Biomacromolecules 2005, 6, 483-488
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Structure-Property Relationships of Copolymers Obtained by Ring-Opening Polymerization of Glycolide and E-Caprolactone. Part 1. Synthesis and Characterization Piotr Dobrzynski,*,† Suming Li,*,‡ Janusz Kasperczyk,† Maciej Bero,† Francis Gasc,‡ and Michel Vert‡ Centre of Polymer Chemistry, Polish Academy of Sciences, 34 Sklodowska Curie st. 41-808 Zabrze, Poland, and Centre de Recherche sur les Biopolymeres Artificiels, Faculte de Pharmacie, 15 avenue Charles Flahault, BP 14 491, 34093 Montpellier Cedex 05, France Received September 3, 2004
A series of copolymers with various compositions were synthesized by bulk ring-opening polymerization of glycolide and -caprolactone, using stannous (II) octoate or zirconium (IV) acetylacetonate as initiator. Reaction time and temperature were varied so as to induce different chain microstructures. The resulting copolymers were characterized by 1H NMR, SEC, DSC, and X-ray diffraction. The average lengths of glycolyl (LG) and caproyl sequences (LC) and the degree of randomness (R) were calculated and compared to the values of completely random chains. The concentration of CGC sequences was also obtained which resulted from transesterification reactions. Data showed that stannous (II) octoate leads to less transesterification than zirconium (IV) acetylacetonate, and lower temperatures lead to less transesterification than higher ones. The copolymers exhibited a more or less blocky chain structure because of the reactivity difference between glycolide and -caprolactone. The crystalline structure and thermal properties depend on both the composition and the chain microstructure. PGA- and PCL-type crystallites were obtained for copolymers with intermediate compositions. Introduction Biodegradable polymers have been extensively investigated for temporary therapeutic applications such as surgical sutures, bone fracture internal fixation devices, drug delivery systems, as well as tissue engineering scaffolds.1-3 Recently, these materials also attracted much attention in the field of environmental protection as one of the potential solutions to the problem of plastic waste management.4-6 Two main categories of biodegradable polymers can be distinguished: (1) biopolymers produced by plants, animals and microorganisms such as cellulose, starch, chitin and polyhydroxyalkanoates; (2) synthetic polymers such as polylactide (PLA), poly(-caprolactone) (PCL), polyglycolide (PGA), etc. In the family of biodegradable synthetic polymers, PCL appears most attractive because of its excellent thermal properties and permeability to drugs. In fact, the high decomposition temperature (Td = 350 °C) and low melting temperature (Tm = 65 °C) provide a large processing range. PCL can be degraded hydrolytically in a humid environment although this degradation is very slow.7,8 It can also be degraded in the presence of microorganisms or lipase-type enzymes.9-11 On the other hand, PGA is a fast degrading polymer which is mainly used as suture material due to its high crystallinity and absence of practical solvents. A number * To whom correspondence should be addressed. (P.D.) Tel: +48 32 2716077. E-mail:
[email protected]. (S.L.) Tel: +33 467 418266. E-mail:
[email protected]. † Polish Academy of Sciences. ‡ Centre de Recherche sur les Biopolymeres Artificiels.
of products prepared from PLA, PGA, PCL, and various copolymers have reached the stage of clinical uses such as Dexon, Vicryl, Maxon, and Monocryl sutures, Lactomer and Absolok clips and staples, Biofix and Phusiline plates and screws, as well as Decapeptyl, Lupron Depot, Zoladex, Adriamycin, and Capronordrug delivery devices.1 High molar mass PCL, PGA, and PCL/PGA copolymers are synthesized by ring-opening polymerization of corresponding cyclic lactones, i.e., -caprolactone and/or glycolide, in the presence of an initiator such as stannous (II) octoate (Sn(Oct)2), zirconium (IV) acetylacetonate (Zr(Acac)4), iron chloride (FeCl3), etc.12-16 At present, only a block copolymer known as Monocryl is produced in large scale by a two-stage polymerization with stannous octoate as initiator. This copolymer is used in the form of sutures for wound dressing and connecting blood vessels and organs. The aim of the present work was to investigate the structure-property relationships of copolymers obtained by ring-opening polymerization of glycolide and -caprolactone. The first part deals with the synthesis and characterization. Copolymers with various compositions were synthesized under various polymerization conditions by varying reaction time and temperature. Stannous (II) octoate and zirconium (IV) acetylacetonate were used as initiator. The effects of polymerization parameters on the chain microstructures and physicochemical properties were investigated, which is of major importance for the understanding of degradation behaviors of the copolymers as will be shown in the second part.
