is the ratio of the molar volume of polymer to the slightly watersoluble molecule, χ is the Flory-Huggins interaction parameter, γ is the interfacial energy, r is the radius of the particles, and V h S is the partial molar volume of the slightly water-soluble molecule. The elastic free energy change, ∆G h el, is an entropy term associated with the change in configuration of the polymer network17,18 and is described as follows:
(
h S φP1/3 ∆G h el ) RTNV
)
φP 2
(3)
where N is the effective number of chains in the network per unit volume. Combining eqs 2 and 3, the partial molar free energy, ∆G h *, of the solvent in the cross-linked polymer particles during the diffusion gives
[
(
∆G h * ) RT ln φS + 1 -
)
2V h 1γ 1 + φP + φP2χ + jP rRT φP NV h S φP1/3 2
(
(
∆G h * ) RT ln φS + 1 -
)]
(4)
Effective solvent diffusion can be achieved by incorporating the solvent in the form of emulsions.12,13,19,20 When considering solvent emulsion diffusion, the partial molar free energy of the solvent in the cross-linked polymer particles during the diffusion is expressed in terms of the droplet size of the solvent emulsions, giving (16) Morton, M.; Altier, M. W. J. Colloid Sci. 1954, 9, 300. (17) Flory, J. P., Ed. Principles of Polymer Chemistry; Cornell University Press: Ithaca, NY, 1953. (18) Candau, F., Ottewill, R. H., Eds. Scientific Methods for the Study of Polymer Colloids and Their Applications; Kluwer Publishers: Dordrecht, The Netherlands, 1990. (19) Ugelstad, J.; Berge, A.; Ellingsen, T.; Schmid, R.; Nilsen, T. N.; Mork, P. C.; Stenstad, P.; Hornes, E.; Olsvik, O. Prog. Polym. Sci. 1992, 17, 87. (20) Okubo, M.; Yamashita, T.; Shiozaki, M. J. Appl. Polym. Sci. 1996, 60, 1025.
(
)
1 φ + φP2χ + jP P
)]
(
)
φP 2V h Sγ 1 1 + NV h S φP1/3 RT rG rS 2
(5)
where rG is the radius of growing particles and rS is the radius of solvent emulsions. At equilibrium states, the following thermodynamic equation is obtained
(
ln φS + 1 -
)
(
)
2V h Sγ 1 1 1 φP + φP2χ + + jP RT rG rS φP NV h S φP1/3 ) 0 (6) 2
(
)
Particle radius, rG, is represented as follows:
[
r G ) r0
]
VS + V P VP
1/3
(7)
where r0 is the initial particle radius. On the basis of eqs 5 and 6, the diffusion process of solute-containing solvent emulsions was predicted in the presence of the monosized polymer particles. Experimental Section Materials. Pluronic L64 diacrylate (PDA) was synthesized by the reaction of poly(ethylene oxide)x-poly(propylene oxide)ypoly(ethylene oxide)z triblock diol (1 mol, x ) 17, y ) 30, z ) 17, BASF) with acryloyl chloride (2 mol, Acros Organics), which was catalyzed with triethylamine.21 Methyl methacrylate (MMA, Junsei Chemical Co.), poly(vinyl pyrrolidone) (PVP K-30, Mw ) 4.0 × 104, Aldrich Chemical Co.), 2,2-azobis(isobutyronitrile) (AIBN, Junsei), methylene chloride (MC, Aldrich), and indomethacin (IMC, Aldrich) were all reagent grade. Monosized Poly(methyl methacrylate) (PMMA) Substrate Particles. The monosized PMMA particles were produced by dispersion polymerization.22 Especially when producing crosslinked PMMA particles, we employed the diffusion-controlled polymerization method, DPM, where PDA was used as a crosslinker.21,23,24 MMA, PDA (in the case of DPM), AIBN, PVP, and methanol were weighed into 50 mL glass vials. After the vials were sealed in a nitrogen atmosphere, polymerization was carried out by rotating at the speed of 40 rpm at 55 °C for 24 h. Then, PMMA particles were recovered by washing repeatedly after six consecutive centrifugations and drying under a vacuum. A standard recipe is summarized in Table 1. Microencapsulation by SCM. The monosized PMMA particles (2 g) were redispersed in a 0.1 wt % PVP K-30 aqueous solution (48 g) by 10 min of sonification. They were swollen with an IMC/MC (0.86/7.74, g/g) emulsion, prepared by ultrasonic homogenizing in a 0.25% aqueous solution (50 g). The swelling was carried out by stirring with a magnetic bar at 10 °C for 3 h until all of the emulsion droplets disappeared completely. The