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In situ generation of biodegradable poly(p-dioxanone) micro-particles by polymerization in supercritical carbon dioxide
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Chinese Chemical Letters 22 (2011) 1509–1512 www.elsevier.com/locate/cclet
In situ generation of biodegradable poly( p-dioxanone) microparticles by polymerization in supercritical carbon dioxide Tian Qiang Wang a, Xiu Li Zhao b, Jian Yuan Hao a,* a
State Key Lab of Electronic Films and Integrated Devices, School of Microelectronics and Solid State Electronics, University of Electronic Science and Technology of China, Chengdu 610054, China b Institute of Chemical Materials, China Academy of Engineering Physics, Mianyang 621900, China Received 5 May 2011 Available online 12 October 2011
Abstract Ring-opening suspension polymerization of p-dioxanone (PDO) in supercritical carbon dioxide (scCO2) was investigated in the presence of poly(caprolactone)–perfluropolyether–poly(caprolactone) (PCL–PFPE–PCL). The molecular weight, yield and particle morphology of poly( p-dioxanone) (PPDO) were studied. The stabilizer was effective to stabilize the ring-opening polymerization (ROP) of PDO in scCO2, leading to the formation of resorbable microparticles in a ‘‘one pot’’ procedure. The mean size of PPDO microparticles obtained from suspension polymerizations was sensitive to the rate of agitation and the stabilizer concentration. The method to generate PPDO microparticles has overcome its unprocessable drawback with common organic solvents and provided new product form for biomedical applications. # 2011 Jian Yuan Hao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Biodegradable; Poly( p-dioxanone); Polymerization; Stabilizer; Microparticle
Nowadays, particles of biodegradable polymers are used extensively in biomedical fields, especially in controlled drug delivery [1]. However, potentially toxic organic solvents are often required to process these polymers into particles. The use of scCO2 as an alternative replacement for traditional organic solvent has attracted many attentions in recent years to carry out chemical synthesis or materials processing [2]. This novel medium is an environmentally friendly alternative to organic solvents due to its inert, nontoxic, nonflammable nature and natural abundance [3]. Moreover, the availability of CO2 as a byproduct of many industrial processes, its possible recycling, and easily accessible critical parameters (Pc = 7.38 MPa/Tc = 31.1 8C) account for its steadily increased use [4]. Here we firstly demonstrate that scCO2 could be utilized as the solvent for the ring-opening polymerization of PDO in the presence of a well-defined fluorinated triblock copolymer stabilizer (Scheme 1). We then discuss how the stabilizer concentration and stirring rate affect the final morphology of PPDO in scCO2. 1. Experimental The stabilizer synthesis was adapted from that of Pilati et al. [5]. PFPE (7 g) was reacted in bulk with e-CL (6.2 mL, 1:6 PFPE:CL molar ratio) at 120 8C for 18 h using Sn(Oct)2 (0.16 g) as catalyst. The hydroxyl terminal functionalities * Corresponding author. E-mail address: [email protected] (J.Y. Hao). 1001-8417/$ – see front matter # 2011 Jian Yuan Hao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2011.07.011
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T.Q. Wang et al. / Chinese Chemical Letters 22 (2011) 1509–1512
O O
Sn(Oct)2 25 MPa, 70 ºC PCL-PFPE-PCL
O
HO
CCH2OCH2CH2O O
n
H
Scheme 1. Ring-opening polymerization of PDO in scCO2.
