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Synthesis and characterization of biodegradable polymer: Poly (ethene maleic acid ester-co-d ,l -lactide acid)
Chinese Chemical Letters 18 (2007) 605–608 www.elsevier.com/locate/cclet
Synthesis and characterization of biodegradable polymer: Poly (ethene maleic acid ester-co-D,L-lactide acid) Mei Na Huang, Yan Feng Luo, Jia Chen, Yong Gang Li, Chun Hua Fu, Yuan Liang Wang * Research Center of Bioinspired Material Science and Engineering (BIMSEC), Bioengineering College of Chongqing University, Chongqing 400044, China Received 30 October 2006
Abstract A novel biodegradable polymer—poly (ethene maleic acid ester-co-D,L-lactide acid) was synthesized by copolymerizing lactide and prepolymer, which was prepared by the condensation of maleic anhydride and glycol, using p-toluene sulphonic acid as a catalyst, attempting to improve the hydrophilicity, increase flexibility and modulate the degradation rate. FTIR, 1H NMR, MALLS and DSC were employed to characterize these polymers. # 2007 Yuan Liang Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Maleic anhydride; Glycol; Lactide; Copolymerization
Weak hydrophilicity, shortage of flexibility and uncontrollable degradation rate of poly (D,L-lactic acid) are major drawbacks that restrict its applications in drug controlled release [1–4]. Chemical modifications are often used to overcome these drawbacks and some good results were obtained [5–9]. In this study, a novel D,L-lactic acid-based biodegradable polymer was successfully synthesized by copolymerization modification. The copolymer, which comprises flexible glycol and ring-opened maleic anhydride, overcomes the weak hydrophilicity and increases the flexibility of polymer. At the same time, the double bond of the maleic anhydride could provide highly reactive group for the further linking reaction. 1. Experimental The synthetic route of poly (ethene maleic acid ester-co-D,L-lactide acid) (PEMLA) is shown in Scheme 1. The prepolymer (PEMA) was firstly prepared as follows: 9.8 g maleic anhydride and 6.51 g glycol were dissolved in 50 mL toluene, followed by addition of 0.05 g p-toluene sulphonic acid. The reaction was allowed to last for 24 h in vacuum at 100 8C. After reaction, ethylether was added to the prepolymer for dissolving the unreacted maleic anhydride. The prepolymer was characterized via FTIR and 1H NMR. Its number–average molecular weight was titrated by KOH–ethanol solution (0.5 mol/L). * Corresponding author. E-mail address: [email protected] (Y.L. Wang). 1001-8417/$ – see front matter # 2007 Yuan Liang Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2007.03.007
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Scheme 1. Synthesis of the prepolymer and copolymer.
1.5 g prepolymer was mixed with 10 g lactide in a three-necked flask, then Sn(Oct)2 (1/7000, 1/5000, 1/3000 of the prepolymer in mol) was added to the mixture, respectively. The reaction was allowed to last for 48 h at 160 8C in vacuum, and then 30 mL THF was added, the reaction mixture was precipitated with excessive distilled water to yield copolymer (PEMLA). The product was dried in vacuum. FTIR, 1H NMR, MALLS and DSC were employed to characterize these copolymers. FTIR were obtained on a Nicolet Magna 560 FTIR. Spectrophotometer and Nicolet data station with software at the resolution of 2 cm 1 in the region of 4000–400 cm 1. 1H NMR were measured on NMR instrument using CDCl3 as solvent. The Mw and Mw/Mn were determined on a GPC-MALLS with RI detector at 25 8C. THF was used as solvent at a flow rate of 1.0 mL/min. Glass transition of the copolymer was measured by DSC under nitrogen at heating rate of 10 8C min 1. The flexibility was charactered by the water absorption. 2. Results and discussion The FTIR spectra are shown in Fig. 1. Comparing the FTIR spectra of prepolymer with that of glycol and maleic anhydride, two characteristic absorption bands at 1755.07 and 1647.76 cm 1 in Fig. 1c are attributed to the C–O stretching vibration of ester groups and the C C stretching vibration, respectively. And the characteristic double-peak of anhydride groups in maleic anhydride disappeared in the prepolymer. These indicated that maleic anhydride has successfully reacted with glycol. Then the characteristic peak of CH (2994, 2944 cm 1) and CH3 (1455 cm 1) of lactide in Fig. 1d indicated that the copolymer was obtained successfully. The 1H NMR spectrum was shown in Fig. 2. The peak at d 6.0–7.0 ppm (Fig. 2A) was attributed to the proton of –CH CH–, the peak at d 3.8, 4.4 ppm (b and c) were due to the proton of –CH2– from glycol next to
Fig. 1. FTIR spectra of glycol (a), maleic anhydride (b), prepolymer (c), and the PEMLA (d).