MC in the swollen PMMA particles was evaporated fully with a rotary evaporator at 30 °C for 1 h. The dispersion was passed repeatedly through a sintered glassing filter (average 2-µm pore diameter) and dried under a vacuum at ambient temperature. Finally, fine IMC-loaded PMMA microcapsules were obtained. To confirm the morphology of the microcapsules, the same process was carried out, except that the IMC was replaced with a blue dye. Observations. The diffusion of solvent emulsions into the PMMA particles was monitored by measuring the diameter (21) Kim, J. W.; Ko, J. Y.; Suh, K. D. Macromol. Rapid Commun. 2001, 22, 257. (22) Kim, J. W.; Suh, K. D. Colloid Polym. Sci. 1998, 276, 870. (23) Kim, J. W.; Suh, K. D. Colloid Polym. Sci. 1999, 277, 66. (24) Kim, J. W.; Kim, B. S.; Suh, K. D. Colloid Polym. Sci. 2000, 278, 591.
Monosized Polymer Microcapsules
Figure 1. Simulated SLE (Vsolute/VP) with the diameter (r0) of substrate polymer particles at different χ (dotted lines, at a fixed N of 100 mol m-3) and cross-linking density (N, mol m-3, solid lines, at a fixed χ of 0.35) under the conditions of Vsolute = VS/10, jP ) ∞, V h S ) 10-4 m3 mol-1, T ) 283 K, γ ) 5 mN m-1, and rS ) 0.35 × 10-6 m. The line of open circles is the most similar system to the experimental system.
Langmuir, Vol. 17, No. 18, 2001 5437
Figure 2. Simulated SLE (Vsolute/VP) with the diameter (r0) of the substrate polymer particles at different radii of solvent emulsions (rS) under the conditions of χ ) 0.35, N ) 100 mol m-3, Vsolute = VS/10, jP ) ∞, VS ) 10-4 m3 mol-1, T ) 283 K, and γ ) 5 mN m-1. The line of open circles is the most similar system to the experimental system.
change with an optical microscope (OM, Nikon Microphot Fax). The morphology of the particles produced was observed with a scanning electron microscope (SEM, JSM-6300, JEOL). To determine the particle diameter, about 100 individual particles were counted from SEM photographs, and the average was taken.
Results and Discussion There has been intensive research to produce polymer microcapsules loading a variety of active materials.4-10 From the viewpoint of size control, however, researchers could not overcome the problem of broad size distribution in almost all of the techniques. The difficulties arose because the processes applied mainly utilize droplet breakup or random heterocoagulation to achieve spherical suspension. However, if monosized polymer microcapsules are obtainable, there are big advantages from the aspects that not only the active inner material can be released at a constant rate but also the microcapsules can be used structurally in many applications. Here, we are proposing SCM, which can produce extremely monosized polymer microcapsules. The basic concept was originated from the activated swelling method that was pioneered to produce large monosized polymer particles by Ugelstad et al.25-27 In SCM, the monosized substrate polymer particles are swollen with the solvent emulsions containing active materials, and the solvent is eliminated consequently in the final stage. In this study, the applicability of SCM in producing monosized polymer microcapsules is considered thermodynamically and experimentally. Thermodynamic Understanding of SCM. Figure 1 shows the solute loading efficiency (SLE) with the diameter of substrate polymer particles at the selected cross-linking density of the particles and the interaction parameter between the solvent and the polymer, which was simulated from eq 6. We found that the cross-linking of substrate polymer particles has a large impact on SLE. In the case of using linear or more slightly cross-linked particles, SLE goes up sharply, meaning that the substrate particles can (25) Ugelstad, J. Makromol. Chem. 1978, 179, 815. (26) Ugelstad, J.; Kaggerud, K. H.; Hansen, F. K.; Berge, A. Makromol. Chem. 1979, 180, 737. (27) Ugelstad, J.; Mork, P. C.; Kaggerud, K. H.; Ellingsen, T.; Berge, A. Adv. Colloid Interface Sci. 1980, 13, 101.