were found to initiate the ROP reaction and weaken its solubility in scCO2. Thus, these functionalities were endcapped with acetic anhydride before use to prevent the undesirable side reaction and improve its scCO2 solubility. Polymerization studies were conducted in a 100 mL stainless steel autoclave equipped with a magnetically driven overhead stirrer at 70 8C for 48 h at 25 MPa. Tin(II) ethyl hexanoate (Sn(Oct)2) was used as catalyst. After 48 h, the autoclave was cooled to room temperature and vented slowly. The products were purified by redispersed in deionized water and then dried in vacuum at 40 8C for 24 h. 2. Results and discussion The solubility of the stabilizer was examined at 70 8C and 25 MPa in scCO2, the stabilizer was observed to be soluble under these conditions, at least up to loadings of 0.005 g/mL. However, PDO was found to be insoluble under these conditions, as was Sn(Oct)2. The molecular weights and yields (determined gravimetrically) of the PPDO obtained can be found in Table 1. The yields for PPDO are lower than those reported for L-lactide (for example, about 90% at 80 8C). This indicates that the free energy change of polymerization for PDO is less negative than that for L-lactide. The polymers that we obtained had similar intrinsic viscosities, ranging from 0.33 to 0.40. These results reveal that low molecular weights were obtained, and this can be attributed to the presence of hydroxyl/water impurities contained in the reaction system and a carbonation reaction in scCO2 compared with in conventional solvent. In the absence of stabilizer, PPDO is obtained as a hard, white, aggregated solid block. This morphology is very similar to that obtained by conventional bulk polymerization at this temperature. The same procedure performed in the presence of 10 wt% of the end capped PCL–PFPE–PCL stabilizer leads to the formation of a fine, free flowing powder, after further being redispersed in water (sample 2, Table 1). SEM analysis reveals that the powder consists of irregularly shaped microparticles of PPDO (Fig. 1A). This is consistent with a powder suspension polymerization, in which the product polymer is gradually crystallized and phase-separated from the droplets. The mean size of sample 2 shown in Fig. 1A is 10 mm. The stabilizer remains effective down to 5 wt% loading (sample 5, Table 1), however, further decrease of loading gives rise to significant change in morphology. At the same stirrer rate, the particle size distribution of sample 5 shifts significantly to higher particle size as compared to sample 2, with the mean size of 22 mm (Fig. 2). At lower stabilizer concentrations, larger particle sizes are produced as the available stabilizer can Table 1 ROP of PDO in scCO2 in the presence of PCL–PFPE–PCL. Samplea
Stabilizerb (wt%)
Stirring rate (rpm)
[h]c (dl/g)
Mvd (103 g/mol)
Yielde (wt%)
Appearance
1 2 3 4 5 6
0 10 10 10 5 20
560 560 200 0 560 560
0.18 0.35 0.40 0.36 0.39 0.33
5.461 15.932 19.658 16.750 18.887 14.560
>80 75 78 >79 76 74
Aggregated Powder Powder Aggregated Powder Powder
a b c d e
PPDO synthesized at 70 8C, 4 g monomer loading, 0.16 g Sn(Oct)2 for 48 h. Amount of stabilizer added as % with respect to the mass of monomer. [h] was measured in phenol/1,1,2,2-tetrachloroethane (1:1, v/v) at 25 8C. Mv of PPDO was calculated according to the Mark–Houwink equation [h] = KMa (a = 0.63, K = 7.9 104 cm3/g) [6]. Yield determined gravimetrically, based on mass of polymer obtained after subtraction of the mass of stabilizer added.
T.Q. Wang et al. / Chinese Chemical Letters 22 (2011) 1509–1512
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Fig. 1. SEM images of PPDO synthesized in scCO2: (A) 10 wt% stabilizer, stirred at 560 rpm and (B) 10 wt% stabilizer, stirred at 200 rpm. The effect of stirring rate can clearly be seen in (A) and (B).
cover only a smaller surface area of droplets. When 20 wt% stabilizer was added (sample 6, Table 1), the particle size distribution shows two peaks, with mean size of 10 mm and 120 mm, respectively. The excess stabilizer which cannot dissolve in scCO2 and precipitated may weaken the overall effect of stabilization. In suspension polymerization, the morphology of the particles is known to be sensitive to the rate of stirring during the reaction [7]. The stirring rate is important in controlling formation of a fine, powdered product. And we have confirmed that in the absence of stirring, no particles are formed (sample 4, Table 1). Fig. 1 shows that at a lower stirring rate (200 rpm, sample 3, Table 1), there is a very distinct change in morphology compared with sample 2, demonstrating the expected inverse relationship between stirrer speed and particle size. This sample consists mainly of larger particles on the order of 30–40 mm (Fig. 1B). The particle size distributions of samples 2 and 3 also show that at 560 rpm with 10 wt% stabilizer the particles formed are smaller than those formed at 200 rpm. That indicates that at higher stirring speeds, smaller particles are formed as the monomer is dispersed into smaller droplets. Further experiments have demonstrated the reproducibility of this process. It is well known that to produce discrete particles via suspension polymerization, the samples must be resistant to the plasticizing effects of scCO2, and semi-crystalline polymers are less prone to plasticization than their amorphous
Fig. 2. Particle size distributions of particles obtained with (&) 10 wt% stabilizer, 560 rpm stirring; (*) 10 wt% stabilizer, 200 rpm stirring; (~) 5 wt% stabilizer, 560 rpm stirring; (!) 20 wt% stabilizer, 560 rpm stirring. It can be seen that particle size is inversely proportional to stabilizer concentration and stirring rate.