10.1021/bm0494592 CCC: $30.25 © 2005 American Chemical Society Published on Web 11/23/2004
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Table 1. Characterization of the Obtained PGA/PCL Copolymers sample
reaction conditions
initiator
GG/Ca molar ratio
Cop1 Cop2 Cop3 Cop4
48 h, 150°C 48 h, 100°C 48 h, 150°C 1 h, 110°C 47 h,150°C 48 h, 100°C 48 h, 150°C 36 h, 100°C 36 h, 100°C 36 h, 150°C
Zr(Acac)4 Zr(Acac)4 Zr(Acac)4 Sn(Oct)2
70/30 48/52 47/53 28/72
Zr(Acac)4 Zr(Acac)4 Sn(Oct)2 Zr(Acac)4 Zr(Acac)4
29/71 29/71 9/91 9/91 8/92
Cop5 Cop6 Cop7 Cop8 Cop9
LCc
LRGd
LRCe
Rf
Sg (%)
Mh (%)
Li (%)
[η]j (dL/g)
TIIk
5.8 7.0 2.6 3.3
1.2 3.7 1.4 4.2
5.85 2.9 2.8 1.8
1.2 1.5 1.6 2.3
1.0 0.41 1.11 0.55
8 (2.5) 5 (8.0) 15 (8.3) 6 (13.8)
21 18 23 10
53 42 26 28
1.5 1.6 1.3 1.6
3.20 0.63 1.81 0.43
2.0 1.6 ∼1.0 ∼1.0 ∼1.0
2.5 2.1 5.2 4.8 4.6
1.8 1.8 1.2 1.2 1.2
2.2 2.2 5.9 5.9 6.7
0.89 1.05 1.13 1.23 1.45
16 (13.6) 20 (13.6) 11 (11.7) 13 (11.7) 12 (10.9)
8 21 4 3 3
21 4 2 1 0
1.8 1.1 1.4 1.5 1.4
1.18 1.47 0.94 1.11 1.10
LG b
a GG/C - molar ratio determined by 1H NMR. b L , average length of glycolyl sequences. c L , average length of caproyl sequences. d LR , average G C G length of glycolyl sequences in completely random chains. e LRC, average length of caproyl sequences in completely random chains. f R, degree of randomness. g S, concentration of CGC sequence (signal 7 on the 1H NMR spectra), in brackets is the calculated concentration of CGC sequence in completely random chains. h M, concentration of CGGGC (signal 3), GGGGC (signal 4), CGGGG + CGGGC (signal 5) and CGGC (signal 6) sequences. i L, concentration of GGGGGG (signal 1) and CGGGG+GGGGC (signal 2) sequences. j [η], inherent viscosity. k T , transesterification coefficient of the II second mode.
Experimental Section Materials. Glycolide was purchased from Purac, and purified by recrystallization from dry ethyl acetate. -Caprolactone was supplied by Fluka. It was dried and distilled under argon before use. Zr(Acac)4 and Sn(Oct)2 (Aldrich Corp.) were used as received. Copolymerization Procedure. Poly(glycolide-co--caprolactone), abbreviated as PGA/PCL in this paper, was synthesized by bulk ring-opening copolymerization of glycolide with -caprolactone according to the procedure described earlier.15,16 Zr(Acac)4 or Sn(Oct)2 was used as initiator with an I/M molar ratio of 1/800. Polymerization was performed under argon atmosphere at high temperature (100-150 °C) for predetermined periods of time. The obtained copolymers were ground, washed with methyl alcohol to remove unreacted traces of monomers, and then vacuum-dried at 50 °C up to constant weight. Measurements. Proton nuclear magnetic resonance (1H NMR) spectra were recorded with a Varian Unity Inowa spectrometer operating at 300 MHz, using dried dimethyl sulfoxide-d6 as solvent. Chemical shifts (δ) were given in ppm using tetramethylsilane (TMS) as an internal reference. The spectra were obtained at 80 °C with 32 scans and a 3.74 s acquisition time. The viscosity of the obtained copolymers was determined in 1,1,1,3,3,3-hexafluoro 2-propanol at 25 °C with a Ubbelhode viscometer. The concentration of the solutions was 2 mg/mL. Size-exclusion chromatography (SEC) measurements were performed for the copolymers soluble in chloroform with a Physics SP 8800 chromatograph apparatus equipped with a Shoedex SE 61 detector. Chloroform was used as the mobile phase at a flow rate of 1.0 mL/min. The Styragel columns were calibrated with polystyrene standards (Polysciences, USA). Differential scanning calorimetry (DSC) was performed with a Perkin-Elmer DSC 6 instrument, with a heating rate of 10 °C/min. X-ray diffraction spectra were registered with a Philips diffractometer composed of a Cu KR (λ ) 0.154 nm) source, a quartz monochromator and a goniometric plate.