Figure 3. Simulated partial molar free energy (∆G h */RT) change with the SLE (Vsolute/VP) at different cross-linking densities (N, mol m-3) of substrate polymer particles under the conditions of χ ) 0.35, Vsolute = VS/10, jP ) ∞, VS ) 10-4 m3 mol-1, T ) 283 K, γ ) 5 mN m-1, rS ) 0.35 × 10-6 m, and r0 ) 2.5 × 10-6 m. The line of open circles is the most similar system to the experimental system.
uptake a large amount of solvent emulsions. This result shows the same trend as that of other research on seeded swellings.19,20,25-30 However, it should be noticed that the higher cross-linking of the substrate polymer particles results in a lower SLE. This happens because the elasticretractile force caused by the cross-linked network of substrate polymer particles restricts the effective diffusion of the solvent emulsions during the swelling stage.14,15 As a result, the cross-linking of the substrate polymer particles shifted the partial molar free energy of the solvent in the particles toward the positive side. In Figure 1, the solvent-polymer interaction parameter also influences SLE. Therefore, it can be deduced from the simulation that, to obtain a reasonable SLE, the cross-linking degree (28) Okubo, M.; Nakagawa, T. Colloid Polym. Sci. 1992, 270, 853. (29) Okubo, M.; Shiozaki, M. Polym. Int. 1993, 30, 469. (30) Omi, S. Colloid Surf., A 1996, 109, 97.
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Kim et al. Table 2. Particle Characteristics of PMMA Substrate Particles symbola L-PMMA X-PMMA
PSDa
Dn (µm) 4.65 5.23
1.02 1.01
Mw 5.0 ×
104
MWDb
N (mol m-3)
2.50 100c
b
a
Particle size distribution, Dw/Dn. Molecular weight distribution, Mw/Mn. c On the basis of our previous studies,12,13 we assumed the effective number of chains in the cross-linked network to be located around 100 mol m-3. Table 3. Particle Characteristics of IMC-loaded PMMA Microcapsules Dn (µm)
Figure 4. OM image for the linear (a) and cross-linked (b) PMMA particles swollen uniformly with MC/IMC emulsion (9/ 1, w/w).
of substrate polymer particles should fall within the proper region, around 100 mol m-3 and solvents that have good miscibility with the substrate polymer should be selected.
symbol
calcd
measd
PSD
remarks
IMC/L-PMMA
5.07
5.22
1.38
IMC/X-PMMA
5.71
6.16
1.01
fibrils, irregular shape, aggregation monosize, clear surface
Figure 2 shows the dependence of SLE on the droplet size of the solvent emulsions. As shown, the SLE of the cross-linked substrate polymer particles is dependent largely on the droplet size of the solvent emulsions. This simulation enables us to predict that a maximized SLE of the cross-linked seed particles requires the smaller droplet of the solvent emulsions. Partial molar free energy changes were simulated with the SLE at different cross-linking densities of substrate polymer particles and the droplet size of the solvent emulsions from eq 5, as shown in Figure 3. In the swelling of the substrate polymer particles, the main contributor to total partial molar free energy, ∆G h *, is the mixing force, ∆G h m. However, when the substrate polymer particles are cross-linked, the elastic-retractile force, ∆G h el, makes a positive contribution to ∆G h *, resulting in the restricted diffusion of the solvent emulsions into the cross-linked
Figure 5. OM and SEM images for the linear (panels a and c) and cross-linked (panels b and d) PMMA microcapsules. 30 wt % IMC was loaded in the PMMA particles.