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counterparts [8]. PPDO is also semi-crystalline polymer, and during the polymerization process, the soft droplets gradually became solidified due to the crystallization effect, that leading to preservation of particulate morphology. So suspension polymerization of PPDO in scCO2 can succeed. Acknowledgments This work was supported by the National Natural Sciences Fund of China (No. 30970725) and the Fund of Science and Technology Development from China Academy of Engineering Physics (No. 2008A0302012). References [1] [2] [3] [4] [5] [6] [7] [8]
L.S. Nair, C.T. Laurencin, Adv. Biochem. Eng. Biotechnol. 102 (2006) 47. A.I. Cooper, J. Mater. Chem. 10 (2000) 207. K.A. Shaffer, J.M. DeSimone, Trends Polym. Sci. 3 (1995) 146. D.A. Canelas, J.M. DeSimone, Adv. Polym. Sci. 133 (1997) 103. F. Pilati, M. Toselli, M. Messori, Macromolecules 32 (1999) 6969. M.A. Sabino, J.L. Feijoo, A.J. Mu¨ller, Macromol. Chem. Phys. 201 (2000) 2687. H.G. Yuan, G. Kalfas, W.H. Ray, Rev. Macromol. Chem. Phys. C31 (2–3) (1991) 215. D.L. Tomasko, H. Li, D. Liu, Ind. Eng. Chem. Res. 42 (2003) 6431.
Chinese Chemical Letters 22 (2011) 1509–1512 www.elsevier.com/locate/cclet
In situ generation of biodegradable poly( p-dioxanone) microparticles by polymerization in supercritical carbon dioxide Tian Qiang Wang a, Xiu Li Zhao b, Jian Yuan Hao a,* a
State Key Lab of Electronic Films and Integrated Devices, School of Microelectronics and Solid State Electronics, University of Electronic Science and Technology of China, Chengdu 610054, China b Institute of Chemical Materials, China Academy of Engineering Physics, Mianyang 621900, China Received 5 May 2011 Available online 12 October 2011
Abstract Ring-opening suspension polymerization of p-dioxanone (PDO) in supercritical carbon dioxide (scCO2) was investigated in the presence of poly(caprolactone)–perfluropolyether–poly(caprolactone) (PCL–PFPE–PCL). The molecular weight, yield and particle morphology of poly( p-dioxanone) (PPDO) were studied. The stabilizer was effective to stabilize the ring-opening polymerization (ROP) of PDO in scCO2, leading to the formation of resorbable microparticles in a ‘‘one pot’’ procedure. The mean size of PPDO microparticles obtained from suspension polymerizations was sensitive to the rate of agitation and the stabilizer concentration. The method to generate PPDO microparticles has overcome its unprocessable drawback with common organic solvents and provided new product form for biomedical applications. # 2011 Jian Yuan Hao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Biodegradable; Poly( p-dioxanone); Polymerization; Stabilizer; Microparticle
Nowadays, particles of biodegradable polymers are used extensively in biomedical fields, especially in controlled drug delivery [1]. However, potentially toxic organic solvents are often required to process these polymers into particles. The use of scCO2 as an alternative replacement for traditional organic solvent has attracted many attentions in recent years to carry out chemical synthesis or materials processing [2]. This novel medium is an environmentally friendly alternative to organic solvents due to its inert, nontoxic, nonflammable nature and natural abundance [3]. Moreover, the availability of CO2 as a byproduct of many industrial processes, its possible recycling, and easily accessible critical parameters (Pc = 7.38 MPa/Tc = 31.1 8C) account for its steadily increased use [4]. Here we firstly demonstrate that scCO2 could be utilized as the solvent for the ring-opening polymerization of PDO in the presence of a well-defined fluorinated triblock copolymer stabilizer (Scheme 1). We then discuss how the stabilizer concentration and stirring rate affect the final morphology of PPDO in scCO2. 1. Experimental The stabilizer synthesis was adapted from that of Pilati et al. [5]. PFPE (7 g) was reacted in bulk with e-CL (6.2 mL, 1:6 PFPE:CL molar ratio) at 120 8C for 18 h using Sn(Oct)2 (0.16 g) as catalyst. The hydroxyl terminal functionalities * Corresponding author. E-mail address: [email protected] (J.Y. Hao). 1001-8417/$ – see front matter # 2011 Jian Yuan Hao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2011.07.011