Scheme 1. Structure of Glycolide/Caprolactone Copolymers
Results and Discussion PGA/PCL copolymers were synthesized by ring opening polymerization of glycolide and -caprolactone, in the presence of Zr(Acac)4 or Sn(Oct)2. Various reaction conditions were used for obtaining different chain microstructures. Table 1 presents the molecular characteristics of the various copolymers. The glycolide/caprolactone ratio (GG/C) (Scheme 1) in the feeds ranged from 70/30 to 10/90, and the GG/C ratio in the copolymers was obtained from the methylene integrations of glycolidyl units (-OCH2COOCH2CO-) and caproyl units (-OCH2CH2CH2CH2CH2CO-) on the NMR spectra. A good agreement was obtained between the initial and final ratios. In fact, nearly 100% conversion of caprolactone were obtained for all of the reactions, whereas the contents of glycolidyl units were slightly lower than theoretical data due to sublimation. The inherent viscosity of the copolymers is in the range of 1.1-1.8, indicating that high molar mass polymers are obtained. The copolymer composition, chain microstructure and transesterification were determined with 1H NMR spectroscopy as described previously.17 Two types of transesterification reactions were introduced, i.e., the first and second modes.18,19 Glycolidyl sequences (GG) undergo bond cleavage, which leads to the formation of -CGC- and -CGGGC- sequences, both with an odd number of glycolyl (G) units. This phenomenon is named second mode transesterification with the coefficient defined as follows: TII ) [CGC]/[CGC]R
(1)
where [CGC] is the experimental concentration of the CGC sequence from NMR spectra and [CGC]R is the calculated concentration for completely random chains: [CGC]R ) k2/(k + 1)3 where k ) [C]/[G].
(2)
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Polymerization of PGA and PCL. Part 1
Figure 1. 1H NMR spectra of the copolymers containing ca. 50% of glycolide: (A) Cop2 obtained at 100 °C, with Zr(Acac)4; (B) Cop3 obtained at 150 °C, with Zr(Acac)4.
The experimental average lengths of caproyl and glycolyl blocks are calculated according to the following equations: LC ) ([CC] + [GC])/[GC]
(3)
LG ) LC/k
(4)
The lengths of caproyl and glycolyl blocks in completely random chains can be calculated from the following equations: LRC ) k + 1
(5)
LRG ) (k + 1)/k
(6)
Consequently, the degree of randomness (R) of the copolymer chains can be calculated from eq 7 R ) LRG/LG ) LRC/LC
(7)
The coefficient R is equal to 1 for completely random chains and to 0 for diblock copolymers. Values above 1 indicate increased concentration of alternating sequences, i.e., CGC sequences. Small differences were observed in the chain structures of the copolymers with high concentrations of glycolyl units (GG/C molar ratio of ca. 70/30), although different initiators or reaction conditions were employed (data not shown). The sample Cop1 obtained with zirconium initiator, as shown in Table 1, is completely random with R equal to 1. Relatively long glycolyl sequences and very short caproyl ones are obtained. This is a typical microstructure of the copolymers with high glycolyl concentrations. With higher caproyl contents, the copolymers exhibited more differences in their chain microstructures. Figure 1 shows the 1H NMR spectra of Cop2 and Cop3 containing about 50% of glycolidyl units in copolymer chains which
Figure 2. 1H NMR spectra of the copolymers containing c.a. 30% of glycolide: (A) Cop4 obtained at 110° and 150 °C, with Sn(oct.)2; (B) Cop5 obtained at 100 °C, with Zr(Acac)4; (C) Cop6 obtained at 150 °C, with Zr(Acac)4.