Monosized Polymer Microcapsules
substrate polymer particles. Therefore, to achieve a reasonable SLE, there should be a compromise between h el. The contribution by the interfacial tension ∆G h m and ∆G force, ∆G h t, also plays an important role in determining ∆G h *, which is attributed to the difference in the sizes between the substrate polymer particles and the solvent emulsions. When the difference is big, the SLE reaches decades fold, even in the case of using the substrate polymer particles of high cross-linking densities. From these results, we can obtain the basic requirements for an acceptable SLE in SCM: preferentially lower cross-linking densities of the substrate polymer particles and absolutely smaller sizes of the solvent emulsions as compared with that of the substrate polymer particles. Uniform Particle Swelling by SCM. The monosized linear and cross-linked PMMA substrate particles were produced by dispersion polymerization. In the production of the cross-linked PMMA particles, DPM was employed using PDA, which promotes effective diffusion of MMA monomers during the stage of particle growth.21 All of the particles produced had a high monodispersity and a clear surface. The particle characteristics are summarized in Table 2. Here, the cross-linking density of the PMMA particles was estimated by fitting the transport rate of the monomers from the aqueous medium into the particles.14,15 Figure 4 shows the OM photographs for the PMMA particles fully swollen by the IMC/MC emulsions under appropriate conditions, constructed on the basis of thermodynamic considerations. Regardless of the chain characteristics, the PMMA substrate particles were uniformly swollen, maintaining their spherical shape throughout the swelling process. This means that the selected conditions for SCM (especially the cross-linking density of PMMA substrate particles and the size difference between PMMA particles and IMC/MC emulsions) were acceptable. Morphology of PMMA Microcapsules. After the complete swelling of the IMC/MC emulsions, the MC in the swollen PMMA particles was evaporated, and the image of PMMA microcapsules was observed. The OM and SEM photographs of the IMC-loaded PMMA microcapsules are shown in Figure 5. The characteristics of the microcapsules are summarized in Table 3. From the images of the PMMA microcapsules, it is obvious that the morphology was dependent seriously upon the chain characteristics of substrate polymer particles. When the linear PMMA was used as substrate polymer particles, a portion of the polymer phase formed fibrils during the evaporation process. Moreover, many large particles, as compared with the substrate particles, were generated. This happened because the polymer droplets swollen by the MC could not maintain their spherical shape under such a high shear condition. As a result, they have a tendency toward aggregating each other and forming fibrils macroscopically. However, when using cross-linked PMMA particles, such phenomena were not observed. All of the microcapsules recovered were of uniform size and
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Figure 6. OM images for the PMMA microcapsules stained with a water-insoluble blue dye. 0.01 wt % dye was loaded in the PMMA particles.
spherical in shape. This implies that the MC in the swollen polymer droplets was eliminated selectively without the aggregation of droplets or formation of fibrils. The chainchain interbinding caused by the cross-linked network structure seems to enhance individual droplet stability during the evaporation of MC. From Figure 5, it is difficult to estimate precisely the loading state of IMC in the PMMA phase. To confirm the loading state of the IMC in the PMMA microcapsules, a water-insoluble blue dye was incorporated into the capsules. Figure 6 shows the OM photograph for the PMMA microcapsules containing the blue dye. The PMMA microcapsules were stained with a blue color throughout the phase. This result verifies directly that the IMC distributed evenly in the PMMA phase with extremely fine domains. Conclusion In this study, we have presented an approach that can produce monosized polymer microcapsules by the diffusion process of solute/solvent emulsions into the preexisting monosized polymer substrate particles. We have called this SCM. The thermodynamic studies would predict that SLE was largely influenced by interfacial and elasticretractile characteristics. Basically, the solute/solvent emulsions much smaller than the substrate polymer particles were required for an enhanced loading efficiency in the presence of slightly cross-linked seed particles. In the experiments carried out on the basis of thermodynamic considerations, highly monosized IMC-loaded PMMA microcapsules were produced successfully. The importance of SCM is found in the fact that it is very useful for producing monosized polymer microcapsules, and its potential utility is very high in many related fields. Acknowledgment. This work is supported in part by the National Research Laboratory (NRL) program (Project 2000-N-01-C-270) and by the Ministry of Science and Technology, South Korea. LA001654O