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T.Q. Wang et al. / Chinese Chemical Letters 22 (2011) 1509–1512
O O
Sn(Oct)2 25 MPa, 70 ºC PCL-PFPE-PCL
O
HO
CCH2OCH2CH2O O
n
H
Scheme 1. Ring-opening polymerization of PDO in scCO2.
were found to initiate the ROP reaction and weaken its solubility in scCO2. Thus, these functionalities were endcapped with acetic anhydride before use to prevent the undesirable side reaction and improve its scCO2 solubility. Polymerization studies were conducted in a 100 mL stainless steel autoclave equipped with a magnetically driven overhead stirrer at 70 8C for 48 h at 25 MPa. Tin(II) ethyl hexanoate (Sn(Oct)2) was used as catalyst. After 48 h, the autoclave was cooled to room temperature and vented slowly. The products were purified by redispersed in deionized water and then dried in vacuum at 40 8C for 24 h. 2. Results and discussion The solubility of the stabilizer was examined at 70 8C and 25 MPa in scCO2, the stabilizer was observed to be soluble under these conditions, at least up to loadings of 0.005 g/mL. However, PDO was found to be insoluble under these conditions, as was Sn(Oct)2. The molecular weights and yields (determined gravimetrically) of the PPDO obtained can be found in Table 1. The yields for PPDO are lower than those reported for L-lactide (for example, about 90% at 80 8C). This indicates that the free energy change of polymerization for PDO is less negative than that for L-lactide. The polymers that we obtained had similar intrinsic viscosities, ranging from 0.33 to 0.40. These results reveal that low molecular weights were obtained, and this can be attributed to the presence of hydroxyl/water impurities contained in the reaction system and a carbonation reaction in scCO2 compared with in conventional solvent. In the absence of stabilizer, PPDO is obtained as a hard, white, aggregated solid block. This morphology is very similar to that obtained by conventional bulk polymerization at this temperature. The same procedure performed in the presence of 10 wt% of the end capped PCL–PFPE–PCL stabilizer leads to the formation of a fine, free flowing powder, after further being redispersed in water (sample 2, Table 1). SEM analysis reveals that the powder consists of irregularly shaped microparticles of PPDO (Fig. 1A). This is consistent with a powder suspension polymerization, in which the product polymer is gradually crystallized and phase-separated from the droplets. The mean size of sample 2 shown in Fig. 1A is 10 mm. The stabilizer remains effective down to 5 wt% loading (sample 5, Table 1), however, further decrease of loading gives rise to significant change in morphology. At the same stirrer rate, the particle size distribution of sample 5 shifts significantly to higher particle size as compared to sample 2, with the mean size of 22 mm (Fig. 2). At lower stabilizer concentrations, larger particle sizes are produced as the available stabilizer can Table 1 ROP of PDO in scCO2 in the presence of PCL–PFPE–PCL. Samplea
Stabilizerb (wt%)
Stirring rate (rpm)
[h]c (dl/g)
Mvd (103 g/mol)
Yielde (wt%)
Appearance
1 2 3 4 5 6
0 10 10 10 5 20
560 560 200 0 560 560
0.18 0.35 0.40 0.36 0.39 0.33
5.461 15.932 19.658 16.750 18.887 14.560
>80 75 78 >79 76 74
Aggregated Powder Powder Aggregated Powder Powder
a b c d e
PPDO synthesized at 70 8C, 4 g monomer loading, 0.16 g Sn(Oct)2 for 48 h. Amount of stabilizer added as % with respect to the mass of monomer. [h] was measured in phenol/1,1,2,2-tetrachloroethane (1:1, v/v) at 25 8C. Mv of PPDO was calculated according to the Mark–Houwink equation [h] = KMa (a = 0.63, K = 7.9 104 cm3/g) [6]. Yield determined gravimetrically, based on mass of polymer obtained after subtraction of the mass of stabilizer added.