M.N. Huang et al. / Chinese Chemical Letters 18 (2007) 605–608
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Fig. 2. 1H NMR spectra of the prepolymer (A) and PEMLA-1 (B).
Table 1 The number–average molecular weights of the prepolymer and the copolymers
Mw Mw/Mn
Prepolymer
PEMLA-1 (1/7000)
PEMLA-2 (1/5000)
PEMLA-3 (1/3000)
1555 –
26,812 1.386
24,832 1.234
22,864 1.372
the –OH and the–OC O group, respectively. Comparing the 1H NMR spectrum of the prepolymer (Fig. 2A) with the copolymer (Fig. 2B), two new characteristic peaks (d 5.0–6.0 ppm (d) and d 1.0–2.0 ppm (e)) were found in Fig. 2B, which were assigned to the proton of –CH– and –CH3– from lactide. This confirms that prepolymer has copolymerized with lactide. Additionally, based on the integral data of the characteristic peak (4Ia/2(Ib + Ic) = 0.71) in Fig. 2A and ((Ia/2Id)/0.126 = 0.85, 0.126 is the theoretical ratio of the prepolymer to LA) Fig. 2B, the reaction degrees of the two reactions can be calculated as 70% and 85%, respectively. The results of GPC (Table 1) demonstrated that the molecular weights of the three copolymers were 25,000–30,000. In the GPC no homopolymer of lactide and prepolymer could be observed. The water absorption of PEMLA-1, PEMLA-2 and PEMLA-3 were 29.1%, 29.6%, 30.2%, respectively, and the Tg of the PEMLA was about 41.7 8C, which indicated that comparing with PDLLA (Mw = 24341) (water absorption 21%, Tg 56.5 8C), the hydrophilicity and flexibility of PEMLA were increased. These physical properties demonstrated that the PEMLA can be developed to a new kind of controlled released materials.
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M.N. Huang et al. / Chinese Chemical Letters 18 (2007) 605–608
3. Conclusion This new polymer increased the hydrophilicity and the flexibility. At the same time, it also offers an approach to control the degradation velocity of the copolymer for the controlled drug delivery, by modulating the compositions and the ratio of the maleic anhydride, glycol, lactide. The double bond of the maleic anhydride could provide highly reactive group for the further linking reaction, by which, the polymer with interconnected structure between copolymers can be synthesized. Acknowledgment This study was supported by the National Natural Scientific Foundation of China (No. 30470474). References [1] [2] [3] [4] [5] [6] [7] [8] [9]
Y.T. Yu, X.D. Zhang, Shengwu Yiyong Cailiao (Biomedical Materials, in Chinese), 1st ed., Tianjin University Press, Tianjin, 2000, p. 54. Y.L. Wang, Y.P. Wu, S.X. Cai, Gaojishu Tongxun (High Technol. Lett. in Chinese) 7 (5) (1997) 59. Y.F. Luo, Y.L. Wang, X.F. Niu, et al. Chin. Chem. Lett. 15 (5) (2004) 521. X.F. Niu, Y.L. Wang, Y.F. Luo, et al. Chin. Chem. Lett. 16 (8) (2004) 1035. R.A. Quirk, W.C. Chan, M.C. Davies, et al. Biomaterials 22 (8) (2001) 865. J. Zhao, D.B. Guan, Chem. Chin. Univ. 26 (8) (2005) 1570. C.Y. Won, C.C. Chu, Polymers 39 (25) (1998) 6677. B.H. Luo, D.P. Quan, K.R. Liao, et al. Acta Polym. Sinica 3 (2005) 327. P.J. Shi, Y.G. Li, C.Y. Pan, Eur. Polym. J. 40 (2004) 1283.