were obtained at 100 or 150 °C using Zr(Acac)4 as initiator. A lower reaction temperature (100 °C) limited transesterification reactions, leading to a decrease of CGC concentration, TII and R values and an increase of the average length of glycolyl blocks (Table 1, Figure 1A). Increase of the reaction temperature to 150 °C significantly changed the copolymer microstructure (Table 1, Figure 1b). As a result of more transesterification reactions, a dramatic decrease of glycolyl block length and an increase of CGC sequence concentration were observed. These findings are confirmed by the decrease of the sequence lengths (LG and LC) and the increase of the degree of randomness. In the case of the copolymers containing about 30% of glycolidyl units in copolymer chains (Table 1, Cop4, Cop5, and Cop6), three different chain microstructures were observed as shown in Figure 2. The synthesis of Cop4 with stannous octoate as initiator was carried out in two stages, first at 110 °C for 1 h and then at 150 °C for 47 h, with the aim of obtaining a more blocky structure. After the first stage, when the total conversion was about 40%, the copolymer contained up to 80% of glycolidyl units with very long glycolyl block length (LG ) 21) and short caproyl one (LC ) 2.5). After the second stage, LG decreased to 3.3. Nevertheless, transesterification reactions appeared rather limited according to the low R and TII values and low concentration of CGC sequences in comparison with calculated values for random chains (Table
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Figure 4. DSC thermograms of PGA/PCL copolymers: Cop1, Cop2, Cop5, and Cop7 (a. 1st heating, and b. 2nd heating).
Figure 3. X-ray diffraction spectra of the PGA/PCL copolymers: (A) Cop1, Cop2, and Cop3; (B) Cop4, Cop5, and Cop6; (C) Cop7, Cop8, and Cop9.
1, Figure 2a). It seems that when the average length of glycolyl blocks is long enough, the transesterification process is probably restrained because the active center of the growing chains preferentially attacks the units located near the glycolyl sequence ends, as previously observed for the synthesis of PGA/PLA/PCL terpolymers.20 When Zr(Acac)4 was used as initiator with a reaction temperature of 100 °C, Cop5 exhibited a less blocky structure with lower LG and LC, and higher R value and CGC concentration as compared to Cop4 (Table 1, Figure 2b). This indicates that transestrification is enhanced when Zr(Acac)4 is used as initiator instead of Sn(Oct)2. In the case of Cop6 obtained at 150 °C, a highly randomized chain microstructure was observed with
very low LG and LC values, high CGC concentration and high R value (Table 1, Figure 2c). The group of copolymers containing nearly 10% of glycolide (Table 1, Cop7, Cop8, Cop9) exhibited slightly different chain microstructures. Cop7 obtained at 100 °C with Sn(oct)2 presents a slightly more blocky structure with slightly higher LC and lower TII values than Cop8 and Cop9 obtained at 100 or 150 °C with Zr(Acac)4, in agreement with less transesterification. However, the difference between them is very small due to the low glycolide content. In fact, glycolyl units mainly exist in the form of CGC sequences which separate long caproyl ones. PCL and PGA are both intrinsically semicrystalline polymers. Figure 3 presents the X-ray diffraction spectra of the 9 copolymers with various compositions. Cop1 exhibit two diffraction peaks at 11.0° and 14.4° characteristic of the PGA crystallites (Figure 3a).21 In other words, the PCL component is not able to crystallize, in agreement with the low LC values. In the case of the second group with an initial molar ratio of 50/50, Cop2 exhibits two intense peaks at 11.0° and 14.4° due to PGA and a small peak at 10.6° assignable to PCL,8 whereas Cop3 shows only two rather weak peaks of PGA (Figure 3a). This is in good agreement with