T.Q. Wang et al. / Chinese Chemical Letters 22 (2011) 1509–1512
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Fig. 1. SEM images of PPDO synthesized in scCO2: (A) 10 wt% stabilizer, stirred at 560 rpm and (B) 10 wt% stabilizer, stirred at 200 rpm. The effect of stirring rate can clearly be seen in (A) and (B).
cover only a smaller surface area of droplets. When 20 wt% stabilizer was added (sample 6, Table 1), the particle size distribution shows two peaks, with mean size of 10 mm and 120 mm, respectively. The excess stabilizer which cannot dissolve in scCO2 and precipitated may weaken the overall effect of stabilization. In suspension polymerization, the morphology of the particles is known to be sensitive to the rate of stirring during the reaction [7]. The stirring rate is important in controlling formation of a fine, powdered product. And we have confirmed that in the absence of stirring, no particles are formed (sample 4, Table 1). Fig. 1 shows that at a lower stirring rate (200 rpm, sample 3, Table 1), there is a very distinct change in morphology compared with sample 2, demonstrating the expected inverse relationship between stirrer speed and particle size. This sample consists mainly of larger particles on the order of 30–40 mm (Fig. 1B). The particle size distributions of samples 2 and 3 also show that at 560 rpm with 10 wt% stabilizer the particles formed are smaller than those formed at 200 rpm. That indicates that at higher stirring speeds, smaller particles are formed as the monomer is dispersed into smaller droplets. Further experiments have demonstrated the reproducibility of this process. It is well known that to produce discrete particles via suspension polymerization, the samples must be resistant to the plasticizing effects of scCO2, and semi-crystalline polymers are less prone to plasticization than their amorphous
Fig. 2. Particle size distributions of particles obtained with (&) 10 wt% stabilizer, 560 rpm stirring; (*) 10 wt% stabilizer, 200 rpm stirring; (~) 5 wt% stabilizer, 560 rpm stirring; (!) 20 wt% stabilizer, 560 rpm stirring. It can be seen that particle size is inversely proportional to stabilizer concentration and stirring rate.
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counterparts [8]. PPDO is also semi-crystalline polymer, and during the polymerization process, the soft droplets gradually became solidified due to the crystallization effect, that leading to preservation of particulate morphology. So suspension polymerization of PPDO in scCO2 can succeed. Acknowledgments This work was supported by the National Natural Sciences Fund of China (No. 30970725) and the Fund of Science and Technology Development from China Academy of Engineering Physics (No. 2008A0302012). References [1] [2] [3] [4] [5] [6] [7] [8]
L.S. Nair, C.T. Laurencin, Adv. Biochem. Eng. Biotechnol. 102 (2006) 47. A.I. Cooper, J. Mater. Chem. 10 (2000) 207. K.A. Shaffer, J.M. DeSimone, Trends Polym. Sci. 3 (1995) 146. D.A. Canelas, J.M. DeSimone, Adv. Polym. Sci. 133 (1997) 103. F. Pilati, M. Toselli, M. Messori, Macromolecules 32 (1999) 6969. M.A. Sabino, J.L. Feijoo, A.J. Mu¨ller, Macromol. Chem. Phys. 201 (2000) 2687. H.G. Yuan, G. Kalfas, W.H. Ray, Rev. Macromol. Chem. Phys. C31 (2–3) (1991) 215. D.L. Tomasko, H. Li, D. Liu, Ind. Eng. Chem. Res. 42 (2003) 6431.