Synthesis and characterization of biodegradable polymer: Poly (ethene maleic acid ester-co-D,L-lactide acid) Mei Na Huang, Yan Feng Luo, Jia Chen, Yong Gang Li, Chun Hua Fu, Yuan Liang Wang * Research Center of Bioinspired Material Science and Engineering (BIMSEC), Bioengineering College of Chongqing University, Chongqing 400044, China Received 30 October 2006
Abstract A novel biodegradable polymer—poly (ethene maleic acid ester-co-D,L-lactide acid) was synthesized by copolymerizing lactide and prepolymer, which was prepared by the condensation of maleic anhydride and glycol, using p-toluene sulphonic acid as a catalyst, attempting to improve the hydrophilicity, increase flexibility and modulate the degradation rate. FTIR, 1H NMR, MALLS and DSC were employed to characterize these polymers. # 2007 Yuan Liang Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Maleic anhydride; Glycol; Lactide; Copolymerization
Weak hydrophilicity, shortage of flexibility and uncontrollable degradation rate of poly (D,L-lactic acid) are major drawbacks that restrict its applications in drug controlled release [1–4]. Chemical modifications are often used to overcome these drawbacks and some good results were obtained [5–9]. In this study, a novel D,L-lactic acid-based biodegradable polymer was successfully synthesized by copolymerization modification. The copolymer, which comprises flexible glycol and ring-opened maleic anhydride, overcomes the weak hydrophilicity and increases the flexibility of polymer. At the same time, the double bond of the maleic anhydride could provide highly reactive group for the further linking reaction. 1. Experimental The synthetic route of poly (ethene maleic acid ester-co-D,L-lactide acid) (PEMLA) is shown in Scheme 1. The prepolymer (PEMA) was firstly prepared as follows: 9.8 g maleic anhydride and 6.51 g glycol were dissolved in 50 mL toluene, followed by addition of 0.05 g p-toluene sulphonic acid. The reaction was allowed to last for 24 h in vacuum at 100 8C. After reaction, ethylether was added to the prepolymer for dissolving the unreacted maleic anhydride. The prepolymer was characterized via FTIR and 1H NMR. Its number–average molecular weight was titrated by KOH–ethanol solution (0.5 mol/L). * Corresponding author. E-mail address: [email protected] (Y.L. Wang). 1001-8417/$ – see front matter # 2007 Yuan Liang Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2007.03.007
606
M.N. Huang et al. / Chinese Chemical Letters 18 (2007) 605–608
Scheme 1. Synthesis of the prepolymer and copolymer.
1.5 g prepolymer was mixed with 10 g lactide in a three-necked flask, then Sn(Oct)2 (1/7000, 1/5000, 1/3000 of the prepolymer in mol) was added to the mixture, respectively. The reaction was allowed to last for 48 h at 160 8C in vacuum, and then 30 mL THF was added, the reaction mixture was precipitated with excessive distilled water to yield copolymer (PEMLA). The product was dried in vacuum. FTIR, 1H NMR, MALLS and DSC were employed to characterize these copolymers. FTIR were obtained on a Nicolet Magna 560 FTIR. Spectrophotometer and Nicolet data station with software at the resolution of 2 cm 1 in the region of 4000–400 cm 1. 1H NMR were measured on NMR instrument using CDCl3 as solvent. The Mw and Mw/Mn were determined on a GPC-MALLS with RI detector at 25 8C. THF was used as solvent at a flow rate of 1.0 mL/min. Glass transition of the copolymer was measured by DSC under nitrogen at heating rate of 10 8C min 1. The flexibility was charactered by the water absorption. 2. Results and discussion The FTIR spectra are shown in Fig. 1. Comparing the FTIR spectra of prepolymer with that of glycol and maleic anhydride, two characteristic absorption bands at 1755.07 and 1647.76 cm 1 in Fig. 1c are attributed to the C–O stretching vibration of ester groups and the C C stretching vibration, respectively. And the characteristic double-peak of anhydride groups in maleic anhydride disappeared in the prepolymer. These indicated that maleic anhydride has successfully reacted with glycol. Then the characteristic peak of CH (2994, 2944 cm 1) and CH3 (1455 cm 1) of lactide in Fig. 1d indicated that the copolymer was obtained successfully. The 1H NMR spectrum was shown in Fig. 2. The peak at d 6.0–7.0 ppm (Fig. 2A) was attributed to the proton of –CH CH–, the peak at d 3.8, 4.4 ppm (b and c) were due to the proton of –CH2– from glycol next to
Fig. 1. FTIR spectra of glycol (a), maleic anhydride (b), prepolymer (c), and the PEMLA (d).