data in Table 1, Cop3 presenting lower LC and LG values due to stronger transesterification. The PCL component of Cop2 is susceptible to crystallize because of the presence of sufficiently long caproyl sequences. In the third group, Cop4 and Cop5 present the diffraction peaks of both PCL and PGA components, the peak at 10.9° due to PCL being overlapped with the one at 11.0° belonging to PGA (Figure 3b). The peak intensity of Cop4 appears higher than that of Cop5, which can be assigned to the higher LC and LG values of the former. Cop6 appears totally amorphous due to its highly randomized chain structure. Finally the fourth group (Cop7,
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Polymerization of PGA and PCL. Part 1 Table 2. Thermal Properties of PGA/PCL Copolymers sample
Tg1 (°C)a
Cop1 Cop2 Cop3 Cop4 Cop5 Cop6 Cop7 Cop8 Cop9
-11.8 -43.6 -38.0 -55.9 -55.1 -47.8 -60.0 -60.0 -60.9
a
Tg2 (°C)a
Tc1 (°C)a
16.3
-21.6 -30.2 -24.3
Tc2 (°C)a 67.0 62.4 77.0 59.7 50.7
-42.6 -40.2 -44.9
Tm1 (°C)b
∆Hm1 (J/g)b
50.0
7.2
55.0 43.7
36.0 25.1
58.7 54.0 54.2
41.8 32.3 59.9
Tm2 (°C)b
∆Hm2 (J/g)b
210.0 216.0 212.0 213.0 192.7
39.5 45.0 15.9 9.0 14.4
Tg and Tc values are determined from the second heating. b Tm and ∆Hm values are determined from the first heating.
Cop8, and Cop9) with low glycolyl contents and high LC values exhibits three diffraction peaks at 10.6°, 10.9°, and 11.8° (Figure 3c), which are characteristic of the PCL crystalline structure.8 Thermal properties of the copolymers were investigated by DSC as shown in Figure 4 and Table 2. After the first heating, the molten sample was quenched by immersion in liquid nitrogen and a second heating was performed. This process allows the glass transition and crystallization phenomena of polymers which crystallize very rapidly to be observed. Cop1 exhibits a rather large melting peak at 210.0 °C with a ∆Hm of 39.5 J/g due to the fusion of PGA crystallites. The second heating shows a large glass transition zone with Tg around -11.8 °C. A crystallization peak appears at 67.0 °C, followed by a melting peak at 202.6 °C. The first heating of Cop2 shows two melting peaks: a small one at 50.0 °C and a large one at 216.0 °C assigned to PCL and to PGA, respectively, which is in agreement with X-ray diffraction data. At the second heating, the PCL component presents a Tg at -43.6 °C, Tc at -21.6 °C and Tm at 42.0 °C, whereas the PGA component presents a Tg at 16.3 °C, Tc at 62.4 °C and Tm at 213.0 °C. It should be noted that the Tm of PCL is more or less overlapped with the Tg and Tc of PGA. In the case of Cop3, the first heating shows only a Tm at 212.0 °C with a rather low ∆Hm (15.9 J/g), whereas the second one shows a Tg at -38.0 °C, a weak crystallization peak at 77.0 °C and Tm at 207.3 °C. This is in agreement NMR and X-ray diffraction data. Cop4 and Cop5 behave similarly to Cop2 (Table 2, Figure 4). The first heating shows two melting peaks: a large one for PCL and a small one for PGA component. At the second heating, Tg, Tc, and Tm are detected for the PCL component. The PGA component presents Tc and Tm only, Tg being probably overlapped with the Tm of PCL in the 0° to 50 °C range. Insofar as Cop6 is concerned, only a Tg is detected at both runs due to its highly randomized structure. The group with about 90% of caproyl units (Cop7, Cop8, and Cop9) shows only a melting temperature at the first heating which is assigned to PCL crystallites, in agreement with X-ray diffraction data. Tm of Cop7 is higher than those of Cop8 and Cop9, whereas the ∆Hm of Cop9 is the highest. On the second heating, a glass transition is detected, followed by a sharp crystallization peak and a melting peak. The Tg values of the three copolymers are very close to each other. However, the Tc values are in the order of Cop8 > Cop7 > Cop9. Tc reflects the crystallzation ability of the polymers.