M.N. Huang et al. / Chinese Chemical Letters 18 (2007) 605–608
607
Fig. 2. 1H NMR spectra of the prepolymer (A) and PEMLA-1 (B).
Table 1 The number–average molecular weights of the prepolymer and the copolymers
Mw Mw/Mn
Prepolymer
PEMLA-1 (1/7000)
PEMLA-2 (1/5000)
PEMLA-3 (1/3000)
1555 –
26,812 1.386
24,832 1.234
22,864 1.372
the –OH and the–OC O group, respectively. Comparing the 1H NMR spectrum of the prepolymer (Fig. 2A) with the copolymer (Fig. 2B), two new characteristic peaks (d 5.0–6.0 ppm (d) and d 1.0–2.0 ppm (e)) were found in Fig. 2B, which were assigned to the proton of –CH– and –CH3– from lactide. This confirms that prepolymer has copolymerized with lactide. Additionally, based on the integral data of the characteristic peak (4Ia/2(Ib + Ic) = 0.71) in Fig. 2A and ((Ia/2Id)/0.126 = 0.85, 0.126 is the theoretical ratio of the prepolymer to LA) Fig. 2B, the reaction degrees of the two reactions can be calculated as 70% and 85%, respectively. The results of GPC (Table 1) demonstrated that the molecular weights of the three copolymers were 25,000–30,000. In the GPC no homopolymer of lactide and prepolymer could be observed. The water absorption of PEMLA-1, PEMLA-2 and PEMLA-3 were 29.1%, 29.6%, 30.2%, respectively, and the Tg of the PEMLA was about 41.7 8C, which indicated that comparing with PDLLA (Mw = 24341) (water absorption 21%, Tg 56.5 8C), the hydrophilicity and flexibility of PEMLA were increased. These physical properties demonstrated that the PEMLA can be developed to a new kind of controlled released materials.
608
M.N. Huang et al. / Chinese Chemical Letters 18 (2007) 605–608
3. Conclusion This new polymer increased the hydrophilicity and the flexibility. At the same time, it also offers an approach to control the degradation velocity of the copolymer for the controlled drug delivery, by modulating the compositions and the ratio of the maleic anhydride, glycol, lactide. The double bond of the maleic anhydride could provide highly reactive group for the further linking reaction, by which, the polymer with interconnected structure between copolymers can be synthesized. Acknowledgment This study was supported by the National Natural Scientific Foundation of China (No. 30470474). References [1] [2] [3] [4] [5] [6] [7] [8] [9]
Y.T. Yu, X.D. Zhang, Shengwu Yiyong Cailiao (Biomedical Materials, in Chinese), 1st ed., Tianjin University Press, Tianjin, 2000, p. 54. Y.L. Wang, Y.P. Wu, S.X. Cai, Gaojishu Tongxun (High Technol. Lett. in Chinese) 7 (5) (1997) 59. Y.F. Luo, Y.L. Wang, X.F. Niu, et al. Chin. Chem. Lett. 15 (5) (2004) 521. X.F. Niu, Y.L. Wang, Y.F. Luo, et al. Chin. Chem. Lett. 16 (8) (2004) 1035. R.A. Quirk, W.C. Chan, M.C. Davies, et al. Biomaterials 22 (8) (2001) 865. J. Zhao, D.B. Guan, Chem. Chin. Univ. 26 (8) (2005) 1570. C.Y. Won, C.C. Chu, Polymers 39 (25) (1998) 6677. B.H. Luo, D.P. Quan, K.R. Liao, et al. Acta Polym. Sinica 3 (2005) 327. P.J. Shi, Y.G. Li, C.Y. Pan, Eur. Polym. J. 40 (2004) 1283.