The lower the Tc, the higher the ability to crystallize. This is in agreement with the ∆Hm values of the copolymers. Conclusion PGA/PCL copolymers with various chain microstructures can be obtained by using different initiators and varying synthesis conditions. Transesterification is observed during the bulk ring-opening copolymerization of glycolide and -caprolactone, and is stronger at higher temperature and when zirconium (IV) acetylacetonate is used as initiator instead of stannous (II) octoate. The reactivity difference between glycolide and -caprolactone, and the transesterification reactions lead to more or less blocky chain structures. The crystalline structure and thermal properties depend on both the composition and the chain microstructure, PGAand PCL-type crystallites being obtained for copolymers with intermediate compositions. The observed property diversity of glycolide/caprolactone copolymers is of major importance for the design of biodegradable materials aimed at specific medical uses such as drugs carriers, tissue engineering scaffolds, and temporary surgical implants. So is the understanding of the influence of chain microstructures on the degradation which will be presented in the second part of this work. Acknowledgment. This work was conducted in the frame of Joint French-Polish CNRS - PAN scientific project (No. 14472), and was supported by the Polish Committee for Scientific Research, Grant PBZ-KBN-070/T09/2001/6. References and Notes (1) Dunn, R. L. Clinical Applications and Update on the Poly(R-hydroxy acids). In Biomedical Applications of Synthetic Biodegradable Polymers; Hollinger, J. O., Ed.; CRC Press: Boca Raton, FL, 1995; pp 17-31. (2) Li, S. J. Biomed. Mater. Res., Appl. Biomater. 1999, 48, 142-153. (3) Li, S.; Vert, M. Biodegradable polymers: polyesters. In The Encyclopedia of Controlled Drug DeliVery; Mathiowitz, E., Ed.; John Wiley & Sons: New York, 1999; pp 71-93. (4) Mayer, J. M.; Kaplan, D. L. Trends Polym. Sci. 1994, 2, 227. (5) Lunt, J. Polym. Degr. Stab. 1998, 59, 145-152. (6) Sinclair, R. G. J. M. S.-Pure Appl. Chem. 1996, A33, 585-597. (7) Pitt, C. G.; Chasalow, F. I.; Hibionada, Y. M.; Klimas, D. M.; Schindler, A. J. Appl. Polym. Sci. 1981, 26, 3779-3787. (8) Li, S.; Espartero, J. L.; Foch, P.; Vert, M. J. Biomater. Sci. Polym. Ed. 1996, 8 (3), 165. (9) Jarrett, P.; Benedict, C. V.; Bell, J. P.; Cameron, J. A.; Huang, S. J. Mechanism of the biodegradation of polycaprolactone. In Polymers as Biomaterials; Shalaby, S. W., et al., Eds.; Plenum Press: New York, 1984; pp 181-192. (10) Lefebvre, F.; David, C.; Vander Wauven, C. Polym. Degr. Stab. 1994, 45, 347-353.
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(11) Akahori, S. I.; Osawa, Z. Polym. Degr. Stab. 1994, 45, 261-265. (12) Pitt, C. G. Poly--caprolactone and its copolymers. In Drugs and the Pharmaceutical Sciences. Vol. 45, Biodegradable Polymers as drug deliVery systems; Chasin, H., et al., Eds.; Marcel Dekker: New York, 1990; pp 71-120. (13) Pack, J. W.; Kim, S. H.; Cho, I.; Park, S. Y.; Kim, Y. H. J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 544-554. (14) Kricheldorf, H. R.; Mang, T.; Jonte, J. M. Macromolecules 1984, 17, 2173-2181. (15) Bero, M.; Czapla, B.; Dobrzynski, P.; Kasperczyk, J.; Janeczek, H. J. Macromol. Chem. Phys. 1999, 200, 911-916.
Dobrzynski et al. (16) Dobrzynski, P. J. Polym. Sci. Part. A, Polym. Chem. 2002, 40, 13791394. (17) Kasperczyk, J. J. Makromol. Chem. Phys. 1999, 200, 903-910. (18) Kasperczyk, J.; Bero, M. Makromol. Chem. 1991, 192, 1777. (19) Kasperczyk, J.; Bero, M. Makromol. Chem. 1993, 194, 913. (20) Dobrzynski, P. J. Polym. Sci. Part A: Polym. Chem. 2002, 40, 31293143. (21) Wang, Z.-G.; Hsiao, B. S.; Zong, X.-H.; Yeh, F.; Zhou, J. J.; Dormier, E.; Jamiolkowski, D. D. Polymer 2000, 41, 621-628.
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